CN101558059B

CN101558059B - Hepatitis c virus inhibitors

Info

Publication number: CN101558059B
Application number: CN200780037723.7A
Authority: CN
Inventors: C·巴查德; M·贝雷码; D·H·戴昂; A·C·古德; J·古瑞奇; C·A·詹姆斯; R·拉威; O·D·洛裴兹; A·马特尔; N·A·米恩威尔; V·N·恩古颜; J·L·洛明; E·H·鲁迪格; L·B·辛德; D·R·圣罗伦; 杨福康; D·R·兰利; 王敢; L·G·哈曼
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co
Priority date: 2006-08-11
Filing date: 2007-08-09
Publication date: 2014-12-03
Anticipated expiration: 2027-08-09
Also published as: CN101558059A; TW200934486A; AR108411A2; TWI400072B

Abstract

The present disclosure relates to a compound of Formula (I), compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.

Description

Hepatitis C virus inhibitors

The cross reference of related application

The application requires the rights and interests of the U.S. Provisional Application sequence number (SN) 60/836,996 of application on August 11st, 2006.

Present disclosure relates generally to antiviral compound, relates to more precisely and can suppress by the compound of the NS5A protein function of hepatitis C virus (HCV) coding, the composition that comprises this compounds with for suppressing the method for NS5A protein function.

HCV is main human pathogen, estimate to infect the whole world 1.7 hundred million people--be approximately 5 times of human immunodeficiency virus type 1's number of the infected.Major part in the middle of these HCV infected individuals can develop into the serious hepatopathy that carries out, and comprises liver cirrhosis and hepatocellular carcinoma.

At present, the most effective HCV therapy adopts the combination of interferon-alpha and ribavirin, in 40% patient, produces continues the effect.Up-to-date clinical effectiveness shows, during as monotherapy, Pegylation interferon-alpha is better than the interferon-alpha of unmodified.Yet even use the experimental treatment scheme that comprises Pegylation interferon-alpha and ribavirin combination, most of patient also cannot continue to reduce viral load.Therefore apparent and expect for a long time, there are the needs that are used for the treatment of effective curative that HCV infects.

HCV is positive chain RNA virus.According to the comparison to the aminoacid sequence of deriving and the extensive similarity of 5 ' non-translational region, HCV is classified in an independent genus of flaviviridae (Flaviviridae family).All members of flaviviridae are contained the genomic envelope virus particle of positive chain RNA, and this genome is by the translation of single uninterrupted open reading-frame (ORF), all known virus-specific albumen of encoding.

In the genomic Nucleotide of whole HCV and coded aminoacid sequence, there is considerable heterogeneity.Identify at least 6 main genotype, and disclosed more than 50 hypotype.The oligogene type of HCV is different in global distribution, although carried out the research that may act on of lots of genes type to pathogenesis and treatment, but still do not know the clinical importance of HCV genetic heterogeneity.

Strand HCV rna gene group length is about 9500 Nucleotide, has single open reading-frame (ORF) (ORF), single approximately 3000 the amino acid whose large-scale polyproteins of encoding.In cells infected, this polyprotein is cut by leukoprotease and virus protease on a plurality of sites, produces structure and non-structure (NS) albumen.With regard to HCV, the formation of ripe Nonstructural Protein (NS2, NS3, NS4A, NS4B, NS5A and NS5B) realizes by two-strain proteolytic enzyme.It is generally acknowledged that the first is metalloprotease, cuts at NS2-NS3 contact; The second is included in the serine protease of NS3 (also claiming NS3 proteolytic enzyme herein) N end regions, it mediates all follow-up cuttings in NS3 downstream, at NS3-NS4A cleavage site, being cis, is trans in all the other NS4A-NS4B, NS4B-NS5A, NS5A-NS5B site.NS4A albumen has seemed several functions, plays NS3 proteolytic enzyme cofactor, and may assist NS3 and other rdrp virus component to carry out film location.The formation of NS3 albumen and NS4A mixture seemingly processes event, it is necessary on all sites, to improve proteolysis efficiency.NS3 albumen also demonstrates ribonucleoside triphosphote enzyme and DBPA is active.NS5B (also claiming HCV polysaccharase herein) participates in the RNA polymerase that depends on RNA that HCV copies.

What need is the compound that is used for the treatment of HCV infected patient, and this compound selective ground suppresses copying of HCV virus.What specifically, need is the compound that effectively suppresses NS5A protein function.HCV NS5A albumen is referring to for example Tan, S.-L., and Katzel, M.G.Virology 2001,284,1-12; And Park, K.-J.; Choi, S.-H, J.BiologicalChemistry 2003.

The first aspect of present disclosure provides following formula (I) compound or its pharmacy acceptable salt:

Wherein:

M and n are 0,1 or 2 independently;

Q and s are 0,1,2,3 or 4 independently;

U and v are 0,1,2 or 3 independently;

X is selected from O, S, S (O), SO ₂, CH ₂, CHR ⁵and C (R ⁵) ₂;

Precondition is that X is selected from CH when n is 0 ₂, CHR ⁵and C (R ⁵) ₂;

Y is selected from O, S, S (O), SO ₂, CH ₂, CHR ⁶and C (R ⁶) ₂;

Precondition is that Y is selected from CH when m is 0 ₂, CHR ⁶and C (R ⁶) ₂;

Each R ¹with each R ²independently be selected from alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkyl, aryl-alkoxy carbonyl, carboxyl, formyl radical, halogen, haloalkyl, hydroxyl, hydroxyalkyl ,-NR ^ar ^b, (NR ^ar ^b) alkyl and (NR ^ar ^b) carbonyl;

R ³and R ⁴independently be selected from separately hydrogen, R ⁹-C (O)-and R ⁹-C (S)-;

Each R ⁵with each R ⁶independently be selected from alkoxyl group, alkyl, aryl, halogen, haloalkyl, hydroxyl and-NR ^ar ^b, wherein alkyl can be optionally and adjacent carbons form the 3-6 ring condensing, wherein 3-6 ring is optionally replaced by one or two alkyl;

R ⁷and R ⁸independently be selected from separately hydrogen, alkoxy carbonyl, alkyl, aryl-alkoxy carbonyl, carboxyl, haloalkyl, (NR ^ar ^b) carbonyl and trialkylsilkl alkoxyalkyl; And

Each R ⁹independently be selected from alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkoxy carbonyl alkyl, alkyl, alkyl-carbonyl alkyl, aryl, aryl alkenyl, alkoxy aryl, arylalkyl, aryloxy alkyl, cycloalkyl, (cycloalkyl) thiazolinyl, (cycloalkyl) alkyl, cycloalkyl oxy alkyl, haloalkyl, heterocyclic radical, heterocyclic radical thiazolinyl, heterocyclic radical alkoxyl group, heterocyclic radical alkyl, heterocyclyloxy base alkyl, hydroxyalkyl ,-NR ^cr ^d, (NR ^cr ^d) thiazolinyl, (NR ^cr ^d) alkyl and (NR ^cr ^d) carbonyl.

In first embodiment of present disclosure first aspect, formula (I) compound or its pharmacy acceptable salt are provided, wherein m and n respectively do for oneself 1.

In second embodiment of present disclosure first aspect, formula (I) compound or its pharmacy acceptable salt are provided, wherein:

U and v are 0,1 or 2 independently of one another; And

Each R ¹with each R ²independently be selected from alkoxyl group, alkoxyalkyl, alkyl, aryl-alkoxy carbonyl, carboxyl, formyl radical, halogen, haloalkyl, hydroxyalkyl, (NR ^ar ^b) alkyl and (NR ^ar ^b) carbonyl.

In the 3rd embodiment of present disclosure first aspect, formula (I) compound or its pharmacy acceptable salt are provided, wherein:

U and v are 0 or 1 independently of one another; And

When existing, R ¹and/or R ²for halogen.

In the 4th embodiment of present disclosure first aspect, formula (I) compound or its pharmacy acceptable salt are provided, wherein:

U and v are 0 or 1 independently of one another; And

When existing, R ¹and/or R ²for halogen, wherein halogen is fluorine.

In the 5th embodiment of present disclosure first aspect, formula (I) compound or its pharmacy acceptable salt are provided, wherein at least one in X and Y is S.

In the 6th embodiment of present disclosure first aspect, provide formula (I) compound or its pharmacy acceptable salt, wherein X and the Y S that respectively does for oneself.

In the 7th embodiment of present disclosure first aspect, formula (I) compound or its pharmacy acceptable salt are provided, wherein X is selected from CHR ⁵and C (R ⁵) ₂; Y is selected from CH ₂, CHR ⁶and C (R ⁶) ₂.

In the 8th embodiment of present disclosure first aspect, provide formula (I) compound or its pharmacy acceptable salt, wherein R ⁷and R ⁸independently be selected from hydrogen, alkoxy carbonyl, alkyl, aryl-alkoxy carbonyl, carboxyl, haloalkyl and (NR ^ar ^b) carbonyl.

In the 9th embodiment of present disclosure first aspect, provide formula (I) compound or its pharmacy acceptable salt, wherein R ⁷and R ⁸the hydrogen of respectively doing for oneself.

In the tenth embodiment of present disclosure first aspect, formula (I) compound or its pharmacy acceptable salt are provided, wherein:

Q and s are 0,1 or 2 independently; And

Each R ⁵with each R ⁶independently be selected from alkyl, aryl, halogen and hydroxyl, wherein alkyl can be optionally and adjacent carbons form the 3-6 ring condensing, wherein 3-6 ring is optionally replaced by one or two alkyl.

In the 11 embodiment of present disclosure first aspect, formula (I) compound or its pharmacy acceptable salt are provided, wherein:

Q and s are 0 or 1 independently; And

When existing, R ⁵and/or R ⁶the halogen of respectively doing for oneself.

In the 12 embodiment of present disclosure first aspect, formula (I) compound or its pharmacy acceptable salt are provided, wherein:

Q and s are 0 or 1 independently; And

When existing, R ⁵and/or R ⁶the halogen of respectively doing for oneself, wherein halogen is fluorine.

In the 13 embodiment of present disclosure first aspect, provide formula (I) compound or its pharmacy acceptable salt, wherein R ³and R ⁴in at least one be hydrogen.

In the 14 embodiment of present disclosure first aspect, provide formula (I) compound or its pharmacy acceptable salt, wherein R ³and R ⁴r respectively does for oneself ⁹-C (O)-.

In the 15 embodiment of present disclosure first aspect, provide formula (I) compound or its pharmacy acceptable salt, wherein each R ⁹independently be selected from alkoxyl group, alkoxyalkyl, alkyl, alkyl-carbonyl alkyl, aryl, aryl alkenyl, alkoxy aryl, arylalkyl, aryloxy alkyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkyl oxy alkyl, heterocyclic radical, heterocyclic radical alkyl, hydroxyalkyl ,-NR ^cr ^d, (NR ^cr ^d) thiazolinyl, (NR ^cr ^d) alkyl and (NR ^cr ^d) carbonyl.

The second aspect of present disclosure provides following formula (II) compound or its pharmacy acceptable salt:

Wherein:

Q and s are 0,1 or 2 independently;

U and v are 0,1 or 2 independently;

X is selected from S, CH ₂, CHR ⁵and C (R ⁵) ₂;

Y is selected from S, CH ₂, CHR ⁶and C (R ⁶) ₂;

Each R ¹with each R ²independently be selected from alkoxyl group, alkoxyalkyl, alkyl, aryl-alkoxy carbonyl, carboxyl, formyl radical, halogen, haloalkyl, hydroxyalkyl, (NR ^ar ^b) alkyl and (NR ^ar ^b) carbonyl;

R ³and R ⁴independently be selected from separately hydrogen and R ⁹-C (O)-;

Each R ⁵with each R ⁶independently be selected from alkyl, aryl, halogen and hydroxyl, wherein alkyl can be optionally and adjacent carbons form the 3-6 ring condensing, wherein 3-6 ring is optionally replaced by one or two alkyl;

R ⁷and R ⁸independently be selected from separately hydrogen, alkoxy carbonyl, alkyl, aryl-alkoxy carbonyl, carboxyl, haloalkyl and (NR ^ar ^b) carbonyl; And

Each R ⁹independently be selected from alkoxyl group, alkoxyalkyl, alkyl, alkyl-carbonyl alkyl, aryl, aryl alkenyl, alkoxy aryl, arylalkyl, aryloxy alkyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkyl oxy alkyl, heterocyclic radical, heterocyclic radical alkyl, hydroxyalkyl ,-NR ^cr ^d, (NR ^cr ^d) thiazolinyl, (NR ^cr ^d) alkyl and (NR ^cr ^d) carbonyl.

The third aspect of present disclosure provides following formula (III) compound or its pharmacy acceptable salt:

Wherein:

Q and s are 0,1 or 2 independently;

U and v are 0 or 1 independently;

X is selected from CH ₂, CHR ⁵and C (R ⁵) ₂;

Y is selected from CH ₂, CHR ⁶and C (R ⁶) ₂;

When existing, R ¹and/or R ²for halogen, wherein halogen is fluorine;

R ³and R ⁴r respectively does for oneself ⁹-C (O)-;

When existing, R ⁵and/or R ⁶for halogen, wherein halogen is fluorine; And

The fourth aspect of present disclosure provides and is selected from following compound:

(1) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(2) (1R, 1 ' R)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amines);

(3) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(4) ((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-4, the fluoro-1-of 4-bis-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-4, the fluoro-1-pyrrolidyl of 4-bis-) carbonyl)-2-methyl-propyl) Urethylane;

(5) ((1S)-1-(((1R, 3R, 5R)-3-(5-(4 '-(2-((1R, 3R, 5R)-2-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-azabicyclic [3.1.0] oneself-3-yl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-2-azabicyclic [3.1.0] oneself-2-yl) carbonyl)-2-methyl-propyl) Urethylane;

(6) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(7) ((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-2-pyrimidyl-D-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(8) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(9) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (Urethylanes);

(10) (1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(11) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane; With

(12) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3,3-dimethyl butyrate acyl group)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2,2-dimethyl propyl) Urethylane; Or its pharmacy acceptable salt.

In first embodiment aspect the 5th, pharmacy acceptable salt is dihydrochloride.

Present disclosure the 6th aspect, composition is provided, said composition comprises formula (I) compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier.

In first embodiment aspect the 6th, composition also comprises one or both other compounds with anti-HCV activity.In second embodiment, at least one other compound is Interferon, rabbit or ribavirin.In the 3rd embodiment, Interferon, rabbit is selected from interferon alpha 2B, glycol interferon alpha, interferon alfacon-1 (consensus interferon), interferon alpha 2A and lymphocytoblast interferon-tau.

In the 4th embodiment aspect the 6th, composition also comprises one or both other compounds with anti-HCV activity, and wherein at least one other compound is selected from interleukin-22, interleukin 6, interleukin 12, promotion and produces compound that 1 type helper T cell replys, RNA interfering, sense-rna, miaow quinoline not moral (Imiqimod), ribavirin, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine (amantadine) and Rimantadine (rimantadine).

In the 5th embodiment aspect the 6th, composition also comprises one or both other compounds with anti-HCV activity, and the function that wherein at least one other compound effectively suppresses to be selected from following target infects with treatment HCV: HCV metalloprotease, HCV serine protease, HCV polysaccharase, HCV helicase, HCV NS4B albumen, HCV enter, HCV assembles, HCV discharges, HCV NS5A albumen and IMPDH.

Aspect present disclosure the 7th, the method for the treatment of patient's HCV infection is provided, the method comprises formula (I) compound or its pharmacy acceptable salt that gives patient treatment significant quantity.

In first embodiment aspect the 7th, before the method is also included in giving construction (I) compound or its pharmacy acceptable salt, give other compound that one or both have anti-HCV activity afterwards or simultaneously.In second embodiment, at least one other compound is Interferon, rabbit or ribavirin.In the 3rd embodiment, Interferon, rabbit is selected from interferon alpha 2B, glycol interferon alpha, interferon alfacon-1, interferon alpha 2A and lymphocytoblast interferon-tau.

In the 4th embodiment, before the method is also included in giving construction (I) compound or its pharmacy acceptable salt, give other compound that one or both have anti-HCV activity afterwards or simultaneously, wherein at least one other compound is selected from interleukin-22, interleukin 6, interleukin 12, promotion and produces compound that 1 type helper T cell replys, RNA interfering, sense-rna, miaow quinoline not moral, ribavirin, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine and Rimantadine.

In the 5th embodiment, before the method is also included in giving construction (I) compound or its pharmacy acceptable salt, give other compound that one or both have anti-HCV activity afterwards or simultaneously, the function that wherein at least one other compound effectively suppresses to be selected from following target infects with treatment HCV: HCV metalloprotease, HCV serine protease, HCV polysaccharase, HCV helicase, HCV NS4B albumen, HCV enter, HCV assembles, HCV discharges, HCV NS5A albumen and IMPDH.

Other embodiment of present disclosure can comprise the appropriately combined of two or more embodiments disclosed herein and/or aspect.

According to the description providing below, the other embodiment of present disclosure and aspect will be apparent.

The compound of present disclosure also exists with tautomer; Therefore, present disclosure also comprises all tautomeric forms.

The description of present disclosure should be interpreted as consistent with law and the principle of chemical bonding.In some cases, in order to hold substituting group at any given position, hydrogen atom may must be removed.For example,, in structure shown below:

R ⁸can with imidazole ring on the former sub-connection of either carbon, or, R ⁸can replace the imidazoles that the hydrogen atom on azo-cycle replaces to form N-.

It should be understood that, the included compound of present disclosure is moderately stable compound while being used as medicine.

It is also understood that any substituting group on molecule specific position or variable (R for example ¹, R ², R ⁵, R ⁶deng) definition should be independent of this molecule in other locational definition.For example, when u is 2, two R ¹each of group can be identical or different.

All patents, patent application and the reference in this specification sheets, quoted are all attached to herein by reference.In inconsistent situation, with present disclosure (comprising definition), be as the criterion.

In this specification sheets, following term used has the implication of regulation:

Singulative used herein comprises plural scope, unless separately clearly stated in literary composition.

Except as otherwise noted, otherwise its same being substituted described in corresponding definition separately of all aryl, cycloalkyl and the heterocyclic radical of present disclosure.For example, the aryl moiety in arylalkyl can be substituted as described in term " aryl " definition.

Term used herein " thiazolinyl " refers to the straight or branched group of 2-6 the carbon atom that contains at least one carbon-to-carbon double bond.

Term used herein " alkene oxygen base " refers to that thiazolinyl is connected with parent molecular moiety by Sauerstoffatom.

Term used herein " allyloxycarbonyl " refers to that alkene oxygen base is connected with parent molecular moiety by carbonyl.

Term used herein " alkoxyl group " refers to that alkyl is connected with parent molecular moiety by Sauerstoffatom.

Term used herein " alkoxyalkyl " refers to that alkyl is replaced by 1,2 or 3 alkoxyl group.

Term used herein " alkoxyalkyl carbonyl " refers to that alkoxyalkyl is connected with parent molecular moiety by carbonyl.

Term used herein " alkoxy carbonyl " refers to that alkoxyl group is connected with parent molecular moiety by carbonyl.

Term used herein " alkoxy carbonyl alkyl " refers to that alkyl is replaced by 1,2 or 3 alkoxy carbonyl.

Term used herein " alkyl " refers to the group derived from the straight or branched stable hydrocarbon that contains 1-6 carbon atom.In the compound of present disclosure, when m and/or n are 1 or 2, X and/or Y are respectively CHR ⁵and/or CHR ⁶, R ⁵and/or R ⁶for alkyl, each alkyl can be optionally and adjacent carbons form the 3-6 ring condensing, obtain one of lower array structure:

If z is 1,2,3 or 4, w is 0,1 or 2, and R ⁵⁰for alkyl.If w is 2, two R ⁵⁰alkyl can be identical or different.

Term used herein " alkyl-carbonyl " refers to that alkyl is connected with parent molecular moiety by carbonyl.

Term used herein " alkyl-carbonyl alkyl " refers to that alkyl is replaced by 1,2 or 3 alkyl-carbonyl.

Term used herein " alkyl-carbonyl oxygen base " refers to that alkyl-carbonyl is connected with parent molecular moiety by Sauerstoffatom.

Term used herein " alkylthio " refers to that alkyl is connected with parent molecular moiety by sulphur atom.

Term used herein " alkyl sulphonyl " refers to that alkyl is connected with parent molecular moiety by alkylsulfonyl.

Term used herein " aryl " refers to phenyl or bicyclic condensed ring system, and one or two wherein ring is phenyl.Bicyclic condensed ring system is by forming with 4-6 unit's aromatics or non-aromatic carbocyclic fused phenyl.The aryl of present disclosure can be by any can connection with parent molecular moiety by substituted carbon atom in group.The representative example of aryl includes but not limited to indanyl, indenyl, naphthyl, phenyl and tetralyl.The aryl of present disclosure is optionally independently selected from following substituting group by 1,2,3,4 or 5 and replaces: alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkyl, alkyl-carbonyl, the second aryl, alkoxy aryl, arylalkyl, aryl carbonyl, cyano group, halogen, halogenated alkoxy, haloalkyl, heterocyclic radical, heterocyclic radical alkyl, heterocyclic radical carbonyl, hydroxyl, hydroxyalkyl, nitro ,-NR ^xr ^y, (NR ^xr ^y) alkyl, oxo and-P (O) OR ₂, wherein each R is independently selected from hydrogen and alkyl; Wherein the moieties in arylalkyl and heterocyclic radical alkyl is unsubstituted, and wherein aryl moiety, the aryl moiety in aryl carbonyl, heterocyclic radical and the heterocyclic radical alkyl in the second aryl, arylalkyl and the heterocyclic radical in heterocyclic radical carbonyl are partly also optionally independently selected from following substituting group by 1,2 or 3 and replace: alkoxyl group, alkyl, cyano group, halogen, halogenated alkoxy, haloalkyl and nitro.

Term used herein " aryl alkenyl " refers to that thiazolinyl is replaced by 1,2 or 3 aryl.

Term used herein " alkoxy aryl " refers to that aryl is connected with parent molecular moiety by alkoxyl group.

Term used herein " alkoxy aryl alkyl " refers to that alkyl is replaced by 1,2 or 3 alkoxy aryl.

Term used herein " alkoxy aryl alkyl carbonyl " refers to that alkoxy aryl alkyl is connected with parent molecular moiety by carbonyl.

Term used herein " aryl-alkoxy carbonyl " refers to that alkoxy aryl is connected with parent molecular moiety by carbonyl.

Term used herein " arylalkyl " refers to that alkyl is replaced by 1,2 or 3 aryl.Moieties in arylalkyl is also optionally replaced by one or two other following group that is independently selected from: alkoxyl group, alkyl-carbonyl oxygen base, halogen, halogenated alkoxy, haloalkyl, heterocyclic radical, hydroxyl and-NR ^cr ^d, wherein heterocyclic radical is also optionally independently selected from following substituting group by one or two and replaces: alkoxyl group, alkyl, unsubstituted aryl, unsubstituted alkoxy aryl, unsubstituted aryl-alkoxy carbonyl, halogen, halogenated alkoxy, haloalkyl, hydroxyl and-NR ^xr ^y.

Term used herein " aromatic yl alkyl carbonyl " refers to that arylalkyl is connected with parent molecular moiety by carbonyl.

Term used herein " aryl carbonyl " refers to that aryl is connected with parent molecular moiety by carbonyl.

Term used herein " aryloxy " refers to that aryl is connected with parent molecular moiety by Sauerstoffatom.

Term used herein " aryloxy alkyl " refers to that alkyl is replaced by 1,2 or 3 aryloxy.

Term used herein " aryloxycarbonyl " refers to that aryloxy is connected with parent molecular moiety by carbonyl.

Term used herein " aryl sulfonyl " refers to that aryl is connected with parent molecular moiety by alkylsulfonyl.

Term used herein " end group (cap or Cap) " refers to and is positioned at end containing the group on the nitrogen-atoms of azo-cycle, the i.e. pyrrolidine ring of compound 1e.It should be understood that, " end group (cap or Cap) " can refer to for group being attached to end containing the reagent on azo-cycle or final product fragment, i.e. " Cap-51 " or " being present in the Cap-51 fragment on LS-19 ".

Refer to-C of term used herein " carbonyl " (O)-.

Refer to-CO of term used herein " carboxyl " ₂h.

Refer to-CN of term used herein " cyano group ".

Term used herein " cycloalkyl " refers to have 3-7 carbon atom and the heteroatomic saturated mono cyclic hydrocarbon of zero ring system.The representative example of cycloalkyl includes but not limited to cyclopropyl, cyclopentyl and cyclohexyl.The cycloalkyl of present disclosure is optionally independently selected from following substituting group by 1,2,3,4 or 5 and replaces: alkoxyl group, alkyl, aryl, cyano group, halogen, halogenated alkoxy, haloalkyl, heterocyclic radical, hydroxyl, hydroxyalkyl, nitro and-NR ^xr ^y, wherein aryl and heterocyclic radical are also optionally independently selected from following substituting group by 1,2 or 3 and replace: alkoxyl group, alkyl, cyano group, halogen, halogenated alkoxy, haloalkyl, hydroxyl and nitro.

Term used herein " (cycloalkyl) thiazolinyl " refers to that thiazolinyl is by 1,2 or 3 cycloalkyl substituted.

Term used herein " (cycloalkyl) alkyl " refers to that alkyl is by 1,2 or 3 cycloalkyl substituted.Moieties in (cycloalkyl) alkyl is also optionally independently selected from following group by one or two and replaces: hydroxyl and-NR ^cr ^d.

Term used herein " cycloalkyl oxy " refers to that cycloalkyl is connected with parent molecular moiety by Sauerstoffatom.

Term used herein " cycloalkyl oxy alkyl " refers to that alkyl is replaced by 1,2 or 3 cycloalkyl oxy.

Term used herein " naphthene sulfamide base " refers to that cycloalkyl is connected with parent molecular moiety by alkylsulfonyl.

Refer to-CHO of term used herein " formyl radical ".

Term used herein " halo " and " halogen " refer to F, Cl, Br or I.

Term used herein " halogenated alkoxy " refers to that haloalkyl is connected with parent molecular moiety by Sauerstoffatom.

Term used herein " halo alkoxy carbonyl " refers to that halogenated alkoxy is connected with parent molecular moiety by carbonyl.

Term used herein " haloalkyl " refers to that alkyl is replaced by 1,2,3 or 4 halogen atom.

Term used herein " heterocyclic radical " refers to and contains 1,2,3 or 44,5,6 or 7 ring that are independently selected from nitrogen, oxygen and sulfur heteroatom.The unparalleled key of 4 ring, 5 rings have 0-2 two key, and 6 and 7 rings have 0-3 two key.Term " heterocyclic radical " also comprises bicyclic groups, wherein heterocyclic ring and another monocyclic heterocycles base or 4-6 unit aromatics or non-aromatic carbocyclic fused; And bridge joint bicyclic groups, for example 7-azabicyclic [2.2.1] heptan-7-base, 2-azabicyclic [2.2.2] pungent-2-base and 2-azabicyclic [2.2.2] oct-3-yl.The heterocyclic radical of present disclosure can be connected with parent molecular moiety by any carbon atom in group or nitrogen-atoms.The example of heterocyclic radical include but not limited to benzothienyl, furyl, imidazolyl, indolinyl, indyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, piperazinyl, piperidyl, pyrazolyl, pyridyl, pyrrolidyl, pyrrolopyridinyl, pyrryl, thiazolyl, thienyl, thio-morpholinyl, 7-azabicyclic [2.2.1] heptan-7-base, 2-azabicyclic [2.2.2] pungent-2-base and 2-azabicyclic [2.2.2] oct-3-yl.The heterocyclic radical of present disclosure is optionally independently selected from following substituting group by 1,2,3,4 or 5 and replaces: alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkyl, alkyl-carbonyl, aryl, arylalkyl, aryl carbonyl, cyano group, halogen, halogenated alkoxy, haloalkyl, the second heterocyclic radical, heterocyclic radical alkyl, heterocyclic radical carbonyl, hydroxyl, hydroxyalkyl, nitro ,-NR ^xr ^y, (NR ^xr ^y) alkyl and oxo, wherein the moieties in arylalkyl and heterocyclic radical alkyl is unsubstituted, and wherein aryl moiety, the aryl moiety in aryl carbonyl, the second heterocyclic radical and the heterocyclic radical alkyl in aryl, arylalkyl and the heterocyclic radical in heterocyclic radical carbonyl are partly also optionally independently selected from following substituting group by 1,2 or 3 and replace: alkoxyl group, alkyl, cyano group, halogen, halogenated alkoxy, haloalkyl and nitro.

Term used herein " heterocyclic radical thiazolinyl " refers to that thiazolinyl is replaced by 1,2 or 3 heterocyclic radical.

Term used herein " heterocyclic radical alkoxyl group " refers to that heterocyclic radical is connected with parent molecular moiety by alkoxyl group.

Term used herein " heterocyclic radical alkoxy carbonyl " refers to that heterocyclic radical alkoxyl group is connected with parent molecular moiety by carbonyl.

Term used herein " heterocyclic radical alkyl " refers to that alkyl is replaced by 1,2 or 3 heterocyclic radical.Moieties in heterocyclic radical alkyl is also optionally replaced by one or two other following group that is independently selected from: alkoxyl group, alkyl-carbonyl oxygen base, aryl, halogen, halogenated alkoxy, haloalkyl, hydroxyl and-NR ^cr ^d, wherein aryl is also optionally independently selected from following substituting group by one or two and replaces: alkoxyl group, alkyl, unsubstituted aryl, unsubstituted alkoxy aryl, unsubstituted aryl-alkoxy carbonyl, halogen, halogenated alkoxy, haloalkyl, hydroxyl and-NR ^xr ^y.

Term used herein " heterocyclic radical alkyl-carbonyl " refers to that heterocyclic radical alkyl is connected with parent molecular moiety by carbonyl.

Term used herein " heterocyclic radical carbonyl " refers to that heterocyclic radical is connected with parent molecular moiety by carbonyl.

Term used herein " heterocyclyloxy base " refers to that heterocyclic radical is connected with parent molecular moiety by Sauerstoffatom.

Term used herein " heterocyclyloxy base alkyl " refers to that alkyl is replaced by 1,2 or 3 heterocyclyloxy base.

Term used herein " heterocyclyloxy base carbonyl " refers to that heterocyclyloxy base is connected with parent molecular moiety by carbonyl.

Refer to-OH of term used herein " hydroxyl ".

Term used herein " hydroxyalkyl " refers to that alkyl is replaced by 1,2 or 3 hydroxyl.

Term used herein " hydroxyalkyl carbonyl " refers to that hydroxyalkyl is connected with parent molecular moiety by carbonyl.

Refer to-NO of term used herein " nitro " ₂.

Term " NR used herein ^ar ^b" refer to R ^aand R ^btwo groups are connected with parent molecular moiety by nitrogen-atoms.R ^aand R ^bindependently be selected from hydrogen, thiazolinyl and alkyl.

Term " (NR used herein ^ar ^b) alkyl " refer to that alkyl is by 1,2 or 3-NR ^ar ^bgroup replaces.

Term " (NR used herein ^ar ^b) carbonyl " refer to-NR ^ar ^bgroup is connected with parent molecular moiety by carbonyl.

Term " NR used herein ^cr ^d" refer to R ^cand R ^dtwo groups are connected with parent molecular moiety by nitrogen-atoms.R ^cand R ^dindependently be selected from hydrogen, allyloxycarbonyl, alkoxyalkyl carbonyl, alkoxy carbonyl, alkyl, alkyl-carbonyl, alkyl sulphonyl, aryl, aryl-alkoxy carbonyl, arylalkyl, aromatic yl alkyl carbonyl, aryl carbonyl, aryloxycarbonyl, aryl sulfonyl, cycloalkyl, naphthene sulfamide base, formyl radical, halo alkoxy carbonyl, heterocyclic radical, heterocyclic radical alkoxy carbonyl, heterocyclic radical alkyl, heterocyclic radical alkyl-carbonyl, heterocyclic radical carbonyl, heterocyclyloxy base carbonyl, hydroxyalkyl carbonyl, (NR ^er ^f) alkyl, (NR ^er ^f) alkyl-carbonyl, (NR ^er ^f) carbonyl, (NR ^er ^f) alkylsulfonyl ,-C (NCN) OR ' and-C (NCN) NR ^xr ^y, wherein R ' is selected from alkyl and unsubstituted phenyl, and wherein the moieties in arylalkyl, aromatic yl alkyl carbonyl, heterocyclic radical alkyl and heterocyclic radical alkyl-carbonyl also optionally by one-NR ^er ^fgroup replaces, and aryl wherein, aryl moiety in aryl-alkoxy carbonyl, arylalkyl, aromatic yl alkyl carbonyl, aryl carbonyl, aryloxycarbonyl and aryl sulfonyl, heterocyclic radical, and the heterocyclic radical in heterocyclic radical alkoxy carbonyl, heterocyclic radical alkyl, heterocyclic radical alkyl-carbonyl, heterocyclic radical carbonyl and heterocyclyloxy base carbonyl is partly also optionally independently selected from following substituting group by 1,2 or 3 and replaces: alkoxyl group, alkyl, cyano group, halogen, halogenated alkoxy, haloalkyl and nitro.

Term " (NR used herein ^cr ^d) thiazolinyl " refer to that thiazolinyl is by 1,2 or 3-NR ^cr ^dgroup replaces.

Term " (NR used herein ^cr ^d) alkyl " refer to that alkyl is by 1,2 or 3-NR ^cr ^dgroup replaces.(NR ^cr ^d) moieties in alkyl is also optionally selected from addition following group by one or two and replaces: alkoxyl group, alkoxyalkyl carbonyl, alkoxy carbonyl, alkyl sulfenyl, alkoxy aryl alkyl carbonyl, carboxyl, heterocyclic radical, heterocyclic radical carbonyl, hydroxyl and (NR ^er ^f) carbonyl; Wherein heterocyclic radical is also optionally independently selected from following substituting group by 1,2,3,4 or 5 and replaces: alkoxyl group, alkyl, cyano group, halogen, halogenated alkoxy, haloalkyl and nitro.

Term " (NR used herein ^cr ^d) carbonyl " refer to-NR ^cr ^dgroup is connected with parent molecular moiety by carbonyl.

Term " NR used herein ^er ^f" refer to R ^eand R ^ftwo groups are connected with parent molecular moiety by nitrogen-atoms.R ^eand R ^findependently be selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cycloalkyl) alkyl, unsubstituted heterocyclic radical, unsubstituted heterocyclic radical alkyl, (NR ^xr ^y) alkyl and (NR ^xr ^y) carbonyl.

Term " (NR used herein ^er ^f) alkyl " refer to that alkyl is by 1,2 or 3-NR ^er ^fgroup replaces.

Term " (NR used herein ^er ^f) alkyl-carbonyl " refer to (NR ^er ^f) alkyl is connected with parent molecular moiety by carbonyl.

Term " (NR used herein ^er ^f) carbonyl " refer to-NR ^er ^fgroup is connected with parent molecular moiety by carbonyl.

Term " (NR used herein ^er ^f) alkylsulfonyl " refer to-NR ^er ^fgroup is connected with parent molecular moiety by alkylsulfonyl.

Term " NR used herein ^xr ^y" refer to R ^xand R ^ytwo groups are connected with parent molecular moiety by nitrogen-atoms.R ^xand R ^yindependently be selected from hydrogen, alkoxy carbonyl, alkyl, alkyl-carbonyl, unsubstituted aryl, unsubstituted aryl-alkoxy carbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclic radical and (NR ^x' R ^y') carbonyl, wherein R ^x' and R ^y' be independently selected from hydrogen and alkyl.

Term " (NR used herein ^xr ^y) alkyl " refer to that alkyl is by 1,2 or 3-NR ^xr ^ygroup replaces.

Refer to=O of term used herein " oxo ".

Refer to-SO of term used herein " alkylsulfonyl " ₂-.

Refer to-SiR of term used herein " trialkylsilkl " ₃, wherein R is alkyl.Each R group can be identical or different.

Term used herein " trialkylsilkl alkyl " refers to that alkyl is replaced by 1,2 or 3 trialkylsilkl.

Term used herein " trialkylsilkl alkoxyl group " refers to that trialkylsilkl alkyl is connected with parent molecular moiety by Sauerstoffatom.

Term used herein " trialkylsilkl alkoxyalkyl " refers to that alkyl is replaced by 1,2 or 3 trialkylsilkl alkoxyl group.

In the compound of present disclosure, there is asymmetric center.These are symbol " R " or " S " mark for center, and this depends on chiral carbon atom substituent configuration around.It should be understood that, present disclosure comprises all three-dimensional chemical isomers or its mixture with the ability that suppresses NS5A.Each steric isomer of compound can be prepared by the following method: synthetic by the marketable material that contains chiral centre; Or by preparing after the mixture of enantiomorph product, by for example changing into after the separation of mixture of diastereomer, then by separation or recrystallization, chromatographic technique; Or from chiral chromatographic column, directly isolate enantiomorph.The initial compounds of specific stereochemical structure is commercially available, or can be prepared and be split by technology known in the art.

The all right different Stable conformation form of some compound of present disclosure exists, and this class conformation form is separable.Torsion asymmetry by due to asymmetric singly-bound surrounding obstacles rotation (for example, because of steric hindrance or ring strain), can make different conformers separate.Present disclosure comprises each conformer of these compounds and composition thereof.

Term " compound of present disclosure " and equivalents refer to and comprise formula (I) compound and pharmaceutically acceptable enantiomorph, diastereomer and salt thereof.While equally, mentioning intermediate, refer to the salt that comprises the intermediate allowing herein.

The compound of present disclosure can be used as pharmacy acceptable salt and exists.Term used herein " pharmacy acceptable salt " represents salt or the zwitterionic form of the compound of present disclosure, they are water-soluble or oil-soluble, or dispersible, within the scope of rational medical judgment, be applicable to contact with patient tissue and without excessive toxicity, pungency, transformation reactions or with rational interests/risk than symmetrical other problem or complication, and be effective to its set purposes.Can during the final separation of compound and purifying, prepare its salt, or can make separately suitable nitrogen-atoms and suitable acid-respons prepare the salt of compound.Representational acid salt comprises acetate, adipate, alginates, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, digluconate, two hydrobromates, dihydrochloride, two hydriodates, glycerophosphate, Hemisulphate, enanthate, hexanoate, formate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-isethionate, lactic acid salt, maleate, 1, 3, 5-trimethylbenzene sulfonate, mesylate, naphthylidene sulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphoric acid salt, glutaminate, supercarbonate, tosilate and undecane hydrochlorate.The sour example that can be used for forming pharmaceutically acceptable addition salt comprises mineral acid and organic acid, and mineral acid is hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid for example, and organic acid is oxalic acid, toxilic acid, succsinic acid and citric acid for example.

Can be by making carboxyl for example, react or prepare base addition salt with ammonia or organic primary amine, secondary amine or reactive tertiary amine with suitable alkali (oxyhydroxide of metallic cation, carbonate or supercarbonate) during the final separation of compound and purifying.The positively charged ion of pharmacy acceptable salt (comprising lithium, sodium, potassium, calcium, magnesium and aluminium) and nontoxic quaternary ammonium cation, for example ammonium, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethylamine, Trimethylamine 99, triethylamine, diethylamine, ethamine, Tributylamine, pyridine, N, accelerine, N-methyl piperidine, N-methylmorpholine, dicyclohexyl amine, PROCAINE HCL, PHARMA GRADE, dibenzylamine, N, N-dibenzyl phenylethylamine and N, N '-dibenzyl-ethylenediamin.Other the representational organic amine that is used to form base addition salt comprises quadrol, thanomin, diethanolamine, piperidines and piperazine.

When can be used for treating, formula (I) compound for the treatment of significant quantity and pharmacy acceptable salt thereof can be used as unprocessed pharmaceutical chemicals and give, and the activeconstituents that also can be used as pharmaceutical composition provides.Therefore, present disclosure also provides pharmaceutical composition, and this pharmaceutical composition comprises formula (I) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers, thinner or the vehicle for the treatment of significant quantity.Term used herein " treatment significant quantity " refers to the total amount of each active ingredient that is enough to demonstrate significant patient's benefit (for example viral load minimizing).When using independent activeconstituents individually dosed, this term only refers to this composition.When applied in any combination, no matter this term refers to combination, successively or during simultaneously administration, all causes the combined amount of the activeconstituents of result for the treatment of.Formula (I) compound and pharmacy acceptable salt thereof are as mentioned above.From compatible with other composition of preparation and harmless to its recipient meaning, carrier, thinner or vehicle must be acceptable.According to present disclosure on the other hand, be also provided for the method for useful in preparing drug formulations, the method comprises formula (I) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers, thinner or vehicle is mixed.Term used herein " pharmaceutically acceptable " refers to such compound, raw material, composition and/or formulation, they are in the scope of rational medicine judgement, be applicable to contact with patient tissue and without excessive toxicity, pungency, transformation reactions or with rational interests/risk than symmetrical other problem and complication, and be effective to set purposes.

Pharmaceutical preparation can be unit dosage, the activeconstituents that each unitary dose contains predetermined amount.The dosage level of the compound of present disclosure is between approximately 0.01 mg/kg (" mg/kg ") body weight/day and approximately 250 mg/kg body weight/day, preferably, between about 0.05mg/kg body weight/day and about 100mg/kg body weight/day, usually with monotherapy, be used for preventing or treating the disease of HCV mediation.Conventionally can or as continuous infusion, give the pharmaceutical composition of present disclosure by every day approximately 1 to approximately 5 time.This class dose regimen can be used as long-term or short-term therapy.The amount of mixing to prepare the activeconstituents of single formulation with solid support material will change according to the discharge rate of the severity of disease to be treated, disease, administration time, route of administration, compound used therefor, treatment time and patient age, sex, body weight and situation.Preferred unit dosage is to contain the per daily dose of above-mentioned activeconstituents or the unit dosage of divided dose or its appropriate fraction herein.The available obvious low dose of begin treatment lower than compound optimal dose.After this, with less increment, carry out escalated dose until reach in this case best effect.Generally speaking, the concentration level that most desirably gives compound is conventionally can effective result is provided and be unlikely at anti-virus aspect to cause any harmful or poisonous side effect.

When the compound that comprises present disclosure when the composition of present disclosure and the combination of one or more other curatives or prophylactic agent, the dosage level of compound and other medicine is conventionally in monotherapy scheme, account for the approximately 10-150% of bio-occlusion pharmaceutical quantities, more preferably account for approximately 10% to 80% of bio-occlusion pharmaceutical quantities.

Pharmaceutical preparation is suitable for by any suitable administration, for example, by oral (comprising oral cavity or hypogloeeis), rectum, nose, part (comprise oral cavity, hypogloeeis or through skin), vagina or parenteral (comprise in subcutaneous, intracutaneous, intramuscular, intraarticular, synovial membrane, in breastbone, in sheath, intralesional, intravenously or corium hemostasis or infusion) approach.Can prepare this class preparation by any currently known methods in pharmaceutics field, for example, pass through activeconstituents and carrier or mixed with excipients.Preferred oral administration or drug administration by injection.

The pharmaceutical preparation that is suitable for oral administration provides by unit independently, for example capsule or tablet; Powder or granule; Solution in water-based or non-aqueous liquid or suspensoid; Edible foam formulations or foaming preparations (whip); Or O/w emulsion agent or water in oil emulsion liquor.

For instance, for the oral administration with tablet or Capsule form, active medicine component can mix mutually with pharmaceutically acceptable oral nontoxic inert support (such as ethanol, glycerine, water etc.).By compound powder being broken into suitable fine sizes, and mix to prepare powder with the pharmaceutical carrier of being pulverized equally (edible carbohydrates such as starch or N.F,USP MANNITOL).Also can there is correctives, sanitas, dispersion agent and tinting material.

By preparing pulverulent mixture as above, and be loaded in the gelatin shell of shaping, prepare capsule.Before filling operation, glidant and lubricant (for example colloidal silica, talcum powder, Magnesium Stearate, calcium stearate or solid polyethylene glycol) can be added in pulverulent mixture.Also can add when the lower capsule of clothes and will improve disintegrating agent or the solubilizing agent (for example agar, calcium carbonate or sodium carbonate) of medicine utilizability.

In addition need, or when essential, also suitable tackiness agent, lubricant, disintegrating agent and tinting material can be mixed in mixture.Suitable tackiness agent comprises starch, gelatin, natural sugar (such as glucose or beta lactose), corn sweetener, natural and synthetic gum (such as Sudan Gum-arabic, tragakanta or sodiun alginate), carboxymethyl cellulose, polyoxyethylene glycol etc.Lubricant for these formulations comprises sodium oleate, sodium-chlor etc.Disintegrating agent includes but not limited to starch, methylcellulose gum, agar, bentonite, xanthan gum etc.For example, by making pulverulent mixture, granulate or pre-compressing tablet, add lubricant and disintegrating agent, compacting is in blocks, thereby makes tablet.By the compound of suitably pulverizing and thinner as above or base-material, optionally for example, for example, for example, for example, mix with tackiness agent (carboxymethyl cellulose, alginate, gelatin or polyvinylpyrrolidone), dissolving retarding agent (paraffin), absorption accelerator (quaternary salt) and/or absorption agent (bentonite, kaolin or Si Liaodengji dicalcium phosphate feed grade), prepare pulverulent mixture.For example, after useful binders (syrup, starch slurry, mucialga of arabic gummy (acadiamucilage) or cellulose materials or polymeric material solution) is wetting, pressurization is sieved, and pulverulent mixture is granulated.An alternative method of granulating is, can be by pulverulent mixture by tabletting machine, and result is that the not good agglomerate that is shaped is smashed to granulation again.Can be by adding stearic acid, stearate, talcum powder or mineral oil that particle lubrication is adhered on the punch die of tabletting machine preventing.Then by the mixture compacting through lubricated in flakes.The compound of present disclosure also can mix with free-pouring inert support, without just suppressing in flakes by granulation or pre-compressing tablet step.Transparent or the opaque protectiveness coating material being comprised of shellac seal coat, sugar-coat or polymeric material clothing and wax polishing clothing (polishcoating of wax) can be provided.Dyestuff can be added in these coating materials to distinguish different unitary doses.

Oral liquid for example solution, syrup and elixir can be prepared by dosage unit form, thus the compound that specified rate contains predetermined amount.Syrup can be by compound is dissolved in the suitably seasoned aqueous solution and is prepared, and elixir can be by preparing with nontoxic solvent.Also can add solubilizing agent and emulsifying agent (such as ethoxylation isooctadecanol and polyoxyethylene sorbitol ether), sanitas, flavoring additive (such as spearmint oil or natural sweeteners or asccharin or other artificial sweetner) etc.

If appropriate, can be by the dosage unit preparations micro encapsulation for oral administration.Also preparation can be made to time delay or sustained release, such as by dressing or be embedded in the microparticle materials such as polymkeric substance, wax.

Formula (I) compound and pharmacy acceptable salt thereof can also give by liposome delivery system, for example small unilamellar vesicle, large unilamellar liposome and multilamellar liposome.Liposome can for example, consist of multiple phosphatide (cholesterol, octadecylamine or phosphatidylcholine).

Formula (I) compound and pharmacy acceptable salt thereof also can by use monoclonal antibody as independent carrier (compound molecule is coupling with it) pass medicine.Compound also can with the soluble polymer coupling as can target medicine carrier.This base polymer can comprise polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropylmethyl acrylamide phenol, poly-hydroxyethyl l-asparagine phenol or the polyoxyethylene polylysine being replaced by palmityl residue.In addition, compound can with a class Biodegradable polymeric coupling, for reaching the controlled release of medicine, this base polymer is cross-linking copolymer or the amphipathic nature block polymer of poly(lactic acid), poly-epsilon-caprolactone, polyhydroxybutyrate, poe, polyacetal, poly-dihydropyrane, polybutylcyanoacrylate and hydrogel for example.

The pharmaceutical preparation that is suitable for percutaneous dosing can be used as discrete patch (discrete patch) to keep and recipient's epidermis close contact in long-time.For example, activeconstituents can be by passing medicine by iontophoresis patch, conventionally can be referring to Pharmaceutical Research1986, and 3 (6), 318.

The pharmaceutical preparation that is suitable for topical can be made into ointment, ointment, suspensoid, lotion, powder, solution, paste, gelifying agent, sprays, aerosol or oil formulation.

The pharmaceutical preparation that is suitable for rectal administration can be used as suppository or provides as enema.

The pharmaceutical preparation (wherein carrier is solid) that is suitable for nose administration comprises that particle diameter is the dust base of 20-500 micrometer range for example, by with the administration of snuffing mode, by nasal passage, from approach the dust base container of nose, sucks fast.Wherein carrier is liquid, is suitable for comprising as the appropriate formulation of nasal mist or nasal drop administration aqueous solution agent or the oily solution agent of activeconstituents.

Be suitable for comprising minuteness particle pulvis (dust) or mist agent (mist) by the pharmaceutical preparation of inhalation the dosage compresed gas aerosol of available dissimilar metering, nebulizer or insufflator preparation.

The pharmaceutical preparation that is suitable for vagina administration can vaginal suppository, vagina plug, ointment, gelifying agent, paste, foaming agent or sprays provide.

The pharmaceutical preparation that is suitable for parenteral admin comprises water-based and non-aqueous aseptic injectable solution agent and water-based and non-aqueous aseptic suspensoid, and water-based and non-aqueous aseptic injectable solution agent can contain antioxidant, buffer reagent, fungistat and make preparation and the solute for the treatment of that recipient's blood etc. oozes; Water-based and non-aqueous aseptic suspensoid can comprise suspension agent and thickening material.Preparation can unitary dose or multi-dose container provide, for example ampoule and the bottle of sealing, and can be kept under lyophilize (freeze-drying) condition, only need add sterile liquid carrier, for example water for injection before use.Facing injection solution and the suspensoid of used time preparation can be prepared by sterile powder injection, granule and tablet.

It should be understood that, except the composition of mentioning especially above, preparation also comprises other composition that this area relevant with described preparation type is conventional, and this class preparation that is for example suitable for oral administration can comprise correctives.

Term " patient " comprises people and other animal.

Term " treatment " refers to: (i) in susceptible disease, obstacle and/or illness but prevent disease, obstacle or illness in not yet making a definite diagnosis the patient who suffers from disease, obstacle and/or illness; (ii) suppress disease, obstacle or illness, stop its development; (iii) palliate a disease, obstacle or illness, even if disease, obstacle and/or illness disappear.

The compound of present disclosure also can for example, together with S-Neoral (cyclosporin A) administration.Research shows, cyclosporin A has anti-HCV activity (Hepatology2003,38,1282 in clinical trial; Biochem.Biophys.Res.Commun.2004,313,42; J.Gastroenterol.2003,38,567).

In following table 1, exemplified can with the example of some exemplary compounds of administration together with the compound of present disclosure.In conjoint therapy, the compound of present disclosure is can be with the active compound of other anti-HCV common or separate administration, or compound is mixed in composition.

Table 1

Trade(brand)name	Physiology classification	The type of inhibitor or target	Source company
				NIM811		Cyclophilin inhibitor	Novartis
Zadaxin (Zadaxin)		Immunomodulator	Sciclone
				Suvus		Methylene blue	Bioenvision
Actilon (CPG10101)		TLR9 agonist	Coley
				Ba Tabulin (Batabulin) (T67)	Anticarcinogen	'beta '-tubulin inhibitor	Tularik Inc.，South San Francisco，CA
ISIS 14803	Antiviral drug	Antisense	ISIS Pharmaceuticals Inc， Carlsbad，CA/Elan Phamaceuticals Inc.，New York，NY
				Summetrel	Antiviral drug	Antiviral	Endo Pharmaceuticals Holdings Inc.，Chadds Ford，PA
GS-9132 (ACH-806)	Antiviral drug	HCV inhibitor	Achillion/Gilead
				Pyrazolopyrimidine compound and salt (deriving from WO-2005047288, on May 26th, 2005)	Antiviral drug	HCV inhibitor	Arrow Therapeutics Ltd.
Levovirin	Antiviral drug	IMPDH inhibitor	Ribapharm Inc.，Costa Mesa，CA
				U.S. mooring basin cloth (Merimepodib) (VX-497)	Antiviral drug	IMPDH inhibitor	Vertex Pharmaceuticals Inc.，Cambridge，MA
XTL-6865 (XTL-002)	Antiviral drug	Monoclonal antibody	XTL Biopharmaceuticals Ltd.，Rehovot，Isreal
				TVR (Telaprevir) (VX-950, LY-570310)	Antiviral drug	NS3 serpin	Vertex Pharmaceuticals Inc.，Cambridge，MA/Eli Lilly and Co.Inc.， Indianapolis，IN

Trade(brand)name	Physiology classification	The type of inhibitor or target	Source company
				HCV-796	Antiviral drug	NS5B replicative enzyme inhibitor	Wyeth/Viropharma
NM-283	Antiviral drug	NS5B replicative enzyme inhibitor	Idenix/Novartis
				GL-59728	Antiviral drug	NS5B replicative enzyme inhibitor	Gene Labs/Novartis
GL-60667	Antiviral drug	NS5B replicative enzyme inhibitor	Gene Labs/Novartis
				2’C MeA	Antiviral drug	NS5B replicative enzyme inhibitor	Gilead
PSI 6130	Antiviral drug	NS5B replicative enzyme inhibitor	Roche
				R1626	Antiviral drug	NS5B replicative enzyme inhibitor	Roche
2 ' C methyladenosine	Antiviral drug	NS5B replicative enzyme inhibitor	Merck
				JTK-003	Antiviral drug	RdRp inhibitor	Japan Tobacco Inc.， Tokyo，Japan
Levovirin	Antiviral drug	Ribavirin	ICN Pharmaceuticals， Costa Mesa，CA
				Ribavirin	Antiviral drug	Ribavirin	Schering-Plough Corporation，Kenilworth， NJ
Viramidine	Antiviral drug	Prodrugs of ribavirin with	Ribapharm Inc.，Costa Mesa，CA
				Heptazyme	Antiviral drug	Ribozyme	Ribozyme Pharmaceuticals Inc.， Boulder，CO
BILN-2061	Antiviral drug	Serpin	BoehringerIngelheim Pharma KG，Ingelheim， Germany
				SCH 503034	Antiviral drug	Serpin	Schering Plough

Trade(brand)name	Physiology classification	The type of inhibitor or target	Source company
				Zadazim	Immunomodulator	Immunomodulator	SciClone Pharmaceuticals Inc.，San Mateo，CA
Ceplene	Immunomodulator	Immunomodulator	Maxim Pharmaceuticals Inc.，San Diego，CA
				MMF (CellCept)	Immunosuppressor	HCV IgG immunosuppressor	F.Hoffmann-La Roche LTD，Basel，Switzerland
Civacir	Immunosuppressor	HCV IgG immunosuppressor	Nabi Biopharmaceuticals Inc.，Boca Raton，FL
				Albuferon-α	Interferon, rabbit	Albumin IFN-α 2b	Human Genome Sciences Inc.，Rockville，MD
Infergen A (Infergen A)	Interferon, rabbit	IFN alfacon-1	InterMune Pharmaceuticals Inc.， Brisbane，CA
				Omega IFN	Interferon, rabbit	IFN-ω	Intarcia Therapeutics
IFN-β and EMZ701	Interferon, rabbit	IFN-β and EMZ701	Transition Therapeutics Inc.，Ontario，Canada
				Libiee (Rebif)	Interferon, rabbit	IFN-β1a	Serono，Geneva， Switzerland
Rodferon-A (RoferonA)	Interferon, rabbit	IFN-α2a	F.Hoffmann-La Roche LTD，Basel，Switzerland
				Intron A (Intron A)	Interferon, rabbit	IFN-α2b	Schering-Plough Corporation，Kenilworth， NJ
Intron A and Zadaxin	Interferon, rabbit	IFN-α 2b/ α 1-thymosin	RegeneRx Biopharmiceuticals Inc.， Bethesda，MD/ SciClone Pharmaceuticals Inc，San Mateo，CA
				Rebetron	Interferon, rabbit	IFN-α 2b/ ribavirin	Schering-Plough Corporation，Kenilworth， NJ
Actimmune	Interferon, rabbit	INF-γ	InterMune Inc.，Brisbane， CA

Trade(brand)name	Physiology classification	The type of inhibitor or target	Source company
				Interferon-beta	Interferon, rabbit	Interferon-beta-1a	Serono
Multiferon	Interferon, rabbit	Long-acting IFN	Viragen/Valentis
				Wellferon (Wellferon)	Interferon, rabbit	Lymphocytoblast IFN-α n1	GlaxoSmithKline plc， Uxbridge，UK
Omniferon	Interferon, rabbit	Natural IFN-α	Viragen Inc.，Plantation， FL
				Pai Luoxin (Pegasys)	Interferon, rabbit	Pegylation IFN-α 2a	F.Hoffmann-La Roche LTD，Basel，Switzerland
Pai Luoxin and Ceplene	Interferon, rabbit	Pegylation IFN-α 2a/ immunomodulator	Maxim Pharmaceuticals Inc.，San Diego，CA
				Pai Luoxin and ribavirin	Interferon, rabbit	Pegylation IFN-α 2a/ ribavirin	F.Hoffmann-La Roche LTD，Basel，Switzerland
PEG-Intron	Interferon, rabbit	Pegylation IFN-α 2b	Schering-Plough Corporation，Kenilworth， NJ
				PEG-Intron/ ribavirin	Interferon, rabbit	Pegylation IFN-α 2b/ ribavirin	Schering-Plough Corporation，Kenilworth， NJ
IP-501	Hepatoprotective	Fibrosis	Indevus Pharmaceuticals Inc.，Lexington，MA
				IDN-6556	Hepatoprotective	Caspase inhibitor	Idun Pharmaceuticals Inc.，San Diego，CA
ITMN-191 (R-7227)	Antiviral drug	Serpin	InterMune Pharmaceutic als Inc.， Brisbane，CA
				GL-59728	Antiviral drug	NS5B replicative enzyme inhibitor	Genelabs
ANA-971	Antiviral drug	TLR-7 agonist	Anadys

The compound of present disclosure also can be used as laboratory reagent.Compound can play a role providing for design virus replication experiment, checking animal experiment system and structure biology research aspect research tool, further to deepen the understanding to HCV disease mechanisms.In addition, the compound of present disclosure can be used for being set up or being determined and the binding site of other antiviral compound by for example competitive inhibition.

The compound of present disclosure also can be used to process or prevent viral polluting material, thereby reduce the contact lab assistant of this class material or the risk of medical worker or patient infection's virus, described material is blood, tissue, instruments and clothing, Laboratory Instruments and clothing and blood sampling or blood transfusion apparatus and material for example.

When preparing by synthetic method, or while producing by metabolic process (comprise and occur in (in body) in human or animal's health) or external generating process, present disclosure often comprises the compound with formula (I).

For the application's abbreviation, comprise that special abbreviation in following exemplary flow and embodiment is well known to those skilled in the art.Some abbreviations of using are as follows: HATU represents phosphofluoric acid O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea; Boc or BOC represent tertbutyloxycarbonyl; NBS represents N-bromo-succinimide; TBu or t-Bu represent the tertiary butyl; Represent-(trimethyl silyl) ethoxyl methyl of SEM; DMSO represents methyl-sulphoxide; MeOH represents methyl alcohol; TFA represents trifluoroacetic acid; RT represents room temperature or retention time (will make stipulations in literary composition); t _rrepresent retention time; EDCI represents 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride; DMAP represents DMAP; THF represents tetrahydrofuran (THF); DBU represents 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene; T-Bu; DEA represents diethylamine; HMDS represents hexamethyldisilane base nitrine; DMF represents DMF; Bzl represents benzyl; EtOH represents ethanol; IPrOH or i-PrOH represent Virahol; Me ₂s represents dimethyl thioether; Et ₃n or TEA represent triethylamine; Ph represents phenyl; OAc represents acetoxyl; EtOAc represents ethyl acetate; Dppf represents 1,1 '-bis-(diphenyl phosphine) ferrocene; iPr ₂etN or DIPEA represent diisopropylethylamine; Cbz represents carbobenzoxy-(Cbz) (carbobenzyloxy); N-BuLi represents n-Butyl Lithium; ACN represents acetonitrile; H or hr represent hour; M or min represent minute; S represents second; LiHMDS represents hexamethyl dimethyl silanyl Lithamide; DIBAL represents diisobutyl aluminium hydride; TBDMSCl represents TERT-BUTYL DIMETHYL CHLORO SILANE; Me represents methyl; Ca. represent approximately; OAc represents acetoxyl; IPr represents sec.-propyl; Et represents ethyl; Bn represents benzyl; Represent 1-hydroxyl-7-azepine benzotriazole with HOAT.

For the application's abbreviation, comprise that special abbreviation in following exemplary flow and embodiment is well known to those skilled in the art.Some abbreviations of using are as follows:

In conjunction with the synthesis flow below by illustrating the compounds process for production thereof of present disclosure, can understand better the Compounds and methods for of present disclosure.Raw material can be available from commercial source, or prepares by the literature method of a large amount of records known to persons of ordinary skill in the art.It will be obvious to those skilled in the art that and can, by suitable reactant and reagent in synthesis method shown in replacement below, prepare the above compound of definition.It will be apparent to one skilled in the art that and can optionally protect the order with deprotection steps and step itself by different order, this depends on and is successfully completed following synthetic variable character.Described variable as above defines, unless be hereinafter otherwise noted.

Flow process 1: symmetrical or asymmetric biphenyl class

Aryl halide 1 and boric acid ester 2 can adopt standard Suzuki-Miayura coupling condition (AngewChem.Int.Ed.Engl 2001,40,4544) to carry out coupling to obtain biaryl 3.It should be noted in the discussion above that 2 boric acid analogue can be used to replace this ester.Work as R ¹²and R ¹³when different, can realize single deprotection of tetramethyleneimine part.Work as R ¹²=benzyl, and R ¹³during=the tertiary butyl, hydrogenolysis condition (hydrogenolytic condition) is processed and is obtained 4.For example, for example, under alkali (salt of wormwood) exists, can use Pd/C catalyzer.4 acylations can complete under standard acylations condition.Coupling reagent (for example HATU) for example, can be used for this aspect with the combination of amine alkali (Hunig alkali).Or 4 can react with isocyanic ester or urea chloride, obtain wherein R ⁹formula 5 compounds for amine.Can be by for example, finish dealing with 5 further deprotection with strong acid (HCl or trifluoroacetic acid).Can adopt to be similar to and be converted into 5 standard conditions used by 6 preparations 7 by 4.In another embodiment, work as R ¹²=R ¹³during=t-Bu, can be by for example, processing directly to change into 8 with strong acid (HCl or trifluoroacetic acid) to 3.By completing 8 to 7 conversion by 4 preparations 5 or by the similar fashion of 6 preparation 7 method therefors.Yet in this case, 7 end group (cap) will be identical.

Flow process 2: the biphenyl class of asymmetric end-blocking

Can adopt standard amide coupling condition (for example HATU and amine alkali (for example Hunig alkali)) to realize 6 (deriving from flow process 1) and change into 10.Available strong acid (for example HCl or trifluoroacetic acid) completes deprotection and obtains 11.Then use respectively acyl chlorides, isocyanic ester or urea chloride or chloro-formic ester, compound 11 is changed into 12,13 or 14.

Flow process 3: the biphenyl class of the symmetrical end group of tape complexity

Can, by for example, processing with strong acid (HCl or trifluoroacetic acid), make wherein each R ⁹be all-CH (NHBoc) R ¹⁸) compound 15 (15=7 (flow process 1)) change into 16.Can with suitable chloro-formic ester, isocyanic ester or urea chloride or acyl chlorides, to 16, process respectively, by 16, prepare compound 17,18 and 19.

Flow process 4: symmetrical biphenyl class

Symmetrical biphenyl analogue (wherein the two halves of molecule are equal formula 7 compounds) can be started to synthesize by bromoketone 20.For example, with nucleophilic reagent (trinitride, phthalic imidine or preferably diformyl sodium amide (sodium diformylamide) (Yinglin and Hongwen; Synthesis1990; 122)) deprotection after alternative amination, obtains 21.For example, at the lower amino acid condensation with suitably protecting of standard amination condition (HATU and Hunig alkali), obtain 22.Under heating or microwave condition, heat together with ammonium acetate, cause forming 3,3 and can use strong acid (for example HCl or trifluoroacetic acid) (R ¹²=R ¹³=t-Bu) deprotection, or for example, with hydrogen and transition-metal catalyst (Pd/C) (R ¹²=R ¹³=benzyl) hydrogenolysis.Carboxylic acid (R ⁹cO ₂h) can be converted into 22 mode acylations is exerted an influence by being similar to 21.Can pass through with suitable isocyanic ester (R ⁹=R ²⁴r ²⁵n; R ²⁵=H) or urea chloride (R ⁹=R ²⁴r ²⁵n; R ²⁵hydrogen) process, complete the formation of urea.

Flow process 5: raw material 25 and 2

Flow process 5 has been described the preparation of some required raw materials of synthetic order shown in flow process 1-4.By heating, by ketone-acid amides 24 or ketone-ester 27, prepare key intermediate 25 (being similar to 1 in flow process 1) together with ammonium acetate under heating or microwave condition.Can, by the ring-type with suitable or non-annularity amino acid condensation under standard amide formation condition, by 23, prepare ketone-acid amides 24.Bromide 26 use nucleophilic reagents (for example trinitride, phthalic imidine or diformyl sodium amide (Synthesis 1990,122)) are processed rear deprotection, can obtain 23.Can for example, under alkali (salt of wormwood or sodium bicarbonate) exists, by bromide 26, react with suitable ring-type or the protected amino acid of non-annularity N-, bromizate thing 26 and change into 27.28 with source of bromide ions (for example bromine, NBS or CBr ₄) bromination cause forming 26.Can be according to (the Journal ofOrganic Chemistry 1995 of method described in document, 60,7508) or its alternative, under palladium catalytic condition, with hypoboric acid two pinacol esters (bis-pinacalotodiboron), process, bromizate thing 25 and change into boric acid ester 2.

Flow process 6: raw material 31a

In another embodiment, can be under Suzuki type coupling condition, by making bromine imdazole derivatives 31 and the aromatic yl acid reaction that various chlorine replaces carry out for example 31a (being similar to 1 in 25 and the flow process 1 in flow process 5) of raw materials, the aryl boric acid that described chlorine replaces can be prepared by standard method (referring to for example Organic Letters 2006,8,305 and the reference wherein quoted) or purchased from supplier.Available source of bromide ions (for example bromine, CBr ₄or N-bromo-succinimide) make imidazoles 30 brominations, to obtain bromine imidazoles 31.Can, in the methanol solution of ammonium hydroxide, by the protected amino acid of the N-suitably replacing and glyoxal reaction, prepare imidazoles 30.

Flow process 7: heteroaryl compound class

In another embodiment of present disclosure, can make aryl halide 32 carry out coupling under Suzuki-Miyaura palladium catalytic condition, form heteroaryl derivative 34.By under hydrogenolysis condition, for example, with hydrogen and transition-metal catalyst (palladium on carbon) (R ¹³=benzyl) process, compound 34 is refined into 35.35 acylations can complete under the following conditions: can be for example, under alkali (triethylamine) exists, with suitable acyl chlorides (R ⁹cOCl); For example, under standard coupling reagent (HATU) exists, with the carboxylic acid (R suitably replacing ⁹cO ₂h); Or with isocyanic ester (R ²⁷nCO, wherein R ⁹=R ²⁷r ²⁸n-; R ²⁸=H) or urea chloride (R ²⁷r ²⁸nCOCl, wherein R ⁹=R ²⁷r ²⁸n-).Can be by for example, processing with strong acid (HCl or trifluoroacetic acid), by 36 (R ¹²=t-Bu) prepare compound 37.Can change in the of 36 as 35, make gained amine in 37 carry out acylations to obtain 38.R therein ¹²=R ¹³situation under, can be by for example, with strong acid (HCl or trifluoroacetic acid) (R ¹²=R ¹³=t-Bu) process or by adopting hydrogenolysis condition, use hydrogen and transition-metal catalyst (for example palladium on carbon) (R ¹²=R ¹³=benzyl), make 34 directly to change into 39.Can change into the similar fashion described in 36 by 35 and complete 39 acylations.

Flow process 8

Can at high temperature, under four (dimethylamino) ethene exists, by for example, processing with palladium source (two (cyanobenzene) palladiums of dichloro), make heteroaryl muriate 29 change into symmetrical analogue 40.Can be by for example, processing with strong acid (HCl or trifluoroacetic acid), the SEM ether and the t-butyl carbamate (Boc carbamate) that exist make 40 in a step in are sloughed, and obtain 41.By making 38 similar fashion that change into 39 conditions used in flow process 7, complete the conversion to 42.

Flow process 9: with the substituted heteroaryl compounds of symmetrical end group

Can, by the similar approach of method described in flow process 3, compound 43 (be similar to 42, wherein R ₂₃=-CH (NHBoc) R ₂₄) be refined into 45,46 and 47.R therein ₂₀in the situation of=alkoxy methyl (being SEM), can for example, with strong acid (HCl or trifluoroacetic acid) deaminize t-butyl formate (referring to 43 to 44) in, slough SEM.

R ²⁰=alkoxy methyl or H

W, X, Y, Z=C or N, wherein at least one in W, X, Y and Z is necessary for C,

At least one in W, X, Y and Z is necessary for N

Flow process 10: raw material 29

Can for example, under palladium source (dichloro two (triphenylphosphine) closes palladium (II)) exists, heteroaryl bromide 54 for example, is reacted with vinyl stannane (tributyl (1-vinyl ethyl ether base) tin), obtain 55, can be by for example, with source of bromide ions (N-bromo-succinimide, CBr ₄or bromine) process, even change into bromoketone 51 with 55.Or, can be by for example, with source of bromide ions (bromine, CBr ₄or N-bromo-succinimide) process, the heteroaryl bromide 53 that ketone group is replaced directly changes into 51.Can, by adding sodiumazide, potassium phthalimide or diformyl sodium amide (Synthesis1990122) deprotection afterwards, bromizate thing 51 and change into keto-amine 48.Then, can for example, under standard amide formation condition (be coupling reagent, HATU, under the weak base such as Hunig alkali exist), make keto-amine 48 and the amino acid coupling suitably replacing, obtain 49.Can, under heating or microwave condition, by reacting with ammonium acetate, make compound 49 further change into imidazoles 50 subsequently.Or, can for example, under alkali (sodium bicarbonate or salt of wormwood) exists, make 51 directly to react with the amino acid that suitably replace, obtain 52,52 so that heat or microwave condition under react with ammonium acetate, obtain 50.First for example pass through, with after highly basic (sodium hydride) deprotonation, then use suitable alkoxy methyl halogenide (for example 2-(trimethyl silyl) ethoxyl methyl chlorine) to process, available alkoxy methyl protects imidazoles 50.

Flow process 11: the phenylglycine derivatives of replacement

The phenylglycine derivatives replacing can be prepared by several different methods hereinafter described.Can, in acidic medium, for example, with suitable aldehyde and reductive agent (sodium cyanoborohydride), make phenylglycocoll tert-butyl ester standard reductive alkylation (approach A).The available strong acid of hydrolysis of the tert-butyl ester (for example HCl or trifluoroacetic acid) completes.For example, for example, or available alkyl halide (iodoethane) and alkali (sodium bicarbonate or salt of wormwood) make phenylglycocoll alkylation (approach B).Approach C is illustrated under reductive agent and acid existence, as approach A, after phenylglycocoll standard reductive alkylation, for example, with other aldehyde (formaldehyde), carries out standard reductive alkylation for the second time.Approach D represents to synthesize by corresponding amygdalic acid analogue the phenylglycocoll replacing.Secondary alcohol changes into and can realize with Tosyl chloride by leavings group (competent leavinggroup).Available suitable amine is replaced toluenesulphonic acids base and is sloughed benzyl ester by reductibility, obtains the phenylglycine derivatives replacing.In approach E, the phenylglycine derivatives that racemize replaces is emanated by the chiral auxiliary(reagent) with enantiomer-pure (such as but not limited to the pantolactone (pantolactone) of (+)-1-phenylethyl alcohol, (-)-1-phenylethyl alcohol, Evan oxazolidone or enantiomer-pure) esterification.The separation of diastereomer is removed chiral auxiliary(reagent) after by chromatography (silica gel, HPLC, crystallization process etc.) and is completed, and obtains the phenylglycine derivatives of enantiomer-pure.Approach H represents the synthetic order of intersecting with approach E, and wherein aforementioned chiral auxiliary(reagent) is just installed before adding amine.For example, or the ester of Arylacetic acids can be used source of bromide ions (bromine, N-bromo-succinimide or CBr ₄) carry out bromination.Gained bromotoluene compound can be for example, under tertiary amine base (triethylamine) or the existence of Hunig alkali, with various monosubstituted or dibasic amine displacements.With lithium hydroxide, process at low temperatures or at high temperature with 6N HCl, process and make methyl ester hydrolysis, obtaining the phenylglycine derivatives replacing.Another kind method is shown in approach G.For example, palladium source (0) (two (tributylphosphine)), for example close, under palladium and alkali (potassiumphosphate) exists, glycine analogue can be with various aryl halide derivatizes.Then, available bases or acid treatment, make the hydrolysis of gained ester.It should be understood that, there is the preparation method of other well-known phenylglycine derivatives in this area, in content of the present invention, can, to its correct, obtain needed compound.Also to be appreciated that, can pass through preparation HPLC, final phenylglycine derivatives is purified to the above enantiomeric purity of 98% enantiomeric excess (ee).

Flow process 12: acylated amino derivative

In another embodiment of present disclosure, acidylate phenylglycine derivatives can be prepared by the following method.Wherein the protected phenylglycine derivatives that becomes the ester of easily sloughing of carboxylic acid can for example, carry out acidylate with acyl chlorides under alkali (triethylamine) exists, and obtains corresponding acid amides (approach A).Approach B represents to make initial phenylglycine derivatives acylations with suitable chloro-formic ester, and approach C represents and the reacting of suitable isocyanic ester or urea chloride.Each of 3 kinds of intermediates shown in approach A-C all can be by method known to those skilled in the art deprotection (being for example HCl or trifluoroacetic acid processing of highly basic for the tert-butyl ester).

Flow process 13

Can process chloromethylbenzene guanidine-acetic acid with excessive amine and prepare amino substituted phenylacetic acid class.

Compound analysis condition

By Shimadzu LC system and the coupling of Waters Micromass ZQ MS system, carry out purity evaluation and Low Resolution Mass Spectra analysis.It should be noted in the discussion above that retention time is slightly different between different instruments.The LC condition that mensuration retention time (RT) adopts is:

Condition 1

Post=Phenomenex-Luna 3.0 * 50mm S10

Start %B=0

Final %B=100

Gradient time=2 minute

Stand-by time=3 minute

Flow velocity=4ml/ minute

Wavelength=220nm

10% methyl alcohol/90%H of solvent orange 2 A=0.1%TFA ₂o

90% methyl alcohol/10%H of solvent B=0.1%TFA ₂o

Condition 2

Post=Phenomenex-Luna 4.6 * 50mm S10

Start %B=0

Final %B=100

Gradient time=2 minute

Stand-by time=3 minute

Flow velocity=5ml/ minute

Wavelength=220nm

10% methyl alcohol/90%H of solvent orange 2 A=0.1%TFA ₂o

90% methyl alcohol/10%H of solvent B=0.1%TFA ₂o solution

Condition 3

Post=HPLC XTERRA C183.0 * 50mm S7

Start %B=0

Final %B=100

Gradient time=3 minute

Stand-by time=4 minute

Flow velocity=4ml/ minute

Wavelength=220nm

10% methyl alcohol/90%H of solvent orange 2 A=0.1%TFA ₂o solution

90% methyl alcohol/10%H of solvent B=0.1%TFA ₂o solution

Condition M1

Post: Luna 4.6 * 50mm S10

Start %B=0

Final %B=100

Gradient time=3 minute

Stand-by time=4 minute

Flow velocity=4ml/ minute

Solvent orange 2 A :=95%H ₂o: 5%CH ₃cN, 10mm ammonium acetate

Solvent B:=5%H ₂o: 95%CH ₃cN; 10mm ammonium acetate

Synthesizing of general end group (Cap)

The methyl alcohol of 10%Pd/C (2.0g) (10ml) suspension is added to (R)-2-phenylglycocoll (10g, 66.2mmol), in the mixture of formaldehyde (aqueous solution of 33ml 37% (weight)), 1N HCl (30ml) and methyl alcohol (30ml), and be exposed to H ₂(60psi) in, reach 3 hours.Make reaction mixture through diatomite after filtration, vacuum concentrated filtrate.Gained crude product Virahol recrystallization, obtains the HCl salt (4.0g, white spicule) of Cap-1.Opticity :-117.1 ° of [c=9.95mg/ml, H ₂in O; λ=589nm]. ¹h NMR (DMSO-d ₆, δ=2.5ppm, 500MHz): δ 7.43-7.34 (m, 5H), 4.14 (s, 1H), 2.43 (s, 6H); LC (condition 1): RT=0.25; LC/MS: for [M+H] ⁺c ₁₀h ₁₄nO ₂analytical calculation value: 180.10; Measured value: 180.17; HRMS: for [M+H] ⁺c ₁₀h ₁₄nO ₂analytical calculation value: 180.1025; Measured value: 180.1017.

Cap-2

In several minutes, by NaBH ₃cN (6.22g, 94mmol) is added in the mixture of cooling (ice/water) (R)-2-phenylglycocoll (6.02g, 39.8mmol) and MeOH (100ml) in batches, and stirs 5 minutes.In 10 minutes, drip acetaldehyde (10ml), under identical cooling temperature, continue to stir after 45 minutes, in envrionment temperature, stir～6.5 hours.Reaction mixture uses ice-water bath cooling again, and water (3ml) dripped dense HCl quencher, until the pH of mixture is～1.5-2.0 after processing in～45 minutes.Remove after cooling bath, adding dense HCl to continue stirring with when keeping the about pH 1.5-2.0 of mixture.Reaction mixture is stirred and spent the night, remove by filter after white suspension thing vacuum concentrated filtrate.Crude product ethyl alcohol recrystallization, obtains the HCl salt of Cap-2, and two kinds of products are bright white solid (product-1:4.16g; Product-2:2.19g). ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): 10.44 (1.00, br s, 1H), 7.66 (m, 2H), 7.51 (m, 3H), 5.30 (s, 1H), 3.15 (br m, 2H), 2.98 (br m, 2H), 1.20 (apparent br s, 6H).Product-1:[α] ²⁵-102.21 ° of (c=0.357, H ₂o); Product-2:[α] ²⁵-99.7 ° of (c=0.357, H ₂o).LC (condition 1): RT=0.43 minute; LC/MS: for [M+H] ⁺c ₁₂h ₁₈nO ₂analytical calculation value: 208.13; Measured value: 208.26.

By acetaldehyde (5.0ml, 89.1mmol) and 10%Pd/C (720mg) and methyl alcohol/H ₂the suspension of O (4ml/1ml) is added in the mixture of (R)-2-phenylglycocoll (3.096g, 20.48mmol), 1N HCl (30ml) and methyl alcohol (40ml) of cooling (～15 ℃) successively.Remove after cooling bath, by reaction mixture at H ₂air bag (balloon) is lower to be stirred 17 hours.Add again after acetaldehyde (10ml, 178.2mmol), at H ₂under atmosphere, continue to stir and [note: in whole reaction, supplement on demand H for 24 hours ₂supply].Reaction mixture is through diatomite after filtration, vacuum concentrated filtrate.Gained crude product Virahol recrystallization, obtains the HCl salt (2.846g, light white solid) of (R)-2-(ethylamino)-2-phenylacetic acid. ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 14.15 (br s, 1H), 9.55 (br s, 2H), 7.55-7.48 (m, 5H), 2.88 (br m, 1H), 2.73 (br m, 1H), 1.20 (apparent t, J=7.2,3H).LC (condition 1): RT=0.39 minute; Homogeneity index (homogeneity index) > 95%; LC/MS: for [M+H] ⁺c ₁₀h ₁₄nO ₂analytical calculation value: 180.10; Measured value: 180.18.

By methyl alcohol/H of 10%Pd/C (536mg) ₂o (3ml/1ml) suspension is added in the mixture of (R)-2-(ethylamino)-2-phenylacetic acid/HCl (1.492g, 6.918mmol), formaldehyde (aqueous solution of 20ml 37% (weight)), 1N HCl (20ml) and methyl alcohol (23ml).By reaction mixture at H ₂under air bag, stir～72 hours, while needing, supplement H ₂supply.Reaction mixture is through diatomite after filtration, vacuum concentrated filtrate.Gained is Virahol (50ml) recrystallization for crude product, obtains the HCl salt (985mg, white solid) of Cap-3. ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 10.48 (br s, 1H), 7.59-7.51 (m, 5H), 5.26 (s, 1H), 3.08 (apparent br s, 2H), 2.65 (br s, 3H), 1.24 (br m, 3H).LC (condition 1): RT=0.39 minute; Homogeneity index > 95%; LC/MS: for [M+H] ⁺c ₁₁h ₁₆nO ₂analytical calculation value: 194.12; Measured value: 194.18; HRMS: for [M+H] ⁺c ₁₁h ₁₆nO ₂analytical calculation value: 194.1180; Measured value: 194.1181.

In 6 minutes, by ClCO ₂me (3.2ml, 41.4mmol) be added drop-wise to (the R)-2-amino-2-phenylacetic acid tert-butyl ester/HCl (9.877g of cooling (ice/water), 40.52mmol) and diisopropylethylamine (14.2ml, 81.52mmol) with half solution (semi-solution) of THF (410ml) in, and at same temperature, stir 5.5 hours.Vacuum is removed after volatile component, and resistates is distributed between water (100ml) and ethyl acetate (200ml).1N HCl (25ml) and saturated NaHCO for organic layer ₃solution (30ml) washing, dry (MgSO ₄), filter final vacuum concentrated.Gained colorless oil is ground with hexane, after filtering, with hexane (100ml) washing, obtains (R)-2-(methoxycarbonyl is amino)-2-phenylacetic acid tert-butyl ester (7.7g, white solid). ¹H NMR(DMSO-d ₆，δ＝2.5ppm，400MHz)：7.98(d，J＝8.0，1H)，7.37-7.29(m，5H)，5.09(d，J＝8，1H)，3.56(s，3H)，1.33(s，9H)。LC (condition 1): RT=1.53 minute; Homogeneity index～90%; LC/MS: for [M+Na] ⁺c ₁₄h ₁₉nNaO ₄analytical calculation value: 288.12; Measured value: 288.15.

In 7 minutes, TFA (16ml) is added drop-wise to the CH of cooling (ice/water) of above-mentioned product ₂cl ₂(160ml) in solution, remove after cooling bath stirred reaction mixture 20 hours.Because deprotection reaction remains unfulfilled, therefore add again TFA (1.0ml), and continue again to stir 2 hours.Vacuum is removed after volatile component, and gained oiliness is ether (15ml) and hexane (12ml) processing for resistates, is precipitated thing.Throw out after filtering, is used ether/hexane (ratio～1: 3; 30ml), after washing, vacuum-drying, obtains Cap-4 (5.57g, fine hair shape white solid).Opticity :-176.9 ° of [c=3.7mg/ml, H ₂in O; λ=589nm]. ¹H NMR(DMSO-d ₆，δ＝2.5ppm，400MHz)：δ12.84(br s，1H)，7.96(d，J＝8.3，1H)，7.41-7.29(m，5H)，5.14(d，J＝8.3，1H)，3.55(s，3H)。LC (condition 1): RT=1.01 minute; Homogeneity index > 95%; LC/MS: for [M+H] ⁺c ₁₀h ₁₂nO ₄analytical calculation value: 210.08; Measured value: 210.17; HRMS: for [M+H] ⁺c ₁₀h ₁₂nO ₄analytical calculation value: 210.0766; Measured value: 210.0756.

By (R)-2-phenylglycocoll (1.0g, 6.62mmol), Isosorbide-5-Nitrae-dibromobutane (1.57g, 7.27mmol) and Na ₂cO ₃(2.10g, 19.8mmol) heats 21 hours with the mixture of ethanol (40ml) at 100 ℃.Make reaction mixture be cooled to envrionment temperature, filter, and vacuum concentrated filtrate.Resistates is dissolved in to ethanol, with 1N HCl, is acidified to after pH 3-4, vacuum is removed volatile component.Gained crude product is purified (water/methyl alcohol/TFA) with reversed-phase HPLC, obtains the tfa salt (1.0g, half sticky white foam) of Cap-5. ¹h NMR (DMSO-d ₆, δ=2.5,500MHz) δ 10.68 (br s, 1H), 7.51 (m, 5H), 5.23 (s, 1H), 3.34 (apparent br s, 2H), 3.05 (apparent br s, 2H), 1.95 (apparent br s, 4H); RT=0.30 minute (condition 1); Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₁₂h ₁₆nO ₂analytical calculation value: 206.12; Measured value: 206.25.

Adopt the preparation method of Cap-5, by the tfa salt of (R)-2-phenylglycocoll and the synthetic Cap-6 of the bromo-2-of 1-(2-bromine oxethyl) ethane. ¹h NMR (DMSO-d ₆, δ=2.5,500MHz) δ 12.20 (br s, 1H), 7.50 (m, 5H), 4.92 (s, 1H), 3.78 (apparent br s, 4H), 3.08 (apparent br s, 2H), 2.81 (apparent br s, 2H); RT=0.32 minute (condition 1); > 98%; LC/MS: for [M+H] ⁺c ₁₂h ₁₆nO ₃analytical calculation value: 222.11; Measured value: 222.20; HRMS: for [M+H] ⁺c ₁₂h ₁₆nO ₃analytical calculation value: 222.1130; Measured value: 222.1121.

By the CH of Tosyl chloride (8.65g, 45.4mmol) ₂cl ₂(200ml) solution is added drop-wise to (S)-2-hydroxyl-2-phenylacetic acid benzyl ester (10.0g of cooling (5 ℃), 41.3mmol), triethylamine (5.75ml, 41.3mmol) and the CH of DMAP (0.504g, 4.13mmol) ₂cl ₂(200ml), in solution, maintain the temperature between-5 ℃ and 0 ℃ simultaneously.Reactant is stirred at 0 ℃ after 9 hours, in refrigerator (25 ℃), preserve 14 hours.Be melted to after envrionment temperature water (200ml), 1N HCl (100ml) and salt solution (100ml) washing, dry (MgSO ₄), filter final vacuum concentrated, obtain 2-phenyl-2-(tosyloxy) jasmal (16.5g, viscosity oily matter solidify when standing).The chirality integrity (chiral integrity) that does not check this product, this product is just used to next step without being further purified. ¹H NMR(DMSO-d ₆，δ＝2.5，500MHz)δ7.78(d，J＝8.6，2H)，7.43-7.29(m，10H)，7.20(m，2H)，6.12(s，1H)，5.16(d，J＝12.5，1H)，5.10(d，J＝12.5，1H)，2.39(s，3H)。RT=3.00 (condition 3); Homogeneity index > 90%; LC/MS: for [M+H] ⁺c ₂₂h ₂₀naO ₅s analytical calculation value: 419.09; Measured value: 419.04.

By 2-phenyl-2-(tosyloxy) jasmal (6.0g, 15.1mmol), 1-methylpiperazine (3.36ml, 30.3mmol) and the THF of DIPEA (13.2ml, 75.8mmol) (75ml) solution at 65 ℃, heat 7 hours.Reactant is cooled to after envrionment temperature, and vacuum is removed volatile component.Resistates is distributed between ethyl acetate and water, organic layer water and salt water washing, dry (MgSO ₄), filter final vacuum concentrated.Gained is purified by flash chromatography (silica gel, ethyl acetate) for crude product, obtains 2-(4-methylpiperazine-1-yl)-2-phenylacetic acid benzyl ester (4.56g, the tenne oily matter of viscosity).Chirality HPLC analyzes (Chiralcel OD-H) and shows that this sample is mixture of enantiomers, ratio 38.2: 58.7.The separation of enantiomorph is carried out as follows: product is dissolved in to 120ml ethanol/heptane (1: 1), and injection (5ml/ injection) chirality HPLC post (ChiracelOJ, 5cm ID * 50cm L, 20 μ m), under 220nm monitoring, with 85: 15 heptane/ethanol with 75ml/ minute wash-out.Recovery obtains enantiomorph-1 (1.474g) and enantiomorph-2 (2.2149g), is viscosity oily matter. ¹h NMR (CDCl ₃, δ=7.26,500MHz) 7.44-7.40 (m, 2H), 7.33-7.24 (m, 6H), 7.21-7.16 (m, 2H), (5.13 d, J=12.5,1H), (5.08 d, J=12.5,1H), 4.02 (s, 1H), 2.65-2.38 (apparent br s, 8H), 2.25 (s, 3H).RT=2.10 (condition 3); Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₂₀h ₂₅n ₂o ₂analytical calculation value: 325.19; Measured value: 325.20.

Any methyl alcohol (10ml) solution of 2-(4-methylpiperazine-1-yl)-2-phenylacetic acid benzyl ester (1.0g, 3.1mmol) enantiomorph is added in methyl alcohol (5.0ml) suspension of 10%Pd/C (120mg).Under the guns, by reaction mixture at 50 minutes with the interior hydrogen capsule that is exposed to.React once completing, just through diatomite after filtering catalyst, vacuum concentrated filtrate, the Cap-7 (867.6mg that obtains being polluted by phenylacetic acid; Quality exceeds theoretical yield, tawny foam).Product is just used to next step without purifying. ¹h NMR (DMSO-d ₆, δ=2.5,500MHz) δ 7.44-7.37 (m, 2H), 7.37-7.24 (m, 3H), 3.92 (s, 1H), 2.63-2.48 (apparent bs, 2H), 2.48-2.32 (m, 6H), 2.19 (s, 3H); RT=0.31 (condition 2); Homogeneity index > 90%; LC/MS: for [M+H] ⁺c ₁₃h ₁₉n ₂o ₂analytical calculation value: 235.14; Measured value: 235.15; HRMS: for [M+H] ⁺c ₁₃h ₁₉n ₂o ₂analytical calculation value: 235.1447; Measured value: 235.1440.

According to Cap-7 synthesis method, adopt suitable amine displacement SN ₂step (being 4-hydroxy piperidine for Cap-8, is (S)-3-fluoropyrrolidine for Cap-9) and the improvement condition for separating of corresponding steric isomer intermediate as described below, carry out the synthetic of Cap-8 and Cap-9.

The Chiral Separation of intermediate 2-(4-hydroxy piperidine-1-yl)-2-phenylacetic acid benzyl ester adopts following condition to carry out: compound (500mg) is dissolved in to ethanol/heptane (5ml/45ml).Gained solution is injected to (5ml/ injection) chirality HPLC post (Chiracel OJ, 2cm ID * 25cm L, 10 μ m), with 80: 20 heptane/ethanol, press 10ml/ minute wash-out, under 220nm, monitor, obtaining 186.3mg enantiomorph-1 and 209.1mg enantiomorph-2, is viscosity light yellow oil.These benzyl esters according to Cap-7 preparation method hydrogenolysis, obtain Cap-8: ¹h NMR (DMSO-d ₆, δ=2.5,500MHz) 7.40 (d, J=7,2H), 7.28-7.20 (m, 3H), 3.78 (s 1H), 3.46 (m, 1H), 2.93 (m, 1H), 2.62 (m, 1H), 2.20 (m, 2H), 1.70 (m, 2H), 1.42 (m, 2H).RT=0.28 (condition 2); Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₁₃h ₁₈nO ₃analytical calculation value: 236.13; Measured value: 236.07; HRMS: for [M+H] ⁺c ₁₃h ₁₈nO ₃calculated value: 236.1287; Measured value: 236.1283.

The following condition of the separated employing of diastereomer of intermediate 2-((S)-3-fluoropyrrolidine-1-yl)-2-phenylacetic acid benzyl ester is carried out: chirality HPLC post (Chiracel OJ-H for ester (220mg), 0.46cmID * 25cm L, 5 μ m) carry out separation, at pressure 10 bar, flow velocity 70ml/ minute and 35 ℃ of temperature, use 95%CO ₂/ 5% methyl alcohol (containing 0.1%TFA) wash-out.The HPLC effluent of corresponding steric isomer, after concentrated, is dissolved in CH by resistates ₂cl ₂(20ml), with water-bearing media (the saturated NaHCO of 10ml water+1ml ₃solution) washing.Organic phase drying (MgSO ₄), filter final vacuum concentrated, obtain 92.5mg flow point-1 and 59.6mg flow point-2.According to Cap-7 preparation method, make these benzyl ester hydrogenolysis, obtain Cap-9a and Cap-9b.Cap-9a (diastereomer-1; Sample is to purify with reversed-phase HPLC the tfa salt obtaining, and uses H ₂o/ methyl alcohol/TFA solvent): ¹hNMR (DMSO-d ₆, δ=2.5,400MHz) 7.55-7.48 (m, 5H), 5.38 (d of m, J=53.7,1H), 5.09 (br s, 1H), 3.84-2.82 (br m, 4H), 2.31-2.09 (m, 2H).RT=0.42 (condition 1); Homogeneity index > 95%; LC/MS: for [M+H] ⁺c ₁₂h ₁₅fNO ₂analytical calculation value: 224.11; Measured value: 224.14; Cap-9b (diastereomer-2): ¹h NMR (DMSO-d ₆, δ=2.5,400MHz) 7.43-7.21 (m, 5H), 5.19 (d of m, J=55.9,1H), 3.97 (s, 1H), 2.95-2.43 (m, 4H), 2.19-1.78 (m, 2H).RT=0.44 (condition 1); LC/MS: for [M+H] ⁺c ₁₂h ₁₅fNO ₂analytical calculation value: 224.11; Measured value: 224.14.

To D-PROLINE (2.0g, 17mmol) and the formaldehyde (H of 2.0ml 37% (weight) ₂o solution) methyl alcohol (5ml) suspension that adds 10%Pd/C (500mg) in methyl alcohol (15ml) solution.Mixture is stirred 23 hours under hydrogen capsule.Reaction mixture is through diatomite after filtration, vacuum concentration, obtains Cap-10 (2.15g, pale solid). ¹H NMR(DMSO-d ₆，δ＝2.5，500MHz)3.42(m，1H)，3.37(dd，J＝9.4，6.1，1H)，2.85-2.78(m，1H)，2.66(s，3H)，2.21-2.13(m，1H)，1.93-1.84(m，2H)，1.75-1.66(m，1H)。RT=0.28 (condition 2); Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₆h ₁₂nO ₂analytical calculation value: 130.09; Measured value: 129.96.

By (2S, 4R)-4-fluoropyrrolidine-2-formic acid (0.50g, 3.8mmol), the formaldehyde (H of 0.5ml 37% (weight) ₂o solution), 12N HCl (0.25ml) and 10%Pd/C (50mg) stir 19 hours with the mixture of methyl alcohol (20ml) under hydrogen capsule.Reaction mixture is through diatomite after filtration, vacuum concentrated filtrate.Resistates Virahol recrystallization, obtains the HCl salt (337.7mg, white solid) of Cap-11. ¹H NMR(DMSO-d ₆，δ＝2.5，500MHz)5.39(d m，J＝53.7，1H)，4.30(m，1H)，3.90(ddd，J＝31.5，13.5，4.5，1H)，3.33(dd，J＝25.6，13.4，1H)，2.85(s，3H)，2.60-2.51(m，1H)，2.39-2.26(m，1H)。RT=0.28 (condition 2); Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₆h ₁₁fNO ₂analytical calculation value: 148.08; Measured value: 148.06.

ALANINE (2.0g, 22.5mmol) is dissolved in to 10% aqueous sodium carbonate (50ml), then adds THF (50ml) solution of methyl-chloroformate (4.0ml).Reaction mixture is stirred under envrionment conditions after 4.5 hours to vacuum concentration.After gained white solid is water-soluble, with 1N HCl, be acidified to pH～2-3.Gained is ethyl acetate (3 * 100ml) extraction for solution, by the dry (Na of the organic phase merging ₂sO ₄), filter final vacuum concentrated, obtain colorless oil (2.58g).This product 500mg is purified (H with reversed-phase HPLC ₂o/ methyl alcohol/TFA), obtaining 150mg Cap-12, is colorless oil. ¹H NMR(DMSO-d ₆，δ＝2.5，500MHz)7.44(d，J＝7.3，0.8H)，7.10(br s，0.2H)，3.97(m，1H)，3.53(s，3H)，1.25(d，J＝7.3，3H)。

By ALANINE (2.5g, 28mmol), formaldehyde (8.4g, 37% (weight)), 1N HCl (30ml) and 10%Pd/C (500mg) stir 5 hours under nitrogen atmosphere (50psi) with the mixture of methyl alcohol (30ml).Reaction mixture is through diatomite after filtration, vacuum concentrated filtrate, obtains the HCl salt (4.4g of Cap-13; Quality surpasses theoretical yield, and oily matter solidifies when standing under vacuum).Product can be used without being further purified just. ¹H NMR(DMSO-d ₆，δ＝2.5，500MHz)δ12.1(br s，1H)，4.06(q，J＝7.4，1H)，2.76(s，6H)，1.46(d，J＝7.3，3H)。

Step 1: at 0 ℃, by (R)-(-)-D-PG tert-butyl ester (3.00g, 12.3mmol), NaBH ₃the mixture of CN (0.773g, 12.3mmol), KOH (0.690g, 12.3mmol) and acetic acid (0.352ml, 6.15mmol) stirs in methyl alcohol.In 5 minutes, in this mixture, drip glutaraldehyde (2.23ml, 12.3mmol).When making reaction mixture be warming up to envrionment temperature, stir, continue at the same temperature to stir 16 hours.Except desolventizing, resistates distributes with the 10%NaOH aqueous solution and ethyl acetate subsequently.Organic phase, after separation, is dried (MgSO ₄), after filtration, be concentrated into dryly, obtain transparent oily matter.This product is purified (Primesphere C-18,30 * 100mm with anti-phase preparation HPLC; CH ₃cN-H ₂o-0.1%TFA), obtaining intermediate ester (2.70g, 56%), is transparent oily matter. ¹H NMR(400MHz，CDCl ₃)δ7.53-7.44(m，3H)，7.40-7.37(m，2H)，3.87(d，J＝10.9Hz，1H)，3.59(d，J＝10.9Hz，1H)，2.99(t，J＝11.2Hz，1H)，2.59(t，J＝11.4Hz，1H)，2.07-2.02(m，2H)，1.82(d，J＝1.82Hz，3H)，1.40(s，9H)。LC/MS: for C ₁₇h ₂₅nO ₂analytical calculation value: 275; Measured value: 276 (M+H) ⁺.

Step 2: add TFA (3ml) in the stirred solution of intermediate ester (1.12g, 2.88mmol) and methylene dichloride (10ml).Reaction mixture is stirred after 4 hours at ambient temperature, be concentrated into dryly, obtain light yellow oil.Oily matter is purified (Primesphere C-18,30 * 100mm with anti-phase preparation HPLC; CH ₃cN-H ₂o-0.1%TFA).Merge after suitable flow point, vacuum concentration is to dry.Then resistates is dissolved in minimum methyl alcohol, and is added on MCX LP extraction cylinder (2 * 6g).After methyl alcohol for cylinder (40ml) rinses, methanol solution (50ml) wash-out of 2M ammonia for required compound.Merge after the flow point that contains product, concentrated and resistates is water-soluble.Making after this solution freeze-drying, obtain title compound (0.492g, 78%), is light yellow solid. ¹H NMR(DMSO-d ₆)δ7.50(s，5H)，5.13(s，1H)，3.09(brs，2H)，2.92-2.89(m，2H)，1.74(m，4H)，1.48(br s，2H)。LC/MS: for C ₁₃h ₁₇nO ₂analytical calculation value: 219; Measured value: 220 (M+H) ⁺.

The bromo-2-phenylacetic acid of step 1:2-((S)-1-phenylethyl) ester: to α-bromophenyl acetic acid (10.75g, 0.050mol), (S)-(-)-1-phenylethyl alcohol (7.94g, 0.065mol) and DMAP (0.61g, 5.0mmol) with the mixture of anhydrous methylene chloride (100ml) in the disposable solid EDCI (12.46g, 0.065mol) that adds.Gained solution is stirred under argon atmospher, room temperature after 18 hours, with ethyl acetate dilution, washing (H ₂ox2, salt solution), dry (Na ₂sO ₄), concentrated after filtering, obtain light yellow oil.This oily matter carries out flash chromatography (SiO ₂/ hexane-ethyl acetate, 4: 1), obtain title compound (11.64g, 73%), be white solid. ¹H NMR(400MHz，CDCl ₃)δ7.53-7.17(m，10H)，5.95(q，J＝6.6Hz，0.5H)，5.94(q，J＝6.6Hz，0.5H)，5.41(s，0.5H)，5.39(s，0.5H)，1.58(d，J＝6.6Hz，1.5H)，1.51(d，J＝6.6Hz，1.5H)。

Step 2:(R)-2-(4-hydroxy-4-methyl piperidin-1-yl)-2-phenylacetic acid ((S)-1-phenylethyl) ester: to the bromo-2-phenylacetic acid of 2-((S)-1-phenylethyl) ester (0.464g, in THF 1.45mmol) (8ml) solution, add successively triethylamine (0.61ml, 4.35mmol) and tetrabutylammonium iodide (0.215g, 0.58mmol).Reaction mixture was at room temperature stirred after 5 minutes, add THF (2ml) solution of 4-methyl-4-hydroxy piperidine (0.251g, 2.18mmol).Mixture was at room temperature stirred after 1 hour, be heated to 55-60 ℃ (oil bath temperature) and reach 4 hours.Then through cooling ethyl acetate for reaction mixture (30ml) dilution, washing (H ₂o x2, salt solution), dry (MgSO ₄), concentrated after filtering.Resistates is purified (0-60% ethyl acetate-hexane) with silica gel chromatography, first obtains (S, R)-isomer (0.306g of title compound, 60%), be white solid, then obtain corresponding (S, S)-isomer (0.120g, 23%) is also white solid.(S, R)-isomer: ¹h NMR (CD ₃oD) δ 7.51-7.45 (m, 2H), 7.41-7.25 (m, 8H), 5.85 (q, J=6.6Hz, 1H), 4.05 (s, 1H), 2.56-2.45 (m, 2H), 2.41-2.29 (m, 2H), 1.71-1.49 (m, 4H), 1.38 (d, J=6.6Hz, 3H), 1.18 (s, 3H).LCMS: for C ₂₂h ₂₇nO ₃analytical calculation value: 353; Measured value: 354 (M+H) ⁺.(S, S)-isomer: ¹hNMR (CD ₃oD) δ 7.41-7.30 (m, 5H), 7.20-7.14 (m, 3H), 7.06-7.00 (m, 2H), 5.85 (q, J=6.6Hz, 1H), 4.06 (s, 1H), 2.70-2.60 (m, 1H), 2.51 (dt, J=6.6,3.3Hz, 1H), 2.44-2.31 (m, 2H), 1.75-1.65 (m, 1H), 1.65-1.54 (m, 3H), 1.50 (d, J=6.8Hz, 3H), 1.20 (s, 3H).LCMS: for C ₂₂h ₂₇nO ₃analytical calculation value: 353; Measured value: 354 (M+H) ⁺.

Step 3:(R)-2-(4-hydroxy-4-methyl piperidin-1-yl)-2-phenylacetic acid: to (R)-2-(4-hydroxy-4-methyl piperidin-1-yl)-2-phenylacetic acid ((S)-1-phenylethyl) ester (0.185g, in methylene dichloride 0.52mmol) (3ml) solution, add trifluoroacetic acid (1ml), mixture is at room temperature stirred 2 hours.With final vacuum, remove volatile matter, resistates is purified (Primesphere C-18,20 * 100mm with anti-phase preparation HPLC; CH ₃cN-H ₂o-0.1%TFA), obtain title compound (for tfa salt) (0.128g, 98%), light blue solid.LCMS: for C ₁₄h ₁₉nO ₃analytical calculation value: 249; Measured value: 250 (M+H) ⁺.

Step 1:2-(2-fluorophenyl) acetic acid ((S)-1-phenylethyl) ester: by 2-fluorophenyl acetic acid (5.45g, 35.4mmol), (S)-1-phenylethyl alcohol (5.62g, 46.0mmol), EDCI (8.82g, 46.0mmol) and DMAP (0.561g, 4.60mmol) and CH ₂cl ₂(100ml) mixture at room temperature stirs 12 hours.After solvent is concentrated, resistates H ₂o-ethyl acetate is distributed.Separation of phases, ethyl acetate reextraction (twice) for water layer.The organic phase merging is through washing (H ₂o, salt solution), dry (Na ₂sO ₄), filter final vacuum concentrated.Resistates is purified (Biotage/0-20% ethyl acetate-hexane) with silica gel chromatography, obtains title compound (8.38g, 92%, colorless oil). ¹H NMR(400MHz，CD ₃OD)δ7.32-7.23(m，7H)，7.10-7.04(m，2)，5.85(q，J＝6.5Hz，1H)，3.71(s，2H)，1.48(d，J＝6.5Hz，3H)。

Step 2:(R)-2-(2-fluorophenyl)-2-(piperidin-1-yl) acetic acid ((S)-1-phenylethyl) ester: at 0 ℃, to 2-(2-fluorophenyl) acetic acid ((S)-1-phenylethyl) ester (5.00g, in THF 19.4mmol) (1200ml) solution, add DBU (6.19g, 40.7mmol), when making solution be warming up to room temperature, stir 30 minutes.Then make solution be cooled to after-78 ℃, add CBr ₄the THF of (13.5g, 40.7mmol) (100ml) solution, makes mixture be warming up to-10 ℃, and at this temperature, stirs 2 hours.The saturated NH of reaction mixture ₄after the quencher of the Cl aqueous solution, separated each layer.Water layer is stripped (twice) by ethyl acetate, and the organic phase of merging is through washing (H ₂o, salt solution), dry (Na ₂sO ₄), filter final vacuum concentrated.In resistates, add piperidines (5.73ml, 58.1mmol), solution is at room temperature stirred 24 hours.Then vacuum concentration volatile matter, resistates is purified (Biotage/0-30% ether-hexane) with silica gel chromatography, obtain pure non-enantiomer mixture (according to ¹h NMR judgement, its ratio is 2: 1) (2.07g, 31%, yellow oil) and unreacted raw material (2.53g, 51%).Non-enantiomer mixture, further through chromatography purification (Biotage/0-10% ether-toluene), obtains title compound (0.737g, 11%, colorless oil). ¹H NMR(400MHz，CD ₃OD)δ7.52(ddd，J＝9.4，7.6，1.8Hz，1H)，7.33-7.40(m，1H)，7.23-7.23(m，4H)，7.02-7.23(m，4H)，5.86(q，J＝6.6Hz，1H)，4.45(s，1H)，2.39-2.45(m，4H)，1.52-1.58(m，4H)，1.40-1.42(m，1H)，1.38(d，J＝6.6Hz，3H)。LCMS: for C ₂₁h ₂₄fNO ₂analytical calculation value: 341; Measured value: 342 (M+H) ⁺.

Step 3:(R)-2-(2-fluorophenyl)-2-(piperidin-1-yl) acetic acid: by (R)-2-(2-fluorophenyl)-2-(piperidin-1-yl) acetic acid ((S)-1-phenylethyl) ester (0.737g, 2.16mmol) and 20%Pd (OH) ₂the mixture of/C (0.070g) and ethanol (30ml) is at room temperature and normal atmosphere (H ₂air bag) lower hydrogenation is 2 hours.Then solution use argon gas purge, through diatomite after filtration, vacuum concentration.This can obtain title compound (0.503g, 98%, colorless solid). ¹H NMR(400MHz，CD ₃OD)δ7.65(ddd，J＝9.1，7.6，1.5Hz，1H)，7.47-7.53(m，1H)，7.21-7.30(m，2H)，3.07-3.13(m，4H)，1.84(br s，4H)，1.62(br s，2H)。LCMS: for C ₁₃h ₁₆fNO ₂analytical calculation value: 237; Measured value: 238 (M+H) ⁺.

Step 1:(R)-2-(4-hydroxy-4-phenyl piperidine-1-yl)-2-phenylacetic acid ((S)-1-phenylethyl) ester: to the bromo-2-phenylacetic acid of 2-((S)-1-phenylethyl) ester (1.50g, in THF 4.70mmol) (25ml) solution, add successively triethylamine (1.31ml, 9.42mmol) and tetrabutylammonium iodide (0.347g, 0.94mmol).Reaction mixture was at room temperature stirred after 5 minutes, add THF (5ml) solution of 4-phenyl-4-hydroxy piperidine (1.00g, 5.64mmol).Mixture was stirred after 16 hours, with ethyl acetate (100ml) dilution, washing (H ₂o x2, salt solution), dry (MgSO ₄), concentrated after filtering.Resistates is purified (0-60% ethyl acetate-hexane) with silicagel column, obtains the approximately mixture of 2: 1 diastereomers, uses ¹h NMR judgement.These isomer carry out separation (Chiralcel OJ-H, 30 * 250mm by supercritical fluid chromatography; 20% ethanol, at CO ₂, at 35 ℃), first obtain (the R)-isomer (0.534g, 27%, yellow oil) of title compound, then obtain corresponding (S)-isomer (0.271g, 14%, be similarly yellow oil).(S, R)-isomer: ¹hNMR (400MHz, CD ₃oD) δ 7.55-7.47 (m, 4H), 7.44-7.25 (m, 10H), 7.25-7.17 (m, 1H), 5.88 (q, J=6.6Hz, 1H), 4.12 (s, 1H), 2.82-2.72 (m, 1H), 2.64 (dt, J=11.1,2.5Hz, 1H), 2.58-2.52 (m, 1H), 2.40 (dt, J=11.1,2.5Hz, 1H), 2.20 (dt, J=12.1,4.6Hz, 1H), 2.10 (dt, J=12.1,4.6Hz, 1H), 1.72-1.57 (m, 2H), (1.53 d, J=6.5Hz, 3H).LCMS: for C ₂₇h ₂₉nO ₃analytical calculation value: 415, measured value: 416 (M+H) ⁺, (S, S)-isomer: ¹h NMR (400MHz, CD ₃oD) δ 7.55-7.48 (m, 2H), 7.45-7.39 (m, 2H), 7.38-7.30 (m, 5H), 7.25-7.13 (m, 4H), 7.08-7.00 (m, 2H), 5.88 (q, J=6.6Hz, 1H), 4.12 (s, 1H), 2.95-2.85 (m, 1H), 2.68 (dt, J=11.1, 2.5Hz, 1H), 2.57-2.52 (m, 1H), 2.42 (dt, J=11.1, 2.5Hz, 1H), 2.25 (dt, J=12.1, 4.6Hz, 1H), 2.12 (dt, J=12.1, 4.6Hz, 1H), 1.73 (dd, J=13.6, 3.0Hz, 1H), 1.64 (dd, J=13.6, 3.0Hz, 1H), 1.40 (d, J=6.6Hz, 3H).LCMS: for C ₂₇h ₂₉nO ₃analytical calculation value: 415; Measured value: 416 (M+H) ⁺.

Following ester adopts the similar fashion preparation of the step 1 of synthetic Cap-17.

For measuring the chirality SFC condition of the retention time of intermediate 17b-17d

Condition 1

Post: Chiralpak AD-H post, 4.6 * 250mm, 5 μ m

Solvent: 90%CO ₂-10% methyl alcohol (containing 0.1%DEA)

Temperature: 35 ℃

Pressure: 150 bar

Flow velocity: 2.0ml/ minute.

UV monitoring under 220nm

Inject: 1.0mg/3ml methyl alcohol

Condition 2

Post: Chiralcel OD-H post, 4.6 * 250mm, 5 μ m

Solvent: 90%CO ₂-10% methyl alcohol (containing 0.1%DEA)

Temperature: 35 ℃

Pressure: 150 bar

Flow velocity: 2.0ml/ minute.

UV monitoring under 220nm

Inject: 1.0mg/ml methyl alcohol

Cap-17, step 2:(R)-2-(4-hydroxy-4-phenyl piperidine-1-yl)-2-phenylacetic acid: to (R)-2-(4-hydroxy-4-phenyl piperidine-1-yl)-2-phenylacetic acid ((S)-1-phenylethyl) ester (0.350g, in methylene dichloride 0.84mmol) (5ml) solution, add trifluoroacetic acid (1ml), mixture is at room temperature stirred 2 hours.With final vacuum, remove volatile matter, resistates is purified (Primesphere C-18,20 * 100mm with anti-phase preparation HPLC; CH ₃cN-H ₂o-0.1%TFA), obtain title compound (for tfa salt) (0.230g, 88%, white solid).LCMS: for C ₁₉h ₂₁nO ₃analytical calculation value: 311; Measured value: 312 (M+H) ⁺.

Following carboxylic acid is prepared in a similar manner:

For measuring the LCMS condition of the retention time of Cap-17a to Cap-17d

Condition 1

Post: Phenomenex-Luna 4.6 * 50mm S10

Start %B=0

Final %B=100

Gradient time=4 minute

Flow velocity=4ml/ minute

Wavelength=220

Solvent orange 2 A=10% methyl alcohol-90%H ₂o-0.1%TFA

Solvent B=90% methyl alcohol-10%H ₂o-0.1%TFA

Condition 2

Post: Waters-Sunfire 4.6 * 50mm S5

Start %B=0

Final %B=100

Gradient time=2 minute

Flow velocity=4ml/ minute

Wavelength=220

Solvent orange 2 A=10% methyl alcohol-90%H ₂o-0.1%TFA

Solvent B=90% methyl alcohol-10%H ₂o-0.1%TFA

Condition 3

Post: Phenomenex 10 μ 3.0 * 50mm

Start %B=0

Final %B=100

Gradient time=2 minute

Flow velocity=4ml/ minute

Wavelength=220

Solvent orange 2 A=10% methyl alcohol-90%H ₂o-0.1%TFA

Solvent B=90% methyl alcohol-10%H ₂o-0.1%TFA

Step 1:(R, S)-2-(4-pyridyl)-2-ethyl bromoacetate: at argon atmospher, 0 ℃, in anhydrous THF (150ml) solution of 4-pyridyl ethyl acetate (1.00g, 6.05mmol), add DBU (0.99ml, 6.66mmol).Reaction mixture was warming up to after room temperature in 30 minutes, is cooled to-78 ℃.In this mixture, add CBr ₄(2.21g, 6.66mmol) continues to stir 2 hours at-78 ℃.Then reaction mixture NH ₄the quencher of Cl saturated aqueous solution, separation of phases.Organic phase, through washing (salt solution), is dried (Na ₂sO ₄), filter final vacuum concentrated.Gained yellow oil is used purified by flash chromatography (SiO immediately ₂/ hexane-ethyl acetate, 1: 1), obtain title compound (1.40g, 95%, slightly unsettled yellow oil). ¹H NMR(400MHz，CDCl ₃)δ8.62(dd，J＝4.6，1.8Hz，2H)，7.45(dd，J＝4.6，1.8Hz，2H)，5.24(s，1H)，4.21-4.29(m，2H)，1.28(t，J＝7.1Hz，3H)。LCMS: for C ₉h ₁₀brNO ₂analytical calculation value: 242,244; Measured value: 243,245 (M+H) ⁺.

Step 2:(R, S)-2-(4-pyridyl)-2-(N, N-dimethylamino) ethyl acetate: at room temperature, to (R, S)-2-(4-pyridyl)-2-ethyl bromoacetate (1.40g, in DMF 8.48mmol) (10ml) solution, add dimethylamine (the THF solution of 2M, 8.5ml, 17.0mmol).After having reacted (judging with TLC), vacuum is removed volatile matter, purified by flash chromatography for resistates (Biotage, 40+M SiO ₂post; 50%-100% ethyl acetate-hexane), obtain title compound (0.539g, 31%, light yellow oil). ¹H NMR(400MHz，CDCl ₃)δ8.58(d，J＝6.0Hz，2H)，7.36(d，J＝6.0Hz，2H)，4.17(m，2H)，3.92(s，1H)，2.27(s，6H)，1.22(t，J＝7.0Hz)。LCMS: for C ₁₁h ₁₆n ₂o ₂analytical calculation value: 208; Measured value: 209 (M+H) ⁺.

Step 3:(R, S)-2-(4-pyridyl)-2-(N, N-dimethylamino) acetic acid: at room temperature, to (R, S)-2-(4-pyridyl)-2-(N, N-dimethylamino) ethyl acetate (0.200g, 0.960mmol) and THF-methyl alcohol-H ₂o (1: 1: 1,6ml) in the solution of mixture, add LiOH powder (0.120g, 4.99mmol).Solution stirring, after 3 hours, is acidified to pH 6 with 1N HCl.Water is with after ethyl acetate washing, and freeze-drying obtains the dihydrochloride of title compound, is yellow solid (containing LiCl).Product is same as before for subsequent step. ¹H NMR(400MHz，DMSO-d ₆)δ8.49(d，J＝5.7Hz，2H)，7.34(d，J＝5.7Hz，2H)，3.56(s，1H)，2.21(s，6H)。

The similar fashion preparation of method described in embodiment 4 for the following example:

Step 1:(R, S)-2-(quinoline-3-yl)-2-(N, N-dimethylamino)-ethyl acetate: with Argon Bubble stream, make N, N-dimethylamino ethyl acetate (0.462g, 3.54mmol), K ₃pO ₄(1.90g, 8.95mmol), Pd (t-Bu ₃p) ₂degassed 15 minutes of the mixture of (0.090g, 0.176mmol) and toluene (10ml).Then reaction mixture is heated 12 hours at 100 ℃, be cooled to afterwards room temperature and pour H into ₂in O.Mixture is extracted with ethyl acetate (twice), and the organic phase of merging is through washing (H ₂o, salt solution), dry (Na ₂sO ₄), filter final vacuum concentrated.Resistates is first purified (Primesphere C-18,30 * 100mm with anti-phase preparation HPLC; CH ₃cN-H ₂o-5mMNH ₄then use purified by flash chromatography (SiO OAc), ₂/ hexane-ethyl acetate, 1: 1), obtain title compound (0.128g, 17%, orange). ¹H NMR(400MHz，CDCl ₃)δ8.90(d，J＝2.0Hz，1H)，8.32(d，J＝2.0Hz，1H)，8.03-8.01(m，2H)，7.77(ddd，J＝8.3，6.8，1.5Hz，1H)，7.62(ddd，J＝8.3，6.8，1.5Hz，1H)，4.35(s，1H)，4.13(m，2H)，2.22(s，6H)，1.15(t，J＝7.0Hz，3H)。LCMS: for C ₁₅h ₁₈n ₂o ₂analytical calculation value: 258; Measured value: 259 (M+H) ⁺.

Step 2; (R, S)-2-(quinoline-3-yl)-2-(N, N-dimethylamino) acetic acid: by (R, S)-2-(quinoline-3-yl)-2-(N, N-dimethylamino) mixture of ethyl acetate (0.122g, 0.472mmol) and 6M HCl (3ml) heats 12 hours at 100 ℃.After solvent removed in vacuo, obtain the dihydrochloride (0.169g, > 100%, light yellow foam) of title compound.This impure product just can be used for subsequent step without being further purified.LCMS: for C ₁₃h ₁₄n ₂o ₂analytical calculation value: 230; Measured value: 231 (M+H) ⁺.

Step 1:(R)-2-(dimethylamino)-2-(2-fluorophenyl) acetic acid ((S)-1-styroyl) ester and (S)-2-(dimethylamino)-2-(2-fluorophenyl) acetic acid ((S)-1-styroyl) ester: to (RS)-2-(dimethylamino)-2-(2-fluorophenyl) acetic acid (2.60g, 13.19mmol), DMAP (0.209g, 1.71mmol) with (S)-1-phenylethyl alcohol (2.09g, 17.15mmol) and CH ₂cl ₂(40ml) in mixture, add EDCI (3.29g, 17.15mmol), mixture is at room temperature stirred 12 hours.Then solvent removed in vacuo, ethyl acetate-H for resistates ₂o distributes.After separated each layer, water layer is stripped (twice) by ethyl acetate, and the organic phase of merging is through washing (H ₂o, salt solution), dry (Na ₂sO ₄), filter final vacuum concentrated.Resistates is purified (Biotage/0-50% ether-hexane) with silica gel chromatography.Then, anti-phase preparation HPLC separated (Primesphere C-18,30 * 100mm for the non-enantiomer mixture that gained is pure; CH ₃cN-H ₂o-0.1%TFA), first obtain (R)-2-(dimethylamino)-2-(2-fluorophenyl) acetic acid (S)-1-phenethyl ester (0.501g, 13%), obtain again (S)-2-(dimethylamino)-2-(2-fluorophenyl)-acetic acid (S)-1-phenethyl ester (0.727g, 18%), be its tfa salt.(S, R)-isomer: ¹h NMR (400MHz, CD ₃oD) δ 7.65-7.70 (m, 1H), 7.55-7.60 (ddd, J=9.4,8.1,1.5Hz, 1H), 7.36-7.41 (m, 2H), 7.28-7.34 (m, 5H), 6.04 (q, J=6.5Hz, 1H), 5.60 (s, 1H), 2.84 (s, 6H), 1.43 (d, J=6.5Hz, 3H).LCMS: for C ₁₈h ₂₀fNO ₂analytical calculation value: 301; Measured value: 302 (M+H) ⁺; (S, S)-isomer: ¹h NMR (400MHz, CD ₃oD) δ 7.58-7.63 (m, 1H), 7.18-7.31 (m, 6H), 7.00 (dd, J=8.5,1.5Hz, 2H), 6.02 (q, J=6.5Hz, 1H), 5.60 (s, 1H), 2.88 (s, 6H), 1.54 (d, J=6.5Hz, 3H).LCMS: for C ₁₈h ₂₀fNO ₂analytical calculation value: 301; Measured value: 302 (M+H) ⁺.

Step 2:(R)-2-(dimethylamino)-2-(2-fluorophenyl) acetic acid: at normal atmosphere (H ₂air bag), under room temperature, make tfa salt (1.25g, 3.01mmol) and the 20%Pd (OH) of (R)-2-(dimethylamino)-2-(2-fluorophenyl) acetic acid ((S)-1-styroyl) ester ₂the mixture hydrogenation of/C (0.125g) and ethanol (30ml) 4 hours.Then solution use argon gas purge, through diatomite after filtration, vacuum concentration.This just obtains title compound (0.503g, 98%, colorless solid). ¹H NMR(400MHz，CD ₃OD)δ7.53-7.63(m，2H)，7.33-7.38(m，2H)，5.36(s，1H)，2.86(s，6H)。LCMS: for C ₁₀h ₁₂fNO ₂analytical calculation value: 197; Measured value: 198 (M+H) ⁺.

S-isomer can be in a similar manner obtained by the tfa salt of (S)-2-(dimethylamino)-2-(2-fluorophenyl) acetic acid ((S)-1-styroyl) ester.

Cap-39

At normal atmosphere (H ₂air bag), under room temperature, make (R)-(2-chloro-phenyl-) glycine (0.300g, 1.62mmol), formaldehyde (35% aqueous solution, 0.80ml, 3.23mmol) and 20%Pd (OH) ₂the mixture hydrogenation of/C (0.050g) 4 hours.Then solution use argon gas purge, through diatomite after filtration, vacuum concentration.Resistates is purified (Primesphere C-18,30 * 100mm with anti-phase preparation HPLC; CH ₃cN-H ₂o-0.1%TFA), obtain the tfa salt (0.290g, 55%, colorless oil) of title compound (R)-2-(dimethylamino)-2-(2-chloro-phenyl-) acetic acid. ¹H NMR(400MHz，CD ₃OD)δ7.59-7.65(m，2H)，7.45-7.53(m，2H)，5.40(s，1H)，2.87(s，6H)。LCMS: for C ₁₀h ₁₂clNO ₂analytical calculation value: 213,215; Measured value: 214,216 (M+H) ⁺.

To ice-cold (R)-(2-chloro-phenyl-) glycine (1.00g, 5.38mmol) and NaOH (0.862g, 21.6mmol) and H ₂in the solution of O (5.5ml), drip methyl-chloroformate (1.00ml, 13.5mmol).Mixture is stirred after 1 hour at 0 ℃, add dense HCl (2.5ml) by its acidifying.Mixture is extracted with ethyl acetate (twice), and the organic phase of merging is through washing (H ₂o, salt solution), dry (Na ₂sO ₄), filter final vacuum concentrated, obtain title compound (R)-2-(methoxycarbonyl is amino)-2-(2-chloro-phenyl-) acetic acid (1.31g, 96%, orange-yellow foam). ¹H NMR(400MHz，CD ₃OD)δ7.39-7.43(m，2H)，7.29-7.31(m，2H)，5.69(s，1H)，3.65(s，3H)。LCMS: for C ₁₀h ₁₀clNO ₄analytical calculation value: 243,245; Measured value: 244,246 (M+H) ⁺.

In THF (20ml) suspension of 2-(2-(chloromethyl) phenyl) acetic acid (2.00g, 10.8mmol), add morpholine (1.89g, 21.7mmol), solution is at room temperature stirred 3 hours.Then reaction mixture dilutes by ethyl acetate, uses H ₂o extracts (twice).By after water freeze-drying, resistates is purified (Biotage/0-10% methyl alcohol-CH with silica gel chromatography ₂cl ₂), obtain title compound 2-(2-(morpholino methyl) phenyl) acetic acid (2.22g, 87%, colorless solid). ¹H NMR(400MHz，CD ₃OD)δ7.37-7.44(m，3H)，7.29-7.33(m，1H)，4.24(s，2H)，3.83(br s，4H)，3.68(s，2H)，3.14(br s，4H)。LCMS: for C ₁₃h ₁₇nO ₃analytical calculation value: 235; Measured value: 236 (M+H) ⁺.

The following example is equally with the preparation of method described in Cap-41:

HMDS (1.85ml, 8.77mmol) is added to (R)-2-amino-2-phenylacetic acid tosilate (2.83g, 8.77mmol) and CH ₂cl ₂(10ml), in suspension, mixture is at room temperature stirred 30 minutes.The disposable methyl isocyanate (0.5g, 8.77mmol) that adds, continues to stir 30 minutes.Reactant is by adding H ₂o (5ml) quencher, filters gained throw out, uses H ₂after O and normal hexane washing, vacuum-drying.Recovery obtains (R)-2-(3-methyl urea groups)-2-phenylacetic acid (1.5g; 82%), be white solid, without being further purified just, can use. ¹HNMR(500MHz，DMSO-d ₆)δppm 2.54(d，J＝4.88Hz，3H)5.17(d，J＝7.93Hz，1H)5.95(q，J＝4.48Hz，1H)6.66(d，J＝7.93Hz，1H)7.26-7.38(m，5H)12.67(s，1H)。LCMS: for C ₁₀h ₁₂n ₂o ₃analytical calculation value: 208.08; Measured value: 209.121 (M+H) ⁺; HPLC Phenomenex C-183.0 * 46mm, 0-100%B, in 2 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, RT=1.38 minute, homogeneity index 90%.

Cap-46

Required product is prepared according to method described in Cap-45. ¹H NMR(500MHz，DMSO-d ₆)δppm 0.96(t，J＝7.17Hz，3H)2.94-3.05(m，2H)5.17(d，J＝7.93Hz，1H)6.05(t，J＝5.19Hz，1H)6.60(d，J＝7.63Hz，1H)7.26-7.38(m，5H)12.68(s，1H)。LCMS: for C ₁₁h ₁₄n ₂o ₃analytical calculation value: 222.10; Measured value: 209.121 (M+H) ⁺.

HPLC XTERRA C-183.0 * 506mm, 0-100%B, in 2 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.2%H ₃pO ₄, B=10% water, 90% methyl alcohol, 0.2%H ₃pO ₄, RT=0.87 minute, homogeneity index 90%.

Step 1:(R)-2-(3,3-dimethyl urea groups)-2-phenylacetic acid tert-butyl ester: in 10 minutes, to (R)-2-amino-2-phenylacetic acid tert-butyl ester (1.0g, 4.10mmol) with Hunig alkali (1.79ml, 10.25mmol) and in the stirred solution of DMF (40ml) drip dimethylaminoethyl chloride (0.38ml, 4.18mmol).At room temperature stir after 3 hours, concentrating under reduced pressure reactant, is dissolved in ethyl acetate by gained resistates.Organic layer H ₂o, the 1N HCl aqueous solution and salt water washing, dry (MgSO ₄), concentrating under reduced pressure after filtering.Obtain (R)-2-(3,3-dimethyl the urea groups)-2-phenylacetic acid tert-butyl ester (0.86g; 75%, white solid), without being further purified just, can use. ¹H NMR(500MHz，DMSO-d ₆)δppm 1.33(s，9H)2.82(s，6H)5.17(d，J＝7.63Hz，1H)6.55(d，J＝7.32Hz，1H)7.24-7.41(m，5H)。LCMS: for C ₁₅h ₂₂n ₂o ₃analytical calculation value: 278.16; Measured value: 279.23 (M+H) ⁺; HPLC Phenomenex LUNAC-184.6 * 50mm, 0-100%B, in 4 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, RT=2.26 minute, homogeneity index 97%.

Step 2:(R)-2-(3,3-dimethyl urea groups)-2-phenylacetic acid: to ((R)-2-(3,3-dimethyl urea groups)-the 2-phenylacetic acid tert-butyl ester (0.86g, 3.10mmol) and CH ₂cl ₂(250ml) in stirred solution, drip TFA (15ml), gained solution is at room temperature stirred 3 hours.Then use EtOAC: the mixture of hexane (5: 20) is separated out needed compound from solution, leaches rear drying under reduced pressure.Isolate (R)-2-(3,3-dimethyl urea groups)-2-phenylacetic acid (0.59g, 86%, white solid), without being further purified just, can use. ¹HNMR(500MHz，DMSO-d ₆)δppm2.82(s，6H)5.22(d，J＝7.32Hz，1H)6.58(d，J＝7.32Hz，1H)7.28(t，J＝7.17Hz，1H)7.33(t，J＝7.32Hz，2H)7.38-7.43(m，2H)12.65(s，1H)。LCMS: for C ₁₁h ₁₄n ₂o ₃analytical calculation value: 222.24; Measured value: 223.21 (M+H) ⁺.HPLC XTERRAC-183.0 * 50mm, 0-100%B, in 2 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.2%H ₃pO ₄, B=10% water, 90% methyl alcohol, 0.2%H ₃pO ₄, RT=0.75 minute, homogeneity index 93%.

Step 1:(R)-2-(3-cyclopentyl urea groups)-2-phenylacetic acid tert-butyl ester: in 10 minutes, to (R)-2-amino-2-phenylacetic acid hydrochloride (1.0g, 4.10mmol) with Hunig alkali (1.0ml, 6.15mmol) and in the stirred solution of DMF (15ml) drip cyclic isocyanate pentyl ester (0.46ml, 4.10mmol), at room temperature stir after 3 hours, concentrating under reduced pressure reactant, is dissolved in ethyl acetate by gained resistates.Organic layer H ₂o and salt water washing, dry (MgSO ₄), concentrating under reduced pressure after filtering, obtains (R)-2-(3-cyclopentyl the urea groups)-2-phenylacetic acid tert-butyl ester (1.32g; 100%, opaque oily matter), without being further purified just, can use. ¹HNMR(500MHz，CD ₃Cl-D)δppm 1.50-1.57(m，2H)1.58-1.66(m，2H)1.87-1.97(m，2H)3.89-3.98(m，1H)5.37(s，1H)7.26-7.38(m，5H)。LCMS: for C ₁₈h ₂₆n ₂o ₃analytical calculation value: 318.19; Measured value: 319.21 (M+H) ⁺; HPLCXTERRAC-183.0 * 50mm, 0-100%B, in 4 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, RT=2.82 minute, homogeneity index 96%.

Step 2:(R)-2-(3-cyclopentyl urea groups)-2-phenylacetic acid: to (R)-2-(3-cyclopentyl urea groups)-the 2-phenylacetic acid tert-butyl ester (1.31g, 4.10mmol) and CH ₂cl ₂(25ml) in stirred solution, drip TFA (4ml) and triethyl silicane (1.64ml; 10.3mmol), gained solution is at room temperature stirred 6 hours.Decompression is removed after volatile component, and crude product is recrystallization in ethyl acetate/pentane, obtains (R)-2-(3-cyclopentyl urea groups)-2-phenylacetic acid (0.69g, 64%, white solid). ¹H NMR(500MHz，DMSO-d ₆)δppm 1.17-1.35(m，2H)1.42-1.52(m，2H)1.53-1.64(m，2H)1.67-1.80(m，2H)3.75-3.89(m，1H)5.17(d，J＝7.93Hz，1H)6.12(d，J＝7.32Hz，1H)6.48(d，J＝7.93Hz，1H)7.24-7.40(m，5H)12.73(s，1H)。LCMS: for C ₁₄h ₁₈n ₂o ₃analytical calculation value: 262.31; Measured value: 263.15 (M+H) ⁺.HPLC XTERRA C-183.0 * 50mm, 0-100%B, in 2 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.2%H ₃pO ₄, B=10% water, 90% methyl alcohol, 0.2%H ₃pO ₄, RT=1.24 minute, homogeneity index 100%.

In the stirred solution of 2-(benzylamino) acetic acid (2.0g, 12.1mmol) and formic acid (91ml), add formaldehyde (6.94ml, 93.2mmol).At 70 ℃, after 5 hours, reaction mixture is evaporated to after 20ml, white solid is separated out.After filtering, collect mother liquor, concentrating under reduced pressure, obtains crude product again.With anti-phase preparation HPLC purify (Xterra 30 * 100mm detects under 220nm, flow velocity 35ml/ minute, 0-35%B, in 8 minutes; A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA), obtains the tfa salt (723mg, 33%, colourless wax) of title compound 2-(benzyl (methyl)-amino) acetic acid. ¹H NMR(300MHz，DMSO-d ₆)δppm 2.75(s，3H)4.04(s，2H)4.34(s，2H)7.29-7.68(m，5H)。LCMS: for C ₁₀h ₁₃nO ₂analytical calculation value: 179.22; Measured value: 180.20 (M+H) ⁺.

In the stirred solution of 3-methyl-2-(methylamino) butyric acid (0.50g, 3.81mmol) and water (30ml), add K ₂cO ₃(2.63g, 19.1mmol) and benzyl chloride (1.32g, 11.4mmol).Reaction mixture is stirred 18 hours at ambient temperature.Ethyl acetate for reaction mixture (30ml * 2) extraction, water layer, after concentrating under reduced pressure, obtains crude product, with anti-phase preparation HPLC purify (Xterra 30 * 100mm detects under 220nm, flow velocity 40ml/ minute, 20-80%B, in 6 minutes; A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA), obtains the tfa salt (126mg, 19%, colourless wax) of 2-(benzyl (methyl) amino)-3 Methylbutanoic acid. ¹H NMR(500MHz，DMSO-d ₆)δppm 0.98(d，3H)1.07(d，3H)2.33-2.48(m，1H)2.54-2.78(m，3H)3.69(s，1H)4.24(s，2H)7.29-7.65(m，5H)。LCMS: for C ₁₃h ₁₉nO ₂analytical calculation value: 221.30; Measured value: 222.28 (M+H) ⁺.

By Na ₂cO ₃(1.83g, 17.2mmol) is added to NaOH (the 33ml 1M/H of Valine (3.9g, 33.29mmol) ₂o, 33mmol) in solution, gained solution is cooling with ice-water bath.In 15 minutes, drip methyl-chloroformate (2.8ml, 36.1mmol), remove after cooling bath, reaction mixture is stirred 3.25 hours at ambient temperature.Ether for reaction mixture (50ml, 3x) washing, water is cooling with ice-water bath, is acidified to after the scope of pH 1-2 with dense HCl, uses CH ₂cl ₂(50ml, 3x) extraction.Organic phase drying (MgSO ₄), filter final vacuum concentrated, obtain Cap-51 (6g, white solid).Main rotational isomer ¹h NMR (DMSO-d ₆, δ=2.5ppm, 500MHz): 12.54 (s, 1H), 7.33 (d, J=8.6,1H), 3.84 (dd, J=8.4,6.0,1H), 3.54 (s, 3H), 2.03 (m, 1H), 0.87 (m, 6H).HRMS: for [M+H] ⁺c ₇h ₁₄nO ₄analytical calculation value: 176.0923; Measured value: 176.0922.

According to the described method for the synthesis of Cap-51, by ALANINE, synthesize Cap-52.For characterizing object, part crude product is purified (H with reversed-phase HPLC ₂o/MeOH/TFA), obtain Cap-52 viscosity colorless oil. ¹h NMR (DMSO-d ₆, δ=2.5ppm, 500MHz): 12.49 (br s, 1H), 7.43 (d, J=7.3,0.88H), 7.09 (apparent br s, 0.12H), 3.97 (m, 1H), 3.53 (s, 3H), 1.25 (d, J=7.3,3H).

According to the method for the synthesis of Cap-51, by suitable raw material, prepare Cap-53 to Cap-64, if change, will indicate.

Methyl-chloroformate (0.65ml, 8.39mmol) is added drop-wise to the Na of cooling (frozen water) in 5 minutes ₂cO ₃(0.449g, 4.23mmol), NaOH (8.2ml 1M/H ₂o, 8.2mmol) and the mixture of (S)-3-hydroxyl-2-(methoxycarbonyl amino)-3 Methylbutanoic acid (1.04g, 7.81mmol) in.After stirred reaction mixture 45 minutes, remove cooling bath, then continue to stir 3.75 hours.Reaction mixture CH ₂cl ₂washing, after water is cooling with ice-water bath, is acidified to the scope of pH 1-2 with dense HCl.Vacuum is removed volatile component, and resistates is dissolved in to 2: 1MeOH/CH ₂cl ₂(15ml) mixture, filters and makes filtrate rotary evaporation, obtains Cap-65 (1.236g, half sticky white foam). ¹H NMR(DMSO-d ₆，δ＝2.5ppm，400MHz)：δ6.94(d，J＝8.5，0.9H)，6.53(br s，0.1H)，3.89(d，J＝8.8，1H)，2.94(s，3H)，1.15(s，3H)，1.13(s，3H)。

Adopt the described method of synthetic Cap-65, by suitable marketable material, prepare Cap-66 and Cap-67.

¹H NMR(DMSO-d ₆，δ＝2.5ppm，400MHz)：δ12.58(br s，1H)，7.07(d，J＝8.3，0.13H)，6.81(d，J＝8.8，0.67H)，4.10-4.02(m，1.15H)，3.91(dd，J＝9.1，3.5，0.85H)，3.56(s，3H)，1.09(d，J＝6.2，3H)。[noting: the main signal that only records NH].

¹H NMR(DMSO-d ₆，δ＝2.5ppm，400MHz)：12.51(br s，1H)，7.25(d，J＝8.4，0.75H)，7.12(br d，J＝0.4，0.05H)，6.86(br s，0.08H)，3.95-3.85(m，2H)，3.54(s，3H)，1.08(d，J＝6.3，3H)。[noting: the main signal of only indicating NH].

Cap-68

Methyl-chloroformate (0.38ml, 4.9mmol) is added drop-wise to 1N NaOH (aqueous solution) (9.0ml, 9.0mmol), 1M NaHCO ₃(1.0g, 4.5mmol) is with in the mixture of diox (9ml) for (aqueous solution) (9.0ml, 9.0mol), L-Aspartic acid β-benzyl ester.Reaction mixture is stirred under envrionment conditions after 3 hours, with ethyl acetate (50ml, 3x) washing.Water layer is acidified to after pH～1-2 with 12N HCl, with ethyl acetate (3 * 50ml) extraction.The organic layer salt water washing merging, dry (Na ₂sO ₄), filter final vacuum concentrated, obtain Cap-68 (1.37g; Light yellow oil, quality surpasses theoretical yield, product just can be used without purifying). ¹H NMR(DMSO-d ₆，δ＝2.5ppm，500MHz)：δ12.88(br s，1H)，7.55(d，J＝8.5，1H)，7.40-7.32(m，5H)，5.13(d，J＝12.8，1H)，5.10(d，J＝12.9，1H)，4.42-4.38(m，1H)，3.55(s，3H)，2.87(dd，J＝16.2，5.5，1H)，2.71(dd，J＝16.2，8.3，1H)。LC (condition 2): RT=1.90 minute; LC/MS: for [M+H] ⁺c ₁₃h ₁₆nO ₆analytical calculation value: 282.10; Measured value: 282.12.

By NaCNBH ₃(2.416g, 36.5mmol) adds in water (17ml)/MeOH (10ml) solution of L-Ala (1.338g, 15.0mmol) of ice-cold (～15 ℃) in batches.After several minutes, in 4 minutes, drip acetaldehyde (4.0ml, 71.3mmol), remove cooling bath, reaction mixture is stirred 6 hours under envrionment conditions.Again add after acetaldehyde (4.0ml) reaction stirred 2 hours.Dense HCl is slowly added in reaction mixture, until pH reach～1.5 after, gained mixture is heated 1 hour at 40 ℃.Vacuum is removed most of volatile component, and resistates is used (post washes with water 50WX8-100 ion-exchange resin purification, compound NH by 18ml ₄oH and 282ml water mix and rare NH of making ₄oH wash-out), obtain Cap-69 (2.0g, canescence water absorbability soft solid). ¹H NMR(DMSO-d ₆，δ＝2.5ppm，400MHz)：δ3.44(q，J＝7.1，1H)，2.99-2.90(m，2H)，2.89-2.80(m，2H)，1.23(d，J＝7.1，3H)，1.13(t，J＝7.3，6H)。

According to the described method for the synthesis of Cap-69, adopt suitable raw material to prepare Cap-70 to Cap-74.

Cap-75, step a

By NaBH ₃in water (25ml)/methyl alcohol (15ml) solution of the H-D-Ser-OBzlHCl (2.0g, 8.6mmol) that CN (1.6g, 25.5mmol) is added to cooling (ice/water bath).In 5 minutes, drip after acetaldehyde (1.5ml, 12.5mmol), remove cooling bath, reaction mixture is stirred 2 hours under envrionment conditions.Careful with after 12N HCl quencher reactant, vacuum concentration.Resistates is water-soluble, with reversed-phase HPLC, purify (MeOH/H ₂o/TFA), obtain the tfa salt (1.9g, viscosity colorless oil) of (R)-2-(diethylin)-3-hydroxy-propionic acid benzyl ester. ¹HNMR(DMSO-d ₆，δ＝2.5ppm，500MHz)：δ9.73(br s，1H)，7.52-7.36(m，5H)，5.32(d，J＝12.2，1H)，5.27(d，J＝12.5，1H)，4.54-4.32(m，1H)，4.05-3.97(m，2H)，3.43-3.21(m，4H)，1.23(t，J＝7.2，6H)。LC/MS (condition 2): RT=1.38 minute; LC/MS: for [M+H] ⁺c ₁₄h ₂₂nO ₃analytical calculation value: 252.16; Measured value: 252.19.

Cap-75

By NaH (0.0727g, 1.82mmol, 60%) be added to the tfa salt (0.3019g of (R)-2-(diethylin)-3-hydroxy-propionic acid benzyl ester of preparation above of cooling (frozen water), in THF 0.8264mmol) (3.0ml) solution, mixture is stirred 15 minutes.Add methyl-iodide (56 μ l, 0.90mmol), when being melted up to envrionment conditions in ice-water bath, continue to stir 18 hours.After the quencher of reactant water, be added on the pretreated MCX of MeOH (6g) cylinder, with after methanol wash, compound 2N NH ₃/ methanol-eluted fractions.Vacuum is removed volatile component, obtains Cap-75 (100mg, is polluted by (R)-2-(diethylin)-3-hydroxy-propionic acid, yellow semi-solid).Product is used same as before without being further purified.

By NaCNBH ₃(1.60g, 24.2mmol) is added in water/MeOH (being respectively 12ml) solution of (S)-4-amino-2-(tert-butoxycarbonyl is amino) butyric acid (2.17g, 9.94mmol) of ice-cold (～15 ℃) in batches.After several minutes, in 2 minutes, drip acetaldehyde (2.7ml, 48.1mmol), remove cooling bath, reaction mixture is stirred 3.5 hours under envrionment conditions.Again add after acetaldehyde (2.7ml, 48.1mmol) reaction stirred 20.5 hours.Vacuum is removed most of MeOH composition, and residual mixture is processed with dense HCl, until reach behind pH～1.0, heats 2 hours at 40 ℃.Vacuum is removed volatile component, and resistates is processed with 4M HCl/ diox (20ml), and under envrionment conditions, stirs 7.5 hours.Vacuum is removed volatile component, and resistates is used (post washes with water 50WX8-100 ion-exchange resin purification, compound NH by 18ml ₄rare NH prepared by OH and 282ml water ₄oH wash-out), obtain intermediate (S)-2-amino-4-(diethylin) butyric acid (1.73g, pale solid).

In 11 minutes, methyl-chloroformate (0.36ml, 4.65mmol) is added drop-wise to the Na of cooling (frozen water) ₂cO ₃(0.243g, 2.29mmol), NaOH (4.6ml 1M/H ₂o, 4.6mmol) and the mixture of above-mentioned product (802.4mg) in.After stirred reaction mixture 55 minutes, remove cooling bath, then continue to stir 5.25 hours.Equal-volume water dilution for reaction mixture, uses CH ₂cl ₂(30ml, 2x) washing, water is cooling with ice-water bath, is acidified to the scope of pH 2 with dense HCl.Then vacuum is removed volatile component, the free alkalization of MCX resin (free-based) (6.0g for crude product; Post washes with water, sample 2.0M NH ₃/ MeOH wash-out), obtain impure Cap-76 (704mg, pale solid). ¹H NMR(MeOH-d ₄，δ＝3.29ppm，400MHz)：δ3.99(dd，J＝7.5，4.7，1H)，3.62(s，3H)，3.25-3.06(m，6H)，2.18-2.09(m，1H)，2.04-1.96(m，1H)，1.28(t，J＝7.3，6H)。LC/MS: for [M+H] ⁺c ₁₀h ₂₁n ₂o ₄analytical calculation value: 233.15; Measured value: 233.24.

Carry out as follows the synthetic of Cap-77: according to method described in Cap-7, adopt 7-azabicyclic [2.2.1] heptane to be used for replacing SN ₂step, and by adopting following condition, intermediate 2-(7-azabicyclic [2.2.1] heptan-7-yl)-2-phenylacetic acid benzyl ester is carried out to Chiral Separation: intermediate (303.7mg) is dissolved in to ethanol, gained solution is injected to chirality HPLC post (Chiracel AD-H post, 30 * 250mm, 5 μ m), at 35 ℃ of temperature, use 90%CO ₂-10%EtOH, with 70ml/ minute wash-out, obtains 124.5mg enantiomorph-1 and 133.8mg enantiomorph-2.These benzyl ester classes are carried out hydrogenolysis according to the preparation method of Cap-7, obtain Cap-77: ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 7.55 (m, 2H), 7.38-7.30 (m, 3H), 4.16 (s, 1H), 3.54 (apparent br s, 2H), 2.08-1.88 (m, 4H), 1.57-1.46 (m, 4H).LC (condition 1): RT=0.67 minute; LC/MS: for [M+H] ⁺c ₁₄h ₁₈brNO ₂analytical calculation value: 232.13; Measured value: 232.18.HRMS: for [M+H] ⁺c ₁₄h ₁₈brNO ₂analytical calculation value: 232.1338; Measured value: 232.1340.

By NaCNBH ₃(0.5828g, 9.27mmol) is added to (R)-2-(ethylamino)-2-phenylacetic acid HCl salt (intermediate during Cap-3 is synthetic; 0.9923mg, 4.60mmol) and the mixture of (1-ethoxy basic ring propoxy-) trimethyl silane (1.640g, 9.40mmol) and MeOH (10ml) in, half heterogeneous mixture heats 20 hours with oil bath at 50 ℃.Again add (1-ethoxy basic ring propoxy-) trimethyl silane (150mg, 0.86mmol) and NaCNBH ₃(52mg, 0.827mmol), and reheat reaction mixture 3.5 hours.Then be cooled to envrionment temperature, with dense HCl, be acidified to after the scope of about pH 2, mixture is filtered, made filtrate rotary evaporation.Gained crude product is dissolved in to i-PrOH (6ml) and heats and dissolve, leach and do not dissolve after part, vacuum concentrated filtrate.Approximately 1/3 gained crude product is purified (H with reversed-phase HPLC ₂o/MeOH/TFA), obtain the tfa salt (353mg, viscosity colorless oil) of Cap-78. ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz; D ₂after O exchange): δ 7.56-7.49 (m, 5H), 5.35 (S, 1H), 3.35 (m, 1H), 3.06 (apparent br s, 1H), 2.66 (m, 1H), 1.26 (t, J=7.3,3H), 0.92 (m, 1H), 0.83-0.44 (m, 3H).LC (condition 1): RT=0.64 minute; LC/MS: for [M+H] ⁺c ₁₃h ₁₈nO ₂analytical calculation value: 220.13; Measured value: 220.21.HRMS: for [M+H] ⁺c ₁₃h ₁₈nO ₂analytical calculation value: 220.1338; Measured value: 220.1343.

Ozone is passed into the CH of the Cap-55 (369mg, 2.13mmol) of cooling (78 ℃) ₂cl ₂(5.0ml) in solution approximately 50 minutes, until that reaction mixture occurs is light blue.Add Me ₂s (10, transfer pipet), stirred reaction mixture 35 minutes.-78 ℃ of baths use-10 ℃ of baths for it, and continue to stir after 30 minutes again, and vacuum is removed volatile component, obtains viscosity colorless oil.

By NaBH ₃cN (149mg, 2.25mmol) is added in MeOH (5.0ml) solution of above-mentioned crude product and morpholine (500 μ l, 5.72mmol), and mixture is stirred 4 hours under envrionment conditions.Be cooled to frozen water temperature, with dense HCl, process to pH～2.0, stir 2.5 hours.Vacuum is removed volatile component, (the MeOH washing of MCX resin for resistates; 2.0NNH ₃/ MeOH wash-out) in conjunction with reversed-phase HPLC (H ₂o/MeOH/TFA) carry out purifying, obtain Cap-79, wherein contain the not clear morpholine of content.

In order to consume morpholine pollutent, above-mentioned product is dissolved in to CH ₂cl ₂(1.5ml), use successively Et ₃n (0.27ml, 1.94mmol) and diacetyl oxide (0.10ml, 1.06mmol) are processed, and under envrionment conditions, stir 18 hours.Add THF (1.0ml) and H ₂o (0.5ml), continues to stir 1.5 hours.Vacuum is removed after volatile component, makes gained resistates by (the MeOH washing of MCX resin; 2.0N NH ₃/ MeOH wash-out), obtaining impure Cap-79, is viscosity brown oil, without being further purified, just can be used for next step.

In 15 minutes, by SOCl ₂(6.60ml, 90.5mmol) be added drop-wise to (S)-3-amino-4-(benzyloxy)-4-ketobutyric acid (10.04g of cooling (frozen water), 44.98mmol) and in the mixture of MeOH (300ml), remove after cooling bath, reaction mixture is stirred 29 hours under envrionment conditions.Vacuum is removed most of volatile component, makes carefully resistates at EtOAc (150ml) and saturated NaHCO ₃between solution, distribute.EtOAc for water (150ml, 2x) extraction, the organic phase drying (MgSO of merging ₄), filter final vacuum concentrated, obtain (S)-2-aminosuccinic acid 1-benzyl ester 4-methyl esters (9.706g, colorless oil). ¹hNMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 7.40-7.32 (m, 5H), 5.11 (s, 2H), 3.72 (apparent t, J=6.6,1H), 3.55 (s, 3H), 2.68 (dd, J=15.9,6.3,1H), 2.58 (dd, J=15.9,6.8,1H), 1.96 (s, 2H).LC (condition 1): RT=0.90 minute; LC/MS: for [M+H] ⁺c ₁₂h ₁₆nO ₄analytical calculation value: 238.11; Measured value: 238.22.

In 1 minute, by Pb (NO ₃) ₂(6.06g, 18.3mmol) is added to (S)-2-aminosuccinic acid 1-benzyl ester 4-methyl esters (4.50g, 19.0mmol), the bromo-9-phenyl-9H-fluorenes of 9-(6.44g, 20.0mmol) and Et ₃the CH of N (3.0ml, 21.5mmol) ₂cl ₂(80ml), in solution, heterogeneous mixture is stirred 48 hours under envrionment conditions.Mixture is filtered to filtrate MgSO ₄after processing, again filter concentrated final filtrate.Gained crude product is carried out to Biotage purifying (350g silica gel, CH ₂cl ₂wash-out), obtain (S)-2-(9-phenyl-9H-fluorenes-9-base is amino) succsinic acid 1-benzyl ester 4-methyl esters (7.93g, the very colorless oil of thickness). ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 7.82 (m, 2H), 7.39-7.13 (m, 16H), 4.71 (d, J=12.4,1H), 4.51 (d, J=12.6,1H), 3.78 (d, J=9.1, NH), 3.50 (s, 3H), 2.99 (m, 1H), 2.50-2.41 (m, 2H overlap with solvent).LC (condition 1): RT=2.16 minute; LC/MS: for [M+H] ⁺c ₃₁h ₂₈nO ₄analytical calculation value: 478.20; Measured value: 478.19.

In 10 minutes, by LiHMDS (9.2ml 1.0M/THF, 9.2mmol) be added drop-wise to (S)-2-(9-phenyl-9H-fluorenes-9-base is amino) succsinic acid 1-benzyl ester 4-methyl esters (3.907g of cooling (78 ℃), in THF 8.18mmol) (50ml) solution, and stir～1 hour.After in MeI (0.57ml, 9.2mmol) being added drop-wise to mixture in 8 minutes, when making cooling bath be melted up to room temperature, continue to stir 16.5 hours.Use saturated NH ₄after Cl solution (5ml) quencher, vacuum is removed most of organic composition, makes resistates at CH ₂cl ₂(100ml) and between water (40ml) distribute.Organic layer drying (MgSO ₄), filtering final vacuum concentrated, gained crude product is purified (350g silica gel with Biotage; 25%EtOAc/ hexane), obtain 2S/3S and the 2S/3R non-enantiomer mixture of 3.65g 3-methyl-2-(9-phenyl-9H-fluorenes-9-base is amino) succsinic acid 1-benzyl ester 4-methyl esters, ratio～1.0: 0.65 ( ¹h NMR).Now do not determine the stereochemical structure of main isomer, mixture just can carry out next step without separation.Part ¹h NMR data (DMSO-d ₆, δ=2.5ppm, 400MHz): main diastereomer, δ 4.39 (d, J=12.3, CH ₂1H), 3.33 (s, 3H, with H ₂o signal overlap), 3.50 (d, J=10.9, NH), 1.13 (d, J=7.1,3H); Less important diastereomer, δ 4.27 (d, J=12.3, CH ₂1H), 3.76 (d, J=10.9, NH), 3.64 (s, 3H), 0.77 (d, J=7.0,3H).LC (condition 1): RT=2.19 minute; LC/MS: for [M+H] ⁺c ₃₂h ₃₀nO ₄analytical calculation value: 492.22; Measured value: 492.15.

In 10 minutes, by the diisobutyl aluminium hydride (hexane solution of 20.57ml 1.0M, 20.57mmol) be added drop-wise to (2S)-3-methyl-2-(9-phenyl-9H-fluorenes-9-base is amino) succsinic acid 1-benzyl ester 4-methyl esters (3.37g of the above-mentioned preparation of cooling (78 ℃), in THF 6.86mmol) (120ml) solution, at-78 ℃, stir 20 hours.Reaction mixture, from cooling bath is taken out, is poured under stirring～1M H fast ₃pO ₄/ H ₂in O (250ml), ether for mixture (100ml, 2x) extraction.The organic phase salt water washing merging, dry (MgSO ₄), filter final vacuum concentrated.The silica gel sieve mesh (mesh) of preparing crude product, the circumstances in which people get things ready for a trip of going forward side by side spectrometry is processed (25%EtOAc/ hexane; Gravity wash-out), obtain 1.1g (2S, 3S)-4-hydroxy-3-methyl-2-(9-phenyl-9H-fluorenes-9-base is amino) benzyl butyrate (is polluted by phenylcarbinol, viscosity colorless oil), and (2S, 3R)-4-hydroxy-3-methyl-2-(9-phenyl-9H-fluorenes-9-base is amino) benzyl butyrate, contains (2S, 3R) steric isomer impurity.A rear sample carries out purifying again by same column chromatography purification condition, obtains 750mg pure products, is white foam shape thing.[noting: under these conditions, (2S, 3S) isomer prior to (2S, 3R) isomer wash-out out].(2S, 3S) isomer: ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): 7.81 (m, 2H), 7.39-7.08 (m, 16H), 4.67 (d, J=12.3,1H), 4.43 (d, J=12.4,1H), 4.21 (apparent t, J=5.2, OH), 3.22 (d, J=10.1, NH), 3.17 (m, 1H), 3.08 (m, 1H) ,～2.5 (m, 1H, overlapping with solvents signals), 1.58 (m, 1H), 0.88 (d, J=6.8,3H).LC (condition 1): RT=2.00 minute; LC/MS: for [M+H] ⁺c ₃₁h ₃₀nO ₃analytical calculation value: 464.45; Measured value: 464.22.(2S, 3R) isomer: ¹hNMR (DMSO-d ₆, δ=2.5ppm, 400MHz): 7.81 (d, J=7.5,2H), 7.39-7.10 (m, 16H), 4.63 (d, J=12.1,1H), 4.50 (apparent t, J=4.9,1H), 4.32 (d, J=12.1,1H), 3.59-3.53 (m, 2H), 3.23 (m, 1H), 2.44 (dd, J=9.0,8.3,1H), 1.70 (m, 1H), 0.57 (d, J=6.8,3H).LC (condition 1): RT=1.92 minute; LC/MS: for [M+H] ⁺c ₃₁h ₃₀nO ₃analytical calculation value: 464.45; Measured value: 464.52.

The relative stereochemistry of DIBAL reduzate is arranged and is studied and make according to NOE, this research adopts following scheme, use the lactone derivatives of being prepared by each isomer to carry out: by LiHMDS (50 μ l 1.0M/THF, 0.05mmol) be added to (2S of cooling (frozen water), 3S)-4-hydroxy-3-methyl-2-(9-phenyl-9H-fluorenes-9-base is amino) benzyl butyrate (62.7mg, 0.135mmol) with THF (2.0ml) solution in, reaction mixture is approximately stirred 2 hours at same temperature.Vacuum is removed volatile component, makes resistates at CH ₂cl ₂(30ml), water (20ml) and saturated NH ₄between the Cl aqueous solution (1ml), distribute.Organic layer drying (MgSO ₄), filtering final vacuum concentrated, gained crude product carries out Biotage purifying (40g silica gel; 10-15%EtOAc/ hexane), obtain (3S, 4S)-4-methyl-3-(9-phenyl-9H-fluorenes-9-base is amino) dihydrofuran-2 (3H) ketone (28.1mg, colorless solid membranoid substance).(2S, 3R)-4-hydroxy-3-methyl-2-(9-phenyl-9H-fluorenes-9-base is amino) benzyl butyrate is refined into (3S, 4R)-4-methyl-3-(9-phenyl-9H-fluorenes-9-base is amino) dihydrofuran-2 (3H) ketone by same method.(3S, 4S)-Nei ester isomer: ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz), 7.83 (d, J=7.5,2H), 7.46-7.17 (m, 11H), 4.14 (apparent t, J=8.3,1H), 3.60 (d, J=5.8, NH), 3.45 (apparent t, J=9.2,1H),～2.47 (m, 1H overlap with solvents signals), 2.16 (m, 1H), 0.27 (d, J=6.6,3H).LC (condition 1): RT=1.98 minute; LC/MS: for [M+Na] ⁺c ₂₄h ₂₁nNaO ₂analytical calculation value: 378.15; Measured value: 378.42.(3S, 4R)-Nei ester isomer: ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz), 7.89 (d, J=7.6,1H), 7.85 (d, J=7.3,1H), 7.46-7.20 (m, 11H), 3.95 (dd, J=9.1,4.8,1H), 3.76 (d, J=8.8,1H), 2.96 (d, J=3.0, NH), 2.92 (dd, J=6.8,3, NCH), 1.55 (m, 1H), 0.97 (d, J=7.0,3H).LC (condition 1): RT=2.03 minute; LC/MS: for [M+Na] ⁺c ₂₄h ₂₁nNaO ₂analytical calculation value: 378.15; Measured value: 378.49.

Successively by TBDMS-Cl (48mg, 0.312mmol) and imidazoles (28.8mg, 0.423mmol) be added to the CH of (2S, 3S)-4-hydroxy-3-methyl-2-(9-phenyl-9H-fluorenes-9-base is amino) benzyl butyrate (119.5mg, 0.258mmol) ₂cl ₂(3ml), in solution, mixture is stirred 14.25 hours under envrionment conditions.Then reaction mixture CH ₂cl ₂(30ml) after dilution, water (15ml) washing, organic layer drying (MgSO ₄), filter final vacuum concentrated.Gained crude product is purified (40g silica gel with Biotage; 5%EtOAc/ hexane), obtain (2S, 3S)-4-(t-butyldimethylsilyl oxygen base)-3-methyl-2-(9-phenyl-9H-fluorenes-9-base is amino) benzyl butyrate (124.4mg, by TBDMS type contaminating impurity, viscosity colorless oil).By (2S, 3R)-4-hydroxy-3-methyl-2-(9-phenyl-9H-fluorenes-9-base is amino) benzyl butyrate is refined into (2S, 3R)-4-(t-butyldimethylsilyl oxygen base)-3-methyl-2-(9-phenyl-9H-fluorenes-9-base is amino) benzyl butyrate by same method.(2S, 3S)-silyl ether isomer: ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz), 7.82 (d, J=4.1,1H), 7.80 (d, J=4.0,1H), 7.38-7.07 (m, 16H), 4.70 (d, J=12.4,1H), 4.42 (d, J=12.3,1H), 3.28-3.19 (m, 3H), 2.56 (dd, J=10.1,5.5,1H), 1.61 (m, 1H), 0.90 (d, J=6.8,3H), 0.70 (s, 9H) ,-0.13 (s, 3H) ,-0.16 (s, 3H).LC (condition 1 is wherein crossed post time lengthening to 4 minute): RT=3.26 minute; LC/MS: for [M+H] ⁺c ₃₇h ₄₄nO ₃si analytical calculation value: 578.31; Measured value: 578.40.(2S, 3R)-silyl ether isomer: ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz), 7.82 (d, J=3.0,1H), 7.80 (d, J=3.1,1H), 7.39-7.10 (m, 16H), 4.66 (d, J=12.4,1H), 4.39 (d, J=12.4,1H), 3.61 (dd, J=9.9,5.6,1H), 3.45 (d, J=9.5,1H), 3.41 (dd, J=10,6.2,1H), 2.55 (dd, J=9.5,7.3,1H), 1.74 (m, 1H), 0.77 (s, 9H), 0.61 (d, J=7.1,3H),-0.06 (s, 3H) ,-0.08 (s, 3H).

By hydrogen capsule and (2S, 3S)-4-(t-butyldimethylsilyl oxygen base)-3-methyl-2-(9-phenyl-9H-fluorenes-9-base is amino) benzyl butyrate (836mg, 1.447mmol) and 10%Pd/C (213mg) be communicated with the mixture of EtOAc (16ml), mixture is at room temperature stirred～21 hours, while needing, air bag is filled with H again ₂.Reaction mixture CH ₂cl ₂dilution, by diatomite (Celite- ) pad filters, EtOAc Celite pad for (200ml), EtOAc/MeOH (1: 1 mixture, 200ml) and MeOH (750ml) wash.After the organic phase merging is concentrated, by gained crude product, prepare silica gel sieve mesh, carry out flash chromatography processing (8: 2: 1EtOAc/i-PrOH/H ₂the mixture of O), obtain (2S, 3S)-2-amino-4-(t-butyldimethylsilyl oxygen base)-3 Methylbutanoic acid (325mg, white fine hair shape solid).By (2S, 3R)-4-(t-butyldimethylsilyl oxygen base)-3-methyl-2-(9-phenyl-9H-fluorenes-9-base is amino) benzyl butyrate is refined into (2S, 3R)-2-amino-4-(t-butyldimethylsilyl oxygen base)-3 Methylbutanoic acid by same method.(2S, 3S)-amino acid isomer: ¹h NMR (methyl alcohol-d ₄, δ=3.29ppm, 400MHz), 3.76 (dd, J=10.5,5.2,1H), 3.73 (d, J=3.0,1H), 3.67 (dd, J=10.5,7.0,1H), 2.37 (m, 1H), 0.97 (d, J=7.0,3H), 0.92 (s, 9H), 0.10 (s, 6H).LC/MS: for [M+H] ⁺c ₁₁h ₂₆nO ₃si analytical calculation value: 248.17; Measured value: 248.44.(2S, 3R)-amino acid isomer: ¹h NMR (methyl alcohol-d ₄, δ=3.29ppm, 400MHz), 3.76-3.75 (m, 2H), 3.60 (d, J=4.1,1H), 2.16 (m, 1H), 1.06 (d, J=7.3,3H), 0.91 (s, 9H), 0.09 (s, 6H).For [M+H] ⁺c ₁₁h ₂₆nO ₃si analytical calculation value: 248.17; Measured value: 248.44.

By water (1ml) and NaOH (0.18ml 1.0M/H ₂o, 0.18mmol) be added to (2S, 3S)-2-amino-4-(t-butyldimethylsilyl oxygen base)-3 Methylbutanoic acid (41.9mg, 0.169mmol) and Na ₂cO ₃in the mixture of (11.9mg, 0.112mmol), supersound process approximately 1 minute is so that reactants dissolved.Then mixture is cooling with ice-water bath, adds methyl-chloroformate (0.02ml, 0.259mmol) in 30 seconds, vigorous stirring after 40 minutes at same temperature, then stir at ambient temperature 2.7 hours.Reaction mixture water (5ml) dilution, after using ice-water bath cooling, dropwise adds the 1.0N HCl aqueous solution (～0.23ml) to process.Mixture water (10ml) dilution again, uses CH ₂cl ₂(15ml, 2x) extraction.Organic phase drying (the MgSO merging ₄), filter final vacuum concentrated, obtain Cap-80a, be pale solid.(2S, 3R)-2-amino-4-(t-butyldimethylsilyl oxygen base)-3 Methylbutanoic acid is refined into Cap-80b by same method.Cap-80a: ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz), 12.57 (br s, 1H), 7.64 (d, J=8.3,0.3H), 7.19 (d, J=8.8,0.7H), 4.44 (dd, J=8.1,4.6,0.3H), 4.23 (dd, J=8.7,4.4,0.7H), (two are unimodal for 3.56/3.53,3H), 3.48-3.40 (m, 2H), 2.22-2.10 (m, 1H), 0.85 (s, 9H) ,～0.84 (d, 0.9H, with t-Bu signal overlap), 0.79 (d, J=7,2.1H), (three overlapping unimodal, 6H) for 0.02/0.01/0.00.LC/MS: for [M+Na] ⁺c ₁₃h ₂₇nNaO ₅si analytical calculation value: 328.16; Measured value: 328.46.Cap-80b： ¹H NMR(CDCl ₃，δ＝7.24ppm，400MHz)，6.00(br d，J＝6.8，1H)，4.36(dd，J＝7.1，3.1，1H)，3.87(dd，J＝10.5，3.0，1H)，3.67(s，3H)，3.58(dd，J＝10.6，4.8，1H)，2.35(m，1H)，1.03(d，J＝7.1，3H)，0.90(s，9H)，0.08(s，6H)。LC/MS: for [M+Na] ⁺c ₁₃h ₂₇nNaO ₅si analytical calculation value: 328.16; Measured value: 328.53.Crude product can be used without being further purified just.

According to scheme preparation (Falb etc., Synthetic Communications1993,23,2839) described in the people such as Falb.

Cap-82 to Cap-85

According to method described in Cap-51, by the synthetic Cap-82 to Cap-85 of suitable raw material.The spectral signature of sample is similar to the spectral signature of its enantiomorph (being respectively Cap-4, Cap-13, Cap-51 and Cap-52).

At 0 ℃, to O-methyl-L-threonine (3.0g, 22.55mmol), NaOH (0.902g, 22.55mmol) and H ₂in the mixture of O (15ml), drip ClCO ₂me (1.74ml, 22.55mmol).Mixture was stirred after 12 hours, with 1N HCl, be acidified to pH 1.The CH of EtOAc for water (2 * 250ml) and 10%MeOH ₂cl ₂solution (250ml) extraction, the organic phase of merging, after vacuum concentration, obtains colorless oil (4.18g, 97%), and its purity is enough to be used in subsequent step. ¹H NMR(400MHz，CDCl ₃)δ4.19(s，1H)，3.92-3.97(m，1H)，3.66(s，3H)，1.17(d，J＝7.7Hz，3H)。LCMS: for C ₇h ₁₃nO ₅analytical calculation value: 191; Measured value: 190 (M-H) ^-.

At 0 ℃, to L-homoserine (2.0g, 9.79mmol), Na ₂cO ₃(2.08g, 19.59mmol) and H ₂in the mixture of O (15ml), drip ClCO ₂me (0.76ml, 9.79mmol).Mixture was stirred after 48 hours, with 1N HCl, be acidified to pH 1.EtOAc for water (2 * 250ml) extraction, the organic phase of merging, after vacuum concentration, obtains colorless solid (0.719g, 28%), and its purity is enough to be used in subsequent step. ¹H NMR(400MHz，CDCl ₃)δ4.23(dd，J＝4.5，9.1Hz，1H)，3.66(s，3H)，3.43-3.49(m，2H)，2.08-2.14(m，1H)，1.82-1.89(m，1H)。LCMS: for C ₇h ₁₃nO ₅analytical calculation value: 191; Measured value: 192 (M+H) ⁺.

By Valine (1.0g, 8.54mmol), 3-bromopyridine (1.8ml, 18.7mmol), K ₂cO ₃(2.45g, 17.7mmol) and CuI (169mg, 0.887mmol) heat 12 hours with the mixture of DMSO (10ml) at 100 ℃.Reaction mixture is cooled to after room temperature, pours H into ₂in O (about 150ml), with EtOAc washing (twice).The a small amount of H of organic layer ₂o extraction, the water of merging is acidified to about pH 2 with 6N HCl.Volume reduces at about 1/3 o'clock, adds 20g Zeo-karb (Strata).Make soup compound after standing 20 minutes, be added on Zeo-karb pad (Strata) (about 25g).This pad is used H successively ₂o (200ml), MeOH (200ml) and NH ₃(the MeOH solution of 3M, 2 * 200ml) washing.Suitable flow point, through vacuum concentration, is dissolved in H by resistates (about 1.1g) ₂o, freezing and freeze-drying.Obtain title compound (1.02g, 62%, foam). ¹H NMR(400MHz，DMSO-d ₆)δ8.00(s，br，1H)，7.68-7.71(m，1H)，7.01(s，br，1H)，6.88(d，J＝7.5Hz，1H)，5.75(s，br，1H)，3.54(s，1H)，2.04-2.06(m，1H)，0.95(d，J＝6.0Hz，3H)，0.91(d，J＝6.6Hz，3H)。LCMS: for C ₁₀h ₁₄n ₂o ₂analytical calculation value: 194; Measured value: 195 (M+H) ⁺.

By Valine (1.0g, 8.54mmol), 5-bromo pyrimi piperidine (4.03g, 17.0mmol), K ₂cO ₃(2.40g, 17.4mmol) and CuI (179mg, 0.94mmol) heat 12 hours with the mixture of DMSO (10ml) at 100 ℃.Reaction mixture is cooled to after room temperature, pours H into ₂in O (about 150ml), and wash (twice) with EtOAc.The a small amount of H of organic layer ₂o extraction, the water of merging is acidified to about pH 2 with 6N HCl.Volume reduces at about 1/3 o'clock, adds 20g Zeo-karb (Strata).Soup compound, after standing 20 minutes, is added on Zeo-karb pad (Strata) (about 25g).This pad is used H successively ₂o (200ml), MeOH (200ml) and NH ₃(the MeOH solution of 3M, 2 * 200ml) washing.Suitable flow point, after vacuum concentration, is dissolved in H by resistates (about 1.1g) ₂o, freezing and freeze-drying.Obtain title compound (1.02g, 62%, foam). ¹h NMR (400MHz, CD ₃oD) show that mixture contains α-amino-isovaleric acid, thereby be unable to estimate its purity.This product is same as before for subsequent reactions.LCMS: for C ₉h ₁₃n ₃o ₂analytical calculation value: 195; Measured value: 196 (M+H) ⁺.

According to method described in Cap-1 preparation, prepare Cap-90.Crude product is same as before for subsequent step.LCMS: for C ₁₁h ₁₅nO ₂analytical calculation value: 193; Measured value: 192 (M-H) ^-.

Following end group (Cap) is prepared according to the method for embodiment 51:

Cap-117 to Cap-123

For the preparation of end group Cap-117 to Cap-123, Boc amino acid is commercially available, with the CH of 25%TFA ₂cl ₂solution-treated just can deprotection.After judging and reacted by LCMS, solvent removed in vacuo, according to the method for Cap-51, amino acid whose corresponding tfa salt carries out formamyl with methyl-chloroformate.

The preparation of Cap-124. (4S, 5R)-5-methyl-2-Yang Dai oxazolidine-4-formic acid

According to the method for Cap-51, make the hydrochloride formamyl of the L-threonine tert-butyl ester.Crude reaction mixture is acidified to pH～1 with 1N HCl, EtOAc for mixture (2 * 50ml) extraction.The organic phase merging, after vacuum concentration, obtains colorless solid curing when standing.Vacuum concentration water layer, the mixture EtOAc-CH of products therefrom and inorganic salt ₂cl ₂-MeOH (1: 1: 0.1) grinds, and after vacuum concentration organic phase, obtains colorless oil, with LCMS, is shown as needed product.Merge product twice, obtain 0.52g solid. ¹H NMR(400MHz，CD ₃OD)δ4.60(m，1H)，4.04(d，J＝5.0Hz，1H)，1.49(d，J＝6.3Hz，3H)。LCMS: for C ₅h ₇nO ₄analytical calculation value: 145; Measured value: 146 (M+H) ⁺.

Cap-125. the preparation of (S)-2-(tert-butoxycarbonyl is amino)-4-(dimethylamino) butyric acid.

According to the preparation method for Cap-1, prepare Cap-125.Crude product is same as before for subsequent reactions.LCMS: for C ₁₁h ₂₂n ₂o ₄analytical calculation value: 246; Measured value: 247 (M+H) ⁺.

(S) preparation of-2-(methoxycarbonyl is amino)-3-(1-methyl isophthalic acid H-imidazoles-2-yl) propionic acid (Cap-126).

Present method is improving one's methods for the preparation of Cap-51.At 0 ℃, to (S)-2-amino-3-(1-methyl isophthalic acid H-imidazoles-2-yl) propionic acid (0.80g, 4.70mmol) and THF (10ml) and H ₂in the suspension of O (10ml), add NaHCO ₃(0.88g, 10.5mmol).Gained mixture ClCO ₂me (0.40ml, 5.20mmol) processes, and mixture is stirred at 0 ℃.After stir about 2 hours, LCMS shows noresidue raw material.With 6N HCl, make reactant be acidified to pH 2.

After solvent removed in vacuo, resistates is suspended in to the CH of 20ml 20%MeOH ₂cl ₂in solution.Mixture is filtered, concentrated, obtain light yellow foam (1.21g).LCMS and ¹h NMR shows that this product is the mixture of 9: 1 methyl esters and required product.This product is dissolved in to THF (10ml) and H ₂in O (10ml), be cooled to after 0 ℃, add LiOH (249.1mg, 10.4mmol).After stir about 1 hour, LCMS shows noresidue ester.Therefore mixture is used after 6N HCl acidifying, solvent removed in vacuo.LCMS and ¹h NMR confirms not exist ester.Obtain title compound, be its HCl salt (1.91g, > 100%, polluted by inorganic salt).This compound just can be same as before for subsequent step without being further purified.

¹h NMR (400MHz, CD ₃oD) δ 8.84, (s, 1H), 7.35 (s, 1H), 4.52 (dd, J=5.0,9.1Hz, 1H), 3.89 (s, 3H), 3.62 (s, 3H), 3.35 (dd, J=4.5,15.6Hz, 1H, is partly sheltered by solvent), 3.12 (dd, J=9.0,15.6Hz, 1H).

LCMS: for C ₁₇h ₁₅nO ₂analytical calculation value: 392; Measured value: 393 (M+H) ⁺.

(S) preparation of-2-(methoxycarbonyl is amino)-3-(1-methyl isophthalic acid H-imidazol-4 yl) propionic acid (Cap-127).

According to the above-mentioned method for Cap-126, by (S)-2-amino-3-(1-methyl isophthalic acid H-imidazol-4 yl) propionic acid (1.11g, 6.56mmol), NaHCO ₃(1.21g, 14.4mmol) and ClCO ₂me (0.56ml, 7.28mmol) starts to prepare Cap-127.Obtain title compound, be its HCl salt (1.79g, > 100%, polluted by inorganic salt).LCMS and ¹h NMR shows the methyl esters that has about 5%.This crude mixture can be used same as before without being further purified just.

¹H NMR(400MHz，CD ₃OD)δ8.90(s，1H)，7.35(s，1H)，4.48(dd，J＝5.0，8.6Hz，1H)，3.89(s，3H)，3.62(s，3H)，3.35(m，1H)，3.08(m，1H)。

(S) preparation of-2-(methoxycarbonyl is amino)-3-(1H-1,2,3-triazole-4-yl) propionic acid (Cap-128).

The preparation of step 1:(S)-2-(tert-butoxycarbonyl is amino) penta-4-alkynes acid benzyl ester (cj-27b).

At 0 ℃, to cj-27a (1.01g, 4.74mmol), DMAP (58mg, 0.475mmol) and iPr ₂nEt (1.7ml, 9.8mmol) and CH ₂cl ₂(100ml) in solution, add Cbz-Cl (0.68ml, 4.83mmol).Solution is stirred 4 hours at 0 ℃ to washing (1N KHSO ₄, salt solution), dry (Na ₂sO ₄), filter final vacuum concentrated.Resistates is purified (6: 1 hexanes of TLC: EtOAc), obtain title compound (1.30g, 91%, colorless oil) with flash column chromatography. ¹H NMR(400MHz，CDCl ₃)δ7.35(s，5H)，5.35(d，br，J＝8.1Hz，1H)，5.23(d，J＝12.2Hz，1H)，5.17(d，J＝12.2Hz，1H)，4.48-4.53(m，1H)，2.68-2.81(m，2H)，2.00(t，J＝2.5Hz，1H)，1.44(s，9H)。LCMS: for C ₁₇h ₂₁nO ₄analytical calculation value: 303; Measured value: 304 (M+H) ⁺.

The preparation of step 2:(S)-3-(1-benzyl-1H-1,2,3-triazole-4-yl)-2-(tert-butoxycarbonyl is amino) benzyl propionate (cj-28).

At room temperature, to (S)-2-(tert-butoxycarbonyl is amino) penta-4-alkynes acid benzyl ester (0.50g, 1.65mmol), sodium ascorbate (0.036g, 0.18mmol), CuSO ₄-5H ₂o (0.022g, 0.09mmol) and NaN ₃(0.13g, 2.1mmol) and DMF-H ₂in the mixture of O (5ml, 4: 1), add BnBr (0.24ml, 2.02mmol), make mixture be warming up to 65 ℃.After 5 hours, LCMS shows that conversion is slower.Add again a NaN ₃(100mg), continue heating 12 hours.Pour reactant into EtOAc and H ₂vibration after in O.Separated each layer, EtOAc extraction 3 times for water layer, the organic phase of merging is through washing (H ₂o x3, salt solution), dry (Na ₂sO ₄), concentrated after filtering.Resistates is through fast purifying (Biotage, 40+M 0-5%MeOH/CH ₂cl ₂; TLC 3%MeOH/CH ₂cl ₂), obtain light yellow oil (748.3mg, 104%) curing when standing.NMR is consistent with required product, but shows to exist DMF.Product can be used same as before without being further purified just. ¹H NMR(400MHz，DMSO-d ₆)δ7.84(s，1H)，7.27-7.32(m，10H)，5.54(s，2H)，5.07(s，2H)，4.25(m，1H)，3.16(dd，J＝1.0，5.3Hz，1H)，3.06(dd，J＝5.3，14.7Hz)，2.96(dd，J＝9.1，14.7Hz，1H)，1.31(s，9H)。

LCMS: for C ₂₄h ₂₈n ₄o ₄analytical calculation value: 436; Measured value: 437 (M+H) ⁺.

The preparation of step 2:(S)-3-(1-benzyl-1H-1,2,3-triazole-4-yl)-2-(methoxycarbonyl is amino) benzyl propionate (cj-29).

CH to (S)-3-(1-benzyl-1H-1,2,3-triazole-4-yl)-2-(tert-butoxycarbonyl is amino) benzyl propionate (0.52g, 1.15mmol) ₂cl ₂in solution, add TFA (4ml).Mixture is at room temperature stirred 2 hours.Mixture, after vacuum concentration, obtains colorless oil curing when standing.This product is dissolved in to THF-H ₂after O, be cooled to 0 ℃.Add successively solid NaHCO ₃(0.25g, 3.00mmol) and ClCO ₂me (0.25ml, 3.25mmol).Stir after 1.5 hours, mixture is acidified to pH～2 and pours H into 6N HCl ₂in O-EtOAc.Separated each layer, EtOAc extraction 2 times for water.The organic layer merging is through washing (H ₂o, salt solution), dry (Na ₂sO ₄), filter final vacuum concentrated, obtain colorless oil (505.8mg, 111%, NMR shows to exist uncertain impurity), when standing in pump, solidify.Product can be used same as before without being further purified just. ¹H NMR(400MHz，DMSO-d ₆)δ7.87(s，1H)，7.70(d，J＝8.1Hz，1H)，7.27-7.32(m，10H)，5.54(s，2H)，5.10(d，J＝12.7Hz，1H)，5.06(d，J＝12.7Hz，1H)，4.32-4.37(m，1H)，3.49(s，3H)，3.09(dd，J＝5.6，14.7Hz，1H)，2.98(dd，J＝9.6，14.7Hz，1H)。LCMS: for C ₂₁h ₂₂n ₄o ₄analytical calculation value: 394; Measured value: 395 (M+H) ⁺.

The preparation of step 3:(S)-2-(methoxycarbonyl is amino)-3-(1H-1,2,3-triazole-4-yl) propionic acid (Cap-128).

Under the MeOH solution (5ml) of Pd-C (82mg) exists, make (S)-3-(1-benzyl-1H-1,2,3-triazole-4-yl)-2-(methoxycarbonyl is amino) under atmospheric pressure hydrogenation of benzyl propionate (502mg, 1.11mmol) 12 hours.Mixture is through diatomite after filtration, vacuum concentration.Obtain (S)-2-(methoxycarbonyl is amino)-3-(1H-1,2,3-triazole-4-yl) propionic acid (266mg, 111%, colourless jelly), by approximately 10% methyl esters, polluted.Product can be used same as before without being further purified just.

¹H NMR(400MHz，DMSO-d ₆)δ12.78(s，br，1H)，7.59(s，1H)，7.50(d，J＝8.0Hz，1H)，4.19-4.24(m，1H)，3.49(s，3H)，3.12(dd，J＝4.8Hz，14.9Hz，1H)，2.96(dd，J＝9.9，15.0Hz，1H)。LCMS: for C ₇h ₁₀n ₄o ₄analytical calculation value: 214; Measured value: 215 (M+H) ⁺.

(S) preparation of-2-(methoxycarbonyl is amino)-3-(1H-pyrazol-1-yl) propionic acid (Cap-129).

The preparation of step 1:(S)-2-(benzyloxycarbonyl is amino)-3-(1H-pyrazol-1-yl) propionic acid (cj-31).

By (S)-2-oxo trimethylene oxide-3-aminocarbamic acid benzyl ester (0.67g, 3.03mmol) and pyrazoles (0.22g, 3.29mmol) and CH ₃the suspension of CN (12ml) heats 24 hours at 50 ℃.Mixture is cooled to after ambient temperature overnight, by solid filtering, obtains (S)-2-(benzyloxycarbonyl is amino)-3-(1H-pyrazol-1-yl) propionic acid (330.1mg).After vacuum concentrated filtrate, use a small amount of CH ₃cN (about 4ml) grinds, and obtains the second product (43.5mg).Ultimate production 370.4mg (44%).

Fusing point 165.5-168 ℃.168.5-169.5 ℃ of document fusing point (Vederas etc., J.Am.Chem.Soc.1985,107,7105).

¹H NMR(400MHz，CD ₃OD)δ7.51(d，J＝2.0，1H)，7.48(s，J＝1.5Hz，1H)，7.24-7.34(m，5H)，6.23(m，1H)，5.05(d，12.7H，1H)，5.03(d，J＝12.7Hz，1H)，4.59-4.66(m，2H)，4.42-4.49(m，1H)。LCMS: for C ₁₄h ₁₅n ₃o ₄analytical calculation value: 289; Measured value: 290 (M+H) ⁺.

The preparation of step 2:(S)-2-(methoxycarbonyl is amino)-3-(1H-pyrazol-1-yl) propionic acid (Cap-129).

Under the MeOH solution (5ml) of Pd-C (45mg) exists, make (S)-2-(benzyloxycarbonyl is amino) under atmospheric pressure hydrogenation of-3-(1H-pyrazol-1-yl) propionic acid (0.20g, 0.70mmol) 2 hours.Product demonstration is insoluble to MeOH, therefore by reaction mixture 5ml H ₂o and several 6N HCl dilutions.Homogeneous solution is through diatomite filter, vacuum is removed MeOH.Remaining solution, through freezing and freeze-drying, obtains yellow foam (188.9mg).This product is suspended in to THF-H ₂o (1: 1,10ml) in after, be cooled to 0 ℃.In cold mixture, add NaHCO carefully ₃(146.0mg, 1.74mmol) (emits CO ₂).Stop emitting (approximately 15 minutes) after gas, drip ClCO ₂me (0.06ml, 0.78mmol).Stir the mixture after 2 hours, with 6N HCl, be acidified to pH～2 and pour in EtOAc.Separated each layer, EtOAC extraction (5 times) for water.The organic layer merging, through washing (salt solution), is dried (Na ₂sO ₄), concentrated after filtering, obtain title compound (117.8mg, 79%, colorless solid).

¹h NMR (400MHz, DMSO-d ₆) δ 13.04 (s, 1H), 7.63 (d, J=2.6Hz, 1H), 7.48 (d, J=8.1Hz, 1H), 7.44 (d, J=1.5Hz, 1H), 6.19 (apparent t, J=2.0Hz, 1H), 4.47 (dd, J=3.0,12.9Hz, 1H), 4.29-4.41 (m, 2H), 3.48 (s, 3H).LCMS: for C ₈h ₁₁n ₃o ₄analytical calculation value: 213; Measured value: 214 (M+H) ⁺.

Cap-130.N-ethanoyl-(R)-phenylglycocoll

By the method (Calmes, the M. that are similar to document and provide; Daunis, J.; Jacquier, R.; Verducci, J.Tetrahedron, 1987,43 (10), 2285), make commercially available (R)-phenylglycocoll acylations prepare Cap-130.

Embodiment

Below in conjunction with some embodiment, to present disclosure, will be described, described embodiment does not limit the scope of the disclosure.On the contrary, present disclosure is contained all substituting within the scope of claims, modification and equivalents of being included in.Therefore, the following example, comprises specific embodiments, by a kind of enforcement method of present disclosure, be appreciated that, the object of embodiment is for some embodiment is described, and believes in the most useful and the most intelligible mode its method and design are described.

Solution percentage ratio represents weight and volume relationship, and solution is than representing volume and volume relationship, except as otherwise noted.Nucleus magnetic resonance (NMR) is Bruker 300,400 or 500MHz spectrometer record for spectrum; Chemical shift (δ) is reported with ppm.According to Still flash chromatography technology (J.Org.Chem.1978,43,2923), with silica gel (SiO ₂) carry out flash chromatography.

Condition 1

Post=Phenomenex-Luna 3.0 * 50mm S10

Start %B=0

Final %B=100

Gradient time=2 minute

Stand-by time=3 minute

Flow velocity=4ml/ minute

Wavelength=220nm

10% methyl alcohol/90%H of solvent orange 2 A=0.1%TFA ₂o

90% methyl alcohol/10%H of solvent B=0.1%TFA ₂o

Condition 2

Post=Phenomenex-Luna 4.6 * 50mm S10

Start %B=0

Final %B=100

Gradient time=2 minute

Stand-by time=3 minute

Flow velocity=5ml/ minute

Wavelength=220nm

10% methyl alcohol/90%H2O of solvent orange 2 A=0.1%TFA

90% methyl alcohol/10%H of solvent B=0.1%TFA ₂o

Condition 3

Post=HPLC XTERRA C183.0 * 50mm S7

Start %B=0

Final %B=100

Gradient time=3 minute

Stand-by time=4 minute

Flow velocity=4ml/ minute

Wavelength=220nm

10% methyl alcohol/90%H2O of solvent orange 2 A=0.1%TFA

90% methyl alcohol/10%H of solvent B=0.1%TFA ₂o

Method A:LCMS-Xterra MS C-183.0 * 50mm, gradient 0-100%B, in 30.0 minutes, 1 minute residence time, A=5% acetonitrile, 95% water, 10mm ammonium acetate, B=95% acetonitrile, 5% water, 10mm ammonium acetate.

Method B:HPLC-X-Terra C-184.6 * 50mm, gradient 0-100%B, in 10.0 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.1%TFA, B=90% methyl alcohol 10% water 0.1%TFA.

Method C:HPLC-YMC C-184.6 * 50mm, gradient 0-100%B, in 10.0 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.2%H ₃pO ₄, B=90% methyl alcohol 10% water 0.2%H ₃pO ₄.

Method D:HPLC-Phenomenex C-184.6 * 150mm, gradient 0-100%B, in 10.0 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.2%H ₃pO ₄, B=90% methyl alcohol 10% water 0.2%H ₃pO ₄.

Method E:LCMS-Gemini C-184.6 * 50mm, gradient 0-100%B, in 10.0 minutes, 1 minute residence time, A=5% acetonitrile, 95% water, 10mm ammonium acetate, B=95% acetonitrile, 5% water, 10mm ammonium acetate.

Method F:LCMS-Luna C-183.0 * 50mm, gradient 0-100%B, in 7.0 minutes, 1 minute residence time, A=5% acetonitrile, 95% water, 10mm ammonium acetate, B=95% acetonitrile, 5% water, 10mm ammonium acetate.

Embodiment 1

(1R, 1 ' R)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amines)

Embodiment 1, step a

In 15 minutes, by N, N-diisopropylethylamine (18ml, 103.3mmol) be added drop-wise to N-Boc-L-proline(Pro) (7.139g, 33.17mmol), HATU (13.324g, 35.04mmol), in the heterogeneous mixture of 2-amino-1-(4-bromophenyl) ethyl ketone HCl salt (8.127g, 32.44mmol) and DMF (105ml), under envrionment conditions, stir 55 minutes.Vacuum is removed after most of volatile component, and gained resistates is distributed between ethyl acetate (300ml) and water (200ml).Organic layer water (200ml) and salt water washing, dry (MgSO ₄), filter final vacuum concentrated.By resistates, prepare silica gel sieve mesh, and carry out flash chromatography processing (silica gel; 50-60% ethyl acetate/hexane), obtain keto-amide 1a (12.8g, white solid). ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 8.25-8.14 (m, 1H), 7.92 (br d, J=8.0,2H), 7.75 (brd, J=8.6,2H), 4.61 (dd, J=18.3,5.7,1H), 4.53 (dd, J=18.1,5.6,1H), 4.22-4.12 (m, 1H), 3.43-3.35 (m, 1H), 3.30-3.23 (m, 1H), 2.18-2.20 (m, 1H), 1.90-1.70 (m, 3H), 1.40/1.34 (two apparent br s, 9H).LC (condition 1): RT=1.70 minute; LC/MS: for [M+Na] ⁺c ₁₈h ₂₃brN ₂naO ₄analytical calculation value: 433.07; Measured value: 433.09.

The similar compounds such as intermediate 1-1a to 1-5a can be prepared by mixing amino acid and the aromatic bromide isomer of suitable replacement.

¹h NMR (500MHz, DMSO-d ₆) δ ppm 1.35/1.40 (two br s, 9H), 2.27-2.42 (m, 1H), 2.73-2.95 (m, 1H), 3.62-3.89 (m, 2H), 4.36-4.50 (m, 1H), 4.51-4.60 (m, 1H), 4.62-4.73 (m, 1H), 7.75 (d, J=8.24Hz, 2H), 7.92 (d, J=7.63Hz, 2H), 8.31-8.49 (m, 1H).HPLC XTERRA C-184.6 * 30mm, 0-100%B, in 4 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.2%H ₃pO ₄, B=10% water, 90% methyl alcohol, 0.2%H ₃pO ₄, RT=1.59 minute, homogeneity index 99%.LCMS: for C ₁₈h ₂₁brF ₂n ₂o ₄analytical calculation value: 446.06; Measured value: 445.43 (M-H) ^-.

¹H NMR(500MHz，DMSO-d ₆)δppm(8.251H，s)，7.91(2H，d，J＝8.24Hz)，7.75(2H，d，J＝8.24Hz)，4.98(1H，s)，4.59-4.63(1H，m)，4.46-4.52(1H，m)，4.23(1H，m)，3.37(1H，s)，3.23-3.28(1H，m)，2.06(1H，m)，1.88(1H，s)，1.38(3H，s)，1.33(6H，s)。LCMS-PhenomenexC-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.1%TFA, B=90% methyl alcohol 10% water 0.1%TFA moving phase, RT=3.34 minute, for C ₁₈h ₂₃brN ₂o ₅analytical calculation value: 427.30; Measured value: 428.08 (M+H) ⁺.

¹H NMR(500MHz，DMSO-d ₆)δppm 8.30(1H，s)7.93-7.96(2H，m)7.76(2H d，J＝8.24Hz)5.13(1H，s)4.66-4.71(1H，m)4.52-4.55(1H，m)4.17(1H，m)3.51(1H，s)3.16-3.19(1H，m)2.36(1H，m)1.78(1H，s)1.40(s，3H)，1.34(s，6H)。LCMS-Phenomenex C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.1%TFA, B=90% methyl alcohol 10% water 0.1%TFA, RT=3.69 minute, for C ₁₈h ₂₃brN ₂o ₅analytical calculation value: 427.30; Measured value: 428.16 (M+H) ⁺.

¹H NMR(500MHz，DMSO-d ₆)δppm 1.29-1.47(m，9H)，1.67-1.90(m，3H)，2.00-2.20(m，1H)，3.23-3.30(m，1H)，3.34-3.44(m，1H)，4.16(dd，1H)，4.57(q，2H)，7.51(t，J＝7.78Hz，1H)，7.86(dd，J＝7.93，1.22Hz，1H)，7.98(d，J＝7.63Hz，1H)，8.11(s，1H)，8.15-8.29(m，1H)。LC/MS(M+Na) ⁺＝433.12/435.12。

LCMS condition: Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 2 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, 220nm, 5 μ l inject volume.RT=1.93 minute; LRMS: for C ₁₉h ₁₈brN ₂o ₄analytical calculation value: 418.05; Measured value: 419.07 (M+H) ⁺.

Embodiment 1, step b

By keto-amide 1a (12.8g, 31.12mmol) and NH ₄oAc (12.0g, 155.7mmol) heats 2 hours in 140 ℃ in sealed tube with the mixture of dimethylbenzene (155ml).Vacuum is removed after volatile component, makes carefully resistates distribute between ethyl acetate and water, after vibration biphasic system, by adding enough saturated NaHCO ₃solution, makes water pH be slight alkalinity.After separated each layer, water layer is extracted with ethyl acetate again.The organic phase salt water washing merging, dry (MgSO ₄), filter final vacuum concentrated.Products therefrom ethyl acetate/hexane recrystallization, obtains two kinds of products of imidazoles 1b, is light yellow closely knit solid, weight 5.85g.By mother liquor vacuum concentration, and carry out flash chromatography processing (silica gel; Then obtain 2.23g imidazoles 1b 30% ethyl acetate/hexane). ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 12.17/11.92/11.86 (m, 1H), 7.72-7.46/7.28 (m, 5H), 4.86-4.70 (m, 1H), 3.52 (apparent br s, 1H), 3.36 (m, 1H), 2.30-1.75 (m, 4H), 1.40/1.15 (apparent br s, 9H).LC (condition 1): RT=1.71 minute; Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₁₈h ₂₃brN ₃o ₂analytical calculation value: 392.10; Measured value: 391.96; HRMS: for [M+H] ⁺c ₁₈h ₂₃brN ₃o ₂analytical calculation value: 392.0974; Measured value: 392.0959.

By following chirality HPLC condition, for the optical purity of two samples of 1b, carried out evaluating (the enantiomeric excess > 99% that merges product; Enantiomeric excess=96.7% of flash chromatography sample):

Post: Chiralpak AD, 10 μ m, 4.6 * 50mm

Solvent: 2% ethanol/heptane (isocratic elution)

Flow velocity: 1ml/ minute

Wavelength: 220nm or 254nm

Relative retention time: 2.83 minutes (R), 5.34 minutes (S).

The similar compounds such as intermediate 1-1b to 1-4b can be prepared by mixing suitable keto-amide.

¹h NMR (500MHz, DMSO-d ₆) δ ppm 1.17/1.40 (two br s, 9H), 2.50-2.74 (m, J=25.64Hz, 1H), 2.84-3.07 (m, 1H), 3.88 (d, J=10.07Hz, 2H), 5.03 (s, 1H), 7.50 (d, J=8.55Hz, 2H), 7.60 (s, 1H), 7.70 (d, J=8.55Hz, 2H), 12.10 (s, 1H).HPLC XTERRA C-184.6 * 30mm, 0-100%B, in 4 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.2%H ₃pO ₄, B=10% water, 90% methyl alcohol, 0.2%H ₃pO ₄, RT=1.59 minute, homogeneity index 99%; LCMS: for C ₁₈h ₂₀brF ₂n ₃o ₂analytical calculation value: 428.27; Measured value: 428.02 (M) ⁺.

¹h NMR (500MHz, DMSO-d ₆) δ ppm 11.89-11.99 (1H, m), 7.68 (2H, d, J=8.54Hz), 7.52-7.59 (1H, m), 7.48 (2H, d, J=8.54Hz), (4.80 1H, m), 4.33 (1H, s), 3.51-3.60 (1H, m), 3.34 (1H, d, J=10.99Hz), 2.14 (1H, s), 1.97-2.05 (1H, m), 1.37 (3H, s), 1.10 (6H, s); LCMS-PhenomenexC-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.1%TFA, B=90% methyl alcohol 10% water 0.1%TFA, (RT=3.23 minute) is for C ₁₈h ₂₂brN ₃o ₃analytical calculation value: 408.30; Measured value: 409.12 (M+H) ⁺.

¹h NMR (500MHz, DMSO-d ₆) δ ppm 12.06-12.24 (1H, m), 7.58-7.69 (5H, m), 4.84-4.95 (1H, m), 4.34 (1H, s), 3.61 (1H, s), 3.34-3.40 (1H, m), 2.52 (1H, s), 1.92-2.20 (1H, m), 1.43 (3H, s), 1.22 (6H, s); LCMS-Phenomenex C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.1%TFA, B=90% methyl alcohol 10% water 0.1%TFA, (RT=3.41 minute).For C ₁₈h ₂₂brN ₃o ₃analytical calculation value: 408.30; Measured value: 409.15 (M+H) ⁺.

¹H NMR(500MHz，DMSO-d ₆)δppm 0.98-1.51(m，9H)，1.82-2.12(m，3H)，2.31-2.48(m，1H)，3.30-3.51(m，1H)，3.52-3.66(m，1H)，4.88-5.16(m，1H)，7.47(t，J＝7.93Hz，1H)，7.61(d，J＝7.93Hz，1H)，7.81(d，J＝7.93Hz，1H)，8.04(s，1H)，8.12(d，J＝28.38Hz，1H)，14.65(s，1H)。LC/MS(M+H) ⁺＝391.96/393.96。

Other imidazoles analogue is prepared according to above-mentioned similar approach.

LC condition: condition 1:Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 3 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, 220nm, 5 μ l inject volume.

Condition 2:Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 2 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, 220nm, 5 μ l inject volume.

Embodiment 1, step c

By Pd (Ph ₃p) ₄(469mg, 0.406mmol) be added to bromide 1b (4.008g, 10.22mmol), hypoboric acid two pinacol esters (5.422g, 21.35mmol), potassium acetate (2.573g are housed, 26.21mmol) and in the pressure piping of the mixture of Isosorbide-5-Nitrae-dioxs (80ml).Reaction flask purging with nitrogen gas, jumps a queue, and with oil bath, heats 16.5 hours at 80 ℃.Reaction mixture after filtering, vacuum concentrated filtrate.Make carefully crude product at CH ₂cl ₂(150ml) and water-bearing media (the saturated NaHCO of 50ml water+10ml ₃solution) between, distribute.Water layer CH ₂cl ₂extraction, the organic phase drying (MgSO of merging ₄), filter final vacuum concentrated.(sample is application of sample together with eluting solvent for purified by flash chromatography for products therefrom; 20-35% ethyl acetate/CH ₂cl ₂), obtaining boric acid ester 1c, it is polluted by tetramethyl ethylene ketone, is the closely knit solid of canescence; 1c be about 10: 1 with the relative mol ratio of tetramethyl ethylene ketone ( ¹h NMR).After high vacuum exposes～2.5 days, example weight is 3.925g. ¹hNMR (DMSO-d ₆, δ=2.5ppm, 400MHz): 12.22/11.94/11.87 (m, 1H), 7.79-7.50/7.34-7.27 (m, 5H), 4.86-4.70 (m, 1H), 3.52 (apparent br s, 1H), 3.36 (m, 1H), 2.27-1.77 (m, 4H), 1.45-1.10 (m, 21H).LC (condition 1): RT=1.64 minute; LC/MS: for [M+H] ⁺c ₂₄h ₃₅bN ₃o ₄analytical calculation value: 440.27; Measured value: 440.23.

The similar compounds such as intermediate 1-1c to 1-4c can be prepared by mixing suitable aryl bromide.

¹h NMR (500MHz, DMSO-d ₆) δ ppm 1.16 (s, 8H), 1.29 (s, 13H), 2.51-2.72 (m, 1H), 2.84-3.03 (m, 1H), 3.79-4.00 (m, 2H), 4.88-5.21 (m, 1H), 7.62 (d, J=7.93Hz, 2H), 7.67 (s, 1H), 7.76 (d, J=7.93Hz, 2H), 12.11/12.40 (two br s, 1H).HPLC GEMINI C-184.6 * 50mm, 0-100%B, in 4 minutes, 1 minute residence time, A=95% water, 5% acetonitrile, 0.1%NH ₄oAc, B=5% water, 95% acetonitrile, 0.1%NH ₄oAc, RT=1.62 minute, homogeneity index 99%.LCMS: for C ₃₄h ₃₂bF ₂n ₃o ₄analytical calculation value: 475.34; Measured value: 474.78 (M-H) ^-.

¹h NMR (500MHz, DMSO-d ₆) δ ppm 11.97 (1H, m), 7.62-7.75 (5H, m), 5.05 (1H d, J=3.36Hz), 4.82 (m, 1H), 4.35 (m, 1H), 3.58 (1H, m), 2.389 (1H, s), 2.17 (1H, m), (1.38 3H, s), 1.30 (12H, s), 1.1 (6H, s); LCMS-Phenomenex C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=5% acetonitrile, 95% water, 10mm ammonium acetate, B=95% acetonitrile, 5% water, 10mm ammonium acetate, RT=3.63 minute, for C ₂₄h ₃₄bN ₃o ₅analytical calculation value: 455.30; Measured value: 456.31 (M+H) ⁺.

¹h NMR (500MHz, DMSO-d ₆) δ ppm 12.05-12.24 (1H, m), 7.61-7.73 (5H, m), 4.83-5.01 (1H, m), 4.33 (1H, s), 3.54-3.63 (1H, m), 3.39-3.80 (1H, m), 2.38-2.49 (1H, m), 1.98-2.01 (1H, m), 1.42 (3H, s), 1.34 (12H, s), 1.21 (6H, s); LCMS-Phenomenex C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.1%TFA, B=90% methyl alcohol 10% water 0.1%TFA, RT=3.64 minute, for C ₂₄h ₃₄bN ₃o ₅analytical calculation value: 455.30; Measured value: 456.30 (M+H) ⁺.

¹H NMR(500MHz，DMSO-d ₆)δppm 1.02-1.54(m，21H)，1.75-2.07(m，3H)，2.09-2.33(m，1H)，3.32-3.44(m，1H)，3.55(s，1H)，4.69-4.94(m，1H)，7.33(t，J＝7.32Hz，1H)，7.41-7.57(m，2H)，7.84(d，J＝7.32Hz，1H)，8.08(s，1H)，11.62-12.07(m，1H)。LC/MS(M+H) ⁺＝440.32。

The condition of other boric acid ester: 1-5c to 1-10c

LCMS condition: condition 1:Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 3 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, 220nm, 5 μ l inject volume.

Embodiment 1, steps d

(2S, 2 ' S)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases)) two (1-pyrrolidinecarboxylic acid tert-butyl esters)

By Pd (Ph ₃p) ₄(59.9mg, 0.0518mmol) is added to bromide 1b (576.1mg, 1.469mmol), boric acid ester 1c (621.8mg, 1.415mmol), NaHCO ₃(400.4mg, 4.766mmol) and 1, in the mixture of 2-glycol dimethyl ether (12ml) and water (4ml).Reaction mixture nitrogen purging, heats after 5.75 hours at 80 ℃ with oil bath, and vacuum is removed volatile component.Make resistates at 20% methyl alcohol/CHCl ₃(60ml) and between water (30ml) distribute 20% methyl alcohol for water/CHCl ₃(30ml) extraction.The organic phase salt water washing merging, dry (MgSO ₄), filter final vacuum concentrated.By gained crude product, prepare silica gel sieve mesh, and carry out flash chromatography processing (ethyl acetate), (563mg, by Ph to obtain dimer 1d ₃pO pollutes, pale solid). ¹H NMR(DMSO-d ₆，δ＝2.5ppm，400MHz)：δ12.21-12-16/11.95-11.78(m，2H)，7.85-7.48/7.32-7.25(m，10H)，4.90-4.71(m，2H)，3.60-3.32(m，4H)，2.30-1.79(m，8H)，1.46-1.10(m，18H)。LC (condition 1b): RT=1.77 minute; LC/MS: for [M+H] ⁺analytical calculation value: C ₃₆h ₄₅bN ₆o ₄: 625.35; Measured value: 625.48.

Other symmetrical analogue can be prepared in a similar manner.

Intermediate 1-2c and 1-2b preparation for embodiment 1-1d. ¹h NMR (500MHz, DMSO-d ₆) δ ppm 11.94-12.22 (2H, m) 7.53-7.82 (10H, m) 4.82-4.92 (2H, m) 4.34-4.43 (2H, m) 3.55-3.64 (2H, m) 3.36 (2H, d, J=11.29Hz) 2.12-2.22 (2H, m) 2.02-2.11 (2H, m) 1.40 (6H, s) 1.14 (12H, s); LCMS-Phenomenex C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.1%TFA, B=90% methyl alcohol 10% water 0.1%TFA, RT=3.32 minute, for analytical calculation value: 656.79; Measured value: 657.40 (M+H) ⁺.Nominal/LRMS-(M+H) ^+-657.42, (M-H) ^--655.28.

Intermediate 1-3b and 1-3c preparation for embodiment 1-2d. ¹h NMR (500MHz, DMSO-d ₆) δ ppm 12.00-12.20 (2H, m) 7.56-7.76 (10H, m) 4.90 (1H, s) 4.82 (1H, s) 4.25-4.34 (2H, m) 3.56 (2H, s) 3.34-3.47 (2H, m) 1.97-2.13 (4H, m) 1.39 (9H, m) 1.20 (9H, s); LCMS-Phenomenex C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.1%TFA, B=90% methyl alcohol 10% water 0.1%TFA; RT=3.35 minute, for analytical calculation value: 656.79; Measured value: 657.30 (M+H) ⁺.

(2S)-2-(4-(3 '-(2-((2S)-1-(tertbutyloxycarbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-3-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester

Intermediate 1-4c and 1-4b preparation for embodiment 1-2d-1. ¹HNMR(500MHz，DMSO-d ₆)δppm 1.09-1.51(m，18H)，1.84-2.15(m，6H)，2.34-2.50(m，2H)，3.35-3.52(m，2H)，3.54-3.67(m，2H)，5.08(d，J＝5.49Hz，2H)，7.68(t，J＝7.78Hz，2H)，7.78-7.92(m，4H)，8.11-8.30(m，4H)，14.81(s，2H)。LC/MS(M+H) ⁺＝625.48。

By the solid (0.15g, 0.23mmol) of glycol 1-1d be added to be cooled to-78 ℃ be dissolved in 1.0ml CH ₂cl ₂two (2-methoxy ethyl) amino sulfur trifluoride (0.1ml, 0.51mmol) solution in.Reactant is stirred after 2 hours at-78 ℃, be warming up to room temperature and stir 2 hours.Reactant is poured in saturated sodium bicarbonate solution, stirred until stop bubbling.After separated each layer, water layer CH ₂cl ₂extraction once.The organism salt water washing merging, dry (MgSO ₄), concentrated after filtering, obtain yellow oil.This oily matter CH ₂cl ₂grind with pentane, obtain required product (0.092g, 61%, tawny solid). ¹H NMR(500MHz，DMSO-d ₆)δppm 11.76-11.94(2H，m)，7.77-7.85(4H，m)，7.66-7.72(4H，m)，7.60-7.66(2H，m，J＝11.60Hz)，5.39(1H，s)，5.28(1H，s)，5.03(2H，s)，3.66-3.79(4H，m)，2.61-2.70(2H，m)，2.28-2.38(2H，m)，1.42(10H，s)，1.24(8H，s)。LCMS-Phenomenex C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.1%TFA, B=90% methyl alcohol 10% water 0.1%TFA, (t _r=3.58 minutes), for C ₃₆h ₄₂f ₂n ₆o ₄analytical calculation value: 660.70; Measured value 661.68 (M+H) ⁺.

According to prepared the same way of 1d by 1b and 1c, by 1-1b and 1-1c, prepared. ¹h NMR (500MHz, DMSO-d ₆) δ ppm 1.18/1.40 (two br.s., 18H), 2.53-2.75 (m, J=25.94Hz, 2H), 2.86-3.06 (m, 2H), 3.78-4.02 (m, 4H), 5.04 (br s, 2H), 7.17-8.24 (m, 10H), 12.07/12.37 (two br.s., 2H); HPLC XTERRA C-183.0 * 50mm, 0-100%B, in 2 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.2%H ₃pO ₄, B=10% water, 90% methyl alcohol, 0.2%H ₃pO ₄, RT=1.31 minute, homogeneity index 99%.LCMS: for C ₃₆h ₄₀f ₄n ₆o ₄analytical calculation value: 696.73; Measured value: 967.64 (M+H) ⁺.

The asymmetric compound same methods preparations such as intermediate 1-3d and 1-4d.For example, according to as mentioned above, for the preparation of the same way of 1d, 1-1c is reacted with 1b, obtain 1-3d.Equally, according to as mentioned above, for the preparation of the same way of 1d, 1-4c is reacted with 1b, obtain 1-4d.

¹h NMR (500MHz, DMSO-d ₆) ppm 1.40/1.18 (two br s, 18H), 1.90-2.02 (m, 2H), 2.02-2.12 (m, 1H), 2.28-2.46 (m, 2H), 2.68-2.87 (m, 1H), 3.35-3.49 (m, 1H), 3.53-3.62 (m, 1H), 3.82-4.10 (m, 2H), 4.92-5.11 (m, 1H), 5.28 (s, 1H), 7.79-8.00 (m, 8H), 8.03-8.25 (m, 2H), 13.77-15.16 (m, 2H); HPLC XTERRA C-183.0 * 50mm, 0-100%B, in 4 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.2%H ₃pO ₄, B=10% water, 90% methyl alcohol, 0.2%H ₃pO ₄, RT=1.22 minute, homogeneity index 99%.LCMS: for C ₃₆h ₄₂f ₂n ₆o ₄analytical calculation value: 660.75; Measured value: 661.98 (M+H) ⁺.

According to prepared the same way of 1d by 1b and 1c, by 1-4c and 1b Preparation Example 1-4d. ¹h NMR (500MHz, DMSO-d ₆) δ ppm 0.99-1.60 (m, 18H) 1.75-2.11 (m, J=73.24Hz, 6H) 2.12-2.32 (m, 2H) 3.32-3.41 (m, 2H) 3.56 (s, 2H) 4.63-5.02 (m, 2H) 6.98-8.28 (m, 10H) 11.67-12.33 (m, 2H); LC condition: Phenomenex Luna 3.0 * 5.0mm S10, the 10%MeOH/90%H of solvent orange 2 A-0.1%TFA ₂o solution, the 90%MeOH/10%H of solvent B-0.1%TFA ₂o solution, 0-100%B, in 2 minutes, stand-by time=3 minute, flow velocity=4ml/ minute, wavelength=220nm, LC/MS (M+H) ⁺=625.32.Retention time=1.438 minute.

Other biphenyl analogue is prepared after the same method.

The LC condition of embodiment 1-5d to embodiment 1-7d: condition 1:Phenomenex LUNAC-184.6 * 50mm, 0-100%B, in 3 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, 220nm, 5 μ l inject volume.

Embodiment 1, step e

5,5 '-(4,4 '-biphenyl, two bases) two (2-((2S)-2-pyrrolidyl)-1H-imidazoles)

By carbamate 1d (560mg) and 25%TFA/CH ₂cl ₂(9.0ml) mixture stirs 3.2 hours under envrionment conditions.Vacuum is removed after volatile component, the free alkalization of MCX post (methanol wash for products therefrom; 2.0M NH ₃/ methanol-eluted fractions), obtain tetramethyleneimine 1e (340mg, dark yellow solid). ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 11.83 (br s, 2H), 7.80 (d, J=8.1,4H), 7.66 (d, J=8.3,4H), 7.46 (br s, 2H), 4.16 (apparent t, J=7.2,2H), (2.99-2.69 m, 6H), 2.09-2.00 (m, 2H), 1.94-1.66 (m, 6H).LC (condition 1): RT=1.27 minute; Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₂₆h ₂₉n ₆analytical calculation value: 425.25; Measured value 425.25; HRMS: for [M+H] ⁺c ₂₆h ₂₉n ₆analytical calculation value: 425.2454; Measured value 425.2448.

Other analogue such as 1-1e to 1-4e can be prepared in a similar manner.

To 1-1d (3R, 3 ' R, 5S, 5 ' S)-5,5 '-(5,5 '-(biphenyl-4,4 '-bis-bases) two (1H-imidazoles-5,2-bis-bases)) add 0.8ml4.0M HCl dioxane solution in the 3ml dioxane solution of two (3-hydroxyl pyrrolidine-1-t-butyl formates).Reactant was at room temperature stirred after 2 hours to concentrating under reduced pressure.By the vacuum-drying of gained tawny solid, obtain 1-1e (3R, 3 ' R, 5S, 5 ' S)-5,5 '-(5,5 '-(biphenyl-4,4 '-bis-bases) two (1H-imidazoles-5,2-bis-bases)) two tetramethyleneimine-3-alcohol, four hydrochlorides (0.55g, yield 100%).Without being further purified just, can use. ¹h NMR (500MHz, DMSO-d ₆) δ ppm 10.33 (s, 2H), 9.85 (s, 2H), 8.09 (s, 2H), 8.01 (d, J=8.24Hz, 4H), 7.88 (d, J=8.24Hz, 4H), 5.14 (m, 2H), 4.62 (m, 2H), 3.61 (m, 2H), 3.23 (d, J=11.29Hz, 2H), 2.64 (m, 2H), (2.44 dd, J=13.43,6.71Hz, 2H); LCMS-Waters-Sunfire C-184.6 * 50mm, gradient 0-100%B, in 4 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.1%TFA, B=90% methyl alcohol 10% water 0.1%TFA, RT=1.35 minute, analytical calculation value: 456.30; Measured value: 457.25 (M+H) ⁺; Nominal/LRMS-(M+H) ⁺-457.35.

By the similar fashion Preparation Example 1-2e for the preparation of method described in 1-1e. ¹hNMR (500MHz, DMSO-d ₆) δ ppm 10.32 (1H, s) 8.01 (2H, s) 7.97 (4H, d, J=8.24Hz) 7.86 (4H, d, J=8.24Hz) 5.01-5.10 (2H, m) 4.52-4.60 (2H, m) 3.36-3.45 (2H, m) 3.25 (2H, s) 2.60-2.68 (2H, m) 2.40-2.48 (2H, m); LCMS-Phenomenex C-183.0 * 50mm, gradient 0-100%B, in 4 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.1%TFA, B=90% methyl alcohol 10% water 0.1%TFA, RT=2.10 minute, analytical calculation value: 456.30; Measured value: 457.22 (M+H) ⁺.

2-((2S)-2-pyrrolidyl)-4-(3 '-(2-((2S)-2-pyrrolidyl)-1H-imidazoles-5-yl)-3-xenyl)-1H-imidazoles

By the described similar fashion for the preparation of 1-1e, by 1-2d-1 Preparation Example 1-2e-1. ¹H NMR(500MHz，DMSO-d ₆)δppm 1.74-2.44(m，12H)，4.83(s，2H)，7.37-7.72(m，4H)，7.74-8.03(m，4H)，8.10(s，2H)，9.14(s，2H)，9.81(s，2H)。LC/MS(M+H) ⁺＝425.30。

In the 1ml dioxane solution of 1-2d-2 (0.084g, 0.13mmol), add 0.5ml 4.0MHCl dioxane solution.Reactant was at room temperature stirred after 2 hours to concentrating under reduced pressure.By the vacuum-drying of gained tawny solid, obtain 1-2e-2 (0.077g, yield 100%).Compound can be used without being further purified just. ¹h NMR (500MHz, DMSO-d ₆) δ ppm 8.00 (2H, s), 7.97 (4H, d, J=8.55Hz), 7.85 (4H, d, J=8.24Hz), 5.63 (1H, s), 5.52 (1H, s), 5.09-5.17 (2H, m), 3.67-3.74 (2H, m), 3.63-3.67 (2H, m), 3.07-3.14 (1H, m), 2.89-2.96 (1H, m), 2.81-2.87 (2H, m); LCMS-Phenomenex C-183.0 * 50mm, gradient 0-100%B, in 4 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.1%TFA, B=90% methyl alcohol 10% water 0.1%TFA, (t _r=2.22 minutes), for C ₂₆h ₂₆f ₂n ₆analytical calculation value: 460.53; Measured value: 461.37 (M+H) ⁺.

According to prepared the same way of 1-1e by 1-1d, by 1-2d-3, prepared. ¹h NMR (500MHz, DMSO-d ₆) δ ppm 2.97-3.13 (m, 4H), 3.64-3.91 (m, 4H), 5.16 (d, J=6.41Hz, 2H), 7.84 (d, J=7.93Hz, 4H), 7.96 (d, J=7.93Hz, 4H), 8.00 (s, 2H); HPLC XTERRAC-183.0 * 50mm, 0-100%B, in 4 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.2%H ₃pO ₄, B=10% water, 90% methyl alcohol, 0.2%H ₃pO ₄, RT=1.66 minute, homogeneity index 92%.LCMS: for C ₂₆h ₂₄f ₄n ₆analytical calculation value: 496.50; Measured value: 495.53 (M-H) ^-.

The similarly asymmetric compound same methods preparation such as intermediate 1-3e and 1-4e.

¹h NMR (500MHz, DMSO-d ₆) δ ppm 1.87-2.09 (m, 1H), 2.13-2.26 (m, 1H), 2.37-2.47 (m, 2H), 2.92-3.12 (m, 2H), 3.37 (s, 1H), 3.40-3.49 (m, 1H), 3.67-3.91 (m, 2H), 4.96-5.05 (m, 1H), 5.14 (t, J=8.70Hz, 1H), 7.86 (t, J=9.00Hz, 4H), 7.93-8.03 (m, 5H), 8.10 (s, 1H), 10.26/9.75 (two br s., 2H); HPLC XTERRA C-183.0 * 50mm, 0-100%B, in 4 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.2%H ₃pO ₄, B=10% water, 90% methyl alcohol, 0.2%H ₃pO ₄, RT=0.8622 minute, homogeneity index 99%; LCMS: for C ₂₆h ₂₆f ₂n ₆analytical calculation value: 460.52; Measured value: 461.45 (M+H) ⁺.

By the described similar fashion of being prepared 1-1e by 1-1d, by 1-4d Preparation Example 1-4e. ¹H NMR(500MHz，DMSO-d ₆)δppm 1.90-2.13(m，2H)2.12-2.31(m，2H)2.36-2.60(m，4H)3.29-3.55(m，4H)5.00(s，2H)7.35-8.50(m，10H)9.76(s，2H)10.12-10.45(m，2H)。LC condition: Phenomenex Luna 3.0 * 5.0mm S10, the 10%MeOH/90%H of solvent orange 2 A-0.1%TFA ₂o solution, the 90%MeOH/10%H of solvent B-0.1%TFA ₂o solution, 0-100%B, in 2 minutes, stand-by time=3 minute, flow velocity=4ml/ minute, wavelength=220nm, LC/MS (M+H) ⁺=425.28.Retention time=0.942 minute.

Other analogue is prepared after the same method:

The LC condition of 1-5e to 1-7e: Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 2 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, 220nm, 5 μ l inject volume.

Embodiment 1, the alternative synthesis method of step e

5,5 '-(4,4 '-biphenyl, two bases) two (2-((2S)-2-pyrrolidyl)-1H-imidazoles)

Embodiment A-1e-1

In the 1L tri-neck round-bottomed flasks of outfit nitrogen pipeline, overhead and thermopair, pack 20g (83.9mmol, 1 equivalent) 1,1 '-(biphenyl-4,4 '-bis-bases) diethyl ketone, 200ml CH into ₂cl ₂and 8.7ml (27.1g, 169.3mmol, 2.02 equivalents) bromine.Under envrionment conditions, by mixture stir about 20 hours under nitrogen atmosphere.In gained soup compound, add 200ml CH ₂cl ₂after, by vacuum distilling, be concentrated into about 150ml.Then, by vacuum distilling, make soup compound exchange solvent become THF to target volume 200ml.In 1 hour, make soup compound be cooled to after 20-25 ℃, then stir 1 hour at 20-25 ℃.Canescence crystalline solid is used 150ml CH after filtering ₂cl ₂washing.Product vacuum-drying at 60 ℃, obtains the required product of 27.4g (69.2mmol, 82%): ¹h NMR (400MHz, CDCl ₃) δ 7.95-7.85 (m, 4H), 7.60-7.50 (m, 4H), 4.26 (s, 4H); ¹³c NMR (100MHz, CDCl ₃) δ 191.0,145.1,133.8,129.9,127.9,30.8; IR (KBr, cm-1) 3007,2950,1691,1599, and 1199; For C ₁₆h ₁₂br ₂o ₂analytical calculation value: C, 48.52; H, 3.05; Br, 40.34.Measured value: C, 48.53; H, 3.03; Br, 40.53.HRMS: for C ₁₆h ₁₃br ₂o ₂(M+H; DCI ⁺) calculated value: 394.9282; Measured value: 394.9292.Fusing point 224-226 ℃.

Embodiment A-1e-2

To the 500ml jacket layer flask that is equipped with nitrogen pipeline, thermopair and overhead, pack 20g (50.5mmol into, 1 equivalent) embodiment A-1e-1,22.8g (105.9 moles, 2.10 equivalents) 1-(tertbutyloxycarbonyl)-L-PROLINE and 200ml acetonitrile.Soup compound is cooled to after 20 ℃, adds 18.2ml (13.5g, 104.4mmol, 2.07 equivalents) DIPEA.After making soup compound be warming up to 25 ℃, stir 3 hours.Gained is 3 * 100ml 13% (weight) NaCl solution washing for transparent organic solution.By vacuum distilling, until while being less than 0.5% (volume), being rich in acetonitrile solution exchange solvent, acetonitrile becomes toluene (target volume=215ml).

Embodiment A-1e-3

In the toluene solution of above-mentioned embodiment A-1e-2, add 78g (1.011 moles, 20 equivalents) ammonium acetate, be heated to 95-100 ℃.Mixture is stirred 15 hours at 95-100 ℃.After having reacted, make mixture be cooled to 70-80 ℃, add 7ml acetic acid, 40ml propyl carbinol and 80ml 5% (volume) acetic acid aqueous solution.In 50 ℃ of maintenance temperature >, separating obtained two phase liquid.In 50 ℃ of maintenance temperature >, in dense organic phase, add 80ml 5% (volume) acetic acid aqueous solution, 30ml acetic acid and 20ml propyl carbinol, in 50 ℃ of maintenance temperature >, separating obtained two phase liquid, dense organic phase is used the washing of 80ml 5% (volume) acetic acid aqueous solution again.Then by vacuum distilling, become toluene to reach target volume 215ml dense organic phase exchange solvent.In 60 ℃ of maintenance temperature >, add 64ml MeOH.Gained soup compound is heated to 70-75 ℃, and slaking 1 hour.In 1 hour, make soup compound be cooled to 20-25 ℃, at this temperature, recurring is 1 hour.After soup compound is filtered, 10: 3 toluene of 200ml for filter cake: MeOH washing.By product vacuum-drying at 70 ℃, obtain the required product of 19.8g (31.7mmol, 63%): ¹h NMR (400MHz, DMSO-d ₆) δ 13.00-11.00 (s, 2H), 7.90-7.75 (m, 4H), 7.75-7.60 (m, 4H), 7.60-7.30 (s, 2H), 4.92-4.72 (m, 2H), 3.65-3.49 (m, 2H), 3.49-3.28 (m, 2H), 2.39-2.1 (m, 2H), 2.10-1.87 (m, 6H), 1.60-1.33 (s, 8H), 1.33-1.07 (s, 10H); ¹³c NMR (100MHz, DMSO-d ₆) δ 154.1,153.8,137.5,126.6,125.0,78.9,78.5,55.6,55.0,47.0,46.7,33.7,32.2,28.5,28.2,24.2,23.5; IR (KBr, cm-1) 2975,2876,1663,1407, and 1156,1125; HRMS: for C ₃₆h ₄₅n ₆o ₄(M+H; ESI ⁺) calculated value: 625.3502; Measured value: 625.3502.Fusing point 190-195 ℃ (decomposition).

Embodiment A-1e-4

To 250ml, be equipped with in the reactor of nitrogen pipeline and overhead, pack successively 25.0g embodiment A-1e-3 (40.01mmol, 1 equivalent), 250ml methyl alcohol and 32.85ml (400.1mmol, 10 equivalents) 6M aqueous hydrochloric acid into.Temperature is risen to 50 ℃, and at 50 ℃, stir 5 hours.Make gained soup compound be cooled to 20-25 ℃, keep stir about 18 hours.After soup compound is filtered, obtain solid, solid is used 100ml 90% methanol/water (volume/volume) and 2 * 100ml methanol wash successively.By wet cake in vacuum oven in 50 ℃ of dried overnight, obtain the required product of 18.12g (31.8mmol, 79.4%).

The recrystallization of embodiment A-1e-4

In the reactor of 250ml outfit nitrogen pipeline and overhead, pack successively 17.8g crude product embodiment A-1e-4 and 72ml methyl alcohol into.Gained soup compound is stirred 4 hours at 50 ℃, be cooled to 20-25 ℃, and at 20-25 ℃, keep stirring 1 hour.After soup compound is filtered, obtain crystalline solid, used 60ml methanol wash.By gained wet cake in vacuum oven in 50 ℃ dry 4 days, obtain the required product of 14.7g (25.7mmol, 82.6%): ¹h NMR (400MHz, DMSO-d ₆) δ 10.5-10.25 (br, 2H), 10.1-9.75 (br, 2H), 8.19 (s, 2H), 7.05 (d, J=8.4,4H), 7.92 (d, J=8.5,4H), 5.06 (m, 2H), 3.5-3.35 (m, 4H), 2.6-2.3 (m, 4H), 2.25-2.15 (m, 2H), 2.18-1.96 (m, 2H); ¹³c NMR (100MHz, DMSO-d ₆) δ 156.6,142.5,139.3,128.1,127.5,126.1,116.9,53.2,45.8,29.8,24.3; IR (KBr, cm ^-1) 3429,2627,1636,1567,1493,1428,1028.For C ₂₆h ₃₂n ₆cl ₄analytical calculation value: C, 54.75; H, 5.65; Cl, 24.86; Adjusted value for 1.9% water: C, 53.71; H, 5.76; N, 14.46; Cl, 24.39; Measured value: C, 53.74; H, 5.72; N, 14.50; Cl, 24.49; KF=1.9.240 ℃ of fusing points (decomposition).

Embodiment 1

By HATU (44.6mg, 0.117mmol) be added to tetramethyleneimine 1e (22.9mg, 0.054mmol), diisopropylethylamine (45 μ l, 0.259mmol) and Cap-1 (28.1mg, 0.13mmol) with the mixture of DMF (1.5ml) in, gained mixture is stirred 90 minutes at ambient temperature.Vacuum is removed after volatile component, and resistates is first used MCX (methanol wash; 2.0M NH ₃/ methanol-eluted fractions) purifying, then use reverse-phase HPLC system (H ₂o/ methyl alcohol/TFA) purifying, obtains the tfa salt (44.1mg, canescence foam) of embodiment 1. ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 10.25 (br s, 2H), 8.20-7.10 (m, 20H), 5.79-5.12 (m, 4H), 4.05-2.98 (m, 4H), 2.98-2.62 (m, 6H), 2.50-1.70 (m, 14H), [note: the signal of imidazoles NH too wide so that cannot deterministic displacement study]; LC (condition 1): RT=1.40 minute; Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₄₆h ₅₁n ₈o ₂analytical calculation value: 747.41; Measured value 747.58.

Embodiment 2 to embodiment 24-4d

By same procedure described in embodiment 1, with corresponding acid, replace the tfa salt that Cap-1 carrys out Preparation Example 2 to embodiment 24-4h.End group (Cap) without numbering in following table is commercially available.

Embodiment 24-5 to embodiment 24-18

¹the LC condition of 24-18-1 to 24-18-6: Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 2 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, 220nm, 5 μ l inject volume.

Embodiment 24-19 to embodiment 24-20

By same procedure described in embodiment 1, by the tfa salt of 1-2e-1 and corresponding sour Preparation Example 24-19 and embodiment 24-20.

The LC condition of 24-19 and 24-20:

Post=Phenomenex-Luna 3.0 * 50mm S10

Start %B=0

Final %B=100

Gradient time=2 minute

Stand-by time=3 minute

Flow velocity=4ml/ minute

Wavelength=220nm

10% methyl alcohol/90%H of solvent orange 2 A=0.1%TFA ₂o

90% methyl alcohol/10%H of solvent B=0.1%TFA ₂o

Embodiment 24-21 to embodiment 24-22

By same procedure described in embodiment 1, by the tfa salt of 1-4e and corresponding carboxylic acid Preparation Example 24-21 and embodiment 24-22.

The LC condition of 24-21 and 24-22:

Post=Phenomenex-Luna 3.0 * 50mm S10

Start %B=0

Final %B=100

Gradient time=2 minute

Stand-by time=3 minute

Flow velocity=4ml/ minute

Wavelength=220nm

10% methyl alcohol/90%H of solvent orange 2 A=0.1%TFA ₂o

90% methyl alcohol/10%H of solvent B=0.1%TFA ₂o

Embodiment 24-23

((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane

In the 50ml flask of outfit stirring rod, pack successively 2.5ml acetonitrile, 0.344g (2.25mmol into, 2.5 equivalents) hydroxy benzotriazole hydrate, 0.374g (2.13mmol, 2.4 equivalents) N-(methoxycarbonyl)-Valine, 0.400g (2.09mmol, 2.4 equivalents) 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, reinstalls 2.5ml acetonitrile.Gained solution is stirred after 1 hour at 20 ℃, pack the embodiment A-1e-4 of 0.501g (0.88mmol, 1 equivalent) into.Make soup compound be cooled to approximately 0 ℃, when keeping temperature below 10 ℃, in 30 minutes, add 0.45g (3.48mmol, 4 equivalents) diisopropylethylamine.In 3 hours, solution is slowly heated to 15 ℃, and remains on 15 ℃ and reach 16 hours.Temperature is risen to 20 ℃, stir 3.25 hours.In gained solution, add after 3.3g 13% (weight) the NaCl aqueous solution, be heated to 50 ℃ and reach 1 hour.Be cooled to, after 20 ℃, add 2.5ml isopropyl acetate.Dense organic phase is used 6.9g 0.5N NaOH solution (containing 13% (weight) NaCl) (twice) and 3.3g 13% (weight) NaCl solution washing successively.Then, mixture exchanges solvent by vacuum distilling and becomes isopropyl acetate to target volume 10ml.Gained turbid solution is cooled to after 20 ℃, by 0.45 μ m strainer, filters.Then, clear solution exchanges solvent by vacuum distilling becomes ethanol and reaches target volume 3ml.The ethanolic soln that adds 1.67ml (2.02mmol, 2.3 equivalents) 1.21M HCl.Subsequently mixture is stirred 15 hours at 25 ℃.Gained soup compound is filtered to 2: 1 acetone of 2.5ml for wet cake: washing with alcohol.Solid is dry at 50 ℃ with vacuum oven, obtains the required product of 0.550g (0.68mmol, 77%).

The recrystallization of embodiment 24-23

The above-mentioned product of 0.520g is dissolved in to 3.65ml methyl alcohol, prepares the as above solution of the embodiment 24-23 of preparation.Then to adding the 0.078g 3 type Cuno Zeta carbon that loosens in this solution, and stir 0.25 hour.Then mixture is filtered, use 6ml methanol wash.By vacuum distilling, the solution that is rich in product is concentrated to 2.6ml.Add after 7.8ml acetone, at 25 ℃, stir 15 hours.By solid filtering, use 2: 1 acetone of 2.5ml: washing with alcohol, dry at 70 ℃ with vacuum oven, obtain required product 0.406g (57.0%, white crystals): ¹h NMR (400MHz, DMSO-d ₆, 80 ℃): 8.02 (d, J=8.34Hz, 4H), 7.97 (s, 2H), 7.86 (d, J=8.34Hz, 4H), 6.75 (s, 2H), 5.27 (t, J=6.44Hz, 2H), 4.17 (t, J=6.95Hz, 2H), 3.97-4.11 (m, 2H), 3.74-3.90 (m, 2H), 3.57 (s, 6H), 2.32-2.46 (m, 2H), 2.09-2.31 (m, 6H), 1.91-2.07 (m, 2H), 0.88 (d, J=6.57Hz, 6H), 0.79 (d, J=6.32Hz, 6H); ¹³c NMR (75MHz, DMSO-d ₆): δ 170.9,156.9, and 149.3,139.1,131.7,127.1,126.5,125.9,115.0,57.9,52.8,51.5,47.2,31.1,28.9,24.9,19.6,17.7; IR (pure, cm ^-1): 3385,2971,2873,2669,1731,1650.For C ₄₀h ₅₂n ₈o ₆cl ₂analytical calculation value: C, 59.18; H, 6.45; N, 13.80; Cl, 8.73; Measured value: C, 59.98; H, 6.80; N, 13.68; Cl, 8.77.267 ℃ of fusing points (decomposition).Characteristic diffraction peak position (number of degrees 2 θ ± 0.1) (at room temperature, high quality mode based on gathering with diffractometer (CuK α) (thering are rotation kapillary 2 θ with other appropriate criteria calibration of NIST)) as follows: 10.3,12.4,12.8,13.3,13.6,15.5,20.3,21.2,22.4,22.7,23.7.

Embodiment 25

N, N '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) diethylamide

Embodiment 25 step a:

(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (t-butyl carbamates)

With

Embodiment 25 step b:

By HATU (96.2mg, 0.253mmol) be added to tetramethyleneimine 1e (52.6mg, 0.124mmol), in the mixture of diisopropylethylamine (100 μ l, 0.57mmol) and BOC-D-Phg-OH (69mg, 0.275mmol) and DMF (3.0ml).Reaction mixture was stirred after 25 minutes, with methyl alcohol dilution, and purify (H by reverse-phase HPLC system ₂o/ methyl alcohol/TFA).The excessive 2.0M/NH of HPLC effluent ₃cH ₃the neutralization of OH solution, vacuum is removed volatile component.Carefully by resistates at CH ₂cl ₂with saturated NaHCO ₃between distribute.Water is used CH again ₂cl ₂extraction (2 times).Organic phase drying (the MgSO merging ₄), filter final vacuum concentrated, obtain 25a (78.8mg, semi-solid oily thing film).LC (condition 1): RT=1.99 minute; Homogeneity index > 98%.LC/MS: for [M+H] ⁺c ₅₂h ₅₉n ₈o ₆analytical calculation value: 891.46; Measured value: 891.55.

According to the described method for the preparation of 1e, make carbamate 25a change into amine 25b.LC (condition 1): RT=1.44 minute; Homogeneity index 97%.LC/MS: for [M+H] ⁺c ₄₂h ₄₃n ₈o ₂analytical calculation value: 691.35; Measured value: 691.32.

Embodiment 25

Diacetyl oxide (20 μ l, 0.21mmol) is added in DMF (1.5ml) solution of amine 25b (29mg, 0.042mmol) and triethylamine (30 μ l, 0.22mmol), and stirs 2.5 hours.Then reaction mixture NH ₃/ methyl alcohol (1ml 2M) is processed, then stirs 1.5 hours.Vacuum is removed volatile component, and resistates is purified (H by reverse-phase HPLC system ₂o/ methyl alcohol/TFA), obtain the tfa salt (28.1mg, white foam shape thing) of embodiment 25.LC (condition 1): RT=1.61 minute; Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₄₆h ₄₇n ₈o ₄analytical calculation value: 775.37; Measured value: 775.40; HRMS: for [M+H] ⁺c ₄₆h ₄₇n ₈o ₄analytical calculation value: 775.3720; Measured value: 775.3723.

Embodiment 25-1 to embodiment 25-5

Employing is similar to by the standard amide formation condition described in 1e Preparation Example 1, by 25b and suitable carboxylic acid Preparation Example 25-1 to embodiment 25-5.Embodiment 25-6 to embodiment 25-8 is prepared by 25b and suitable urea chloride or isocyanic ester.

Embodiment 26

((1R)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane

Embodiment 26, step a

(2R, 2 ' R)-1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (3-methyl isophthalic acid-oxo-2-butylamine)

Method described in diamines 26a is synthetic according to diamines 25b, starts preparation by tetramethyleneimine 1e and BOC-D-Val-OH.

Embodiment 26

Methyl-chloroformate (18 μ l, 0.23mmol) is added in THF (1.5ml) solution of diamines 26a (30mg, 0.048mmol) and triethylamine (30 μ l, 0.22mmol), reaction mixture is stirred 3 hours under envrionment conditions.Vacuum is removed after volatile component, resistates NH ₃/ methyl alcohol (2ml2M) is processed, and under envrionment conditions, stirs 15 minutes.Vacuum is removed after all volatile components, and crude product is purified (H with anti-phase preparation HPLC ₂o/ methyl alcohol/TFA), obtain the tfa salt (13.6mg, white solid) of embodiment 26.LC (condition 2): RT=2.00 minute; Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₄₀h ₅₁n ₈o ₆analytical calculation value: 739.39; Measured value: 739.67; HRMS: for [M+H] ⁺c ₄₀h ₅₁n ₈o ₆analytical calculation value: 739.3932; Measured value: 739.3966.

Embodiment 27

N-((1R)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-acetylaminohydroxyphenylarsonic acid 3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) ethanamide

According to method described in Preparation Example 25, diamines 26a is changed into embodiment 27 (tfa salt).LC (condition 2): RT=1.93 minute; Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₄₀h ₅₁n ₈o ₄analytical calculation value: 707.40; Measured value: 707.59; HRMS: for [M+H] ⁺c ₄₀h ₅₁n ₈o ₄analytical calculation value: 707.4033; Measured value: 707.4054.

Embodiment 28

((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane

Embodiment 28, step a

By HATU (19.868g, 52.25mmol) be added to N-Cbz-L-proline(Pro) (12.436g, 49.89mmol) and in the HCl salt (12.157g, 48.53mmol) of 2-amino-1-(4-bromophenyl) ethyl ketone and the heterogeneous mixture of DMF (156ml).After mixture is lowered the temperature in ice-water bath, in 13 minutes, drip wherein immediately DIPEA (27ml, 155mmol).Add after alkali, remove cooling bath, then reaction mixture is stirred 50 minutes.Vacuum is removed volatile component; Water (125ml) is added in the rough solid of gained and stir about 1 hour.After pale solid is filtered, with after a large amount of water washings, vacuum-drying, obtains keto-amide 28a (20.68g, white solid). ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 8.30 (m, 1H), 7.91 (m, 2H), 7.75 (d, J=8.5,2H), 7.38-7.25 (m, 5H), 5.11-5.03 (m, 2H), 4.57-4.48 (m, 2H), 4.33-4.26 (m, 1H), 3.53-3.36 (m, 2H), 2.23-2.05 (m, 1H), 1.94-1.78 (m, 3H); LC (condition 1): RT=1.65 minute; Homogeneity index 98%; LC/MS: for [M+H] ⁺c ₂₁h ₂₂brN ₂o ₄analytical calculation value: 445.08; Measured value: 445.31.

Embodiment 28, step b

According to method described in synthesis of carbamates 1b, keto-amide 28a (10.723g, 24.08mmol) is changed into 28b, just for crude product purified by flash chromatography (sample is application of sample together with eluting solvent; 50% ethyl acetate/hexane).Recovery obtains bromide 28b (7.622g, canescence foam). ¹H NMR(DMSO-d ₆，δ＝2.5ppm，400MHz)：δ12.23/12.04/11.97(m，1H)，7.73-6.96(m，10H)，5.11-4.85(m，3H)，3.61(m，1H)，3.45(m，1H)，2.33-184(m，4H)。LC (condition 1): RT=1.42 minute; Homogeneity index > 95%; LC/MS: for [M+H] ⁺c ₂₁h ₂₁brN ₃o ₂analytical calculation value: 426.08; Measured value: 426.31; HRMS: for [M+H] ⁺c ₂₁h ₂₁brN ₃o ₂analytical calculation value: 426.0817; Measured value: 426.0829.By following chirality HPLC method, the chemical purity of 28b is evaluated, observing enantiomeric excess is 99%.

Post: Chiralpak AD, 10 μ m, 4.6 * 50mm

Solvent: 20% ethanol/heptane (isocratic elution)

Flow velocity: 1ml/ minute

Wavelength: 254nm

Relative retention time: 1.82 minutes (R), 5.23 minutes (S)

Embodiment 28, step c

(2S, 2 ' S)-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases))-2-(1-pyrrolidinecarboxylic acid benzyl ester)-2 '-(the 1-pyrrolidinecarboxylic acid tert-butyl ester)

By Pd (Ph ₃p) ₄(711.4mg, 0.616mmol) is added to boric acid ester 1c (7.582g ,～17mmol), bromide 28b (7.62g, 17.87mmol), NaHCO ₃(4.779g, 56.89mmol) and 1, in the mixture of 2-glycol dimethyl ether (144ml) and water (48ml).Reaction mixture N ₂purge, heats after 15.5 hours at 80 ℃ with oil bath, and vacuum is removed volatile component, makes resistates at CH ₂cl ₂and between water, distribute water layer CH ₂cl ₂extraction.Organic phase drying (the MgSO merging ₄), filter final vacuum concentrated.Products therefrom carries out flash chromatography processing, and (sample is by silica gel sieve mesh application of sample; By ethyl acetate as elutriant), (7.5g, canescence foam, contains Ph to obtain biphenyl 28c ₃pO impurity). ¹h NMR (DMSO-d ₆δ=2.5ppm, 400MHz): δ 12.24-12.19 (m, 0.36H), 12.00-11.82 (m, 1.64H), 7.85-6.98 (15H), 5.12-4.74 (4H), 3.68-3.34 (4H), 2.34-1.79 (8H), 1.41/1.17 (two br s, 9H); LC (condition 1): RT=1.41 minute; LC/MS: for [M+H] ⁺c ₃₉h ₄₃n ₆o ₄analytical calculation value: 659.34; Measured value: 659.52; HRMS: for [M+H] ⁺c ₃₉h ₄₃n ₆o ₄analytical calculation value: 659.3346; Measured value: 659.3374.

Embodiment 28, steps d

(2S)-2-(5-(4 '-(2-((2S)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester

By K ₂cO ₃(187.8mg, 1.36mmol) is added to catalyzer (10%Pd/C; In the mixture that 205.3mg), carbamate 28c (1.018g ,～1.5mmol), methyl alcohol (20ml) and transfer pipet 3 drip.Connect H ₂after air bag, mixture is stirred 6 hours.Then add catalyzer (10%Pd/C, 100.8mg) and K then, ₂cO ₃(101.8mg, 0.738mmol), continues to stir 3.5 hours.In hydrogenation process, change at set intervals H ₂air bag three times.Reaction mixture through diatomite ( 521) pad filters, and vacuum is removed filtrate.Gained crude product carries out flash chromatography processing with short column, and (sample is by silica gel sieve mesh application of sample; With 0-20% methyl alcohol/CH ₂cl ₂as elutriant), obtain 28d (605.6mg, light yellow foam). ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 12.18/11.89/11.82 (three br s, 2H), 7.83-7.29 (m, 10H), 4.89-4.73 (m, 1H), 4.19 (apparent t, J=7.2,1H), 3.55 (apparent br s, 1H), 3.40-3.35 (m, 1H), 3.02-2.96 (m, 1H), 2.91-2.84 (m, 1H), 2.30-1.69 (m, 8H), 1.41/1.16 (two br s, 9H).Attention: the signal demonstration of tetramethyleneimine NH and the signal overlap in 3.6-3.2ppm district; LC (condition 1): RT=1.21 minute; Homogeneity index > 95%; LC/MS: for [M+H] ⁺c ₃₁h ₃₇n ₆o ₂analytical calculation value: 525.30; Measured value: 525.40.

Embodiment 28, step e-f

Embodiment 28 step e

(2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester

Embodiment 28 step f

((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane

Step e: by HATU (316.6mg, 0.833mmol) be added to tetramethyleneimine 28d (427mg, 0.813mmol), Cap-4 (177.6mg, 0.849mmol) and diisopropylethylamine (0.32ml, in DMF 1.84mmol) (7.0ml) solution, stirred reaction mixture 45 minutes.Vacuum is removed after volatile component, by resistates at CH ₂cl ₂(50ml) and water-bearing media (20ml H ₂the saturated NaHCO of O+1ml ₃solution) between, distribute.Water CH ₂cl ₂strip, the organic phase drying (MgSO of merging ₄), filter final vacuum concentrated.Gained is purified by flash chromatography (silica gel for yellow oil; Ethyl acetate), obtain 28e (336mg, yellow foam).LC (condition 1): RT=1.68 minute; Homogeneity index 91%; LC/MS: for [M+H] ⁺c ₄₁h ₄₆n ₇o ₅analytical calculation value: 716.35; Measured value: 716.53.

Step f: adopt the described method that 1d is converted into 1e, carbamate 28e is refined into amine 28f.LC (condition 1): RT=1.49 minute; Homogeneity index > 98%.LC/MS: for [M+H] ⁺c ₃₆h ₃₈n ₇o ₃analytical calculation value: 616.30; Measured value: 616.37; HRMS: for [M+H] ⁺c ₃₆h ₃₈n ₇o ₃analytical calculation value: 616.3036; Measured value: 616.3046.

Embodiment 28

The final step that adopts synthetic example 1, makes amine 28f change into the tfa salt of embodiment 28. ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 8.21-7.03 (m, 21H), 5.78-5.14 (3H), 3.98-3.13 (m, 9H; Comprise OCH ₃signal 3.54 and 3.53), 2.45-1.72 (m, 8H).LC (condition 1): RT=1.66 minute, homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₄₄h ₄₄n ₇o ₄analytical calculation value: 734.35; Measured value: 734.48; HRMS: for [M+H] ⁺c ₄₄h ₄₄n ₇o ₄analytical calculation value: 734.3455; 734.3455.

Embodiment 28-1 to embodiment 28-4

By the mode that is similar to embodiment 28, by the intersexes of intermediate 28d, carry out Preparation Example 28-1 to embodiment 28-4 (R group sees the following form).

Embodiment 28-1

(1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine

Affix Cap-1, with after TFA or HCl deaminize t-butyl formate, affix Cap-14.

Embodiment 28-2

1-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) piperidines

Affix tetrahydrofuran formic acid, with after TFA or HCl deaminize t-butyl formate, affix Cap-14.

Embodiment 28-3

((1R)-1-(2-chloro-phenyl-)-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane

Affix Cap-40, with after TFA or HCl deaminize t-butyl formate, affix affix Cap-14.

Embodiment 28-4

(1R)-1-(2-chloro-phenyl-)-N, N-dimethyl-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine

Affix Cap-39, with after TFA or HCl deaminize t-butyl formate, affix Cap-14.

Embodiment 28-5

(1R)-1-(2-fluorophenyl)-N, N-dimethyl-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine

Affix Cap-38, with after TFA or HCl deaminize t-butyl formate, affix Cap-14.

Embodiment 29

((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((4-methyl isophthalic acid-piperazinyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane

4-methylpiperazine-1-formyl chloride/HCl (11.6mg, 0.58mmol) is added in the mixture of 28f (30mg, 0.049mmol), triethylamine (15 μ l, 0.11mmol) and THF (1.0ml), under envrionment conditions, stirs 1 hour.Vacuum is removed after volatile component, and resistates is purified (H with reversed-phase HPLC ₂o/ methyl alcohol/TFA), obtain the tfa salt (29.3mg, light yellow foam) of embodiment 29.LC (condition 2): RT=1.82 minute, homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₄₂h ₄₈n ₉o ₄analytical calculation value: 742.38; Measured value: 742.49.

Embodiment 30

((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-glycyl-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane

Embodiment 30, step a

((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(tertbutyloxycarbonyl) glycyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane

Employing is prepared method described in 25a by 1e, by tetramethyleneimine 28f and Boc-glycine, prepares carbamate 30a.LC (condition 2): RT=2.12 minute, homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₄₃h ₄₉n ₈o ₆analytical calculation value: 773.38; Measured value: 773.46.

Embodiment 30

According to the described method of being prepared 1e by 1d, make carbamate 30a change into embodiment 30.LC (condition 2): RT=1.81 minute, homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₃₈h ₄₁n ₈o ₄analytical calculation value: 673.33; Measured value: 673.43.

HRMS: for [M+H] ⁺c ₃₈h ₄₁n ₈o ₄analytical calculation value: 673.3251; Measured value: 673.3262.

Embodiment 30-1

((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane

Press three steps by embodiment 28d Preparation Example 30-1.Step 1: adopt by method affix Cap-2 described in the synthetic 28e of 28d.Step 2: adopt by method described in the synthetic 28f of 28e, make t-butyl carbamate hydrolysis.Step 3: adopt by method described in the synthetic 28e of 28d, affix Cap-52.RT=1.70 minute (condition 1b); Homogeneity index > 95%.LC/MS: for [M+H] ⁺c ₄₃h ₅₁n ₈o ₄analytical calculation value: 743.40; Measured value: 743.50.HRMS: for [M+H] ⁺c ₄₃h ₅₁n ₈o ₄analytical calculation value: 743.4033; Measured value: 743.4053.

By suitable acyl chlorides or carboxylic acid substitution embodiment 29 or 30, the tfa salt of (embodiment 31 to the embodiment 84-87) of preparation following compounds.

Embodiment 31 to embodiment 84-88

Step a: press the additional cap-4 end group of embodiment 28

Step b: the method that is converted into 1e with embodiment 1d

Step c: press the final step in embodiment 1, adopt suitable carboxylic acid and the HATU of 1.1 equivalents

Embodiment 85-94

Step a: press the additional cap-1 end group of embodiment 28

Step b: the method that is converted into 1e with embodiment 1d

Embodiment 85-94

Embodiment 95-103

Step a: press the additional cap-5 end group of embodiment 28

Step b: the method that is converted into 1e with embodiment 1d

Embodiment 103-1 to embodiment 103-12

Step a: press additional (the R)-2-tetrahydrofuran formic acid end group of embodiment 28

Step b: the method that is converted into 1e with embodiment 1d

Embodiment 104-107

Step a: press additional (the S)-2-tetrahydrofuran formic acid end group of embodiment 28

Step b: the method that is converted into 1e with embodiment 1d

Embodiment 107-1 to embodiment 107-30

Step a: press the additional cap-14 end group of embodiment 28

Step b: the method that is converted into 1e with embodiment 1d

Embodiment 107-31 to embodiment 107-34

Embodiment 107-31 to embodiment 107-34 is according to the similar fashion preparation of embodiment 28.Cap-38 is attached to intermediate 28d, with after TFA or HCl deaminize t-butyl formate, with suitable carboxylic acid coupling.

Embodiment 107-35 to embodiment 107-38

Embodiment 107-35 to embodiment 107-38 is according to the similar fashion preparation of embodiment 28.Cap-39 is attached to intermediate 28d, with after TFA or HCl deaminize t-butyl formate, with suitable carboxylic acid coupling.

Embodiment 107-39 to embodiment 107-43

Embodiment 107-39 to embodiment 107-44 is according to the similar fashion preparation of embodiment 28.Cap-40 is attached to intermediate 28d, with after TFA or HCl deaminize t-butyl formate, with suitable carboxylic acid coupling.

Embodiment 108

((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(ethylamino formyl radical)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane

Ethyl isocyanate (5 μ l, 0.063mmol) is added in methyl alcohol (1.0ml) solution of 28f (30mg, 0.049mmol), under envrionment conditions, stirs 1.8 hours.Resistates 2.0M NH ₃after/methyl alcohol (2ml) is processed, then stir 30 minutes, vacuum is removed all volatile components.Products therefrom is purified (H with reversed-phase HPLC ₂o/ methyl alcohol/TFA), obtain the tfa salt (16.7mg, light yellow foam) of embodiment 108.LC:1.95 minute (condition 2); Homogeneity index > 98%; LC/MS: for [M+H]+C ₃₉h ₄₃n ₈o ₄analytical calculation value: 687.34; Measured value: 687.53; HRMS: for [M+H] ⁺c ₃₉h ₄₃n ₈o ₄analytical calculation value: 687.3407; Measured value: 687.3417.

Embodiment 109

(2S, 2 ' S)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases)) two (1-pyrrolidinecarboxylic acid benzyl esters)

Embodiment 109, step a

(2S)-2-(5-(4 '-(2-((2S)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid benzyl ester

Employing, by method described in carbamate 1d synthesis of pyrrolidine 1e, makes 28c slough Boc protection and obtains 109a.RT=1.92 minute (condition 2); Homogeneity index > 98%; LC/MS:C ₃₄h ₃₅n ₆o ₂computational analysis value: 559.28; Measured value: 559.44.

Embodiment 109

Chloroformic acid benzyl ester (10.5 μ l, 0.0736mmol) is added in THF (2.0ml) solution of 109a (37.1mg, 0.664mmol) and triethylamine (15 μ l, 0.107mmol), under envrionment conditions, stirs 6 hours.Vacuum is removed after volatile component, resistates 2N NH ₃/ methyl alcohol (2ml) is processed and is stirred 15 minute.Vacuum is removed after volatile component, and resistates is purified (H with reversed-phase HPLC ₂o/ methyl alcohol/TFA), obtain the tfa salt (37.9mg, canescence foam) of embodiment 109.LC (condition 2): RT=2.25 minute; Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₄₂h ₄₁n ₆o ₄analytical calculation value: 693.32; Measured value: 693.59; HRMS: for [M+H] ⁺c ₄₂h ₄₁n ₆o ₄analytical calculation value: 693.3189; Measured value: 693.3220.

Embodiment 110

(2R)-N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) tetrahydrochysene-2-furoylamide

Embodiment 110, step a

(1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine

Adopt successively (by 28d) to prepare 28f and prepare method described in 25b with (by 1e), by 28d and (S)-tetrahydrofuran (THF)-2-formic acid, start synthetic amine 110a.LC (condition 1): RT=1.13 minute; Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₃₉h ₄₂n ₇o ₃analytical calculation value: 656.34; Measured value: 656.49; HRMS: for [M+H] ⁺c ₃₉h ₄₂n ₇o ₃analytical calculation value: 656.3349; Measured value: 656.3377.

Embodiment 110

Employing is by condition described in amine 1e synthetic example 1, by embodiment 110a and (S)-tetrahydrofuran (THF)-2-formic acid Preparation Example 110 (tfa salts).LC (condition 1): RT=1.28 minute; Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₄₄h ₄₈n ₇o ₅analytical calculation value: 754.37; Measured value: 754.60; HRMS: for [M+H] ⁺c ₄₄h ₄₈n ₇o ₅analytical calculation value: 754.3717; Measured value: 754.3690.

Embodiment 111

N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-4-morpholine methane amide

Employing is by method described in amine 28f synthetic example 29, by amine 110a and morpholine 4-formyl chloride Preparation Example 111 (tfa salts).LC (condition 1): RT=1.28 minute; Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₄₄h ₄₉n ₈o ₅analytical calculation value: 769.38; Measured value: 769.60.

Adopt similar approach described in Preparation Example 111, synthetic following compounds (embodiment 112-120), is tfa salt.

Embodiment 112-117

Embodiment 118 to embodiment 120-9

According to method described in Preparation Example 110a, with (R)-tetrahydrofuran base formic acid and suitable formic acid, formyl chloride, urea chloride or isocyanic ester, replace, carry out Preparation Example 118 to embodiment 120-9.

Embodiment 121

(1R, 1 ' R)-2,2 '-((2,2 '-dimethyl-4,4 '-biphenyl, two bases) two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amines)

Embodiment 121, step a-b

By PdCl ₂(Ph ₃p) ₂(257mg, 0.367mmol) be added to the iodo-2-toluene of the bromo-4-of 1-(3.01g, (in 3.826g, 10.59mmol) diox (45ml) solution, at 80 ℃, heating is～17 hours for 10.13mmol) He three normal-butyls (1-vinyl ethyl ether base) stannane.Reaction mixture water (15ml) is processed, and is cooled to～0 ℃ (ice/water), then in 7 minutes, adds NBS (1.839g, 10.3mmol) in batches.After stir about 25 minutes, vacuum is removed volatile component, makes resistates at CH ₂cl ₂and distribute between water.Water layer CH ₂cl ₂extraction, the organic phase drying (MgSO of merging ₄), filter final vacuum concentrated.Gravity chromatography purification (silica gel for gained crude product; 4% ethyl acetate/hexane), obtain bromide 121a (2.699g, isabelline solid); Sample is impure, wherein contains the derivative impurity of stannane. ¹H NMR(CDCl ₃，δ＝7.24，400MHz)：7.83(s，1H)，7.63(s，2H)，4.30(s，2H)，2.46(s，3H)。

By the CH of 121a (2.69g, < 9.21mmol) ₃cN (15ml) solution was added drop-wise to the CH of (S)-Boc-proline(Pro) (2.215g, 10.3mmol) and triethylamine (1.40ml, 10.04mmol) in 3 minutes ₃in CN (30ml) solution and stir 90 minutes.Vacuum is removed after volatile component, makes resistates at water and CH ₂cl ₂between distribute, organic phase drying (MgSO ₄), filter final vacuum concentrated.Gained is purified by flash chromatography (silica gel for crude product; 15-20% ethyl acetate/hexane), obtain 121b (2.74g, viscosity colorless oil). ¹h NMR (DMSO-d ₆, δ=2.50,400MHz): δ 7.98 (m, 1H), 7.78 (d, J=8.3,1H), 7.72-7.69 (m, 1H), 5.61-5.41 (m, 2H), 4.35-4.30 (m, 1H), 3.41-3.30 (m, 2H), 2.43 (s, 3H), 2.33-2.08 (m, 2H), 1.93-1.83 (m, 2H), 1.40/1.36 (s, 9H); LC (condition 1): RT=1.91 minute; Homogeneity index > 95%; LC/MS: for [M+Na] ⁺c ₁₉h ₂₄brNNaO ₅analytical calculation value: 448.07; Measured value: 448.10.

Other keto ester can be prepared in a similar manner.

Embodiment 121, step c

By keto ester 121b (1.445g, 3.39mmol) and NH ₄oAc (2.93g, 38.0mmol) uses microwave heating 80 minutes with the mixture of dimethylbenzene (18ml) at 140 ℃.Vacuum is removed after volatile component, makes carefully resistates at CH ₂cl ₂and distribute between water, wherein add enough saturated NaHCO ₃solution with in and water-bearing media.Water CH ₂cl ₂extraction, the organic phase drying (MgSO of merging ₄), filter final vacuum concentrated.Purified by flash chromatography for crude product (silica gel, 40% ethyl acetate/hexane), obtains imidazoles 121c (1.087g, pale solid). ¹h NMR (DMSO-d ₆, δ=2.50,400MHz): 12.15/11.91/11.84 (br s, 1H), 7.72-7.24 (m, 4H), 4.78 (m, 1H), 3.52 (m, 1H), 3.38-3.32 (m, 1H), 2.35 (s, 3H), 2.28-1.77 (m, 4H), 1.40/1.14 (s, 9H); LC (condition 1): RT=1.91 minute; Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₁₉h ₂₅brN ₃o ₂analytical calculation value: 405.96; Measured value: 406.11.

Embodiment 121, steps d

By PdCl ₂dppfCH ₂cl ₂(50.1mg, 0.061mmol) be added to bromide 121c (538.3mg is housed, 1.325mmol), in the penstock of the mixture of hypoboric acid two pinacol esters (666.6mg, 2.625mmol), potassium acetate (365.8mg, 3.727mmol) and DMF (10ml).Reaction mixture N ₂purge, at 80 ℃, heat 24.5 hours.Vacuum is removed volatile component, makes resistates at CH ₂cl ₂and distribute between water, add wherein enough saturated NaHCO ₃solution is so that the pH of water-bearing media is neutral.Water CH ₂cl ₂extraction, the organic phase drying (MgSO of merging ₄), filter final vacuum concentrated.Products therefrom is purified (silica gel, 40-50% ethyl acetate/hexane) by Biotage system, obtains boric acid ester 121d (580mg, white foam shape thing).According to ¹h NMR, sample contains remaining tetramethyl ethylene ketone, and the ratio of product/tetramethyl ethylene ketone is～3. ¹hNMR (DMSO-d ₆, δ=2.50,400MHz): δ 12.16/11.91/11.83 (br s, 1H), 7.63-7.25 (m, 4H), 4.78 (m, 1H), 3.53 (m, 1H), 3.39-3.32 (m, 1H), 2.48/2.47 (s, 3H), 2.28-1.78 (m, 4H), 1.40/1.14/1.12 (br s, 9H), 1.30 (s, 12H); LC (condition 1): RT=1.62 minute; LC/MS: for [M+H] ⁺c ₂₅h ₃₇bN ₃o ₄analytical calculation value: 454.29; Measured value: 454.15.

Embodiment 121, step e

With

Embodiment 121, step f

According to the preparation method of dimer 1d, by bromide 121c and boric acid ester 121d, prepare carbamate 121e; LC (condition 1): RT=1.43 minute; LC/MS: for [M+H] ⁺c ₃₈h ₄₉n ₆o ₄analytical calculation value: 653.38; Measured value: 653.65.

According to the preparation method of tetramethyleneimine 1e, make carbamate 121e deprotection, obtain 121f, be canescence foam. ¹h NMR (DMSO-d ₆, δ=2.50,400MHz): 11.79 (brs, 2H), 7.66 (s, 2H), 7.57 (d, J=7.8,2H), 7.41 (br s, 2H), 7.02 (d, J=7.8,2H), 4.15 (apparent t, J=7.2,2H), 3.00-2.94 (m, 2H), 2.88-2.82 (m, 2H), 2.09-2.01 (m, 2H), 2.04 (s, 6H), 1.93-1.85 (m, 2H), 1.82-1.66 (m, 4H).Attention: although appear at 2.8-3.2ppm district corresponding to the broad peak signal of tetramethyleneimine NH, cannot record the actual range of its chemical shift.LC (condition 1): RT=1.03 minute; LC/MS: for [M+H] ⁺c ₂₈h ₃₃n ₆analytical calculation value: 453.28; Measured value: 453.53.

Embodiment 121

According to the method by 1e Preparation Example 1, by 121f synthetic example 121 (tfa salt); LC (condition 1): RT=1.14 minute; Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₄₈h ₅₅n ₈o ₂analytical calculation value: 775.45; 775.75; HRMS: for [M+H] ⁺c ₄₈h ₅₅n ₈o ₂analytical calculation value: 775.4448; Measured value: 775.4473.

Embodiment 122

((2,2 '-dimethyl-4,4 '-biphenyl, two bases) two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-second two bases))) two (Urethylanes)

Employing is by method described in tetramethyleneimine 1e Preparation Example 1, by tetramethyleneimine 121f and Cap-4 Preparation Example 122 (tfa salt).LC (condition 1): RT=1.35 minute; Homogeneity index > 98%; HRMS: for [M+H] ⁺c ₄₈h ₅₁n ₈o ₆analytical calculation value: 835.3932; Measured value: 835.3954.

Embodiment 123-125

Described method described in described method in employing embodiment 1 steps d, embodiment 1 step e and final Preparation Example 1 in step, starts Preparation Example 123-125 by boric acid ester 1c and bromide 121c.

Embodiment 126-128

Adopt the described method being started by step c in embodiment 28, by bromide 28b and boric acid ester 121d, start Preparation Example 126-128.

Embodiment 129

((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-2,2 '-dimethyl-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane

Embodiment 129, step a

HATU (104.3mg, 0.274mmol) is added in the mixture of 121f, Cap-4 (58.8mg, 0.281mmol) and diisopropylethylamine (110 μ l, 0.631mmol) and DMF (6.0ml), and stirs 90 minutes.Vacuum is removed volatile component, and gained crude product is purified (H with reversed-phase HPLC ₂o/ methyl alcohol/TFA), by the free alkalization of MCX post (methanol wash; 2.0M NH ₃/ methyl alcohol), obtain 129a (89.9mg).LC (condition 1): RT=1.22 minute; Homogeneity index 95%; LC/MS: for [M+H] ⁺c ₃₈h ₄₂n ₇o ₃analytical calculation value: 644.34; Measured value: 644.55.

Embodiment 129

By for making embodiment 1e change into the method for embodiment 1, by 129a Preparation Example 129 (tfa salt).LC (condition 1): RT=1.27 minute; Homogeneity index 97%; LC/MS: for [M+H] ⁺c ₄₈h ₅₃n ₈o ₄analytical calculation value: 805.42; Measured value: 805.61.

Embodiment 130

(1R, 1 ' R)-2,2 '-((2-(trifluoromethyl)-4,4 '-biphenyl two bases) two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amines)

Embodiment 130, step a

In 11 minutes, oxalic dialdehyde (2.0ml 40%/water) is added drop-wise to NH ₄in the methanol solution of OH (32ml) and (S)-Boc-dried meat ammonium aldehyde (prolinal) (8.564g, 42.98mmol), stir at ambient temperature 19 hours.Vacuum is removed volatile component, purified by flash chromatography for resistates (silica gel, ethyl acetate), then carry out recrystallization (ethyl acetate, room temperature), obtain imidazoles 130a (4.43g, white fine hair shape solid). ¹H NMR(DMSO-d ₆，δ＝2.50，400MHz)：11.68/11.59(br s，1H)，6.94(s，1H)，6.76(s，1H)，4.76(m，1H)，3.48(m，1H)，3.35-3.29(m，1H)，2.23-1.73(m，4H)，1.39/1.15(s，9H)。LC (condition 1): RT=0.87 minute; Homogeneity index > 95%; LC/MS: for [M+H] ⁺c ₁₂h ₂₀n ₃o ₂analytical calculation value: 238.16; Measured value: 238.22.When analyzing under following chirality HPLC condition, the enantiomeric excess of imidazoles 130a is 98.9%.

Post: Chiralpak AD, 10 μ m, 4.6 * 50mm

Solvent: 1.7% ethanol/heptane (isocratic elution)

Flow velocity: 1ml/ minute

Wavelength: 220nm or 256nm

Relative retention time: 3.25 minutes (R), 5.78 minutes (S)

Embodiment 130, step b

In 15 minutes, N-bromo-succinimide (838.4mg, 4.71mmol) is added in batches to the CH of the imidazoles 130a (1.0689g, 4.504mmol) of cooling (ice/water) ₂cl ₂(20ml), in solution, at same temperature, stir 75 minutes.Vacuum is removed volatile component.Crude product is purified (H by reverse-phase HPLC system ₂o/ methyl alcohol/TFA), bromide 130b and its dibromo analogue and not used up raw material are separated.The excessive NH of HPLC effluent ₃in/methyl alcohol and after, vacuum is removed volatile component.Make resistates at CH ₂cl ₂and between water, distribute the extraction of water layer water.Organic phase drying (the MgSO merging ₄), filter final vacuum concentrated, obtain 130b (374mg, white solid). ¹h NMR (DMSO-d ₆, δ=2.50,400MHz): 12.12 (br s, 1H), 7.10 (m, 1H), 4.70 (m, 1H), 3.31 (m, 1H; With water signal overlap), 2.25-1.73 (m, 4H), 1.39/1.17 (s, 3.8H+5.2H).LC (condition 1): RT=1.10 minute; Homogeneity index > 95%; LC/MS: for [M+H] ⁺c ₁₂h ₁₉brN ₃o ₂analytical calculation value: 316.07; Measured value: 316.10.

Embodiment 130, step c

By Pd (Ph ₃p) ₄(78.5mg, 0.0679mmol) is added to bromide 130b (545mg, 1.724mmol), 2-(the chloro-3-of 4-(trifluoromethyl) phenyl-4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane (542.8mg, 1.771mmol) (commercially available), NaHCO ₃(477mg, 5.678mmol) and 1, in the mixture of 2-glycol dimethyl ether (12.5ml) and water (4.2ml).Reaction mixture purging with nitrogen gas, heats after 27 hours at 80 ℃ with oil bath, and vacuum is removed volatile component.Make resistates at CH ₂cl ₂and between water, distribute organic layer drying (MgSO ₄), filter final vacuum concentrated.Gained crude product is used Biotage system (silica gel, 40-50% ethyl acetate/hexane) and reversed-phase HPLC (water/methyl alcohol/TFA) purifying successively.The excessive NH of HPLC effluent ₃/ methyl alcohol is concentrated after processing.Make resistates at water and CH ₂cl ₂between distribute, organic layer drying (MgSO ₄), filter final vacuum concentrated, obtain 130c (317.4mg, white foam shape thing). ¹H NMR(DMSO-d ₆，δ＝2.50，400MHz)：12.36/12.09/12.03(br s，1H)，8.15(d，J＝1.8，0.93H)，8.09(br s，0.07H)，8.01(dd，J＝8.3/1.3，0.93H)，7.93(m，0.07H)，7.74(m，1H)，7.66(d，J＝8.3，0.93H)，7.46(m，0.07H)，4.80(m，1H)，3.53(m，1H)，3.36(m，1H)，2.30-1.77(m，4h)，1.40/1.15(s，3.8H+5.2H)。LC (condition 1): RT=1.52 minute; Homogeneity index > 95%; LC/MS: for [M+H] ⁺c ₁₉h ₂₂clF ₃n ₃o ₂analytical calculation value: 416.14; Measured value: 416.17.

Embodiment 130, steps d-e

By Pd[P (t-Bu) ₃] ₂(48mg, 0.094mmol) be added to muriate 130c (245mg, 0.589mmol), boric acid ester 1c (277.1mg, 0.631mmol), KF (106.7mg, 1.836mmol) with the mixture of DMF (6ml) in, at 110 ℃, heating is～30 hours.Vacuum is removed after volatile component, makes resistates at CH ₂cl ₂(50ml), water (20ml) and saturated NaHCO ₃(1ml) between, distribute.Water layer CH ₂cl ₂extraction (2 times), the organic phase drying (MgSO of merging ₄), filter final vacuum concentrated.Products therefrom is purified (silica gel, ethyl acetate) by Biotage system, obtains carbamate 130d (297mg, canescence foam).LC (condition 1): RT=1.44 minute; Homogeneity index > 95%; LC/MS: for [M+H] ⁺c ₃₇h ₄₄f ₃n ₆o ₄analytical calculation value: 693.34; Measured value: 693.34.

According to the preparation method of tetramethyleneimine 1e, making 130d deprotection, obtain 130e, is light yellow foam. ¹HNMR(DMSO-d ₆，δ＝2.50，400MHz)：11.88(br s，2H)，8.16(d，J＝1.5，1H)，8.02(d，J＝7.8，1H)，7.78(d，J＝8.1，2H)，7.66(br s，1H)，7.48(br s，1H)，7.37(d，J＝8.1，1H)，7.28(d，J＝8.3，2H)，4.18(m，2H)，2.99-2.93(m，2H)，2.89-2.83(m，2H)，2.11-2.01(m，2H)，1.94-1.85(m，2H)，1.82-1.67(m，4H)。Attention: although appear at 2.8-3.2ppm district corresponding to the broad peak signal of tetramethyleneimine NH, cannot record the actual range of its chemical shift.LC (condition 1): RT=1.12 minute; Homogeneity index > 95%; LC/MS: for [M+H] ⁺c ₂₇h ₂₈f ₃n ₆analytical calculation value: 493.23; Measured value: 493.14.

Embodiment 130

According to the method by tetramethyleneimine 1e Preparation Example 1, by 130e and Cap-1 Preparation Example 130 (tfa salt).LC (condition 1): RT=1.17 minute; Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₄₇h ₅₀f ₃n ₈o ₂analytical calculation value: 815.40; Measured value: 815.44; HRMS: for [M+H] ⁺c ₄₇h ₅₀f ₃n ₈o ₂analytical calculation value: 815.4009; Measured value: 815.4013.

Embodiment 131

5,5 '-(2-(trifluoromethyl)-, 4-biphenyl two bases) two (2-((2S)-1-((2R)-2-phenyl-2-(1-pyrrolidyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles)

According to the preparation method of embodiment 130, by 130e and Cap-5 synthetic example 131 (tfa salt).

LC (condition 1): RT=1.19 minute; Homogeneity index > 98%

LC/MS: for [M+H] ⁺c ₅₁h ₅₄f ₃n ₈o ₂analytical calculation value: 867.43; Measured value: 867.51.

HRMS: for [M+H] ⁺c ₅₁h ₅₄f ₃n ₈o ₂analytical calculation value: 867.4322; Measured value: 867.4315.

Embodiment 131.1-1 to embodiment 131.1-2

Step a: make cap-14 and HATU coupling by embodiment 28 step e

Step b: use H ₂, Pd/C sloughs Cbz

Step c: the end group that affix is suitable

According to the similar fashion of embodiment 28, by the intersexes at additional Cap-4 rear center body 1-6e, carry out Preparation Example 131.1-1 to embodiment 131.1-2.

Embodiment 131.1-1

((1R)-2-(((1S)-1-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl) ethyl) (methyl) amino)-2-oxo-1-styroyl) Urethylane

Use Pd/C/H ₂by 1-6e, sloughed after CBz carbamate affix Cap-1.

LCMS condition: Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 3 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, 220nm, 5 μ l inject volume.T _r=1.42 minutes.

LRMS: for C ₄₅h ₄₉n ₈o ₄analytical calculation value: 765.39; Measured value: 765.38 (M+H) ⁺.

HRMS: for C ₄₅h ₄₉n ₈o ₄analytical calculation value: 765.3877; Measured value: 765.3905 (M+H) ⁺.

Embodiment 131.1-2

((1R)-2-(methyl ((1S)-1-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl) ethyl) amino)-2-oxo-1-styroyl) Urethylane

Use Pd/C/H ₂by 1-6e, slough CBz carbamate, affix Cap-14.

LCMS condition: Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 3 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, 220nm, 5 μ l inject volume.T _r=1.45 minutes (> 95%).

LRMS: for C ₄₈h ₅₂n ₈o ₄analytical calculation value: 805.42; Measured value: 805.41 (M+H) ⁺.

HRMS: for C ₄₈h ₅₂n ₈o ₄analytical calculation value: 805.4190; Measured value: 805.4214 (M+H) ⁺.

Embodiment 131.2

(2R)-2-(dimethylamino)-N-methyl-2-phenyl-N-((1S)-1-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl) ethyl) ethanamide

According to the similar fashion of embodiment 131.1-1 and embodiment 131.1-2, by the intersexes at affix Cap-1 rear center body 1-6e, carry out Preparation Example 131.2.

Use Pd/C/H ₂slough after CBz carbamate affix Cap-14.

LCMS condition: Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 3 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, 220nm, 5 μ l inject volume.T _r=1.28 minutes.

LRMS: for C ₄₈h ₅₄n ₈o ₂analytical calculation value: 775.44; Measured value: 775.45 (M+H) ⁺.

HRMS: for C ₄₈h ₅₄n ₈o ₂analytical calculation value: 775.4448 measured values: 775.4460 (M+H) ⁺.

Embodiment 132

(1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl) phenyl)-3-pyridyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine

Embodiment 132, step a-b

In 5 minutes, by Br ₂the CH of (7.63g, 47.74mmol) ₂cl ₂(10ml) solution is added drop-wise to 1-(6-bromopyridine-3-yl) ethyl ketone (9.496g, 47.47mmol) and 48%HBr (0.4ml) and the CH of cooling (ice/water) ₂cl ₂(105ml) in solution.After 40 minutes, remove cooling bath, continue at ambient temperature stir about 66 hours.Leach formed solids cake compresses, use CH ₂cl ₂washing final vacuum is dry, obtains impure 132a (15.94g, pale solid).

By disposable crude product 132a (15.4g) and the CH of being added to of Boc-L-proline(Pro) (9.70g, 45.06mmol) ₃in the heterogeneous mixture of CN (150ml), in 6 minutes, drip Et immediately ₃n (13.0ml, 93.2mmol).Reaction mixture is stirred 50 minutes, and vacuum is removed volatile component, makes resistates at CH ₂cl ₂and distribute between water.CH ₂cl ₂layer drying (MgSO ₄), filter final vacuum concentrated, (the silica gel of purified by flash chromatography for products therefrom; Sample is application of sample together with eluting solvent; 25%EtOAc/ hexane), obtain 132b (11.44g, the very yellow oil of thickness). ¹h NMR (DMSO, δ=2.5ppm; 400MHz): 8.95 (m, 1H), 8.25-8.21 (m, 1H), 7.88 (d, J=8.3,1H), 5.65-5.46 (m, 2H), 4.36-4.31 (m, 1H), 3.41-3.29 (m, 2H), 2.36-2.22 (m, 1H), 2.14-2.07 (m, 1H), 1.93-1.83 (m, 2H), 1.40 and 1.36 (two s, 9H).

LC (condition 1): RT=2.01 minute; Homogeneity index > 90%.

LC/MS: for [M+Na] ⁺c ₁₇h ₂₁naBrN ₂o ₅analytical calculation value: 435.05; Measured value: 435.15.

HRMS: for [M+H] ⁺c ₁₇h ₂₂brN ₂o ₅analytical calculation value: 413.0712; Measured value: 413.0717.

Embodiment 132, step c

By keto ester 132b (1.318g, 3.19mmol) and NH ₄oAc (2.729g, 35.4mmol) uses microwave heating 90 minutes with the mixture of dimethylbenzene (18ml) at 140 ℃.Vacuum is removed volatile component, makes resistates at CH ₂cl ₂and distribute between water, add wherein enough saturated NaHCO ₃solution with in and water-bearing media.Water CH ₂cl ₂extraction, the organic phase drying (MgSO of merging ₄), filter final vacuum concentrated.Gained crude product is purified (silica gel by Biotage system; 50%EtOAc/ hexane), obtain imidazoles 132c (1.025g, canescence foam). ¹hNMR (DMSO, δ=2.5ppm, 400MHz): 12.33/12.09/12.02 (br m, 1H), 8.74 (d, J=2.3,0.93H), 8.70 (apparent br s, 0.07H), 8.03/7.98 (dd of first peak, J=8.3,1H), 7.69/7.67 (br m, 1H), the 7.58/7.43 (d of first peak, J=8.3,1H), 4.80 (m, 1H), 3.53 (m, 1H), 3.36 (m, 1H), 2.33-2.11 (m, 1H), 2.04-1.79 (m, 3H), (1.39/1.15 apparent br s, 3.9H+5.1H).

LC (condition 1): RT=1.52 minute; Homogeneity index > 98%.

LC/MS: for [M+H] ⁺c ₁₇h ₂₂brN ₄o ₂analytical calculation value: 393.09; Measured value: 393.19.

HRMS: for [M+H] ⁺c ₁₇h ₂₂brN ₄o ₂analytical calculation value: 393.0926; Measured value: 393.0909.

Embodiment 132, steps d-e

By Pd (Ph ₃p) ₄(115.1mg, 0.10mmol) is added to bromide 132c (992mg, 2.52mmol), boric acid ester 1c (1.207g, 2.747mmol), NaHCO ₃(698.8mg, 8.318mmol) and 1, in the mixture of 2-glycol dimethyl ether (18ml) and water (4ml).Reaction mixture nitrogen purging, heats after 37 hours at 90 ℃ with oil bath, is cooled to envrionment temperature.By formed suspension filtered, water and the washing of 1,2-glycol dimethyl ether successively, vacuum-drying.By crude product solid, prepare silica gel sieve mesh, and carry out flash chromatography processing (silica gel; EtOAc), obtaining carbamate 132d, is white solid, slightly flavescence (1.124g) when standing under envrionment conditions. ¹h NMR shows that this sample contains remaining MeOH, and the mol ratio of product/MeOH is 1.3.

LC (condition 1): RT=1.71 minute; Homogeneity index > 98%.

LC/MS: for [M+H] ⁺c ₃₅h ₄₄n ₇o ₄analytical calculation value: 626.35; Measured value: 626.64.

HRMS: for [M+H] ⁺c ₃₅h ₄₄n ₇o ₄analytical calculation value: 626.3455; 626.3479.

Carbamate 132d (217mg) uses 25%TFA/CH ₂cl ₂(3.6ml) process, and under envrionment conditions, stir 6 hours.Vacuum is removed after volatile component, the free alkalization of MCX post (MeOH washing for products therefrom; 2.0M NH ₃/ MeOH wash-out), obtaining 132e, is dark yellow foam, solidifies gradually (150.5mg when standing; Quality exceeds theoretical yield). ¹h NMR (DMSO, δ=2.5ppm; 400MHz): 11.89 (utmost point broad peak, 2H), 9.01 (d, J=1.8,1H), 8.13 (dd, J=8.3,2.2,1H), 8.07 (d, J=8.6,2H), 7.92 (d, J=8.3,1H), 7.83 (d, J=8.5,2H), 7.61 (br s, 1H), 7.50 (br s, 1H), 4.18 (m, 2H), 3.00-2.93 (m, 2H), 2.90-2.82 (m, 2H), 2.11-2.02 (m, 2H), 1.94-1.85 (m, 2H), 1.83-1.67 (m, 4H).[noting: do not find tradable tetramethyleneimine hydrogen].

LC (condition 1): RT=1.21 minute; Homogeneity index > 98%.

LC/MS: for [M+H] ⁺c ₂₅h ₂₈n ₇analytical calculation value: 426.24; Measured value: 426.40.

HRMS: for [M+H] ⁺c ₂₅h ₂₈n ₇analytical calculation value: 426.2406; Measured value: 426.2425.

Embodiment 132

HATU (41.4mg, 0.109mmol) is added to tetramethyleneimine 132e (23.1mg, 0.054mmol), (i-Pr) ₂in the mixture of EtN (40 μ l, 0.23mmol) and Cap-1 (25.3mg, 0.117mmol) and DMF (1.5ml), mixture is stirred 1 hour at ambient temperature.Vacuum is removed after volatile component, and resistates is first purified (MeOH washing with MCX; 2.0MNH ₃/ MeOH wash-out), then with reversed-phase HPLC purify (H ₂o/MeOH/TFA), obtain the tfa salt (39.2mg, yellow foam) of embodiment 132.

LC (condition 1): RT=1.37 minute; Homogeneity index > 98%.

LC/MS: for [M+H] ⁺c ₄₅h ₅₀n ₉o ₂analytical calculation value: 748.41; Measured value: 748.53.

HRMS: for [M+H] ⁺c ₄₅h ₅₀n ₉o ₂analytical calculation value: 748.4087; Measured value: 748.4090.

Adopt same procedure and the suitable agent of Preparation Example 132, by the tfa salt of 132e Preparation Example 133-135.

Embodiment 133-135

Embodiment 136

(1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-2-aminomethyl phenyl)-3-pyridyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine

Embodiment 136, step a and b

By PdCl ₂(Ph ₃p) ₂(257mg, 0.367mmol) be added to the iodo-2-toluene of the bromo-4-of 1-(3.01g, (in 3.826g, 10.59mmol) diox (45ml) solution, at 80 ℃, heating is～17 hours for 10.13mmol) He three normal-butyls (1-vinyl ethyl ether base) stannane.Reaction mixture water (15ml) is processed, be cooled to～0 ℃ (ice/water) after, in 7 minutes, add NBS (1.839g, 10.3mmol) in batches.After stir about 25 minutes, vacuum is removed volatile component, makes resistates at CH ₂cl ₂and distribute between water.Water layer CH ₂cl ₂extraction, the organic phase drying (MgSO of merging ₄), filter final vacuum concentrated, gravity chromatography purification (silica gel for gained crude product; 4%EtOAc/ hexane), obtain bromide 136a (2.699g, isabelline solid); Sample is impure, wherein contains the derivative impurity of stannane. ¹H NMR(CDCl ₃，δ＝7.24，400MHz)：7.83(s，1H)，7.63(s，2H)，4.30(s，2H)，2.46(s，3H)。

In 3 minutes, by the CH of 136a (2.69g, < 9.21mmol) ₃cN (15ml) solution is added drop-wise to (S)-Boc-proline(Pro) (2.215g, 10.3mmol) and Et ₃the CH of N (1.40ml, 10.04mmol) ₃in CN (30ml) solution, and stir 90 minutes.Vacuum is removed after volatile component, makes resistates at water and CH ₂cl ₂between distribute, organic phase drying (MgSO ₄), filtering final vacuum concentrated, gained is purified by flash chromatography (silica gel for crude product; 15-20%EtOAc/ hexane), obtain 136b (2.74g, viscosity colorless oil). ¹H NMR(DMSO-d ₆，δ＝2.50，400MHz)：7.98(m，1H)，7.78(d，J＝8.3，1H)，7.72-7.69(m，1H)，5.61-5.41(m，2H)，4.35-4.30(m，1H)，3.41-3.30(m，2H)，2.43(s，3H)，2.33-2.08(m，2H)，1.93-1.83(m，2H)，1.40/1.36(s，9H)。

LC (condition 1): RT=1.91 minute; Homogeneity index > 95%.

LC/MS: for [M+Na] ⁺c ₁₉h ₂₄brNNaO ₅analytical calculation value: 448.07; Measured value: 448.10.

Embodiment 136, step c

By keto ester 136b (1.445g, 3.39mmol) and NH ₄oAc (2.93g, 38.0mmol) uses microwave heating 80 minutes with the mixture of dimethylbenzene (18ml) at 140 ℃.Vacuum is removed after volatile component, makes carefully resistates at CH ₂cl ₂and distribute between water, add wherein enough saturated NaHCO ₃solution with in and water-bearing media.Water CH ₂cl ₂extraction, the organic phase drying (MgSO of merging ₄), filter final vacuum concentrated.Purified by flash chromatography for crude product (silica gel, 40%EtOAc/ hexane), obtains imidazoles 136c (1.087g, pale solid). ¹HNMR(DMSO-d ₆，δ＝2.50，400MHz)：12.15/11.91/11.84(br s，1H)，7.72-7.24(m，4H)，4.78(m，1H)，3.52(m，1H)，3.38-3.32(m，1H)，2.35(s，3H)，2.28-1.77(m，4H)，1.40/1.14(s，9H)。

LC (condition 1): RT=1.91 minute; Homogeneity index > 98%

LC/MS: for [M+H] ⁺c ₁₉h ₂₅brN ₃o ₂analytical calculation value: 405.96; Measured value: 406.11.

Embodiment 136, steps d

By PdCl ₂dppfCH ₂cl ₂(50.1mg, 0.061mmol) be added to bromide 136c (538.3mg is housed, 1.325mmol), in the penstock of the mixture of hypoboric acid two pinacol esters (666.6mg, 2.625mmol), KOAc (365.8mg, 3.727mmol) and DMF (10ml).Reaction mixture N ₂purge, at 80 ℃, heat 24.5 hours.Vacuum is removed volatile component, makes resistates at CH ₂cl ₂and distribute between water, add wherein enough saturated NaHCO ₃solution is so that the pH of water-bearing media is neutral.Water CH ₂cl ₂extraction, the organic phase drying (MgSO of merging ₄), filter final vacuum concentrated.Products therefrom is purified (silica gel, 40-50%EtOAc/ hexane) by Biotage system, obtains boric acid ester 136d (580mg, white foam shape thing).According to ¹h NMR, sample contains remaining tetramethyl ethylene ketone, and the ratio of product/tetramethyl ethylene ketone is～3. ¹HNMR(DMSO-d ₆，δ＝2.50，400MHz)：12.16/11.91/11.83(br s，1H)，7.63-7.25(m，4H)，4.78(m，1H)，3.53(m，1H)，3.39-3.32(m，1H)，2.48/2.47(s，3H)，2.28-1.78(m，4H)，1.40/1.14/1.12(br s，9H)，1.30(s，12H)。

LC (condition 1): RT=1.62 minute.

LC/MS: for [M+H] ⁺c ₂₅h ₃₇bN ₃o ₄analytical calculation value: 454.29; Measured value: 454.15.

Embodiment 136, step e-f

According to preparing coupling condition described in biaryl 132d, by bromide 132c and boric acid ester 136d, prepare biaryl 136e.

LC (condition 1a): RT=1.32 minute; Homogeneity index > 90%.

LC/MS: for [M+H] ⁺c ₃₆h ₄₅n ₇o ₄analytical calculation value: 640.36; Measured value: 640.66.

According to the preparation method of tetramethyleneimine 132e, biaryl 136e is carried out to deprotection, obtain 136f, be light yellow foam. ¹H NMR(DMSO-d ₆，δ＝2.50，400MHz)：11.88(brs，2H)，9.02(d，J＝2，1H)，8.12(dd，J＝8.4，2.3，1H)，7.67(s，1H)，7.64-7.62(m，2H)，7.50(d，J＝8.3，1H)，7.46(br s，1H)，7.40(d，J＝7.8，1H)，4.21-4.14(m，2H)，3.00-2.93(m，2H)，2.90-2.82(m，2H)，2.40(s，3H)，2.11-2.01(m，2H)，1.94-1.85(m，2H)，1.82-1.66(m，4H)。[note: the signal of tetramethyleneimine NH appears at 3.22-2.80 district, and too wide thus cannot deterministic displacement study].

LC (condition 1): RT=0.84 minute.

LC/MS: for [M+H] ⁺c ₂₆h ₃₀n ₇analytical calculation value: 440.26; Measured value: 440.50.

Embodiment 136

According to the method by 132e Preparation Example 132, by 136f synthetic example 136 (tfa salt).

1.05 minutes (condition 1); > 98%.

LC/MS: for [M+H] ⁺c ₄₆h ₅₂n ₉o ₂analytical calculation value: 762.42, measured value: 762.77.

HRMS: for [M+H] ⁺c ₄₆h ₅₂n ₉o ₂analytical calculation value: 762.4244; Measured value: 762.4243.

Embodiment 138

((1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-2-aminomethyl phenyl)-3-pyridyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane

Embodiment 138 is prepared by tetramethyleneimine 136f and Cap-4 equally.

1.60 minutes (condition 1); > 98%.

LC/MS: for [M+H] ⁺c ₄₆h ₄₈n ₉o ₆analytical calculation value: 822.37; Measured value: 822.74.

HRMS: for [M+H] ⁺c ₄₆h ₄₈n ₉o ₆analytical calculation value: 822.3728; Measured value: 822.3760.

Embodiment 139

N-((1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2-acetylaminohydroxyphenylarsonic acid 2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl) phenyl)-3-pyridyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) ethanamide

Embodiment 139, step a

HATU (99.8mg, 0.262mmol) is added to 132e (54.1mg, 0.127mmol), (R)-2-(t-butoxycarbonyl amino)-2-toluylic acid (98.5mg, 0.392mmol) and i-Pr ₂in the mixture of EtN (100 μ l, 0.574mol), and reaction mixture is stirred 70 minutes.Vacuum is removed after volatile component, and resistates is purified (H with reversed-phase HPLC ₂o/MeOH/TFA), excessive 2.0N NH for HPLC effluent wherein ₃after/MeOH processes, vacuum is removed volatile component.Make products therefrom at CH ₂cl ₂and between water, distribute water CH ₂cl ₂extraction (2 times).Organic phase drying (the MgSO merging ₄), filter final vacuum concentrated, obtain carbamate 139a (82.3mg, white foam membranoid substance).

LC (condition 1): RT=1.97 minute; Homogeneity index > 95%.

LC/MS: for [M+H] ⁺c ₅₁h ₅₈n ₉o ₆analytical calculation value: 892.45; Measured value: 892.72.

Embodiment 139b, step b

Employing is prepared method described in tetramethyleneimine 132e by 132d, makes carbamate 139a deprotection obtain amine 139b.

LC (condition 1): RT=1.37 minute; Homogeneity index > 95%.

LC/MS: for [M+H] ⁺c ₄₁h ₄₂n ₉o ₂analytical calculation value: 692.35; Measured value: 692.32.

Embodiment 139

Diacetyl oxide (20 μ l, 0.212mmol) is added in DMF (1.5ml) solution of 139b (31.2mg, 0.045mmol), reaction mixture is stirred 1 hour.By NH ₃/ MeOH (1.0ml2N) is added in reaction mixture, continues to stir 100 minutes.Vacuum is removed volatile component, and gained crude product is purified (H with reversed-phase HPLC ₂o/MeOH/TFA), obtain the tfa salt (24.1mg, light yellow solid) of embodiment 139.

LC (condition 1): RT=1.53 minute; Homogeneity index > 98%.

LC/MS: for [M+H] ⁺c ₄₅h ₄₆n ₉o ₄analytical calculation value: 776.37; Measured value: 776.38.

HRMS: for [M+H] ⁺c ₄₅h ₄₆n ₉o ₄analytical calculation value: 776.3673; Measured value: 776.3680.

Embodiment 140

((1R)-2-((2S)-2-(5-(4-(5-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-2-pyridyl) phenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane

Embodiment 140, step a

By HATU (19.868g, 52.25mmol) be added to N-Cbz-L-proline(Pro) (12.436g, 49.89mmol) and in the HCl salt (12.157g, 48.53mmol) of 2-amino-1-(4-bromophenyl) ethyl ketone and the heterogeneous mixture of DMF (156ml).Mixture is lowered the temperature in ice-water bath, in 13 minutes, drip wherein immediately DIPEA (27ml, 155mmol).After adding alkali and completing, remove cooling bath, then reaction mixture is stirred 50 minutes.Vacuum is removed volatile component, water (125ml) is added in gained crude product solid, and stir about 1 hour.Pale solid is filtered, and after washing by massive laundering, vacuum-drying, obtains keto-amide 140a (20.68g, white solid). ¹H NMR(DMSO-d ₆，δ＝2.5ppm，400MHz)：8.30(m，1H)，7.91(m，2H)，7.75(d，J＝8.5，2H)，7.38-7.25(m，5H)，5.11-5.03(m，2H)，4.57-4.48(m，2H)，4.33-4.26(m，1H)，3.53-3.36(m，2H)，2.23-2.05(m，1H)，1.94-1.78(m，3H)。

LC (condition 1): RT=1.65 minute; Homogeneity index 98%.

LC/MS: for [M+H] ⁺c ₂₁h ₂₂brN ₂o ₄analytical calculation value: 445.08; Measured value: 445.31.

Embodiment 140, step b

According to method described in synthesis of carbamates 132c, make keto-amide 140a (10.723g, 24.08mmol) change into 140b, just purified by flash chromatography (silica gel for crude product; 50%EtOAc/ hexane).Recovery obtains bromide 140b (7.622g, canescence foam). ¹HNMR(DMSO-d ₆，δ＝2.5ppm，400MHz)：12.23/12.04/11.97(m，1H)，7.73-6.96(m，10H)，5.11-4.85(m，3H)，3.61(m，1H)，3.45(m，1H)，2.33-184(m，4H)。

LC (condition 1): RT=1.42 minute; Homogeneity index > 95%.

LC/MS: for [M+H] ⁺c ₂₁h ₂₁brN ₃o ₂analytical calculation value: 426.08; Measured value: 426.31.

HRMS: for [M+H] ⁺c ₂₁h ₂₁brN ₃o ₂analytical calculation value: 426.0817; Measured value: 426.0829.

Adopt the optical purity of following chirality HPLC method evaluation 140b, observing enantiomeric excess is 99%.

Post: Chiralpak AD, 10um, 4.6 * 50mm

Solvent: 20% ethanol/heptane (isocratic elution)

Flow velocity: 1ml/ minute

Wavelength: 254nm

Relative retention time: 1.82 minutes (R), 5.23 minutes (S).

Embodiment 140, step c

By Pd (Ph ₃p) ₄(208mg, 0.180mmol) be added to bromide 140b (1.80g, 4.22mmol), hypoboric acid two pinacol esters (2.146g, 8.45mmol), KOAc (1.8g are housed, 11.0mmol) and in the penstock of the mixture of Isosorbide-5-Nitrae-dioxs (34ml).Reaction flask purging with nitrogen gas, jumps a queue, and with oil bath, heats 23 hours at 80 ℃.Vacuum is removed after volatile component, carefully by resistates at CH ₂cl ₂(70ml) and water-bearing media (the saturated NaHCO of 22ml water+5ml ₃solution) between, distribute.Water layer CH ₂cl ₂extraction, the organic phase drying (MgSO of merging ₄), filter final vacuum concentrated.Oiliness resistates crystallizes out from EtOAc/ hexane, obtains two crowdes of boric acid ester 140c (1.52g, yellow solid).Make after mother liquor vacuum-evaporation the (silica gel of purified by flash chromatography for products therefrom; 20-35%EtOAc/CH ₂cl ₂), obtain another crowd of 140c (772mg), be pale solid, contain remaining tetramethyl ethylene ketone.

LC (condition 1): RT=1.95 minute.

LC/MS: for [M+H] ⁺c ₂₇h ₃₃bN ₃o ₄analytical calculation value: 474.26; Measured value: 474.31.

Embodiment 140, steps d-e

By adopting same procedure described in synthetic biaryl 132d, by aromatic bromide 132c and boric acid ester 140c coupling, obtain 140d.The debrominate form that sample contains 132c is impurity.Without being further purified just, can carry out next step.

LC (condition 1): RT=1.72 minute; Homogeneity index～85%.

LC/MS: for [M+H] ⁺c ₃₈h ₄₂n ₇o ₄analytical calculation value: 660.33; Measured value: 660.30.

The mixture of 10%Pd/C (226mg), biaryl 140d (1.25g) and MeOH (15ml) is stirred～160 hours under hydrogen capsule, wherein if needed, regularly hydrogen make-up supply.Reaction mixture is passed through to diatomite pad filters, and makes filtrate vacuum-evaporation, obtains crude product 140e (911mg, tawny foam).Without being further purified just, can carry out next step.

LC (condition 1): RT=1.53 minute.

LC/MS: for [M+H] ⁺c ₃₀h ₃₆n ₇o ₂analytical calculation value: 526.29; Measured value: 526.23.

Embodiment 140, step f-g

Adopt successively the acid amides for the synthesis of embodiment 132 to form and Boc deprotection scheme, by the intersexes of carbamate 140f, by 140e and Cap-4, prepare tetramethyleneimine 140g.

LC (condition 1): RT=1.09 minute; Homogeneity index～94%.

LC/MS: for [M+H] ⁺c ₃₅h ₃₇n ₈o ₃analytical calculation value: 617.30; Measured value: 617.38.

Embodiment 140

Employing is by method described in intermediate 132e Preparation Example 132, by the tfa salt of tetramethyleneimine 140g and Cap-1 synthetic example 140.

1.15 minutes (condition 1); Homogeneity index > 98%.

LC/MS: for [M+H] ⁺c ₄₅h ₄₀n ₇o ₄analytical calculation value: 778.38; Measured value: 778.48.

HRMS: for [M+H] ⁺c ₄₅h ₄₀n ₇o ₄analytical calculation value: 778.3829; Measured value: 778.3849.

The tfa salt of embodiment 141-143 is synthetic by intermediate 140g and suitable agent in a similar manner.

Embodiment 141-143

Embodiment 144

((1R)-2-((2S)-2-(5-(4-(5-(2-((2S)-1-(4-morpholinyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-2-pyridyl) phenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane

The DMF of morpholine-4-formyl chloride (8.5mg, 0.057mmol) (1.5ml) solution is added to i-Pr ₂in the mixture of EtN (20 μ l, 0.115mmol) and 140g (27.3mg, 0.044mmol), and stir 100 minutes.Vacuum is removed volatile component, and resistates is purified (H with reversed-phase HPLC ₂o/MeOH/TFA), obtain the tfa salt (34.6mg, yellow foam) of embodiment 144.

1.17 minutes (condition 1); > 98%.

LC/MS: for [M+H] ⁺c ₄₀h ₄₄n ₉o ₅analytical calculation value: 730.35; Measured value: 730.42.

HRMS: for [M+H] ⁺c ₄₀h ₄₄n ₉o ₅analytical calculation value: 730.3465; Measured value: 730.3477.

Embodiment 145

(2,2 '-dipyridyl-5,5 '-bis-bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-second two bases))) two (Urethylanes)

Embodiment 145, step a-b

By Pd (Ph ₃p) ₄(9.6mg, 0.008mmol) and LiCl (28mg, 0.67mmol) are added in the mixture of aromatic bromide 132c (98.7mg, 0.251mmol) and hexa methyl ditin (51.6mg, 0.158mmol), and at 80 ℃, heating is～3 days.Vacuum is removed volatile component, and gained crude product is used flash chromatography (silica gel successively; 0-10%MeOH/EtOAc) and reversed-phase HPLC (H ₂o/MeOH/TFA) purifying.Excessive 2.0N NH for HPLC effluent ₃/ MeOH neutralization, vacuum is removed volatile component.Make resistates at CH ₂cl ₂and between water, distribute water CH ₂cl ₂washing (2 times).Organic phase drying (the MgSO merging ₄), filter final vacuum concentrated, obtain carbamate 145a (8.7mg, oily tympan).

LC (condition 1): RT=1.68 minute; Homogeneity index > 98%.

LC/MS: for [M+H] ⁺c ₃₄h ₄₃n ₈o ₄analytical calculation value: 627.34; Measured value: 627.47.

According to prepared the method for 132e by 132d, carbamate 145a is prepared into tetramethyleneimine 145b. ¹h NMR (DMSO, δ=2.5ppm; 400MHz): 12.02 (br signal, 2H), 9.04 (d, J=1.6,2H), 8.34 (d, J=8.3,2H), 8.20 (dd, J=8.3,2.3,2H), 7.67 (br s, 1H), 4.21 (m, 2H), 3.00-2.85 (m, 4H), 2.12-2.04 (m, 2H), 1.95-1.68 (m, 6H).[noting: do not observe tetramethyleneimine-NH signal].

LC (condition 1): RT=1.17 minute; Homogeneity index > 98%.

LC/MS: for [M+H] ⁺c ₂₄h ₂₇n ₈analytical calculation value: 427.24; Measured value: 427.13.

Embodiment 145

According to the method by 132e Preparation Example 132, by 145b synthetic example 145 (tfa salt).

LC (condition 1): RT=1.63 minute; Homogeneity index 98%

LC/MS: for [M+H] ⁺c ₄₄h ₄₅n ₁₀o ₆analytical calculation value: 809.35; Measured value: 809.40.

Embodiment 146

(1R)-2-((2S)-2-(5-(5-(4-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl) phenyl)-2-pyridyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine

Embodiment 146, step a

In 15 minutes, by N-BuLi (12.0ml 2.5M/ hexane, 30mmol) be added drop-wise to cooling (78 ℃) 2, in the toluene of 5-dibromo pyridine (6.040g, 25.5mmol) (300ml) half solution, and stir 2.5 hours.In 7 minutes, add 2-(methoxyl group (methyl) amino)-2-oxoethyl t-butyl carbamate (2.809g, 12.87mmol) in batches, at-78 ℃, continue to stir 1.5 hours.With-60 ℃, bathe and replace-78 ℃ of baths, it was warming up to-15 ℃ in 2.5 hours.The saturated NH of reactant ₄cl solution (20ml) quencher, makes mixture be melted up to envrionment temperature, after separated organic layer, and vacuum-evaporation.Gained is purified by flash chromatography (silica gel for crude product; 15%EtOAc/ hexane), obtain sorrel semisolid, then with hexane washing, to remove coloured resistates.Recovery obtains pyridine 146a (842mg, gray solid). ¹h NMR (DMSO, δ=2.5ppm; 400MHz): 8.89 (d, J=2.3,1H), 8.30 (dd, J=8.4,2.4,1H), 7.90 (d, J=8.3,1H), 7.03 (brt, J=5.7,0.88H), 6.63 (apparent br s, 0.12H), 4.55 (d, J=5.8,2H), 1.40/1.28 (two apparent s, 7.83H+1.17H).

LC (condition 1): RT=2.00 minute; Homogeneity index > 95%.

LC/MS: for [M+Na] ⁺c ₁₂h ₁₅brNaN ₂o ₃analytical calculation value: 337.02; Measured value: 337.13.

Embodiment 146, step b

In 3 minutes, 48%HBr (1.0ml) is added drop-wise to carbamate 146a and (in 840mg, 2.66mmol) diox (5.0ml) solution, reaction mixture is stirred 17.5 hours at ambient temperature.Throw out is filtered, and Yong diox washing final vacuum is dry, obtains the HBr salt (672.4mg of amine 146b; Do not measure the accurate molar equivalent of HBr salt, pale solid). ¹HNMR(DMSO，δ＝2.5ppm；400MHz)：8.95(d，J＝2.3，1H)，8.37(dd，J＝8.4，2.3，1H)，8.2(br s，3H)，8.00(d，J＝8.3，1H)，4.61(s，2H)。

LC (condition 1): RT=0.53 minute.

LC/MS: for [M+H] ⁺c ₇h ₈brN ₂o analytical calculation value: 214.98; Measured value: 215.00.

Embodiment 146, step c

In 15 minutes, by i-Pr ₂etN (2.3ml, 13.2mmol) be added drop-wise to amine 146b (1.365g), (S)-Boc-proline(Pro) (0.957g, 4.44mmol) and in the heterogeneous mixture of HATU (1.70g, 4.47mmol) and DMF (13.5ml), stir at ambient temperature 1 hour.Vacuum is removed volatile component, makes resistates at EtOAc (40ml) and water-bearing media (the saturated NaHCO of 20ml water+1ml ₃solution) between, distribute.EtOAc for water layer (20ml) washing, the organic phase drying (MgSO of merging ₄), filter final vacuum concentrated.Gained is purified by flash chromatography (silica gel for crude product; 40-50%EtOAc/ hexane), obtain keto-amide 146c (1.465g, dark yellow foam). ¹h NMR (DMSO, δ=2.5ppm; 400MHz): 8.90 (d, J=2.3,1H), 8.30 (dd, J=8.5,2.4,1H), and 8.01-8.07 (m, 1H), 7.90 (d, J=8.3,1H), 4.6 (m, 1H), 4.64 (dd, J=19.1,5.5,1H); 4.19 (m, 1H), 3.39 (m, 1H), 3.32-3.26 (m, 1H), 2.20-2.01 (m, 1H), 1.95-1.70 (m, 3H), 1.40/1.35 (two apparent s, 9H).

LC (condition 1): RT=1.91 minute.

LC/MS: for [M+Na] ⁺c ₁₇h ₂₂brN ₃naO ₄analytical calculation value: 434.07; Measured value: 433.96.

Embodiment 146, steps d

By keto-amide 146c (782.2mg, 1.897mmol) and NH ₄the microwave heating for mixture (140 ℃) of OAc (800mg, 10.4mmol) and dimethylbenzene 90 minutes.Vacuum is removed volatile component, makes carefully resistates at CH ₂cl ₂and distribute between water, add wherein enough saturated NaHCO ₃solution so that among and.Water CH ₂cl ₂extraction (2 times), the organic phase drying (MgSO of merging ₄), filter final vacuum concentrated.Gained is purified by flash chromatography (silica gel for crude product; 50%CH ₂cl ₂/ EtOAc), obtain imidazoles 146d (552.8mg, pale solid). ¹h NMR (DMSO, δ=2.5ppm; 400MHz): 12.49/12.39/12.15/12.06 (br s, 1H), 8.62 (apparent br s, 0.2H), 8.56 (d, J=2,0.8H), 8.02 (br d, J=8.5,0.2H), 7.97 (br d, J=7.8,0.8H), 7.77 (d, J=8.6,0.8H), 7.72 (d, J=8.6,0.2H), 7.61-7.49 (m, 1H), 4.93-4.72 (m, 1H), 3.53 (m, 1H), 3.41-3.32 (m, 1H), 2.33-1.77 (m, 4H), 1.39/1.14 (apparent br s, 3.7H+5.3H).

LC (condition 1): RT=1.67 minute; Homogeneity index > 95%

LC/MS: for [M+Na] ⁺c ₁₇h ₂₁brN ₄naO ₂analytical calculation value: 415.08; Measured value: 415.12.

Embodiment 146, step e

146e (R ₁=H, R ₂=SEM) or (R ₁=SEM, R ₂=H)

By NaH (60%; 11.6mg, 0.29mmol) in the disposable heterogeneous mixture that is added to imidazoles 146d (80mg, 0.203mmol) and DMF (1.5ml), and under envrionment conditions, stir 30 minutes.In 2 minutes, SEM-Cl (40 μ l, 0.226mmol) is added drop-wise in above-mentioned reaction mixture, and continues to stir 14 hours.Vacuum is removed volatile component, makes resistates at water and CH ₂cl ₂between distribute.Water layer CH ₂cl ₂extraction, the organic phase drying (MgSO of merging ₄), filter final vacuum concentrated.(the silica gel of purified by flash chromatography for crude product; 20%EtOAc/ hexane), obtain 146e (87.5mg, viscosity colorless oil).Do not measure the accurate regional chemistry structure (regiochemistry) of 146e. ¹H NMR(CDCl ₃，δ＝7.4ppm；400MHz)：8.53(d，J＝2.2，1H)，7.90-7.72(m，2H)，7.52(s，1H)，5.87(m，0.46H)，5.41(m，0.54H)，5.16(d，J＝10.8，1H)，5.03-4.85(m，1H)，3.76-3.42(m，4H)，2.54-1.84(m，4H)，1.38/1.19(br s，4.3H+4.7H)，0.97-0.81(m，2H)，-0.03(s，9H)。

LC (condition 1): RT=2.1 minute.

LC/MS: for [M+H] ⁺c ₂₃h ₃₆brN ₄o ₃si analytical calculation value: 523.17; Measured value: 523.24.

Embodiment 146, step f

146f:(R ₁=H, R ₂=SEM) or (R ₁=SEM, R ₂=H)

By Pd (Ph ₃p) ₄(24.4mg, 0.021mmol) is added to imidazoles 146e (280mg, 0.535mmol), 1c (241.5mg, 0.55mmol) and NaHCO ₃(148.6mg, 1.769mmol) and 1, in the mixture of 2-glycol dimethyl ether (4.8ml) and water (1.6ml).Reaction mixture nitrogen purging, heats after～24 hours at 80 ℃ with oil bath, and vacuum is removed volatile component.Make resistates at CH ₂cl ₂and between water, distribute organic phase drying (MgSO ₄), filter final vacuum concentrated.Crude product is purified (silica gel by Biotage system; 75-100%EtOAc/ hexane), then with reversed-phase HPLC purify (H ₂o/MeOH/TFA).HPLC effluent 2M NH ₃in/MeOH and after, vacuum-evaporation, makes resistates at water and CH ₂cl ₂between distribute.Organic layer drying (MgSO ₄), filter final vacuum concentrated, obtain 146f (162mg, white foam shape thing).

LC (condition 1): RT=2.1 minute.

LC/MS: for [M+H] ⁺c ₄₁h ₅₈n ₇o ₅si analytical calculation value: 756.43; Measured value: 756.55.

Embodiment 146, step g

Carbamate 146f (208mg, 0.275mmol) uses 25%TFA/CH ₂cl ₂(4.0ml) process, and stir at ambient temperature 10 hours.Vacuum is removed volatile component, and resistates is first with the free alkalization of MCX (MeOH washing; 2.0M NH ₃/ MeOH wash-out) after, then purify (H with reversed-phase HPLC ₂o/MeOH/TFA), products therefrom through free alkalization (MCX), obtains tetramethyleneimine 146g (53.7mg, oily tympan) again. ¹h NMR (DMSO, δ=2.5ppm; 400MHz): 1.88 (apparent br s, 2H), 8.83 (d, J=2.1,1H), 8.07 (dd, J=8.3/2.3,1H0,7.87 (d, J=8.5,1H), 7.84 (d, J=8.3,2H), 7.71 (d, J=8.3,2H), 7.55 (s, 1H), 7.50 (br s, 1H), 4.18 (m, 2H), 3.00-2.94 (m, 2H), 2.89-2.83 (m, 2H), 2.11-2.02 (m, 2H), 1.95-1.86 (m, 2H), 1.83-1.67 (m, 4H).

LC (condition 1): RT=0.95 minute; Homogeneity index > 98%.

LC/MS: for [M+H] ⁺c ₂₅h ₂₈n ₇analytical calculation value: 426.24; Measured value: 426.27.

Embodiment 146

According to the method by intermediate 132e Preparation Example 132, by tetramethyleneimine 146g synthetic example 146 (tfa salt).

LC (condition 1): RT=1.42 minute; Homogeneity index 96.5%.

LC/MS: for [M+H] ⁺c ₄₅h ₅₀n ₉o ₂analytical calculation value: 748.41; Measured value: 748.57.

HRMS: for [M+H] ⁺c ₄₅h ₅₀n ₉o ₂analytical calculation value: 748.4087; Measured value: 748.4100.

Embodiment 147

((1R)-2-((2S)-2-(5-(5-(4-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl) phenyl)-2-pyridyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane

Adopt Cap-4, the same tfa salt by intermediate 146g Preparation Example 147.

LC (condition 1): RT=1.66 minute; Homogeneity index 95%.

LC/MS: for [M+H] ⁺c ₄₅h ₄₆n ₉o ₆analytical calculation value: 808.36; Measured value: 808.55.

Embodiment 148

(1R, 1 ' R)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (4R)-1,3-thiazoles alkane-4,3-bis-bases)) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amines)

Embodiment 148, step a

At 50 ℃, the 15ml glacial acetic acid solution of bromine (1.3ml, 25.0mmol) is added drop-wise in the 40ml acetic acid solution of 4-4 '-diacetyl biphenyl (3.0g, 12.5mmol).Complete after liquid feeding, mixture is at room temperature stirred and spent the night.The product of separating out being leached, again use chloroform crystallization, obtain 1,1 '-(biphenyl-4,4 '-bis-bases) two (2-bromine ethyl ketone) (3.84g, 77.5%), is white solid.

¹h NMR (500MHz, chloroform-D) δ ppm 8.09 (4H, d, J=7.93Hz) 7.75 (4H, d, J=8.24Hz) 4.47 (4H, s).

Nominal/LRMS-analytical calculation value: 369.07 measured values:; (M+H) ⁺-397.33, (M-H) ^--395.14.

Embodiment 148, step b

Diformyl sodium amide (Sodium diformylamide) (3.66g, 38.5mmol) is added to 1,1 '-85ml acetonitrile suspension of (biphenyl-4,4 '-bis-bases) two (2-bromine ethyl ketone) (6.1g, 15.4mmol) in.By mixture reflux after 4 hours, concentrating under reduced pressure.Resistates is suspended in the ethanolic soln of 300ml 5%HCl to reflux 3.5 hours.Make reactant be cooled to room temperature, in refrigerator, place 1 hour.The solid that collection is separated out, uses after 1: 1 ethanol/ether of 200ml and the washing of 200ml pentane successively, and vacuum-drying obtains 1,1 '-(biphenyl-4,4 '-bis-bases) two (the amino ethyl ketone of 2-) dihydrochloride (4.85g, 92%).Without purifying, just can use.

¹H NMR(300MHz，DMSO-d ₆)δppm 8.47-8.55(4H，m)8.11-8.17(4H，m)8.00(4H，d，J＝8.42Hz)4.59-4.67(4H，m)。

LCMS-Phenomenex C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.1%TFA, B=90% methyl alcohol 10% water 0.1%TFA, t _r=0.44 minute, for C ₁₆h ₁₆n ₂o ₂analytical calculation value: 268.31; Measured value: 269.09 (M+H) ⁺.

Embodiment 148, step c

In 5 minutes, to 1,1 '-(biphenyl-4,4 '-bis-bases) two (the amino ethyl ketone of 2-) dihydrochloride (0.7g, 2.1mmol), N-(tertbutyloxycarbonyl)-L-Thioproline (0.96g, 4.2mmol) and in the stirred solution of HATU (1.68g, 4.4mmol) and 14ml DMF drip diisopropylethylamine (1.5ml, 8.4mmol).Gained glassy yellow solution is at room temperature stirred and spent the night after (14 hours), concentrating under reduced pressure.Resistates is distributed between 20% methyl alcohol/chloroform and water.20% methyl alcohol for water/chloroform washs once.The organism salt water washing merging, dry (MgSO ₄), after filtration, concentrating under reduced pressure.Crude product is processed (with 10-50% ethyl acetate/CH with silica gel chromatography ₂cl ₂gradient elution), obtain (4S, 4 ' S)-4,4 '-(2,2 '-(biphenyl-4,4 '-bis-bases) two (2-oxo ethane-2,1-bis-bases)) two (azane two bases) two (oxo methylene radical) dithiazole alkane-3-t-butyl formate (0.39g, 27%), be orange foam.

¹H NMR(400MHz，DMSO-d ₆)δppm 8.38(2H，s)8.12(4H，d，J＝8.56Hz)7.94(4H，d，J＝8.56Hz)4.60-4.68(4H，m)4.33-4.38(2H，m)3.58-3.68(2H，m)3.38(2H，s)3.08-3.18(2H，m)1.40(18H，s)。

LCMS-Water-Sunfire C-184.6 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.1%TFA, B=90% methyl alcohol 10% water 0.1%TFA, t _r=3.69 minutes.For C ₃₄h ₄₂n ₄o ₈s ₂analytical calculation value: 698.85 measured values: 699.12 (M+H) ⁺.

Embodiment 148, steps d

By (4S, 4 ' S)-4,4 '-(5,5 '-(biphenyl-4,4 '-bis-bases) two (1H-imidazoles-5,2-bis-bases)) dithiazole alkane-3-t-butyl formate (0.39g, 0.56mmol) and ammonium acetate (0.43g, 5.6mmol) are suspended in 8ml o-Xylol in microwave reaction container.By mixture under standard microwave condition in 140 ℃ heating 70 minutes after, concentrating under reduced pressure.Resistates is dissolved in to 30ml 20% methyl alcohol/chloroform, uses 10%NaHCO ₃(aqueous solution) washing.Organic layer salt water washing, dry (MgSO ₄), concentrating under reduced pressure after filtering.Crude product is processed (with 1-6% methyl alcohol/CH with silica gel chromatography ₂cl ₂gradient elution), obtaining (4S, 4 ' S)-4,4 '-(5,5 '-(biphenyl-4,4 '-bis-bases) two (1H-imidazoles-5,2-bis-bases)) dithiazole alkane-3-t-butyl formate (0.15g, 41%), is yellow solid.

¹H NMR(500MHz，DMSO-d ₆)δppm 12.02(2H，s)7.70-7.88(10H，m)5.28-5.37(2H，m)4.68(2H，d，J＝9.16Hz)4.47-4.55(2H，m)3.46(2H，s)3.23(2H，s)1.26-1.43(18H，m)。

LCMS-Luna C-183.0 * 50mm, gradient 0-100%B, in 3.0 minutes, 1 minute residence time, A=5% acetonitrile, 95% water, 10mm ammonium acetate, B=95% acetonitrile, 5% water, 10mm ammonium acetate, t _r=1.96 minutes.For C ₃₄h ₄₀n ₆o ₄s ₂analytical calculation value: 660.85; Measured value: 661.30 (M+H) ⁺, 659.34 (M-H) ^-.

Embodiment 148, step e

In the 1ml dioxane solution of (4S, 4 ' S)-4,4 '-(5,5 '-(biphenyl-4,4 '-bis-bases) two (1H-imidazoles-5,2-bis-bases)) dithiazole alkane-3-t-butyl formate, add 0.3ml 4.0M HCl dioxane solution.Reactant was at room temperature stirred after 3 hours to concentrating under reduced pressure.Making the vacuum-drying of gained tawny solid, obtain 4,4 '-bis-(2-((S)-thiazolidine-4-yl)-1H-imidazoles-5-yl) biphenyl four hydrochlorides (0.12g, 100%), is yellow solid.

¹H NMR(500MHz，DMSO-d ₆)δppm 8.09(2H，s)8.01(4H，d，J＝8.55Hz)7.90(4H，d，J＝8.55Hz)5.08(2H，t，J＝6.10Hz)4.38(2H，d，J＝9.16Hz)4.23(2H，d，J＝9.46Hz)3.48-3.54(2H，m)3.35-3.41(2H，m)。

LCMS-Luna C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=5% acetonitrile, 95% water, 10mm ammonium acetate, B=95% acetonitrile, 5% water, 10mm ammonium acetate, t _r=1.70 minutes.For C ₂₄h ₂₄n ₆s ₂analytical calculation value: 460.62 measured values: 461.16 (M+H) ⁺, 459.31 (M-H) ^-.

Embodiment 148

To (4,4 '-bis-(2-((S)-thiazolidine-4-yl)-1H-imidazoles-5-yl) biphenyl four hydrochloride (0.028g, 0.046mmol), (R)-2-(dimethylamino)-2-phenylacetic acid (Cap-1,0.017g, 0.0.10mmol) and HATU (0.039g, 0.10mmol) and in the stirred solution of 2ml DMF add diisopropylethylamine (0.05ml, 0.28mmol).Reactant is at room temperature stirred and spend the night after (16 hours), concentrating under reduced pressure.Crude product is purified with anti-phase preparation HPLC, obtain (2R, 2 ' R)-1,1 '-((4S, 4 ' S)-4,4 '-(5,5 '-(biphenyl-4,4 '-bis-bases) two (1H-imidazoles-5,2-bis-bases)) two (thiazolidine-4,3-bis-bases)) two (2-(dimethylamino)-2-Phenyl ethyl ketone) (0.012g, 21%, tfa salts).

¹H NMR(500MHz，DMSO-d ₆)δppm 7.59-7.91(20H，m)5.62(2H，dd，J＝6.56，2.59Hz)4.99(2H，d，J＝8.85Hz)4.82/4.35(2H，s)4.22(2H，s)3.42(2H，s)3.25(2H，s)2.35-2.61(12H，m)。

LCMS-Luna C-183.0 * 50mm, gradient 0-100%B, in 7.0 minutes, 1 minute residence time, A=5% acetonitrile, 95% water, 10mm ammonium acetate, B=95% acetonitrile, 5% water, 10mm ammonium acetate moving phase, t _r=3.128 minutes.

Nominal/LRMS-is for C ₄₄h ₄₆n ₈o ₂s ₂calculated value: 783.03; Measured value: 783.28 (M+H) ⁺.

Accurately/HRMS-is for C ₄₄h ₄₇n ₈o ₂s ₂calculated value: 783.3263; Measured value: 783.3246 (M+H) ⁺.

According to the similar fashion described in Preparation Example 148, Preparation Example 149 and embodiment 150.

Embodiment 151

(1R, 1 ' R)-2,2 '-(4,4 '-biphenyl, two bases two ((1-methyl isophthalic acid H-imidazoles-4,2-bis-bases) (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amines)

Embodiment 151, step a

To 1d, be (2S, 2 ' S)-2,2 '-(4,4 '-(biphenyl-4,4 '-bis-bases) two (1H-imidazoles-4,2-bis-bases)) two tetramethyleneimine-1-t-butyl formate (100mg, 0.16 mmole) and methyl-iodide (40 μ l, 0.16 mmole) and CH ₂cl ₂(2ml) in stirred solution, add sodium hydride (40%) (21.2mg, 0.352 mmole).After 5 hours, this solution decompression is concentrated at ambient temperature.Rough reaction product 151a, i.e. (2S, 2 ' S)-2,2 '-(4,4 '-(biphenyl-4,4 '-bis-bases) two (1-methyl isophthalic acid H-imidazoles-4,2-bis-bases)) two tetramethyleneimine-1-t-butyl formate (～90mg) just can be used for next step (purity～85%), LCMS: for C without being further purified ₃₈h ₄₈n ₆o ₄analytical calculation value: 652.83; Measured value: 653.51 (M+H) ⁺.It should be understood that, this reaction may have the multiple isomer that methylates, and does not attempt determining these isomer.

Embodiment 151, step b

151a, i.e. (2S, 2 ' S)-2,2 '-(4,4 '-(biphenyl-4,4 '-bis-bases) two (1-methyl isophthalic acid H-imidazoles-4,2-bis-bases)) two tetramethyleneimine-1-t-butyl formate (100mg, 0.153 mmole) is processed with 4M HCl/ diox (20ml).After 3 hours, this solution decompression is concentrated at ambient temperature.Rough reaction product 4,4 '-bis-(1-methyl-2-((S)-pyrrolidin-2-yl)-1H-imidazol-4 yl) biphenyl (～110mg, HCl salt) just can be used for next step (purity～85%) without being further purified.LCMS: for C ₂₈h ₃₂n ₆analytical calculation value: 452.59; Measured value: 453.38 (M+H) ⁺.There is multiple imidazoles isomer and can continue to carry out forward.

Embodiment 151

HATU (58.9mg, 0.150mmol) is added to 151b i.e. 4,4 '-bis-(1-methyl-2-((S)-pyrrolidin-2-yl)-1H-imidazol-4 yl) biphenyl (45.0mg, 0.075mmol), (i-Pr) ₂in the mixture of EtN (78 μ l, 0.451mmol) and Cap-1 (R)-2-(dimethylamino)-2-toluylic acid (0.026mg0.150mmol) and DMF (1.0ml).Stir at ambient temperature gained mixture, until complete by the coupling of LC/MS Analysis deterrmination.With anti-phase preparation HPLC carry out purifying (Waters-Sunfire 30 * 100mm S5 detects under 220nm, flow velocity 30ml/ minute, 0-90%B, in 14 minutes; A=90% water, 10%ACN, 0.1%TFA, B=10% water, 90%ACN, 0.1%TFA), obtaining 151 is (2R, 2 ' R)-1,1 '-((2S, 2 ' S)-2,2 '-(4,4 '-(biphenyl-4,4 '-bis-bases) two (1-methyl isophthalic acid H-imidazoles-4,2-bis-bases)) two (tetramethyleneimine-2,1-bis-bases)) two kinds of isomer of two (2-(dimethylamino)-2-Phenyl ethyl ketones), be tfa salt.

Isomer 1:(1R, 1 ' R)-2,2 '-(4, two ((1-methyl isophthalic acid H-imidazoles-4 of 4 '-biphenyl, two bases, 2-bis-bases) (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amine) (8mg, 8.6%, colourless wax).

¹H NMR(500MHz，DMSO-d ₆)δppm 1.84-2.25(m，8H)2.32-2.90(m，12H)3.67-3.92(m，8H)4.07(s，2H)5.23(s，2H)5.51(s，2H)7.51-7.91(m，20H)。

HPLC Xterra 4.6 * 50mm, 0-100%B, in 10 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.2% phosphoric acid, B=10% water, 90% methyl alcohol, 0.2% phosphoric acid, RT=2.74 minute, 98%.

LCMS: for C ₄₈h ₅₄n ₈o ₂analytical calculation value: 775.02; Measured value: 775.50 (M+H) ⁺.

Isomer 2:(1R, 1 ' R)-2,2 '-(4, two ((1-methyl isophthalic acid H-imidazoles-4 of 4 '-biphenyl, two bases, 2-bis-bases) (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amine) (10.2mg, 11%), colourless wax.

¹H NMR(500MHz，DMSO-d ₆)δppm 1.83-2.26(m，8H)2.30-2.92(m，12H)3.68-3.94(m，8H)4.06(s，2H)5.25(d，J＝2.14Hz，2H)5.50(s，2H)7.52-7.91(m，20H)。

HPLC Xterra 4.6 * 50mm, 0-100%B, in 10 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.2% phosphoric acid, B=10% water, 90% methyl alcohol, 0.2% phosphoric acid, RT=2.75 minute, 90%.

LCMS: for C ₄₈h ₅₄n ₈o ₂analytical calculation value: 775.02; Measured value: 775.52 (M+H) ⁺.

Embodiment 152

Embodiment 152a-1, step a

The chloro-5-of 2-(1-vinyl ethyl ether base) pyrimidine

Under nitrogen atmosphere, to the bromo-2-chloropyrimide of 5-(12.5g, in dry DMF 64.62mmol) (175ml) solution, add tributyl (1-vinyl ethyl ether base) tin (21.8ml, 64.62mmol) close palladium (II) (2.27g, 3.23mmol) with dichloro two (triphenylphosphine).Mixture is heated at 100 ℃ after 3 hours, it is at room temperature stirred 16 hours.Then ether (200ml) dilution for mixture, and process with the KF aqueous solution (55g Potassium monofluoride/33ml water).By two-phase mixture vigorous stirring after 1 hour, through diatomite at room temperature filter.Filtrate is used saturated NaHCO ₃dry (Na after solution and salt water washing ₂sO ₄).Initial extracted with diethyl ether for water (2 times), organic phase is as above processed.With the bromo-2-chloropyrimide of 13.5g 5-, repeat the extract Biotage of merging ^tMflash chromatography on silica gel method purifying (by 3.0L 3% ethyl acetate/hexane to 25% ethyl acetate/hexane, in 65M post gradient elution), obtains title compound (18.2g, 73%, white crystalline solid).

¹H NMR(500MHz，DMSO-d ₆)δ8.97(s，2H)，5.08(d，J＝3.7Hz，1H)，4.56(d，J＝3.4Hz，1H)，3.94(q，J＝7.0Hz，2H)，1.35(t，J＝7.0Hz，3H)。

LCMS Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 3 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, RT=2.53 minute, homogeneity index 98.8%.

LCMS: for C ₈h ₁₀clN ₂o analytical calculation value: 185.05; Measured value: 185.04 (M+H) ⁺.

HRMS: for C ₈h ₁₀clN ₂o analytical calculation value: 185.0482; Measured value: 185.0490 (M+H) ⁺.

Adopt same procedure Preparation Example 152a-2 and embodiment 152a-3:

Embodiment 152d-1 to embodiment 152d-6

Embodiment 152b-1, step b

(S)-2-(5-(2-chloropyrimide-5-yl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate or

(S)-2-[5-(the chloro-pyrimidine-5-of 2-yl)-1H-imidazoles-2-yl]-tetramethyleneimine-1-t-butyl formate

At nitrogen atmosphere, 0 ℃, by the disposable chloro-5-of 2-(1-vinyl ethyl ether base) pyrimidine (152a-1,18.2g, 98.6mmol) and THF (267ml) and the H of being added to of NBS (16.1g, 90.7mmol) ₂in the stirred solution of O (88ml).Mixture is stirred 1 hour at 0 ℃, then use H ₂after O dilution, be extracted with ethyl acetate (2 times).The saturated NaHCO of extract merging ₃after solution and salt water washing, dry (Na ₂sO ₄), evaporating solvent after filtering.LCMS Phenomenex LUNAC-184.6 * 50mm, 0-100%B, in 3 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, RT=1.52 minute (unsymmetrical peak).LCMS: for C ₆h ₁₄brClN ₂o analytical calculation value: 235.92; Measured value: 236.85 (M+H) ⁺.

Embodiment 152c-1, step c

By a half rough resistates (the bromo-1-of 2-(2-chloropyrimide-5-yl) ethyl ketone,～14.5g) be dissolved in anhydrous acetonitrile (150ml), directly with N-Boc-L-proline(Pro) (9.76g, 45.35mmol) and diisopropylethylamine (7.9ml, 45.35mmol), process.Stir after 3 hours, solvent removed in vacuo, is assigned in ethyl acetate and water resistates.0.1N hydrochloric acid, saturated NaHCO for organic phase ₃solution and salt water washing, dry (Na ₂sO ₄), concentrated after filtering.LCMS Phenomenex LUNAC-184.6 * 50mm, 0-100%B, in 3 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, RT=2.66 minute.

Adopt same procedure Preparation Example 152c to embodiment 152c-6.

Embodiment 152d-1, steps d

Resistates ((S)-1-2-(2-(2-chloropyrimide-5-yl)-2-oxoethyl) tetramethyleneimine-1, the 2-dioctyl phthalate tert-butyl ester) is dissolved in to dimethylbenzene (200ml), uses NH ₄oAc (17.5g, 0.23mol) processes.Mixture in heavy wall, screw-topped flask is heated after 2 hours at 140 ℃, make it to be cooled to suction strainer after envrionment temperature.Then concentrated filtrate, is assigned to ethyl acetate and saturated NaHCO ₃in solution, with after salt water washing, dry (Na ₂sO ₄), concentrated after filtering, make initial precipitate be assigned to NaHCO ₃in the aqueous solution and ethyl acetate, supersound process is suction strainer after 2 minutes.Filtrate is used salt water washing, dry (Na ₂sO ₄), after filtration, be concentrated into dry.The resistates Biotage merging ^tMflash chromatography on silica gel method purifying (65M post, with after 900ml 2%B pre-equilibration, with 450ml 2%B to 2%B gradient elution, then use 3000ml 2%B to 40%B gradient elution, wherein B=methyl alcohol, A=methylene dichloride), obtain title compound (7.0g, 44%, 2 step of yield, pure flow point), be yellowish-orange foam.Mixed flow divides and carries out Biotage for the second time ^tM(40M post, with after 600ml 1%B pre-equilibration, uses 150ml 1%B to 1%B and 1500ml 1%B to 10%B gradient elution to silica gel chromatography purifying successively, B=MeOH wherein, A=CH ₂cl ₂), then obtain title compound (2.8g, 18%), be tenne foam. ¹hNMR (500MHz, DMSO-d ₆) δ 12.24-12.16 (m, 1H), 9.05 (s, 2H), 7.84-7.73 (m, 1H), 4.90-4.73 (m, 1H), 3.59-3.46 (m, 1H), 3.41-3.31 (m, 1H), 2.32-2.12 (m, 1H), 2.03-1.77 (m, 3H), 1.39 and 1.15 (2s, 9H).

LCMS Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 3 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, RT=1.92 minute, homogeneity index 94.7%.

LRMS: for C ₁₆h ₂₁clN ₅o ₂analytical calculation value: 350.14; Measured value: 350.23 (M+H) ⁺.

HRMS: for C ₁₆h ₂₁clN ₅o ₂analytical calculation value: 350.1384; Measured value: 350.1398 (M+H) ⁺.

Adopt same procedure Preparation Example 152d-2 to embodiment 152d-6.

Embodiment 152e-1, step e

Embodiment 152e-1:(S)-2-(5-(2-chloropyrimide-5-yl)-1-((2-(trimethylammonium-silyl) oxyethyl group) methyl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate

Under nitrogen atmosphere, envrionment temperature, by sodium hydride (60% mineral oil dispersion, 0.23g, 5.72mmol) disposable being added to (S)-2-(5-(2-chloropyrimide-5-yl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate (152d-1,2.0g, 5.72mmol) with the stirred solution of dry DMF (45ml) in.Mixture was stirred after 5 minutes, with the increment of about 0.1ml, add SEM muriate (1.01ml, 5.72mmol).Mixture was stirred after 3 hours, use NH ₄the quencher of Cl saturated solution, and dilute by ethyl acetate.The saturated NaHCO of organic phase ₃solution and salt water washing, dry (Na ₂sO ₄), concentrated after filtering.It is many twice that initial water extracts again, the resistates Biotage of merging ^tMpurified by flash chromatography (40M post, 50ml/ minute, with after 750ml 5%B pre-equilibration, carries out substep gradient elution with 150ml 5%B to 5%B, 1500ml 5%B to 75%B and 750ml75%B to 100%B successively, wherein solvent B is ethyl acetate, and solvent orange 2 A is hexane).After concentrate eluant, obtain title compound (2.35g, 85%, light yellow foam).

¹h NMR (500MHz, DMSO-d ₆) δ 9.04 (s, 2H), 7.98-7.95 (m, 1H), 5.70-5.31 (3m, 2H), 5.02-4.91 (m, 1H), 3.59-3.49 (m, 3H), 3.45-3.35 (m, 1H), 2.30-2.08 (m, 2H), 1.99-1.83 (m, 2H), 1.36 and 1.12 (2s, 9H), 0.93-0.82 (m, 2H) ,-0.02 (s, 9H).

LCMS Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 2 minutes, 2 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, RT=2.38 minute, homogeneity index 95%.

LRMS: for C ₂₂h ₃₅clN ₅o ₃si analytical calculation value: 480.22; Measured value: 480.23 (M+H) ⁺.

HRMS: for C ₂₂h ₃₅clN ₅o ₃si analytical calculation value: 480.2198; Measured value: 480.2194 (M+H) ⁺.

Adopt same procedure to prepare 152e-2 to 152e-4.

Embodiment 152f-1 to embodiment 152f-2

Embodiment 152f-1

(S)-1-(2-(5-(2-chloropyrimide-5-yl)-1H-imidazoles-2-yl) pyrrolidin-1-yl)-2-(pyridin-3-yl) ethyl ketone

With syringe, the 4N HCl/ diox (5ml) of cooling (0 ℃) is added to (S)-2-(5-(2-chloropyrimide-5-yl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate (152d-1 being contained in 100ml pyriform flask, 0.50g, after 1.43mmol), add MeOH (1.0ml).Suspension was at room temperature stirred after 4 hours, be concentrated into dryly, and be placed in high vacuum lower 1 hour.Separation obtains the chloro-5-of intermediate (S)-2-(2-(pyrrolidin-2-yl)-1H-imidazoles-5-yl) pyrimidine tri hydrochloride, for light yellow solid (being with orange), without being further purified just, can use.

At ambient temperature, by HATU (0.60g, 1.57mmol) the disposable chloro-5-of intermediate (S)-2-(2-(the pyrrolidin-2-yl)-1H-imidazoles-5-yl) pyrimidine tri hydrochloride (0.46g that is added to, 1.43mmol, theoretical amount), 2-(pyridin-3-yl) acetic acid (0.25g, 1.43mmol) and in the stirred solution of DIEA (1.0ml, 5.72mmol) and dry DMF (10ml).Mixture was at room temperature stirred after 2 hours, and vacuum is removed DMF.Resistates is dissolved in to CH ₂cl ₂after, carry out Biotage ^tMflash chromatography on silica gel method processes that (40M post, with after 600ml 0%B pre-equilibration, carries out substep gradient elution with 150ml 0%B to 0%B, 1500ml 0%B to 15%B and 999ml 15%B to 25%B successively, B=MeOH wherein, A=CH ₂cl ₂).Separation obtains title compound (0.131g, 25%, 2 step), is yellow solid.

¹h NMR (500MHz, DMSO-d ₆) δ 9.10-9.08 (2s, 2H), 8.72-8.55 (serial m, 2H), 8.21-8.20 and 8.11-8.10 (2m, 1H), 8.00 and 7.93 (2s, 1H), 7.84-7.77 (serial m, 1H), 5.43-5.41 and 5.17-5.15 (2m, 1H), 4.02-3.94 (3m, 2H), 3.90-3.58 (3m, 2H), 2.37-2.26 (m, 1H), 2.16-1.85 (2m, 3H).

LCRMS Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 3 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, RT=0.92 minute, homogeneity index 95.1%.

LRMS: for C ₁₈h ₁₈clN ₆o analytical calculation value: 369.12; Measured value: 369.11 (M+H) ⁺.

HRMS: for C ₁₈h ₁₈clN ₆o analytical calculation value: 369.1231; Measured value: 369.1246 (M+H) ⁺.

Embodiment 152f-2

LCMS condition: Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 3 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, 220nm, 5 μ l inject volume.

Embodiment 152g-1 to embodiment 152g-16

Embodiment 152g-1 is prepared by 1c and 152e-1.(S)-2-[5-(2-{4-[2-((S)-1-tertbutyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4 yl]-phenyl }-pyrimidine-5-yl)-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-yl]-tetramethyleneimine-1-t-butyl formate

Under nitrogen atmosphere, room temperature, by Pd (Ph ₃) ₄(0.12g, 0.103mmol) ((4-(4 for 5-for disposable being added to (S)-2-, 4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) phenyl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate (1c, 1.00g, 2.27mmol), (S)-2-(5-(2-chloropyrimide-5-yl)-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate (152c-1,0.99g, 2.06mmol) and NaHCO ₃(0.87g, 10.3mmol) and DME (20ml) and H ₂in the stirred suspension of O (6ml) solution.By after reaction vessel sealing, the oil bath that mixture is placed in to preheating (80 ℃), and stir after 16 hours at 80 ℃, then add catalyzer (0.12g).Again mixture is heated after 12 hours at 80 ℃, make mixture be cooled to envrionment temperature, with ethyl acetate dilution, use saturated NaHCO ₃solution and salt water washing, after anhydrous sodium sulfate drying, concentrated solvent.Resistates Biotage ^tMflash chromatography on silica gel method purifying (adopts 40M post, with after 40%B pre-equilibration, with 150ml 40%B to 40%B, 1500ml 40%B to 100%B and 1000ml100%B to 100%B, carry out substep gradient elution successively, B=ethyl acetate wherein, A=hexane), obtain title compound (1.533g, 98%, yellow foam).A small amount of yellow foam further with preparation HPLC purify be used for characterizing object (Phenomenex GEMINI, 30 * 100mm, S10,10-100%B, in 13 minutes, 3 minute residence time, 40ml/ minute, A=95% water, 5% acetonitrile, 10mMNH ₄oAc, B=10% water, 90% acetonitrile, 10mM NH ₄oAc), obtaining 95% pure title compound, is white solid.

¹h NMR (500MHz, DMSO-d ₆) δ 12.30-11.88 (3m, 1H), 9.17-9.16 (m, 2H), 8.43-8.31 (m, 2H), 7.99-7.35 (serial m, 4H), 5.72-5.30 (3m, 2H), 5.03-4.76 (2m, 2H), 3.64-3.50 (m, 4H), 3.48-3.31 (m, 2H), 2.36-2.07 (m, 2H), 2.05-1.80 (m, 4H), 1.46-1.08 (2m, 18H), 0.95-0.84 (m, 2H) ,-0.01 (s, 9H).

HPLC Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 3 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, RT=2.91 minute, homogeneity index 95%.

LRMS: for C ₄₀h ₅₇n ₈o ₅si analytical calculation value: 757.42; Measured value: 757.42 (M+H) ⁺.

HRMS: for C ₄₀h ₅₇n ₈o ₅si analytical calculation value: 757.4221; Measured value: 757.4191 (M+H) ⁺.

Adopt same procedure Preparation Example 152g-2 to embodiment 152g-17:

Embodiment 152h-1 to embodiment 152h-7

Embodiment 152h-1 derives from 152g-1.5-((S)-2-pyrrolidin-2-yl-3H-imidazol-4 yl)-2-[4-((S)-2-pyrrolidin-2-yl-3H-imidazol-4 yl)-phenyl]-pyrimidine

At room temperature, by disposable being added to of TFA (8ml) (S)-2-[5-(2-{4-[2-((S)-1-tertbutyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4 yl]-phenyl }-pyrimidine-5-yl)-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-yl]-tetramethyleneimine-1-t-butyl formate (1.50g, 1.98mmol) and anhydrous CH ₂cl ₂(30ml) in stirred solution.By flask sealing, mixture was at room temperature stirred after 16 hours to solvent removed in vacuo.Resistates is dissolved in to methyl alcohol, by PVDF syringe filter (13mm * 0.45 μ m), filters, assign in 8 preparation HPLC tubules, with HPLC carry out chromatography processing (in 13 minutes, by 10%B to 100%B gradient elution, Phenomenex C18 post, 30 * 100mm, 10 μ m, A=90% water wherein, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA).Selected test tube is dissolved in methyl alcohol by product after concentrating by fast evaporation under vacuum, and solution is neutralized by UCTCHQAX110M75 anionresin cylinder.Elutriant is through concentrated, and separation obtains title compound (306.7mg, yield 36%, yellow mustard look solid).

¹H NMR(500MHz，DMSO-d ₆)μ12.50-11.80(br m，2H)，9.18(s，2H)，8.36(d，J＝8.5Hz，2H)，7.89(d，J＝8.2Hz，2H)，7.77(s，1H)，7.61(s，1H)，4.34-4.24(m，2H)，3.09-2.89(m，4H)，2.18-2.07(m，2H)，2.02-1.89(m，2H)，1.88-1.72(m，4H)。

LCMS Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 3 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, RT=1.33 minute, homogeneity index > 95%.

LRMS: for C ₂₄h ₂₇n ₈analytical calculation value: 427.24; Measured value: 427.01 (M+H) ⁺.

HRMS: for C ₂₄h ₂₇n ₈analytical calculation value: 427.2359; Measured value: 427.2363 (M+H) ⁺.

Adopt the same terms Preparation Example 152h-2 to embodiment 152h-14.

Embodiment 152i-1 to embodiment 152i-3

Embodiment 152i-1 derives from 152g-8.(S)-2-(5-{2-[4-((S)-2-pyrrolidin-2-yl-3H-imidazol-4 yl)-phenyl]-pyrimidine-5-yl }-1H-imidazoles-2-yl)-tetramethyleneimine-1-t-butyl formate

Under nitrogen atmosphere, room temperature, by (S)-2-[5-(2-{4-[2-((S)-1-benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4 yl]-phenyl }-pyrimidine-5-yl)-1H-imidazoles-2-yl] MeOH (1ml) solution of-tetramethyleneimine-1-t-butyl formate (317.1mg, 0.48mmol) is added to 10% palladium on carbon (60mg) and K ₂cO ₃(70mg) with MeOH (5ml) and H ₂in the stirred suspension of O (0.1ml) solution.After repeating to be filled with hydrogen in flask, vacuumize 3 times, under atmospheric pressure stir 3 hours.And then add catalyzer (20mg), reaction mixture is stirred after 3 hours, through diatomite again concentrated after suction strainer.Resistates dilutes with MeOH, through PVDF syringe filter (13mm * 0.45 μ m), filter, assign to 4 laggard circumstances in which people get things ready for a trip spectrometries of preparation HPLC tubule and process (20%B to 100%B gradient elution, in 10 minutes, Phenomenex-Gemini C18 post (30 * 100mm, 10 μ m), wherein A=95% water, 5% acetonitrile, 10mM NH ₄oAc, B=10% water, 90% acetonitrile, 10mM NH ₄oAc).Selected test tube is by concentrated after fast evaporation under vacuum, and separation obtains title compound (142.5mg, yield 56%, yellow solid).

¹h NMR (400MHz, DMSO-d ₆) δ 12.35-12.09 (br m, 1H), 9.17 (s, 2H), 8.35 (d, J=8.3Hz, 2H), 7.87 (d, J=8.3Hz, 2H), 7.80-7.72 (m, 1H), 7.56 (s, 1H), 4.92-4.77 (m, 1H), 4.21-4.13 (m, 1H), 3.61-3.05 (2m, 4H), 3.02-2.80 (2m, 2H), 2.37-1.67 (serial m, 6H), 1.41 and 1.17 (2s, 9H).

LCMS Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 3 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, RT=1.77 minute, homogeneity index > 95%.

LRMS: for C ₂₉h ₃₅n ₈o ₂analytical calculation value: 527.29; Measured value: 527.34 (M+H) ⁺.

HRMS: for C ₂₉h ₃₅n ₈o ₂analytical calculation value: 527.2883; Measured value: 527.2874 (M+H) ⁺.

Adopt same procedure Preparation Example 152i-2 to embodiment 152i-3.

Embodiment 152j-1 to embodiment 152j-28

Employing makes embodiment 148e be converted into the method for embodiment 148, isolates TFA or the AcOH salt of prepared embodiment 152j.

Embodiment 152k-1 to embodiment 152k-

Embodiment 152k-1 derives from 152j-27.(R)-2-oxo-1-phenyl-2-[(S) and-2-(5-{4-[5-((S)-2-pyrrolidin-2-yl-3H-imidazol-4 yl)-pyrimidine-2-base]-phenyl }-1H-imidazoles-2-yl)-pyrrolidin-1-yl]-ethyl }-Urethylane

By syringe, the 4N HCl/ diox (4ml) of cooling (0 ℃) is added to (S)-2-{5-[2-(4-{2-[(S)-1-((R)-2-methoxycarbonyl amino-2-phenyl-ethanoyl)-pyrrolidin-2-yl in 100ml pyriform flask]-3H-imidazol-4 yl }-phenyl)-pyrimidine-5-yl]-1H-imidazoles-2-yl }-tetramethyleneimine-1-t-butyl formate (104.6mg; after 0.146mmol), add MeOH (0.5ml).Uniform mixture was at room temperature stirred after 15 minutes, observe precipitate.Stir again after 1.75 hours ether and hexane dilution for suspension.Small part suspension is carried out, after suction strainer, obtaining title compound, is yellow solid, for characterizing object.By remaining suspension be concentrated into dry after, be placed in high vacuum lower 16 hours.Same separation obtains remaining title compound (137.7mg, 123%, yellow solid), without being further purified just, can use.

¹h NMR (500MHz, DMSO-d ₆) δ 15.20 and 14.66 (2m, 1H), 10.29 (brs, 0.7H), 9.38-9.36 (m, 2H), 8.55-8.00 (serial m, 4H), 7.42-7.28 (2m, 3H), 5.53-4.00 (serial m, 7H), 3.99-3.13 (serial m, 4H), 3.57 and 3.52 (2s, 3H), 2.50-1.84 (serial m, 8H).

LCMS Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 3 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, RT=1.79 minute, homogeneity index > 95%.

LRMS: for C ₃₄h ₃₆n ₉o ₃analytical calculation value: 618.29; Measured value: 618.42 (M+H) ⁺.

HRMS: for C ₃₄h ₃₆n ₉o ₃analytical calculation value: 618.2921; Measured value: 618.2958 (M+H) ⁺.

Adopt same procedure Preparation Example 152k-2 to embodiment 152k-3.

Embodiment 152l-1 to embodiment 152l-

Employing makes embodiment 148e be converted into the same procedure of embodiment 148, isolates TFA or the AcOH salt of prepared embodiment 152l-1 to embodiment 152l-3.

Derive from the embodiment 153a-1 of 153a-4

Embodiment 153a-1 is prepared by 152e-1.(S)-2-[5-{5 '-[2-((S)-1-tertbutyloxycarbonyl-pyrrolidin-2-yl)-3-(2-TMS-ethoxyl methyl)-3H-imidazol-4 yl]-[2,2 '] connection pyrimidyl-5-yl }-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-yl]-tetramethyleneimine-1-t-butyl formate

Under argon atmospher, room temperature, to (S)-2-(5-(2-chloropyrimide-5-yl)-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate (1.0g, 2.08mmol) close palladium (40mg with dichloro two (cyanobenzene), in dry DMF 0.104mmol) (10ml) stirred solution, add four pure (dimethylamino) ethene (1.0ml, 4.16mmol).Mixture is heated 15 hours at 60 ℃, with after ethyl acetate dilution, through diatomite suction strainer.Filtrate is used saturated NaHCO ₃solution and salt water washing, through Na ₂sO ₄after dry, evaporating solvent.Resistates Biotage ^tMflash chromatography on silica gel method purifying (carries out substep gradient elution (B=ethyl acetate wherein with 150ml 15%B to 15%B, 1500ml 15%B to 75%B, 1000ml 75%B to 100%B and 1000ml100%B to 100%B successively, A=hexane), with 700ml10%B to 100%B, carry out gradient elution for the second time again, B=methyl alcohol wherein, A=ethyl acetate), obtain title compound (487.8mg, yield 26%, viscosity caramel colour oily matter).

¹h NMR (500MHz, DMSO-d ₆) δ 9.27 (s, 4H), 8.09-8.06 (m, 2H), 5.73-5.66 and 5.50-5.44 (2m, 2H), 5.06-4.93 (m, 2H), 3.60-3.39 (2m, 8H), 2.32-2.08 (3m, 4H), 2.00-1.85 (m, 4H), 1.37 and 1.14 (2s, 18H), 0.95-0.84 (m, 4H) ,-0.01 (s, 18H).

LCMS Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 3 minutes, 1 minute residence time, A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, RT=3.37 minute, homogeneity index > 95%.

LRMS: for C ₄₄h ₆₉n ₁₀o ₆si ₂analytical calculation value: 889.49; Measured value: 889.57 (M+H) ⁺.

HRMS: for C ₄₄h ₆₉n ₁₀o ₆si ₂analytical calculation value: 889.4940; Measured value: 889.4920 (M+H) ⁺.

Adopt same procedure Preparation Example 153a-2 to embodiment 153a-4.

Embodiment 153b-1 to embodiment 153b-3

According to the reaction that is hydrolyzed of embodiment 152h above.

Embodiment 153c-1 to embodiment 153c-7

Employing makes embodiment 148e change into the method for embodiment 148, isolates embodiment 153c-1 to embodiment 153c-7, is TFA or AcOH salt.

The LC condition of LS part:

Condition 1: solvent orange 2 A: 10% methyl alcohol/90% water/0.1%TFA; Solvent B:90% methyl alcohol/10% water/0.1%TFA; Post: Phenomenex-Luna 3.0 * 5.0mm S10; Wavelength: 220nm; Flow velocity: 4ml/ minute; 0%B to 100%B, in 4 minutes, 1 minute residence time.

Condition 2: solvent orange 2 A: 10% methyl alcohol/90% water/0.1%TFA; Solvent B:90% methyl alcohol/10% water/0.1%TFA; Post: Phenomenex 10u C183.0 * 5.0mm; Wavelength: 220nm; Flow velocity: 4ml/ minute; 0%B to 100%B, in 4 minutes, 1 minute residence time.

Condition 3: solvent orange 2 A: 5% acetonitrile/95% water/10mmol ammonium acetate; Solvent B:95% acetonitrile/5% water/10mmol ammonium acetate; Post: Phenomenex 10u C184.6 * 5.0mm; Wavelength: 220nm; Flow velocity: 4ml/ minute; 0%B to 100%B, in 4 minutes, 1 minute residence time.

Condition 4: solvent orange 2 A: 5% acetonitrile/95% water/10mmol ammonium acetate; Solvent B:95% acetonitrile/5% water/10mmol ammonium acetate; Post: Luna 4.6 * 50mm S10; Wavelength: 220nm; Flow velocity: 4ml/ minute; 0%B to 100%B, in 3 minutes, 1 minute residence time.

Condition 5: solvent orange 2 A: 10% methyl alcohol/90% water/0.1%TFA; Solvent B:90% methyl alcohol/10% water/0.1%TFA; Post: Phenomenex 10u C183.0 * 5.0mm; Wavelength: 220nm; Flow velocity: 4ml/ minute; 0%B to 100%B, in 3 minutes, 1 minute residence time.

Condition 6: solvent orange 2 A: 5% acetonitrile/95% water/10mmol ammonium acetate; Solvent B:95% acetonitrile/5% water/10mmol ammonium acetate; Post: Phenomenex-Luna 3.0 * 50mm S10; Wavelength: 220nm; Flow velocity: 4ml/ minute; 0%B to 100%B, in 8 minutes, 2 minute residence time.

Condition 7: solvent orange 2 A: 10% methyl alcohol/90% water/0.1%TFA; Solvent B:90% methyl alcohol/10% water/0.1%TFA; Post: Phenomenex-Luna 3.0 * 5.0mm S10; Wavelength: 220nm; Flow velocity: 4ml/ minute; 0%B to 100%B, in 3 minutes, 1 minute residence time.

Condition 8: solvent orange 2 A: 10% methyl alcohol/90% water/0.2%H ₃pO ₄; Solvent B:90% methyl alcohol/10% water/0.2%H ₃pO ₄; Post: YMC ODS-A 4.6 * 50mm S5; Wavelength: 220nm; Flow velocity: 4ml/ minute; 0%B to 100%B, in 4 minutes, 1 minute residence time.

Condition 9: solvent orange 2 A: 10% methyl alcohol/90% water/0.2%H ₃pO ₄; Solvent B:90% methyl alcohol/10% water/0.2%H ₃pO ₄; Post: YMC ODS-A 4.6 * 50mm S5; Wavelength: 220nm; Flow velocity: 2.5ml/ minute; 0%B to 50%B, in 8 minutes, 3 minute residence time.

Condition 10:Xbridge C18,150 * 4.6mm I.D.S-3.5 μ m; Mobile phase A: 95% water-5% acetonitrile (containing 10mM ammonium acetate) (pH=5); Mobile phase B: 95% acetonitrile-5% water (containing 10mM ammonium acetate) (pH=5); 30%B isocratic elution 20 minutes; Flow velocity: 1ml/ minute; UV detects: 220nm.

Condition 11: solvent orange 2 A: 10% methyl alcohol/90% water/0.1%TFA; Solvent B:90% methyl alcohol/10% water/0.1%TFA; Post: Phenomenex 10u C183.0 * 5.0mm; Wavelength: 220nm; Flow velocity: 4ml/ minute; 30%B to 100%B, in 4 minutes, 1 minute residence time.

Condition 12: solvent orange 2 A: 10% methyl alcohol/90% water/0.1%TFA; Solvent B:90% methyl alcohol/10% water/0.1%TFA; Post: Phenomenex 10u C183.0 * 5.0mm; Wavelength: 220nm; Flow velocity: 4ml/ minute; 20%B to 100%B, in 4 minutes, 1 minute residence time.

Condition 13: solvent orange 2 A: 10% methyl alcohol/90% water/0.2%H ₃pO ₄; Solvent B:90% methyl alcohol/10% water/0.2%H ₃pO ₄; Post: YMC ODS-A 4.6 * 50mm S5; Wavelength: 220nm; Flow velocity: 2.5ml/ minute; 0%B to 100%B, in 8 minutes, 3 minute residence time.

The preparation HPLC condition of LS part:

Condition 1: solvent orange 2 A: 10% methyl alcohol/90% water/0.1%TFA; Solvent B:90% methyl alcohol/10% water/0.1%TFA; Post: Phenomenex-Luna 30 * 100mm S10; Wavelength: 220nm; Flow velocity: 30ml/ minute; 0%B to 100%B, in 10 minutes, 2 minute residence time.

Condition 2: solvent orange 2 A: 10% methyl alcohol/90% water/0.1%TFA; Solvent B:90% methyl alcohol/10% water/0.1%TFA; Post: Xterra Prep MS C1830 * 50mm 5u; Wavelength: 220nm; Flow velocity: 30ml/ minute; 0%B to 100%B, in 8 minutes, 3 minute residence time.

Condition 3: solvent orange 2 A: 10% methyl alcohol/90% water/0.1%TFA; Solvent B:90% methyl alcohol/10% water/0.1%TFA; Post: Xterra Prep MS C1830 * 50mm 5u; Wavelength: 220nm; Flow velocity: 25ml/ minute; 10%B to 100%B, in 8 minutes, 2 minute residence time.

Condition 4: solvent orange 2 A: 10% methyl alcohol/90% water/0.1%TFA; Solvent B:90% methyl alcohol/10% water/0.1%TFA; Post: Xterra 19 * 100mm S5; Wavelength: 220nm; Flow velocity: 20ml/ minute; 30%B to 100%B, in 5 minutes, 3 minute residence time.

Condition 5: solvent orange 2 A: 10% methyl alcohol/90% water/0.1%TFA; Solvent B:90% methyl alcohol/10% water/0.1%TFA; Post: Phenomenex-Luna 30 * 100mm S10; Wavelength: 220nm; Flow velocity: 30ml/ minute; 10%B to 100%B, in 8 minutes, 2 minute residence time.

Condition 6: solvent orange 2 A: 10% acetonitrile/90% water/0.1%TFA; Solvent B:90% acetonitrile/10% water/0.1%TFA; Post: Phenomenex-Luna 21 * 100mm S10; Wavelength: 220nm; Flow velocity: 25ml/ minute; 0%B～60%B, in 10 minutes, 5 minute residence time.

Experimental section:

Compound L S2

(1S, 1 ' S)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (1-cyclohexyl-2-oxo ethanol)

Step a: to 1d (1.4g; 2.24mmol), add 30ml 4N HCl dioxane solution.After 3 hours, add 60ml ether, after precipitate is filtered, high vacuum dry, obtains 1.02g (80%) intermediate LS1, is buff powder. ¹H NMR(DMSO-d ₆，δ＝2.5ppm，500MHz)：δ10.41(s，2H)，9.98(s，2H)，8.22(s，2H)，8.06(d，J＝8.54Hz，4H)，7.92(d，J＝8.55Hz，4H)，5.07(s，2H)，3.43-3.54(m，2H)，3.33-3.43(m，2H)，2.43-2.59(m，4H)，2.16-2.28(m，2H)，1.94-2.09(m，2H)。LC (condition 1): RT=1.28 minute; MS: for [M+H] ⁺c ₂₆h ₂₈n ₆analytical calculation value: 425.24; Measured value: 425.56.

Step b: to intermediate LS1 (200mg; In 2ml DMF solution 0.35mmol), add successively DIPEA (0.30ml; 1.75mmol), (S)-2-cyclohexyl-2-oxyacetic acid (61mg; 0.39mmol) and HATU (147mg; 0.38mmol).Stir at ambient temperature after 18 hours, reaction mixture is divided into two portions, by preparation HPLC purifying (condition 1).Merge the flow point that contains required product, and by MCX cylinder (Oasis; 6g; Methyl alcohol pre-treatment with two column lengths).The methanol wash of two column lengths for cylinder, product, with concentrated after ammonia/methanol-eluted fractions, obtains 65mg LS2 (26%), is colourless powder. ¹h NMR (500MHz, DMSO-d ₆) δ ppm 0.87-1.30 (m, 12H) 1.38-1.53 (m, J=24.72,11.90Hz, 4H) 1.54-1.75 (m, 8H) 1.95-2.21 (m, 6H) 3.72-3.86 (m, 6H) 5.13 (t, J=6.56Hz, 2H) 7.87 (d, J=7.93Hz, 4H) 7.96 (d, J=6.41Hz, 4H) 8.13 (s, 2H) (not counting imidazoles NH and hydroxyl proton).LC (condition 2): RT=3.07 minute; MS: for [M+H] ⁺c ₄₂h ₅₂n ₆o ₄analytical calculation value: 705.9; Measured value: 705.6.

By prepared the similar fashion of LS2 by intermediate LS1, adopt suitable carboxylic acid to prepare following analogue:

Embodiment LS6

(2S, 2 ' S)-1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N-methyl isophthalic acid-oxo-2-propylamine)

Step a: to intermediate LS1 (64mg; In 1ml DMF solution 0.11mmol), add (S)-2-(tertbutyloxycarbonyl (methyl) amino) propionic acid (48mg; 0.24mmol), Hunig alkali (0.12ml; 0.67mmol) and HATU (90mg; 0.24mmol).After 3 hours, reactant is purified (condition 2) with preparation HPLC.After merging the flow point that contains intermediate LS5, concentrate, high vacuum dry, obtains intermediate LS5 (43mg; 48%, colourless powder).LC (condition 4): RT=2.12 minute; MS: for [M+H] ⁺c ₄₄h ₅₈n ₈o ₆analytical calculation value: 795.4; Measured value: 795.5.

Step b: intermediate LS5 is stirred 18 hours in 2ml HCl/ diox (4N), add when the time comes 10ml ether, after filtering, high vacuum dry, obtains LS6 (45mg to gained precipitate; 155%), be colorless solid. ¹h NMR (500MHz, DMSO-d ₆) δ ppm 2.00-2.11 (m, 2H) 2.12-2.27 (m, 4H) 2.38-2.47 (m, 2H) 2.39-2.48 (m, 2H) 2.58 (t, J=5.19Hz, 2H) 3.78-3.85 (m, 2H) 3.91-4.02 (m, 2H) 4.21-4.32 (m, 2H) 5.26 (t, J=7.17Hz, 2H) 7.93 (d, J=7.32Hz, 4H) 8.02 (d, J=7.94Hz, 4H) 8.12-8.21 (m, 2H) 8.69-8.81 (m, 2H) 9.09-9.17 (m, 2H); N-Me proton is sheltered by DMSO peak, does not wherein count 2 other protons.LC (condition 5): RT=1.71 minute; MS: for [M+H] ⁺c ₃₄h ₄₂n ₈o ₂analytical calculation value: 595.3; Measured value: 595.6.

Embodiment LS11

(4S, 4 ' S)-4,4 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two base carbonyls)) two (1,3-oxazas oneself-2-ketone)

Step a: to intermediate LS1 (65mg; In 1ml DMF solution 0.11mmol), add successively HATU (91mg; 0.24mmol), (S)-2-oxo-1,3-morpholine-4-formic acid (intermediate LS10; 35mg; 0.24mmol) and DIPEA (0.12ml; 0.68mmol).After 3 hours, reaction mixture is by twice of preparation HPLC purifying (condition 3).After merging suitable flow point, high vacuum is concentrated, obtains the double T FA LS11 of 8mg (10%), is colorless oil. ¹h NMR (500MHz, CH ₃oD) δ ppm 1.99-2.43 (m, 10H) 2.48-2.66 (m, 1.98Hz, 2H) 3.82-3.95 (m, 4H) 4.17-4.40 (m, 4H) 4.57 (t, J=5.80Hz, 2H) 5.23-5.41 (m, 2H) 7.73-7.97 (m, 10H); Do not count imidazoles and carbamate NH proton.LC (condition 6): RT=2.28 minute; MS: for [M+H] ⁺c ₃₄h ₄₂n ₈o ₂analytical calculation value: 679.3; Measured value: 679.4.

Step b: according to literature method preparation (Baldwin etc., Tetrahedron 1988,44,637).

Step c: by preparing (Sakaitani and Ohfune, J.Am.Chem.Soc.1990,112,1150) for the literature method that makes compound 1 be converted into compound 5.Successively by Biotage (40M cylinder; 1: 1 ether/ethyl acetate) and preparation HPLC (condition 4) purifying, obtaining 77mg (8%) intermediate LS9, is viscosity oily matter. ¹H NMR(300MHz，CDCl ₃)δppm 2.02-2.21(m，1H)2.23-2.41(m，1H)4.11-4.38(m，3H)5.11-5.31(m，2H)6.15(s，1H)7.27-7.46(m，5H)。LC (condition 7): RT=1.24 minute; MS: for [M+H] ⁺c ₃₄h ₄₂n ₈o ₂analytical calculation value: 236.1; Measured value: 236.4.

Steps d: under 1 normal atmosphere hydrogen, make intermediate LS9 carry out hydrogenation 18 hours in 3ml methyl alcohol and 10mg Pd/C (10%).Reaction mixture is through diatomite concentrated after pad filters, obtain intermediate LS10 (40mg; 83%), be colourless powder. ¹H NMR(500MHz，CH ₃OD)δppm 2.08-2.18(m，1H)2.26-2.38(m，1H)4.19(t，J＝5.95Hz，1H)4.25-4.40(m，2H)。

Embodiment LS14

((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(tetrahydrochysene-2H-pyrans-4-yl) ethyl) Urethylane

Step a: to 28 (1.5g; In 25ml DMF solution 2.86mmol), add successively Cap-2 (697mg; 2.86mmol), HATU (1.2g; 3.14mmol) with Hunig alkali (1.5ml; 8.57mmol).After 3 hours, solution is concentrated into 10ml, and distributes between chloroform and water.Organic layer salt water washing, through dried over mgso, filters final vacuum and is condensed into amber oily thing, with silica gel chromatography, purifies (Biotage; Be loaded onto on 40samplet together with methylene dichloride; With 1200ml 0-12% methylene chloride/methanol wash-out in 40M cylinder).After merging the flow point that contains intermediate LS12, concentrate, obtain product, in product, contain remaining DMF.This product is dissolved in to methylene dichloride again, successively water (3 * 50ml) and salt water washing.Organic layer, through dried over mgso, is condensed into 761mg powder after filtration, then purifies (Biotage with silica gel chromatography; Be loaded onto on 40samplet together with methylene dichloride; Use 1500ml 0-80%4: 1 chloroform: methanol/ethyl acetate is wash-out in 40M cylinder), obtain intermediate LS12 (501mg; 25%), be colourless powder.LC (condition 8): RT=1.24 minute.

Step b: to intermediate LS12 (490mg; 0.69mmol), add successively 6ml HCl/ diox and 25ml methylene dichloride.After 24 hours, add 75ml ether, reaction mixture after filtration, by after precipitate vacuum-drying, obtains intermediate LS13 4HCl (434mg; Quantitatively), be tawny solid. ¹H NMR(300MHz，CH ₃OD)δppm 1.16-1.29(m，3H)1.37(t，J＝6.95Hz，3H)1.89-2.06(m，6.95Hz，1H)2.12-2.51(m，5H)2.52-2.85(m，4H)3.02-3.24(m，2H)3.42-3.55(m，7.32Hz，1H)3.58-3.71(m，2H)4.26-4.41(m，1H)5.18-5.37(m，2H)5.65(s，1H)7.57-7.66(m，3H)7.67-7.75(m，1H)7.86-8.04(m，10H)8.14(s，1H)。LC (condition 8): RT=1.92 minute.

Step c: to intermediate LS 134HCl (75mg; In 0.7ml DMF solution 0.099mmol), add successively intermediate LS16 (26mg; 0.118mmol), HATU (45mg; 0.118mmol) with Hunig alkali (0.10ml; 0.591mmol).After 2 hours, reaction mixture is through diatomite filter, Celite pad 0.3ml methanol wash, gained filtrate is injected separately at twice through preparation HPLC purifying (condition 5).Make the flow point that contains required product by MCX cylinder (Oasis; 1g; Methyl alcohol pre-treatment with two column lengths).The methanol wash of two column lengths for cylinder, product is used ammonia/methanol-eluted fractions again, after concentrating, obtains 36mg LS14, is colourless powder, and diastereomer purity is 82% (being likely epimerization on the three-dimensional carbon atom of intermediate 16) by analysis.Be prepared again type HPLC purifying (2 times), obtain LS14 (13mg; 16%), be colorless solid. ¹H NMR(500MHz，CH ₃OD)δppm 0.99(q，J＝6.92Hz，6H)1.25-1.72(m，5H)1.80-2.42(m，10H)2.47-2.61(m，3H)2.66-2.78(m，2H)3.35-3.43(m，2H)3.65-3.71(m，3H)3.89-4.01(m，4H)4.01-4.10(m，1H)4.32(d，J＝8.24Hz，1H)5.11-5.22(m，1H)6.95-7.17(m，3H)7.30-7.44(m，3H)7.53(d，J＝7.02Hz，1H)7.62-7.89(m，8H)。LC (condition 9): RT=5.31 minute.

Steps d: by the similar fashion of method described in synthetic Cap-51, replace Valine with (S)-2-amino-2-(tetrahydrochysene-2H-pyrans-4-yl) acetic acid (can derive from Astatech), prepare intermediate LS16. ¹hNMR (300MHz, DMSO-d ₆) δ ppm 1.15-1.63 (m, 5H) 1.75-2.03 (m, 1H) 3.54 (s, 3H) 3.76-3.98 (m, 4H) 7.45 (d, J=8.42Hz, 1H); A proton is sheltered by water peak.

Embodiment LS20

((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-methyl glycyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane

Step a and step b: press the similar fashion of method described in synthetic intermediate LS13, with Cap-51, replace Cap-2, prepare intermediate LS18.

Step c: to intermediate LS18 (100mg; In 1.4ml DMF solution 0.14mmol), add successively N-Boc sarkosine (30mg; 0.16mmol), Hunig alkali (0.13ml; 0.72mmol) and HATU (60mg; 0.16mmol).After 2 hours, reaction mixture is assigned in methylene dichloride, uses NaHCO ₃(aqueous solution), salt water washing, through dried over mgso, be condensed into rough intermediate LS19 after filtration, can be used directly to next step.LC (condition 5): RT=2.42 minute; MS: for [M+H] ⁺c ₄₁h ₅₂n ₈o ₆analytical calculation value: 753.4; Measured value: 753.9.

Steps d: rough intermediate LS 19 is dissolved in to 0.5ml methyl alcohol and 5ml 4N HCl/ diox.Stir after 1 hour, concentration response thing, and by preparation HPLC purifying (condition 6), make the flow point that contains required product by MCX cylinder (Oasis; 1g; Methyl alcohol pre-treatment with two column lengths).The methanol wash of two column lengths for cylinder, product, with concentrated after ammonia/methanol-eluted fractions, obtains LS20 (32mg; 34%). ¹H NMR(500MHz，DMSO-d ₆)δppm0.74-0.98(m，6H)1.79-2.24(m，9H)2.29-2.38(m，2H)3.19-3.51(m，8H)3.50-3.56(m，3H)3.59-3.71(m，1H)3.81(s，1H)3.97-4.17(m，1H)5.01-5.16(m，2H)7.30(d，J＝7.93Hz，1H)7.51(s，1H)7.59-7.74(m，4H)7.79(d，J＝7.63Hz，4H)11.78(s，1H)。LC (condition 5): RT=2.00 minute; MS: for [M+H] ⁺c ₃₆h ₄₄n ₈o ₄analytical calculation value: 653.4; Measured value: 653.7.

By prepared the similar fashion of LS20 by LS18, with suitable formic acid, replace N-Boc sarkosine, prepare following analogue:

Embodiment LS26

((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-di-isopropyl glycyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane

Step a: according to the similar fashion of preparing intermediate LS19, adopt 2-(diisopropylaminoethyl) acetic acid as carboxylic acid coupling mating partner (coupling partner), prepare compound L S26. ¹H NMR(500MHz，DMSO-d ₆)δppm 0.74-1.04(m，18H)1.74-2.21(m，13H)2.86-3.09(m，3H)3.54(s，3H)3.71-3.89(m，3H)4.06(t，J＝8.55Hz，1H)4.98-5.13(m，2H)5.56(d，J＝8.55Hz，1H)7.21-7.34(m，1H)7.42-7.54(m，1H)7.61-7.87(m，8H)。LC (condition 5): RT=1.98 minute; MS: for [M+H] ⁺c ₄₁h ₅₄n ₈o ₄analytical calculation value: 723.4; Measured value: 723.4.

Embodiment LS27 diastereomer 1

((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-(3-oxetanyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane

Embodiment LS27 diastereomer 2

((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-2-(3-oxetanyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane

Step a: according to the similar fashion of preparing intermediate LS19, adopting 2-(methoxycarbonyl is amino)-2-(trimethylene oxide-3-yl) acetic acid (intermediate LS29) is carboxylic acid coupling mating partner, prepares compound L S27.Two diastereomers of LS27 carry out separation (Xbridge C18,100 * 19mm I.D.S-5 μ m by preparation HPLC; Mobile phase A: 95% water-5% acetonitrile (containing 10mM ammonium acetate) (pH=5); Mobile phase B: 95% acetonitrile-5% water (containing 10mM ammonium acetate) (pH=5); 30%B isocratic elution 7 minutes; Flow velocity: 25ml/ minute; UV detects: 220nm; Sample size: each injection～5mg, the methanol solution (～17mg/ml) of 300 μ l samples).Diastereomer 1: ¹h NMR (500MHz, DMSO-d ₆) δ ppm 0.80-0.96 (m, 6H) 1.91-2.06 (m, 6H) 2.09-2.21 (m, 3H) 3.54 (s, 3H) 3.59 (s, 3H) 3.77-3.83 (m, 2H) 3.87 (t, J=7.63Hz, 1H) 4.06 (t, J=8.24Hz, 1H) 4.31 (t, J=6.41Hz, 1H) 4.43 (t, J=6.10Hz, 1H) 4.49 (t, J=7.17Hz, 1H) 4.51-4.57 (m, 1H) 4.80 (t, J=8.55Hz, 1H) 5.00-5.05 (m, 1H) 5.06-5.11 (m, 1H) 7.30 (d, J=8.55Hz, 1H) 7.50 (s, 1H) 7.58-7.89 (m, 8H) 11.77 (s, 2H).LC (condition 10): RT=7.14 minute; MS: for [M+H] ⁺c ₄₀h ₄₈n ₈o ₇analytical calculation value: 753.4; Measured value: 753.9.Diastereomer 2: ¹hNMR (500MHz, DMSO-d ₆) δ ppm 0.79-0.98 (m, 6H) 1.91-2.06 (m, 4H) 2.07-2.23 (m, 4H) 3.51-3.69 (m, 8H) 3.74-3.90 (m, 2H) 4.06 (t, J=7.48Hz, 1H) 4.20-4.33 (m, 1H) 4.36-4.49 (m, 2H) 4.55 (s, 2H) 4.71 (s, 1H) 4.97-5.05 (m, 1H) 5.08 (s, 1H) 5.53 (s, 1H), 7.30 (d, J=7.93Hz, 1H) 7.51 (s, 1H) 7.58-7.91 (m, 8H), 11.53 (s, 1H) 11.78 (s, 1H).LC (condition 10): RT=8.79 minute; MS: for [M+H] ⁺c ₄₀h ₄₈n ₈o ₇analytical calculation value: 753.4; Measured value: 753.9.

Step b:2-(benzyloxycarbonyl is amino)-2-(trimethylene oxide-3-subunit) methyl acetate (intermediate LS28; Source: Moldes etc., Il Farmaco, 2001,56,609 and Wuitschik etc., Ang.Chem.Int.Ed.Engl, 2006,45,7736; 200mg, 0.721mmol) and ethyl acetate (7ml) and CH ₂cl ₂(4.00ml) solution is by passing into nitrogen degassed 10 minutes.Then add two methylcarbonates (0.116ml, 1.082mmol) and Pd/C (20mg, 0.019mmol), reaction mixture is connected to hydrogen capsule, and stir and spend the night at ambient temperature.Reaction mixture is through diatomite concentrated after filtering.Resistates (is loaded onto on 25samplet by Biotage purifying together with methylene dichloride; In 25S post, use successively methylene dichloride 3CV and 250ml0-5% ethanol/methylene wash-out, be then retained in 250ml 5% ethanol/methylene; 9ml flow point).The flow point that contains required product, after concentrated, obtains 167mg 2-(methoxycarbonyl is amino)-2-(trimethylene oxide-3-yl) methyl acetate, is colorless oil, when standing, solidifies. ¹hNMR (500MHz, chloroform-D) δ ppm 3.29-3.40 (m, 1H) 3.70 (s, 3H) 3.74 (s, 3H) 4.55 (t, J=6.41Hz, 1H) 4.58-4.68 (m, 2H) 4.67-4.78 (m, 2H) 5.31 (brs, 1H).MS: for [M+H] ⁺c ₈h ₁₃nO ₅analytical calculation value: 204.1; Measured value: 204.0.To 2-(methoxycarbonyl is amino)-2-(trimethylene oxide-3-yl) methyl acetate (50mg, 0.246mmol) and in the solution of THF (2ml) and water (0.5ml) add aluminium hydroxide monohydrate (10.33mg, 0.246mmol).After gained solution is stirred at ambient temperature and spent the night, being concentrated into dryly, obtaining intermediate LS29, is colourless powder. ¹H NMR(500MHz，CH ₃OD)δppm3.38-3.50(m，1H)3.67(s，3H)4.28(d，J＝7.63Hz，1H)4.57-4.79(m，4H)。

Embodiment LS36

((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-2-methyl isophthalic acid-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane

Step a: to (S)-1-(((9H-fluorenes-9-yl) methoxyl group) carbonyl)-2-methylpyrrolidin-2-formic acid (intermediate LS30; 1.5g; In 50ml DMF solution 4.3mmol), add successively 2-amino-1-(4-bromophenyl) acetophenone hydrochloride (1.2g; 4.7mmol), HOAT (290mg; 2.1mmol), Hunig alkali (0.7ml; 4.3mmol) and EDCI (1.2g; 6.4mmol).After 1 hour, reaction mixture is poured in 150ml water, and stirred after 15 minutes, filter gained precipitate, be dissolved in after methylene dichloride, through dried over mgso.Dichloromethane mixture after filtering, is added on Biotage 40samplet.At the enterprising circumstances in which people get things ready for a trip spectrometry of 40M post, process (1200ml 25-60% ethyl acetate/hexane), obtain (S)-2-(2-(4-bromophenyl)-2-oxoethyl formamyl)-2-methylpyrrolidin-1-formic acid (9H-fluorenes-9-yl) methyl esters (intermediate LS31; 2.4g; Quantitatively), be yellow foam.LC (condition 11): RT=3.75 minute; MS: for [M+H] ⁺c ₂₉h ₂₇brN ₂o ₄analytical calculation value: 547.1; Measured value: 547.0.

Step b: by ammonium acetate (844mg; 10.97mmol) with (S)-2-(2-(4-bromophenyl)-2-oxoethyl formamyl)-2-methylpyrrolidin-1-formic acid (9H-fluorenes-9-yl) methyl esters (intermediate LS31; 1.00g; Mixture 1.83mmol) heats 2.5 hours in 140 ℃ in 25ml dimethylbenzene, make when the time comes reaction mixture concentrated, be loaded onto together with methylene dichloride on Biotage 40samplet, by Biotage purifying (1000ml 5-60% ethyl acetate/hexane, 400ml residence time wherein), obtain (S)-2-(5-(4-bromophenyl)-1H-imidazoles-2-yl)-2-methylpyrrolidin-1-formic acid (9H-fluorenes-9-yl) methyl esters (intermediate LS32; 469mg; 49%), be amber color liquid.LC (condition 12): RT=3.09 minute; MS: for [M+H] ⁺c ₂₉h ₂₆brN ₃o ₂analytical calculation value: 528.1; Measured value: 528.5.

Step c: to (S)-2-(5-(4-bromophenyl)-1H-imidazoles-2-yl)-2-methylpyrrolidin-1-formic acid (9H-fluorenes-9-yl) methyl esters (intermediate LS32; 329mg; In 3ml DMF solution 0.62mmol), add 1.5ml piperidines.By nitrogen gas stream, spend the night and make reaction mixture concentrated.Gained resistates is with after hexane washing, by MCX cylinder (Oasis; 6g; Methyl alcohol pre-treatment with two column lengths).The methanol wash of two column lengths for cylinder, product is with concentrated after ammonia/methanol-eluted fractions, obtain 193mg (S)-5-(4-bromophenyl)-2-(2-methylpyrrolidin-2-yl)-1H-imidazoles, be dissolved in after 6ml methylene dichloride, with tert-Butyl dicarbonate (413mg; 1.89mmol), DMAP (15mg; 0.13mmol) and TEA (0.17ml; 1.30mmol) mix mutually.After 48 hours, make reaction mixture concentrated, by Biotage system chromatography, carry out purifying, obtain (S)-5-(4-bromophenyl)-2-(1-(tertbutyloxycarbonyl)-2-methylpyrrolidin-2-yl)-1H-imidazoles-1-t-butyl formate (intermediate LS33; 150mg; 48%), be pale solid.LC (condition 5): RT=3.75 minute; MS: for [M+H] ⁺c ₂₄h ₃₂brN ₃o ₄analytical calculation value: 506.2; Measured value: 506.4.

Steps d: according to the similar fashion of preparation 1d, with intermediate LS33, replace 1b, prepare (S)-2-(5-(4 '-(2-((S)-1-(tertbutyloxycarbonyl) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl)-2-methylpyrrolidin-1-t-butyl formate (intermediate LS34). ¹HNMR(300MHz，DMSO-d ₆；100℃)δppm 1.18-1.29(m，9H)1.29-1.40(m，9H)1.75-1.82(m，3H)1.81-2.39(m，8H)3.35-3.75(m，4H)4.81-4.92(m，1H)7.36-7.45(m，1H)7.57-7.74(m，5H)7.76-7.89(m，4H)11.29-11.63(m，2H)。LC (condition 5): RT=2.49 minute; MS: for [M+H] ⁺c ₃₇h ₄₆n ₆o ₄analytical calculation value: 639.4; Measured value: 639.9.

Step e: according to the similar fashion of preparation 1e, with intermediate LS34, replace 1d, prepare 2-((S)-2-methylpyrrolidin-2-yl)-5-(4 '-(2-((S)-pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles (intermediate LS35). ¹h NMR (500MHz, DMSO-d ₆) δ ppm 1.76-1.83 (m, 3H) 1.92-2.23 (m, 6H) 3.31-3.49 (m, 4H) 4.88-4.97 (m, 1H) 7.76-7.88 (m, 5H) 7.90-8.04 (m, 5H) 9.72-9.82 (m, 1H) 10.04-10.16 (m, 1H); Do not count imidazoles and tetramethyleneimine NH proton.LC (condition 5): RT=1.79 minute; MS: for [M+H] ⁺c ₂₇h ₃₀n ₆analytical calculation value: 439.2; Measured value: 439.5.

Step f: according to the similar fashion of embodiment 1, replace 1e with intermediate LS35, and replace Cap-1 with Cap-51, prepare compound L S36. ¹H NMR(500MHz，DMSO-d ₆)δppm 0.72-0.97(m，12H)1.77(s，3H)1.86-2.08(m，8H)2.09-2.19(m，2H)2.25-2.39(m，2H)3.49-3.59(m，6H)3.81(d，J＝6.71Hz，4H)4.06(q，J＝7.83Hz，2H)5.08(dd，J＝7.02，3.05Hz，1H)7.12(d，J＝8.85Hz，1H)7.27-7.34(m，1H)7.46-7.55(m，1H)7.59-7.73(m，4H)7.75-7.86(m，3H)11.66(s，1H)11.77(s，1H)。LC (condition 5): RT=2.25 minute; MS: for [M+H] ⁺c ₄₁h ₅₂n ₈o ₆analytical calculation value: 753.4; Measured value: 754.0.

Embodiment LS37

((1S, 2R)-2-methoxyl group-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-Threonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-2-methyl isophthalic acid-pyrrolidyl) carbonyl) propyl group) Urethylane

By prepared the similar fashion of LS36 by intermediate LS30, with Cap-86, replace Cap-51, prepare compound L S37. ¹H NMR(500MHz，DMSO-d ₆)δppm 0.99-1.17(m，6H)1.76(s，3H)1.87-2.09(m，4H)2.10-2.23(m，2H)2.34-2.38(m，2H)2.56-2.60(m，1H)2.63(d，J＝1.83Hz，1H)3.17(s，3H)3.19(s，3H)3.37-3.51(m，2H)3.54(s，6H)3.75-3.96(m，4H)4.13-4.36(m，2H)5.07(dd，J＝7.48，3.20Hz，1H)7.20(d，J＝8.54Hz，1H)7.24-7.34(m，1H)7.50(dd，J＝7.17，1.98Hz，1H)7.59-7.73(m，4H)7.76-7.86(m，3H)11.65(s，1H)11.77(s，1H)。LC (condition 13): RT=4.30 minute; MS: for [M+H] ⁺c ₄₁h ₅₂n ₈o ₈analytical calculation value: 785.4; Measured value: 785.4.

F is partly for measuring the LC condition of retention time:

Condition 1

Post: Phenomenex-Luna 4.6 * 50mm S10

Start %B=0

Final %B=100

Gradient time=4 minute

Flow velocity=4ml/ minute

Wavelength=220

Solvent orange 2 A=10% methyl alcohol-90%H ₂o-0.1%TFA

Solvent B=90% methyl alcohol-10%H ₂o-0.1%TFA

Condition 2

Post: Waters-Sunfire 4.6 * 50mm S5

Start %B=0

Final %B=100

Gradient time=2 minute

Flow velocity=4ml/ minute

Wavelength=220

Solvent orange 2 A=10% methyl alcohol-90%H ₂o-0.1%TFA

Solvent B=90% methyl alcohol-10%H ₂o-0.1%TFA

Condition 3

Post: Phenomenex 10u 3.0 * 50mm

Start %B=0

Final %B=100

Gradient time=2 minute

Flow velocity=4ml/ minute

Wavelength=220

Solvent orange 2 A=10% methyl alcohol-90%H ₂o-0.1%TFA

Solvent B=90% methyl alcohol-10%H ₂o-0.1%TFA

Condition 4

Post: Phenomenex-Luna 3.0 * 50mm S10

Start %B=0

Final %B=100

Gradient time=3 minute

Flow velocity=4ml/ minute

Wavelength=220

Solvent orange 2 A=10% methyl alcohol-90%H ₂o-0.1%TFA

Solvent B=90% methyl alcohol-10%H ₂o-0.1%TFA

Condition 5

Post: Phenomenex-Luna 4.6 * 50mm S10

Start %B=0

Final %B=100

Gradient time=3 minute

Flow velocity=4ml/ minute

Wavelength=220

Solvent orange 2 A=10% methyl alcohol-90%H ₂o-0.1%TFA

Solvent B=90% methyl alcohol-10%H ₂o-0.1%TFA

Condition 6

Post: Xbridge C184.6 * 50mm S5

Start %B=0

Final %B=100

Gradient time=3 minute

Flow velocity=4ml/ minute

Wavelength=220

Solvent orange 2 A=H ₂o: ACN 95%: 5%10mM ammonium acetate

Solvent B=H ₂o: ACN 5%: 95%10mM ammonium acetate

Condition 7

Post: Phenomenex C1810u 4.6 * 30mm

Start %B=0

Final %B=100

Gradient time=3 minute

Flow velocity=4ml/ minute

Wavelength=220

Solvent orange 2 A=10% methyl alcohol-90%H ₂o-0.1%TFA

Solvent B=90% methyl alcohol-10%H ₂o-0.1%TFA

Condition 8

Post: Phenomenex LunaC1810u 4.6 * 30mm

Start %B=0

Final %B=100

Gradient time=2 minute

Flow velocity=5ml/ minute

Wavelength=220

Solvent orange 2 A=10% methyl alcohol-90%H ₂o-0.1%TFA

Solvent B=90% methyl alcohol-10%H ₂o-0.1%TFA

Condition 9

Post: Phenomenex C18 10u 4.6 * 30mm

Start %B=0

Final %B=100

Gradient time=10 minute

Flow velocity=4ml/ minute

Wavelength=220

Solvent orange 2 A=H ₂o: ACN 95%: 5%10mM ammonium acetate

Solvent B=H ₂o: ACN 5%: 95%10mM ammonium acetate

Condition 10

Post: Phenomenex 10u 3.0 * 50mm

Start %B=0

Final %B=100

Gradient time=3 minute

Flow velocity=4ml/ minute

Wavelength=220

Solvent orange 2 A=10% methyl alcohol-90%H ₂o-0.1%TFA

Solvent B=90% methyl alcohol-10%H ₂o-0.1%TFA

Condition 11

Post: Xterra 4.6 * 30mm S5

Start %B=0

Final %B=100

Gradient time=2 minute

Flow velocity=5ml/ minute

Wavelength=220

Solvent orange 2 A=H ₂o: ACN 95%: 5%10mM ammonium acetate

Solvent B=H ₂o: ACN 5%: 95%10mM ammonium acetate

Compound F 17-hydroxy-corticosterone 1 is by the similar fashion preparation for 1a synthetic method, about being amended as follows: with (2S, 5R)-1-(tertbutyloxycarbonyl)-5-Phenylpyrrolidine-2-formic acid, replace N-Boc-L-proline(Pro).

Compound F 17-hydroxy-corticosterone 2 is by the similar fashion preparation for 1b synthetic method.

Compound F 17-hydroxy-corticosterone 3 is by the similar fashion preparation for 1d synthetic method.

Compound F 17-hydroxy-corticosterone 4 is by the similar fashion preparation for 1e synthetic method.

Compound F 17-hydroxy-corticosterone 5, F6 are prepared by the similar fashion of the method for by compound F 17-hydroxy-corticosterone 4 synthetic examples 1.

Compound F 17-hydroxy-corticosterone 7, F8 are by the similar fashion preparation for F5 synthetic method, relevant being amended as follows: replace (2S, 5R)-1-(tertbutyloxycarbonyl)-5-Phenylpyrrolidine-2-formic acid with (2S)-1-(tertbutyloxycarbonyl) octahydro-1H-indole-2-carboxylic acid.

numbering	compound title	retention time (LC-condition); Homogeneity index; MS data
			f1	rT=3.838 minute (condition 1,94%); LRMS: for C ₂₄h ₂₇brN ₂o ₄analytical calculation value: 486.12; Measured value: 487.26 (M+H) ⁺.
f2		rT=3.175 minute (condition 1,83%); LRMS: for C ₂₄h ₂₇brN ₂o ₄analytical calculation value: 467.12; Measured value: 468.26 (M+H) ⁺.

f3		rT=2.965 minute (condition 1,93%); LRMS: for C ₄₂h ₄₈n ₆o ₄analytical calculation value: 700.37; Measured value: 701.49 (M+H) ⁺.
			f4		rT=2.083 minute (condition 1,98%); LRMS: for C ₃₂h ₃₂n ₆analytical calculation value: 500.27; Measured value: 501.40 (M+H) ⁺.
f5		rT=1.222 minute (condition 3,98%); LRMS: for C ₅₂h ₅₄n ₈o ₂analytical calculation value: 822.44; Measured value: 823.5 (M+H) ⁺.
			f6	((1R)-2-((2R)-2-(5-(4 '-(2-((2S, 5R)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-5-phenyl-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane	rT=1.512 minute (condition 3,98%); LRMS: for C ₅₂h ₅₀n ₈o ₆analytical calculation value: 882.39; Measured value: 883.45 (M+H) ⁺.
f7	rel-(1R)-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl) octahydro-1H-indoles-2-yl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine	rT=1.223 minute (condition 3,98%); LRMS: for C ₅₀h ₅₆n ₈o ₂analytical calculation value: 800.45; Measured value: 801.51 (M+H) ⁺.
			f8	rel-((1R)-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl) octahydro-1H-indoles-2-yl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane	rT=1.513 minute (condition 3,98%); LRMS: for C ₅₀h ₅₆n ₈o ₂analytical calculation value: 860.40; Measured value: 861.42 (M+H) ⁺.

By the similar fashion of the method for the synthesis of Cap-3 first half, with acetaldehyde, propionic aldehyde and butyraldehyde, prepare compound F 17-hydroxy-corticosterone 9, F10 and F11 respectively.

Compound F 17-hydroxy-corticosterone 12

By (Boc) ₂o (2.295g, 10.20mmol) is added to compound F 17-hydroxy-corticosterone 9 (1.0g, 4.636mmol), hunig alkali (1.78ml, 10.20mmol) and CH ₂cl ₂(12ml), in mixture, gained mixture is stirred and spent the night.Vacuum is removed volatile component, and resistates is purified (H by reverse-phase HPLC system ₂o/ methyl alcohol/TFA), obtain compound F 17-hydroxy-corticosterone 12 (0.993g, transparent wax).

LC (condition 3): RT=1.663 minute; Homogeneity index > 95%; LC/MS: for [M+H] ⁺c ₁₅h ₂₁nO ₄analytical calculation value: 279.33; Measured value: [M+Na] ⁺302.30.

Similar fashion by the method for by compound 1e and F12 synthetic example 1 is prepared compound F 17-hydroxy-corticosterone 13.

By the similar fashion of the method for the synthesis of 132e, prepare compound F 17-hydroxy-corticosterone 14.

By the similar fashion of the method for the synthesis of F14, prepare compound F 17-hydroxy-corticosterone 15, F16 and F17.

numbering	compound title	retention time (LC-condition); Homogeneity index; MS data
			f9	rT=0.580 minute (condition 1,94%); LRMS: for C ₁₀h ₁₃nO ₂analytical calculation value: 179.09; Measured value: 180.26 (M+H) ⁺.
f10		rT=0.563 minute (condition 3,94%); LRMS: for C ₁₁h ₁₅nO ₂analytical calculation value: 193.11; Measured value: 194.26 (M+H) ⁺.
			f11	rT=1.023 minute (condition 3,94%); LRMS: for C ₁₂h ₁₇nO ₂analytical calculation value: 207.13; Measured value: 208.31 (M+H) ⁺.
f12		rT=1.663 minute (condition 3,95%); LRMS: for C ₁₅h ₂₁nO ₄analytical calculation value: 279.15; Measured value: 302.30 (Na+H) ⁺.

f13		rT=2.595 minute (condition 4,94%); LRMS: for C ₅₆h ₆₆n ₈o ₆analytical calculation value: 946.51; Measured value: 947.64 (M+H) ⁺.
			f14	(1R)-N-ethyl-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-2-(ethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-phenyl-ethyl amine	rT=1.55 minute (condition 5,90%); LRMS: for C ₄₆h ₅₀n ₈o ₂analytical calculation value: 746.41; Measured value: 747.72 (M+H) ⁺.
f15	(1R)-N-methyl-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-2-(methylamino-)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-phenyl-ethyl amine	rT=1.50 minute (condition 5,94%); LRMS: for C ₄₄h ₄₆n ₈o ₂analytical calculation value: 718.37; Measured value: 719.69 (M+H) ⁺.
			f16	n-((1R)-2-oxo-1-phenyl-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(the third amino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-1-propylamine	rT=1.63 minute (condition 5,90%); LRMS: for C ₄₈h ₅₄n ₈o ₂analytical calculation value: 774.43; Measured value: 775.76 (M+H) ⁺.
f17	n-((1R)-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-2-(fourth is amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl)-1-butylamine	rT=1.81 minute (condition 5,85%); LRMS: for C ₅₀h ₅₈n ₈o ₂analytical calculation value: 802.47; Measured value: 803.79 (M+H) ⁺.

By preparing compound F 17-hydroxy-corticosterone 18 and F23 for the similar fashion of embodiment 1 synthetic method, about being amended as follows: replace N-Boc-L-proline(Pro) with N-Boc-L-L-Ala and N-Boc-L-α-amino-isovaleric acid respectively.

Similar fashion by the method for by compound F 17-hydroxy-corticosterone 19 synthetic examples 1 is prepared compound F 17-hydroxy-corticosterone 22.

By preparing compound F 17-hydroxy-corticosterone 19, F24 for the similar fashion of 132e synthetic method.

Compound F 17-hydroxy-corticosterone 25

((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-((ethoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) urethanum

To F24 (0.06g, in DMF 0.074mmol) (1ml) solution, add Hunig alkali (0.105ml, 0.593mmol) and after chlorine ethyl-carbonate (ethyl carbonochloridate) (0.016ml, 0.163mmol), at room temperature stir.After 2 hours, by LCMS, detect.There are 3 main peaks that represent required compound, three coupling compounds and four coupling compounds.After termination reaction, concentrating under reduced pressure, obtains light brown oily matter, is used 10ml 2M NH ₃methanol solution process after 20 minutes, be again condensed into yellow solid, by preparative, LC is purified, and obtains compound F 17-hydroxy-corticosterone 25 (57.6mg, white tfa salt).

LC (condition 6): RT=1.932 minute, LC/MS: for [M+H] ⁺c ₄₂h ₅₄n ₈o ₆analytical calculation value: 766.42; Measured value: 767.55.

¹H NMR(500MHz，DMSO-d ₆)δppm 0.69-0.94(m，12H)1.16(t，J＝7.02Hz，6H)1.90-2.26(m，8H)2.40(d，J＝4.88Hz，2H)3.73-3.92(m，4H)3.94-4.08(m，4H)4.12(t，J＝7.78Hz，2H)5.15(t，J＝7.02Hz，2H)7.26(d，J＝8.54Hz，2H)7.85-7.93(m，4H)7.93-8.01(m，4H)8.13(s，2H)14.68(s，2H)。

By preparing compound F 17-hydroxy-corticosterone 20, F21 and F26 for the similar fashion of embodiment 1 synthetic method.

numbering	compound title	retention time (LC-condition); Homogeneity index M S data
			f18		rT=2.257 minute (condition 5,96%); LRMS: for C ₄₂h ₅₄n ₈o ₆analytical calculation value: 766.42; Measured value: 767.88 (M+H) ⁺.

f19		rT=1.462 minute (condition 5,95%); LRMS: for C ₃₂h ₃₈n ₈o ₂analytical calculation value: 566.31; Measured value: 567.79 (M+H) ⁺.
			f20	((1S)-1-methyl-2-oxo-2-((2S)-2-(4-(4 '-(2-((2S)-1-(N-(the third oxygen carbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) carboxylamine propyl ester	rT=1.338 minute (condition 3,89%); LRMS: for C ₄₀h ₅₀n ₈o ₆analytical calculation value: 738.39; Measured value: 739.95 (M+H) ⁺.
f21	((1S)-2-((2S)-2-(4-(4 '-(2-((2S)-1-(N-(butoxy carbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) butyl carbamate	rT=1.447 minute (condition 3,96%); LRMS: for C ₄₂h ₅₄n ₈o ₆analytical calculation value: 766.93; Measured value: 768.02 (M+H) ⁺.
			f22	(2S)-2-hydroxy-n-((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-((2S)-2-hydroxy-3-methyl butyryl radicals)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-4-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl)-3-methylbutyryl amine	rT=1.703 minute (condition 4,98%); LRMS: for C ₄₂h ₅₄n ₈o analytical calculation value: 766.93; Measured value: 768.02 (M+H) ⁺.
f23		rT=2.881 minute (condition 7,93%); LRMS: for C ₄₆h ₆₂n ₈o ₆analytical calculation value: 822.48; Measured value: 823.95 (M+H) ⁺.
			f24		rT=1.743 minute (condition 7,98%); LRMS: for C ₃₆h ₄₆n ₈o ₂analytical calculation value: 622.37; Measured value: 624.07 (M+H) ⁺.

f25	((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2 S)-2-((ethoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) urethanum	rT=1.932 minute (condition 6,97%); LRMS: for C ₄₂h ₅₄n ₈o ₆analytical calculation value: 766.42; Measured value: 767.55 (M+H) ⁺.
			f26	((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2 S)-2-((isopropyl oxygen carbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-4-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) carbamic acid isopropyl ester	rT=2.122 minute (condition 6,98%); LRMS: for C ₄₄h ₅₈n ₈o ₆analytical calculation value: 794.45; Measured value: 795.58 (M+H) ⁺.

numbering	compound title	retention time (LC-condition); Homogeneity index; MS data
			f27	(2S)-1-((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-hydroxyl propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-oxo-2-propyl alcohol	rT=1.03 minute (condition 3,98%); LRMS: for C ₃₂h ₃₆n ₆o ₄analytical calculation value: 568.28; Measured value: 569.76 (M+H) ⁺.
f28	((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((tertbutyloxycarbonyl) (methyl) amino)-4-methylpent acyl group)-2-pyrrolidyl)-1H-imidazoles-4-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-3-methyl butyl) methyl carbamic acid tert-butyl ester	rT=1.847 minute (condition 3,95%); LRMS: for C ₅₀h ₇₀n ₈o ₆analytical calculation value: 878.54; Measured value: 879.53 (M+H) ⁺.
			f29	((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((tertbutyloxycarbonyl) (methyl) amino)-3-methylpent acyl group)-2-pyrrolidyl)-1H-imidazoles-4-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl butyl) methyl carbamic acid tert-butyl ester	rT=2.202 minute (condition 8,98%); LRMS: for C ₅₀h ₇₀n ₈o ₆analytical calculation value: 878.54; Measured value: 879.57 (M+H) ⁺.
f30	((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((tertbutyloxycarbonyl) (methyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-4-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) methyl carbamic acid tert-butyl ester	rT=1.743 minute (condition 8,96%); LRMS: for C ₄₈h ₆₆n ₈o ₆analytical calculation value: 850.51; Measured value: 851.52 (M+H) ⁺.
			f31	((1S, 2R)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-(the other isoleucyl of N-(tertbutyloxycarbonyl)-N-methyl-L-)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl butyl) methyl carbamic acid tert-butyl ester	rT=1.82 minute (condition 8,98%); LRMS: for C ₅₀h ₇₀n ₈o ₆analytical calculation value: 878.54; Measured value: 879.54 (M+H) ⁺.

f32	(2S)-N, 4-dimethyl-1-((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-4-methyl-2-(methylamino-) pentanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-oxo-2-amylamine	rT=3.715 minute (condition 9,98%); LRMS: for C ₄₀h ₅₄n ₈o ₂analytical calculation value: 678.44; Measured value: 679.46 (M+H) ⁺.
			f33	(2S)-N, 3-dimethyl-1-((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-3-methyl-2-(methylamino-) pentanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-oxo-2-amylamine	rT=3.058 minute (condition 9,99%); LRMS: for C ₃₆h ₄₆n ₈o ₂analytical calculation value: 678.44; Measured value: 679.61 (M+H) ⁺.
f34	(2S)-N, 3-dimethyl-1-((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-3-methyl-2-(methylamino-) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-oxo-2-butylamine	rT=3.206 minute (condition 9,99%); LRMS: for C ₃₈h ₅₀n ₈o ₂analytical calculation value: 650.41; Measured value: 651.41 (M+H) ⁺.
			f35	(2S; 3R)-N; 3-dimethyl-1-((2S)-2-(4-(4 '-(2-((2S)-1-((2S, 3R)-3-methyl-2-(methylamino-) pentanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-oxo-2-amylamine	rT=3.43 minute (condition 9,98%); LRMS: for C ₄₀h ₅₄n ₈o ₂analytical calculation value: 678.44; Measured value: 679.44 (M+H) ⁺.

By preparing compound F 17-hydroxy-corticosterone 27-F31 for the similar fashion of embodiment 1 synthetic method.

By preparing compound F 17-hydroxy-corticosterone 32-F35 for the similar fashion of 1e synthetic method.

By preparing compound F 17-hydroxy-corticosterone 36 for the similar fashion of Cap-52 synthetic method.

By the similar fashion for embodiment 1 synthetic method, by compound F 17-hydroxy-corticosterone 36 and LS16, prepare compound F 17-hydroxy-corticosterone 37, F38 and F39 respectively.

numbering	compound	retention time (LC-condition); Homogeneity index; MS data
			f36		rT=1.55 minute (condition 10); LRMS: for C ₁₀h ₁₃nO ₂analytical calculation value: 189.1; Measured value: 190.13 (M+H) ⁺. ¹H NMR(500MHz，DMSO-d ₆)δ ppm 0.71-1.00(m，6H)1.16-1.41(m， 3H)1.75-2.09(m，1H)3.39-3.64(m， 3H)7.13(s，1H)12.27(s，1H)。

f37	((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-2; 3-dimethyl butyrate acyl group)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1,2-dimethyl propyl) Urethylane	rT=2.572 minute (condition 4,98%); LRMS: for C ₄₂h ₅₄n ₈o ₆analytical calculation value: 766.42; Measured value: 767.48 (M+H) ⁺.
			f38	((1S)-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2 S)-2-((methoxycarbonyl) amino)-2-(tetrahydrochysene-2H-pyrans-4-yl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(tetrahydrochysene-2H-pyrans-4-yl) ethyl) Urethylane	rT=2.128 minute (condition 7,98%); LRMS: for C ₄₄h ₅₄n ₈o ₈analytical calculation value: 822.41; Measured value: 823.45 (M+H) ⁺.
f39	(2-((2S)-2-(4-(4 '-(2-((2S)-1-(((methoxycarbonyl) amino) (tetrahydrochysene-2H-pyrans-4-yl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(tetrahydrochysene-2H-pyrans-4-yl) ethyl) Urethylane	rT=2.162 minute (condition 7,98%); LRMS: for C ₄₄h ₅₄n ₈o ₈analytical calculation value: 822.42; Measured value: 823.49 (M+H) ⁺.

By preparing compound F 17-hydroxy-corticosterone 41 for the similar fashion of embodiment 1 synthetic method.

By preparing compound F 17-hydroxy-corticosterone 42 for the similar fashion of 1e synthetic method.

numbering	compound title	retention time (LC-condition); Homogeneity index M S data
			f40	rT=2.72 minute (condition 10); LRMS: for C ₄₆h ₅₄n ₈o ₆analytical calculation value: 814.42; Measured value: 815.98 (M+H) ⁺.
f41	((1S)-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2 R)-2-(ethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane	rT=2.048 minute (condition 10,95%); LRMS: for C ₄₁h ₄₆n ₈o ₄analytical calculation value: 714.36; Measured value: 715.84 (M+H) ⁺.

By the similar fashion for embodiment 28f synthetic method, with Cap-2, replace Cap-4 and prepare compound F 17-hydroxy-corticosterone 42.

By the similar fashion for 2 synthetic methods, by compound F 17-hydroxy-corticosterone 42, prepare compound F 17-hydroxy-corticosterone 43.

numbering	compound title	retention time (LC-condition); Homogeneity index; MS data
			f42	rT=2.0 minute (condition 10,95%); LRMS: for C ₃₈h ₄₃n ₇o analytical calculation value: 613.35; Measured value: 614.40 (M+H) ⁺.
f43	((1S)-1-(((2S)-2-(5-4 '-(2-((2S)-1-((2 R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1,2-dimethyl propyl) Urethylane	rT=2.308 minute (condition 10,98%); LRMS: for C ₅₀h ₇₀n ₈o ₆analytical calculation value: 784.44; Measured value: 785.49 (M+H) ⁺.

According to following paper method, prepare compound F 17-hydroxy-corticosterone 44, relevant being amended as follows: replace leucine with glycine.

For the preparation of N-mono--alkylation a-amino acid and N, the simple and easy method of N-bis--alkylation a-amino acid: Yuntao Song etc., Tetrahedron Lett.41, in August, 2000,8225-8230 page.

¹H NMR(500MHz，DMSO-d ₆)δppm 1.37-1.62(m，2H)1.86(dd，J＝12.36，1.98Hz，2H)3.01-3.12(m，1H)3.15(s，2H)3.25(t，J＝11.75Hz，2H)3.86(dd，J＝11.44，4.12Hz，2H)7.67-8.48(m，1H)。

Compound F 17-hydroxy-corticosterone 45

2-(tetrahydrochysene-2H-pyrans-4-base is amino) acetic acid (0.2g, 1.256mmol) F44 is dissolved in to DMF (22.5ml) and Et ₃in N (2.5ml, 17.94mmol).After 5 minutes, add BOC ₂o (0.583ml, 2.51mmol), is heated to 60 ℃ by reaction soln and reaches 1 hour.Concentrating under reduced pressure reactant, obtains light yellow oil, at 0 ℃, adds wherein 20ml HCl/H ₂o, is adjusted to PH 3 and stirs 10 minutes.Ethyl acetate for reaction mixture (3 * 20ml) extraction, dry (MgSO ₄), after filtration, be concentrated into dry.Add ether, mixture filters after supersound process, obtains white solid F45:2-(tertbutyloxycarbonyl (tetrahydrochysene-2H-pyrans-4-yl) amino) acetic acid (0.14g, 0.540mmol, yield 43.0%).

¹H NMR(300MHz，DMSO-d ₆)δppm 1.27-1.44(m，9H)1.43-1.69(m，4H)3.19-3.39(m，2H)3.74(s，2H)3.79-3.92(m，2H)3.97-4.16(m，1H)12.46(s，1H)。

According to hereinafter with reference method, prepare compound F 17-hydroxy-corticosterone 46, relevant being amended as follows: with (S)-2-amino-3 Methylbutanoic acid tert-butyl ester, replace (S)-2-(((9H-fluorenes-9-yl) methoxyl group) carbonylamino)-3 Methylbutanoic acid methyl esters.

Hans-Joachim deng, Synlett 1997; 925-928.

¹H NMR(500MHz，DMSO-d ₆)δppm 0.77-0.97(m，6H)1.32-1.45(m，9H)1.45-1.56(m，2H)1.74-1.91(m，2H)1.94-2.11(m，1H)3.36-3.53(m，2H)3.76(dd，J＝8.09，6.26Hz，1H)3.77-3.90(m，2H)4.69(dd，J＝9.00，4.73Hz，1H)7.35(d，J＝8.24Hz，1H)。

Compound F 17-hydroxy-corticosterone 47

To compound 46 (S)-3-methyl-2-((tetrahydrochysene-2H-pyrans-4-base oxygen base) carbonylamino) tert-butyl acetate (0.21g, 0.697mmol), add HCl dioxane solution (15ml, 60.0mmol), mixture is stirred 3 hours under nitrogen atmosphere, room temperature.After having reacted, concentrating under reduced pressure, obtains F47 (S)-3-methyl-2-((tetrahydrochysene-2H-pyrans-4-base oxygen base) carbonylamino) butyric acid (0.1694g, 0.691mmol, yield 100%), is transparent wax.

¹H NMR(500MHz，DMSO-d ₆)δppm 0.88(t，J＝6.71Hz，6H)1.41-1.60(m，2H)1.85(d，J＝12.21Hz，2H)1.97-2.08(m，1H)3.41(t，J＝10.68Hz，1H)3.45-3.52(m，1H)3.64-3.74(m，1H)3.77-3.89(m，2H)4.63-4.72(m，1H)7.32(d，J＝8.55Hz，1H)12.52(s，1H)。

By preparing compound F 17-hydroxy-corticosterone 48-F58 for the similar fashion of embodiment 1 synthetic method by LS18, except F51.

By the similar fashion for 1e synthetic method, by F50, prepare compound F 17-hydroxy-corticosterone 51.

numbering	compound title	retention time (LC-condition); Homogeneity index; MS data
			f48	((1S)-2-methyl isophthalic acid-(((2S)-2-(4-(4 '-(2-((2S)-1-(N-(tetrahydrochysene-2H-pyrans-4-yl)-L-alanyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane	rT=2.103 minute (condition 7,98%); LRMS: for C ₄₁h ₅₂n ₈o ₅analytical calculation value: 736.41; Measured value: 737.07 (M+H) ⁺.
f49	((1S)-2-methyl isophthalic acid-(((2S)-2-(4-(4 '-(2-((2S)-1-(N-(tetrahydrochysene-2H-pyrans-4-yl)-L-is valyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane	rT=2.117 minute (condition 7,98%); LRMS: for C ₄₃h ₅₆n ₈o ₅analytical calculation value: 764.44; Measured value: 765.75 (M+H) ⁺.
			f50		rT=2.547 minute (condition 7,98%); LRMS: for C ₄₅h ₅₈n ₈o ₇analytical calculation value: 822.44; Measured value: 823.17 (M+H) ⁺.
f51	((1S)-2-methyl isophthalic acid-(((2S)-2-(4-(4 '-(2-((2S)-1-(N-(tetrahydrochysene-2H-pyrans-4-yl) glycyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane	rT=2.138 minute (condition 7,96%); LRMS: for C ₄₀h ₅₀n ₈o ₅analytical calculation value: 722.39; Measured value: 723.63 (M+H) ⁺.

f52	((1S)-2-methyl isophthalic acid-(((2S)-2-(4-(4 '-(2-((2S)-1-(N-(tetrahydrochysene-2H-pyrans-4-yl)-D-is valyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane	rT=2.083 minute (condition 7,98%); LRMS: for C ₄₃h ₅₆n ₈o ₅analytical calculation value: 764.44; Measured value: 765.78 (M+H) ⁺.
			f53	((1S)-2-methyl isophthalic acid-(((2S)-2-(4-(4 '-(2-((2S)-1-(N-(tetrahydrochysene-2H-pyrans-4-yl)-D-alanyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane	rT=0.963 minute (condition 11,95%); LRMS: for C ₄₃h ₅₄n ₈o ₇analytical calculation value: 736.41; Measured value: 737.54 (M+H) ⁺.
f54	(3S)-((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) carboxylamine tetrahydrochysene-3-furans ester	rT=2.378 minute (condition 7,95%); LRMS: for C ₄₃h ₅₄n ₈o ₇analytical calculation value: 794.41; Measured value: 795.94 (M+H) ⁺.
			f55	((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) carboxylamine tetrahydrochysene-2H-pyrans-4-base ester	rT=2.447 minute (condition 7,99%); LRMS: for C ₄₄h ₅₆n ₈o ₇analytical calculation value: 808.43; Measured value: 809.42 (M+H) ⁺.
f56	(3R)-((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) carboxylamine tetrahydrochysene-3-furans ester	rT=2.398 minute (condition 7,96%); LRMS: for C ₄₃h ₅₄n ₈o ₇analytical calculation value: 794.41; Measured value: 795.36 (M+H) ⁺.

f57	((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2 R)-2-((methoxycarbonyl) amino)-2-(tetrahydrochysene-2H-pyrans-4-yl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane	rT=2.272 minute (condition 7,98%); LRMS: for C ₄₂h ₅₂n ₈o ₇analytical calculation value: 780.40; Measured value: 781.34 (M+H) ⁺.
			f58	((1S)-1-(((2S)-2-(4-4 '-(2-((2S)-1-((2 S)-2-((methoxycarbonyl) amino)-2-(tetrahydrochysene-2H-pyrans-4-yl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane	rT=2.225 minute (condition 7,98%); LRMS: for C ₄₂h ₅₂n ₈o ₇analytical calculation value: 780.40; Measured value: 781.27 (M+H) ⁺.

Compound F 17-hydroxy-corticosterone 59

By preparing compound F 17-hydroxy-corticosterone 59 for the similar fashion of 26a synthetic method, relevant being amended as follows: replace Boc-D-val-OH with Boc-L-val-OH.

By the similar fashion for embodiment 29 synthetic methods, by F59, prepare compound F 17-hydroxy-corticosterone 60-F62.

By the similar fashion for Cap45 synthetic method, prepare compound F 17-hydroxy-corticosterone 63 and compound F 17-hydroxy-corticosterone 64.

numbering	compound title	retention time (LC-condition); Homogeneity index; MS data
			f59		rT=1.743 minute (condition 7,98%); LRMS: for C ₃₆h ₄₆n ₈o ₂analytical calculation value: 622.37; Measured value: 624.07 (M+H) ⁺.
f60	n-((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-acetylaminohydroxyphenylarsonic acid 3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) ethanamide	rT=2.047 minute (condition 10,98%); LRMS: for C ₄₀h ₅₀n ₈o ₄analytical calculation value: 706.44; Measured value: 707.77 (M+H) ⁺.
			f61	n-((1S)-2-methyl isophthalic acid-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-3-methyl-2-(propionyl is amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) propionic acid amide	rT=2.215 minute (condition 1098%); LRMS: for C ₄₂h ₅₄n ₈o ₄analytical calculation value: 734.43; Measured value: 735.87 (M+H) ⁺.
f62	2-methoxyl group-N-((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-((methoxyl group ethanoyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-4-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) ethanamide	rT=2.232 minute (condition 10,99%); LRMS: for C ₄₂h ₅₄n ₈o ₆analytical calculation value: 766.93; Measured value: 768.05 (M+H) ⁺.
			f63	1-methyl-3-((1S)-2-methyl isophthalic acid-(((2S)-2-(4-(4 '-(2-((2S)-1-(N-(methylamino formyl radical)-L-is valyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) urea	rT=2.082 minute (condition 10,95%); LRMS: for C ₄₀h ₅₂n ₁₀o ₄analytical calculation value: 736.42; Measured value: 737.86 (M+H) ⁺.

f64

1-ethyl-3-((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-((ethylamino formyl radical) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) urea

rT=1.617 minute (condition 12,93%); LRMS: for C ₄₂h ₅₆n ₁₀o ₄analytical calculation value: 764.45; Measured value: 765.57 (M+H) ⁺.

Compound F 17-hydroxy-corticosterone 65

In DMF (1ml) solution of F59 (0.06g, 0.074mmol), add dimethylamino SULPHURYL CHLORIDE (0.016ml, 0.148mmol) and Hunig alkali (0.078ml, 0.445mmol), at room temperature stir 3 hours.After removal of solvent under reduced pressure; obtain light brown oily matter; with preparation HPLC, purify; obtain F65N-((S)-1-((S)-2-(5-(4 '-(2-((S)-1-((S)-2-(N; N-dimethylamino sulfuryl amino)-3-methylbutyryl base) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) pyrrolidin-1-yl)-3-methyl isophthalic acid-oxo fourth-2-yl) propane-2-sulphonamide (19.0mg; 0.018mmol, yield 24.08%).

¹H NMR(500MHz，DMSO-d ₆)δppm 0.65-1.03(m，12H)1.87-2.08(m，4H)2.06-2.27(m，4H)2.37-2.46(m，2H)2.56-2.69(m，12H)3.66-3.92(m，6H)5.14(t，J＝7.63Hz，2H)7.49(d，J＝9.16Hz，2H)7.89(d，J＝8.24Hz，4H)7.96(s，4H)8.14(s，2H)14.72(s，2H)。

RT=2.047 minute (condition 10,98%); LRMS: for C ₄₀h ₅₀n ₈o ₄analytical calculation value: 706.38; Measured value: 707.77 (M+H) ⁺.

1b Fret(EC ₅₀，μM)＝0.21。

By the similar fashion for F65 synthetic method, by compound F 17-hydroxy-corticosterone 59, prepare compound F 17-hydroxy-corticosterone 66-F69.

numbering	compound title	retention time (LC-condition); Homogeneity index; MS data
			f66	n-((1S)-2-methyl isophthalic acid-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-3-methyl-2-((methylsulfonyl) amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) amsacrine	rT=2.02 minute (condition 10,98%); LRMS: for C ₃₈h ₅₀n ₈o ₆s ₂analytical calculation value: 778.38; Measured value: 779.60 (M+H) ⁺.
f67	n-((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-((ethylsulfonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-4-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) ethane sulphonamide	rT=2.172 minute (condition 10,98%); LRMS: for C ₄₀h ₅₄n ₈o ₆s ₂analytical calculation value: 807.04; Measured value: 808.42 (M+H) ⁺.

f68	n-((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-((cyclopropyl alkylsulfonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-4-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) cyclopropane sulphonamide	rT=2.217 minute (condition 10,93%); LRMS: for C ₄₂h ₅₄n ₈o ₆s ₂analytical calculation value: 831.06; Measured value: 832.49 (M+H) ⁺.
			f69	n-((1S)-1-methyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methylsulfonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) amsacrine	rT=1.983 minute (condition 10,95%); LRMS: for C ₃₄h ₄₂n ₈o ₆s ₂analytical calculation value: 722.27; Measured value: 723.68 (M+H) ⁺.

By following literature method, prepare compound F 17-hydroxy-corticosterone 70:Anna Helms etc., J.Am.Chem.Soc.1992114 (15), 6227-6238 page.

By preparing compound F 17-hydroxy-corticosterone 71 for the similar fashion of embodiment 1 synthetic method.

¹H NMR(500MHz，DMSO-d ₆)δppm 0.69-0.95(m，12H)1.92(s，12H)1.97-2.27(m，8H)2.40(s，2H)3.55(s，6H)3.73-3.97(m，4H)4.12(t，J＝7.78Hz，2H)5.14(t，J＝7.02Hz，2H)7.34(d，J＝8.24Hz，2H)7.49-7.70(m，4H)8.04(s，2H)14.59(s，2H)。

RT=2.523 minute (condition 7,96%); LRMS: for C ₄₄h ₅₈n ₈o ₆analytical calculation value: 794.45; Measured value: 795.48 (M+H) ⁺.

Cj part: the synthesis method of carboxylamine ester interchange

Embodiment cj-2 and embodiment cj-3

(S) preparation of-2-(5-(4 '-(2-((S)-1-((S)-2-amino-3-methylbutyryl base) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate (cj-2)

To (S)-2-(5-(4 '-(2-((S)-pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate (cj-1) (1.00g, 1.91mmol), iPr ₂in the solution of NEt (1.60ml, 9.19mmol) and N-Z-α-amino-isovaleric acid (0.62g, 2.47mmol) and DMF (10ml), add HATU (0.92g, 2.42mmol).Solution is at room temperature stirred 1 hour, after being poured in frozen water (about 250ml), standing 20 minutes.Mixture is filtered, and after solid washes with water, vacuum-drying is spent the night, and obtains colorless solid (1.78g), and itself can be used for next step.LCMS: for C ₄₄h ₅₁n ₇o ₅analytical calculation value: 757; Measured value: 758 (M+H) ⁺.

This product (1.70g) and 10%Pd-C (0.37g) are carried out to hydrogenation (gasbag pressure) 12 hours with the mixture of MeOH (100ml).Then after mixture being filtered, solvent removed in vacuo.Resistates is purified (Biotage system/0-10%MeOH-CH with silica gel chromatography ₂cl ₂), obtain title compound (0.90g, 76%, light yellow foam).

¹H NMR(400MHz，DMSO-d ₆)δ12.18(s，0.35H)，11.73(s，0.65H)，11.89(s，0.65H)，11.82(s，0.35H)，7.77-7.81(m，3H)，7.57-7.71(m，5H)，7.50-7.52(m，2H)，5.17(dd，J＝3.6，6.5Hz，0.3H)，5.08(dd，J＝3.6，6.5Hz，0.7H)，4.84(m，0.3H)，4.76(m，0.7H)，3.67-3.69(m，1H)，3.50-3.62(m，1H)，3.34-3.47(m，2H)，2.22-2.28(m，2H)，2.10-2.17(m，2H)，1.74-2.05(m，6H)，1.40(s，4H)，1.15(s，5H)，0.85-0.91(m，4H)，0.79(d，J＝6.5Hz，2H)。

LCMS: for C ₃₆h ₄₅n ₇o ₃analytical calculation value: 623; Measured value: 624 (M+H) ⁺.

(S) preparation of-2-(5-(4 '-(2-((S)-1-((R)-2-amino-3-methylbutyryl base) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate (cj-3)

Employing is for the preparation of the same procedure of cj-2; preparation (S)-2-(5-(4 '-(2-((S)-1-((R)-2-amino-3-methylbutyryl base) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate (cj-3); obtain colourless foam shape thing (1.15g, 76%). ¹HNMR(400MHz，DMSO-d ₆)δ12.17(s，0.35H)，12.04(s，0.65H)，11.89(s，0.65H)，11.81(s，0.35H)，7.78-7.83(m，3H)，7.60-7.71(m，5H)，7.43-7.52(m，2H)，5.22-5.25(m，0.4H)，5.05-5.07(m，0.6H)，4.83-4.86(m，0.5H)，4.72-4.78(m，0.5H)，3.78-3.84(m，1H)，3.49-3.64(m，2H)，3.35-3.43(m，2H)，2.19-2.32(m，1H)，2.04-2.17(m，3H)，1.95-2.04(m，2H)，1.76-1.90(m，3H)，1.40(s，4H)，1.15(s，5H)，0.85-0.91(m，4H)，0.67(d，J＝6.5Hz，1H)，0.35(d，J＝6.5Hz，1H)。LCMS: for C ₃₆h ₄₅n ₇o ₃analytical calculation value: 623; Measured value: 624 (M+H) ⁺.

Embodiment cj-4 and embodiment cj-5

(S) preparation of-2-(5-(4 '-(2-((S)-1-((S)-3-methyl-2-(pyrimidine-2--amino) butyryl radicals) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate (cj-4)

By (S)-2-(5-(4 '-(2-((S)-1-((S)-2-amino-3-methylbutyryl base) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate (cj-2) (0.45g; 0.72mmol), 2-bromo pyrimi piperidine (0.37g, 2.34mmol) and iPr ₂(4: 1, mixture 5ml) is heated overnight at 90 ℃ with toluene-DMSO for NEt (0.20ml, 1.18mmol).Vacuum is removed volatile matter, and resistates is purified (YMC Pack C-18,30 * 100mm/MeCN-H with preparation HPLC ₂o-TFA), obtaining the tfa salt (0.56g, 74%) of title compound, is orange-yellow glassy mass.

¹h NMR (400MHz, DMSO-d ₆) δ 14.56 (br s, 2H), 8.28 (d, J=5.0Hz, 1H), 8.12-8.20 (m, 2H), 7.94-7.97 (m, 3H), 7.83-7.91 (m, 5H), 7.06 (d, J=8.1Hz, 1H), 6.62 (apparent t, J=5.0Hz, 1H), 4.99-5.10 (m, 2H), 4.50 (apparent t, J=7.7Hz, 1H), 4.07-4.12 (m, 2H), 3.83-3.87 (m, 1H), 3.56-3.62 (m, 1H), 3.40-3.47 (m, 2H), 2.36-2.41 (m, 1H), 1.94-2.22 (m, 6H), 1.40 (s, 4H), 1.17 (s, 5H), 0.88 (apparent t, J=6.5Hz, 6H).

LCMS: for C ₄₀h ₄₇n ₉o ₃analytical calculation value: 701; Measured value: 702 (M+H) ⁺.

(S) preparation of-2-(5-(4 '-(2-((S)-1-((R)-3-methyl-2-(pyrimidine-2--amino) butyryl radicals) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate (cj-5)

According to prepare the tfa salt of title compound for the preparation of the same procedure of cj-4, obtain light yellow solid (0.375g, 59%).

¹h NMR (400MHz, DMSO-d ₆) δ 14.67 (br s, 2H), 8.30 (d, J=4.3Hz, 1H), 8.04-8.19 (m, 2H), 7.84-7.96 (m, 8H), 6.88 (d, J=8.6Hz, 1H), 6.61 (apparent t, J=4.5Hz, 1H), 5.17 (dd, J=4.4, 8.0Hz, 1H), 5.00-5.07 (m, 1H), 4.67 (dd, J=7.3, 8.1Hz, 1H), 3.91-3.96 (m, 1H), 3.70-3.75 (m, 1H), 3.56-3.62 (m, 1H), 3.42-3.45 (m, 1H), 2.39-2.43 (m, 2H), 2.04-2.16 (m, 5H), 1.94-1.97 (m, 2H), 1.40 (s, 4H), 1.17 (s, 5H), 0.95 (d, J=6.6Hz, 2.5H), 0.91 (d, J=6.6Hz, 2.5H), 0.86 (d, J=6.6Hz, 0.5H), 0.81 (d, J=6.6Hz, 0.5H).

Embodiment cj-6 and embodiment cj-7

1-methyl-2-(methylthio group)-4, the preparation of 5-dihydro-1H-imidazoles hydriodate

According to following literature method, prepare title compound: Kister, J.; Assef, G.; Dou, H.J.-M.; Metzger, J.Tetrahedron 1976,32, and 1395.Therefore, by the EtOH-H of N-methyl ethylenediamine (10.8g, 146mmol) ₂(1: 1,90ml) solution was preheated to after 60 ℃ O, drips CS ₂(9.0ml, 150mmol).Gained mixture is heated 3 hours at 60 ℃, more slowly add dense HCl (4.7ml).Temperature is risen to 90 ℃, and continue to stir 6 hours.After cooling mixture is kept at-20 ℃, filtering, by the vacuum-drying of gained solid, obtain 1-Methylimidazole alkane-2-thioketones (8.43g, 50%), is beige solid.

¹H NMR(400MHz，CDCl ₃)δ5.15(s，br，1H)，3.67-3.70(m，2H)，3.53-3.58(m，2H)，3.11(s，3H)。

In acetone (50ml) suspension of 1-Methylimidazole alkane-2-thioketones (5.17g, 44.5mmol), add MeI (2.9ml, 46.6mmol).Solution is at room temperature stirred 4 hours, and by after gained solid fast filtering, vacuum-drying, obtains 1-methyl-2-(methylthio group)-4, and 5-dihydro-1H-imidazoles hydriodate (8.79g, 77%), is beige solid.

¹H NMR(400MHz，CDCl ₃)δ9.83(s，br，1H)，3.99-4.12(m，4H)，3.10(s，3H)，2.99(s，3H)。

(S) preparation of-2-(5-(4 '-(2-((S)-1-((S)-3-methyl-2-(1-methyl-4,5-glyoxalidine-2-base is amino) butyryl radicals) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate (cj-6)

By (S)-2-(5-(4 '-(2-((S)-1-((S)-2-amino-3-methylbutyryl base) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl)-tetramethyleneimine-1-t-butyl formate (cj-2) (0.280g; 0.448mmol) with 1-methyl-2-(methylthio group)-4; 5-dihydro-1H-imidazoles hydriodate (cj-3a) (0.121g, 0.468mmol) and CH ₃the mixture of CN (5ml) heats 12 hours at 90 ℃.Add again 0.030g 1-methyl-2-(methylthio group)-4,5-dihydro-1H-imidazoles hydriodate (cj-3a), and continue again to stir 12 hours.Crude reaction mixture is directly purified (Luna C-18/MeCN-H with preparation HPLC ₂o-TFA), obtaining the tfa salt (0.089g) of title compound, is light yellow solid, and itself can be used for subsequent step.

LCMS: for C ₄₀h ₅₁n ₉o ₃analytical calculation value: 705; Measured value: 706 (M+H) ⁺.

(S) preparation of-2-(5-(4 '-(2-((S)-1-((R)-3-methyl-2-(1-methyl-4,5-glyoxalidine-2-base is amino) butyryl radicals) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate (cj-7)

According to for the synthesis of method described in cj-6, by cj-3, prepare title compound, just reaction mixture is used preparation HPLC (YMC-Pack 25 * 250mm/MeCN-H at first ₂o-NH ₄oAc) after purifying, then use preparation HPLC (Luna phenyl-hexyl/MeCN-H ₂o-NH ₄oAc) purifying.This obtains required product (0.005g), is foam, and itself can be used for subsequent step.

Embodiment cj-8 and cj-9

(S) preparation of-2-(5-(4 '-(2-((S)-1-((S)-3-methyl-2-(3,4-glyoxalidine-2-base is amino) butyryl radicals) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate (cj-8)

By (S)-2-(5-(4 '-(2-((S)-1-((S)-2-amino-3-methylbutyryl base) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate (cj-2) (0.298g; 0.480mmol), 4; 5-dihydro-1H-imidazoles-2-sulfonic acid (AstaTech) (0.090g, 0.60mmol) and iPr ₂nEt (0.083ml, 0.48mmol) heats 12 hours with the mixture of EtOH (4ml) at 100 ℃.Cooling mixture is evaporated to dry, resistates is purified (Luna 5u C 18/MeCN-H with preparation HPLC ₂o-TFA, 2 times), obtain the tfa salt (0.390g, 73%) of title compound, be light yellow solid.

¹H NMR(400MHz，DMSO-d ₆)δ14.66(br s，2H)，8.51(br s，1H)，8.20(d，J＝10.1Hz，2H)，8.10(br s，1H)，7.82-7.91(m，7H)，7.30(br s，1H)，5.12(t，J＝7.1Hz，1H)，4.97-5.05(m，2H)，4.37(dd，J＝4.3，10.1Hz，2H)，3.82-3.86(m，2H)，3.73-3.77(m，2H)，3.59(s，4H)，3.39-3.48(m，2H)，2.15-2.25(m，2H)，1.93-2.07(m，5H)，1.40(s，4H)，1.17(s，5H)，0.93(d，J＝6.6Hz，3H)，0.69(br s，3H)。

LCMS: for C ₃₉h ₄₉n ₉o ₃analytical calculation value: 691; Measured value: 692 (M+H) ⁺.

(S) preparation of-2-(5-(4 '-(2-((S)-1-((R)-3-methyl-2-(3,4-glyoxalidine-2-base is amino) butyryl radicals) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate (cj-9)

According to the same procedure for the preparation of cj-8, by cj-3, prepare title compound, obtain tfa salt (0.199g, 57%), be yellow glass shape thing.

¹h NMR (400MHz, DMSO-d ₆) δ 14.58 (br s, 4H), 8.23 (d, J=9.6Hz, 1H), 8.11 (s, 1H), 7.87-7.89 (m, 6H), 7.25 (br s, 1H), 5.17-5.20 (m, 1H), 4.96-5.04 (m, 1H), 4.37 (dd, J=5.5,9.6Hz, 1H), 3.91-3.95 (m, 2H), (m, part is by H for 3.37-3.46 ₂o shelters, 4H), 2.39-2.42 (m, part is sheltered by solvent, 2H), 2.01-2.09 (m, 4H), 1.94-1.98 (m, 2H), 1.40 (s, 3H), 1.17 (s, 6H), 0.95 (d, J=6.5Hz, 2.5H), 0.85 (d, J=6.5Hz, 2.5H), 0.66 (d, J=7.0Hz, 0.5H), 0.54 (d, J=6.5Hz, 0.5H).

Embodiment cj-11

(S) preparation of-3-methyl-2-(pyrimidine-2--amino)-1-((S)-2-(5-(4 '-(2-((S)-pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) pyrrolidin-1-yl) butane-1-ketone (cj-10a)

Step 1: by the tfa salt (0.208g, 0.199mmol) of (S)-2-(5-(4 '-(2-((S)-1-((S)-3-methyl-2-(pyrimidine-2--amino) butyryl radicals) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate (cj-4) at CH ₂cl ₂(4ml) solution and in TFA (3ml) mixture was in stirring at room 1.5 hours.Then solvent removed in vacuo, resistates is purified (Luna 5u C18/MeCN-H with preparation HPLC ₂o-TFA), obtaining the tfa salt (0.391g) of title compound, is orange jelly.

¹h NMR (400MHz, DMSO-d ₆) δ 14.53 (br s, 3H), 9.52-9.57 (m, 2H), 8.98-9.04 (m, 2H), 8.28 (d, J=4.6Hz, 2H), 8.13 (br s, 1H), 7.79-7.91 (m, 7H), 7.07 (d, J=8.1Hz, 1H), 6.62 (apparent t, J=4.8Hz, 1H), 5.07 (t, J=7.1Hz, 1H), 4.72-4.78 (m, 2H), 4.48-4.51 (m, 1H), 4.08-4.12 (m, 2H), 3.28-3.36 (m, 2H), 2.37-2.42 (m, 2H), 1.97-2.22 (m, 6H), 0.88 (apparent t, J=4.5Hz, 6H).

LCMS: for C ₃₅h ₃₉n ₉o analytical calculation value: 601; Measured value: 602 (M+H) ⁺.

Equally, the following example is prepared according to above-mentioned exemplary process:

The preparation of ((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-2-pyrimidyl-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane (cj-11)

((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-2-pyrimidyl-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane

Step 2: add iPr in DMF (4ml) solution of (S)-3-methyl-2-(pyrimidine-2--amino)-1-((S)-2-(5-(4 '-(2-((S)-pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) pyrrolidin-1-yl) butane-1-ketone (cj-10) tfa salt (0.208g, 0.197mmol) ₂nEt (0.20ml, 1.15mmol), (S)-2-(methoxycarbonyl is amino)-3 Methylbutanoic acid (0.049g, 0.28mmol) and HATU (0.105g, 0.276mmol).This solution is at room temperature stirred 1.5 hours, with after MeOH (2ml) dilution, directly with preparation HPLC, purify (Luna 5uC18/MeCN-H ₂o-NH ₄oAc).Flash chromatography repurity (SiO for this product ₂/ 2-10%MeOH-CH ₂cl ₂), obtain solid, by it from CH ₃cN-H ₂freeze-drying in O, obtains title compound (48.6mg, 32%), is colorless solid.

¹h NMR (400MHz, DMSO-d ₆) δ 11.78 (br s, 1H), 8.28 (d, J=4.5Hz, 1H), 7.76-7.79 (m, 4H), 7.66-7.69 (m, 4H), 7.48-7.51 (m, 2H), 7.29 (d, J=8.6Hz, 1H), 6.93 (d, J=8.1Hz, 1H), 6.60 (apparent t, J=4.5Hz, 1H), 5.03-5.09 (m, 2H), 4.48 (t, J=8.1Hz, 1H), 3.99-4.08 (m, 2H), 3.78-3.85 (m, 2H) 3.53 (s, 3H), 2.12-2.21 (m, 4H), 1.87-2.05 (m, 7H), 0.83-0.97 (m, 12H).

LCMS: for C ₄₂h ₅₀n ₁₀o ₄analytical calculation value: 758; Measured value: 759 (M+H) ⁺.

Equally, the following example is prepared according to above-mentioned exemplary process;

Embodiment-cj-13

(S) preparation of-1-((S)-2-(5-(4 '-(2-((S)-1-((S)-2-amino-3-methylbutyryl base) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) pyrrolidin-1-yl)-3-methyl isophthalic acid-oxo fourth-2-aminocarbamic acid methyl esters (cj-13)

To (S)-3-methyl isophthalic acid-oxo-1-((S)-2-(5-(4 '-(2-((S)-pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) pyrrolidin-1-yl) fourth-2-aminocarbamic acid methyl esters (cj-12) (1.16g, 1.99mmol), Z-Val-OH (0.712g, 2.83mmol) and iPr ₂in the solution of NEt (0.70ml, 5.42mmol) and DMF (40ml), drip HATU (1.10g, 2.89mmol).Mixture was at room temperature stirred after 1 hour, pour in frozen water (400ml), and standing 20 minutes.Mixture is filtered, and solid cold water washing, makes it air dried overnight, obtains the protected intermediate of Z-.LCMS: for C ₄₆h ₅₄n ₈o ₆analytical calculation value: 814; Measured value: 815 (M+H) ⁺.

Gained solid is dissolved in to MeOH (80ml), adds 10%Pd-C (1.0g), by mixture hydrogenation 3 hours under room temperature and normal atmosphere.Then mixture is filtered, by filtrate vacuum concentration.Gained is purified by flash chromatography (SiO for resistates ₂/ 5-20%MeOH-CH ₂cl ₂), obtain title compound (1.05g, 77%), be colourless foam shape thing. ¹H NMR(400MHz，DMSO-d ₆)δ11.75(s，1H)，7.75-7.79(m，3H)，7.61-7.67(m，5H)，7.49(s，1H)，7.26-7.28(m，1H)，5.05-5.09(m，2H)，4.03-4.09(m，2H)，3.77-3.80(m，1H)，3.66-3.70(m，1H)，3.52(s，3H)，3.40-3.47(m，2H)，2.21-2.26(m，1H)，2.10-2.17(m，3H)，1.81-2.02(m，6H)，0.77-0.92(m，12H)。

LCMS: for C ₃₈h ₄₈n ₈o ₄analytical calculation value: 680; Measured value: 681 (M+H) ⁺.

Embodiment cj-15

(S) preparation of-1-((S)-2-(5-(4 '-(2-((S)-1-((S)-2-((Z/E)-(cyanoimino) (phenoxy group) methylamino-)-3-methylbutyryl base) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) pyrrolidin-1-yl)-3-methyl isophthalic acid-oxo fourth-2-aminocarbamic acid methyl esters (cj-14)

By (S)-1-((S)-2-(5-(4 '-(2-((S)-1-((S)-2-amino-3-methylbutyryl base) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) pyrrolidin-1-yl)-3-methyl isophthalic acid-oxo fourth-2-aminocarbamic acid methyl esters (cj-13) (0.329g; 0.527mmol) at room temperature stir 12 hours with cyano group carbon imidic acid diphenyl ester (0.128g, 0.537mmol) and the mixture of iPrOH (10ml).By air-dry after gained solid filtering, obtain title compound (0.187g, 43%), be Off-white solid.This product itself just can be used for next step without being further purified.

LCMS: for C ₄₆h ₅₂n ₁₀o ₅analytical calculation value: 824; Measured value: 825 (M+H) ⁺.

((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(5-amino-1-methyl isophthalic acid H-1; 2; 4-triazole-3-yl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) preparation of Urethylane (cj-15a, R=H)

By (S)-1-((S)-2-(5-(4 '-(2-((S)-1-((S)-2-((Z/E)-(cyanoimino) (phenoxy group) methylamino-)-3-methylbutyryl base) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) pyrrolidin-1-yl)-3-methyl isophthalic acid-oxo fourth-2-aminocarbamic acid methyl esters (cj-14) (0.074g; 0.090mmol) and the solution of hydrazine hydrate (0.05ml, 0.88mmol) and iPrOH (2ml) at 75 ℃, heat 7 hours.Then solvent removed in vacuo, resistates is purified (Luna 5u C18/MeCN-H with preparation HPLC ₂o-NH ₄oAc), obtain foam, by it from CH ₃cN-H ₂freeze-drying in O, obtains title compound (0.032g, 46%), is colorless solid.

¹H NMR(400MHz，DMSO-d ₆)δ12.17(s，1H)，11.75(m，2H)，10.66-10.84(m，2H)，7.76-7.79(m，3H)，7.62-7.74(m，4H)，7.49-7.51(m，1H)，7.24-7.29(m，2H)，5.28-5.32(m，1H)，5.05-5.08(m，2H)，4.04-4.09(m，3H)，3.87-3.94(m，2H)，3.72-3.81(m，2H)，3.53(s，3H)，2.09-2.17(m，2H)，1.90-2.02(m，6H)，0.81-0.99(m，12H)。

LCMS: for C ₄₀h ₅₀n ₁₂o ₄analytical calculation value: 762; Measured value: 763 (M+H) ⁺.

(S)-1-((S)-2-(5-(4 '-(2-((S)-1-((S)-2-(5-amino-1-methyl isophthalic acid H-1; 2; 4-triazole-3-base amino)-3-methylbutyryl base) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) pyrrolidin-1-yl) preparation of-3-methyl isophthalic acid-oxo fourth-2-aminocarbamic acid methyl esters (cj-15b, R=Me)

By (S)-1-((S)-2-(5-(4 '-(2-((S)-1-((S)-2-((Z/E)-(cyanoimino) (phenoxy group) methylamino-)-3-methylbutyryl base) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) pyrrolidin-1-yl)-3-methyl isophthalic acid-oxo fourth-2-aminocarbamic acid methyl esters (cj-14) (0.105g; 0.128mmol) at 75 ℃, heat 3 hours with N-methyl hydrazine (0.010ml, 0.188mmol) and the solution of iPrOH (2ml).Add second part of N-methyl hydrazine (0.010ml, 0.188mmol), continue heating 7 hours.Then vacuum is removed volatile matter, and resistates is purified (Luna 5u C 18/MeCN-H with preparation HPLC ₂o-NH ₄oAc), obtain foam, it is used to purified by flash chromatography (SiO again ₂/ 0-20%MeOH-CH ₂cl ₂).By products therefrom from CH ₃cN-H ₂freeze-drying in O, obtains title compound (0.029g, 29%), is colorless solid.

¹H NMR(400MHz，DMSO-d ₆)δ13.79(s，0.4H)，12.19(s，1H)，11.76(m，1.6H)，7.77-7.85(m，4H)，7.62-7.71(m，4H)，7.49-7.51(m，1H)，7.24-7.29(m，1H)，6.31(d，J＝9.1Hz，0.5H)，6.09(d，J＝9.1Hz，1.5H)，5.87(s，1H)，5.34-5.36(m，1H)，5.04-5.08(m，2H)，4.89(s，1H)，4.75(s，2H)，3.53(s，3H)，2.10-2.17(s，3H)，1.94-2.02(m，6H)，0.81-0.98(m，12H)。

LCMS: for C ₄₁h ₅₂n ₁₂o ₄analytical calculation value: 776; Measured value: 777 (M+H) ⁺.

HRMS: for C ₄₁h ₅₂n ₁₂o ₄analytical calculation value: 776.4234; Measured value: 777.4305 (M+H) ⁺.

Embodiment cj-15c

((1S)-1-(((2S)-2-(5-(4 '-(((N-(4 for (2S)-1-for 2-; 5-dihydro-1,3-thiazoles-2-yl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)

Carbonyl)-2-methyl-propyl) Urethylane

Employing is similar to the condition of preparing intermediate cj-4, and by intermediate cj-13 and 2-(methylthio group)-4,5-thiazoline (Aldrich) condensation, carrys out Preparation Example cj-15c.LCMS: for C ₄₁h ₅₁n ₉o ₄s analytical calculation value: 765; Measured value: 766 (M+H) ⁺.

Embodiment 15-d

((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-4-pyrimidyl-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane

Employing is similar to the method for preparing intermediate cj-4, after intermediate cj-13 and 4,6-dichloro pyrimidine (Aldrich) condensation, with 10%Pd-C, carries out hydrogenation, carrys out Preparation Example cj-15d.LCMS: for C ₄₂h ₅₀n ₁₀o ₄analytical calculation value: 758; Measured value: 759 (M+H) ⁺.

Embodiment cj-16 and embodiment cj-17

((1S)-1-(((2S)-2-(5-(4 '-((((5-amino-1 for N-for (2S)-1-for 2-; 2,4-oxadiazole-3-yl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) preparation of Urethylane (cj-16)

By (S)-1-((S)-2-(5-(4 '-(2-((S)-1-((S)-2-((Z/E)-(cyanoimino) (phenoxy group) methylamino-)-3-methylbutyryl base) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) pyrrolidin-1-yl)-3-methyl isophthalic acid-oxo fourth-2-aminocarbamic acid methyl esters (cj-14) (0.120g; 0.205mmol) and the solution of oxammonium hydrochloride (0.0213g, 0.307mmol) and iPrOH (5ml) at 75 ℃, heat 3 hours.Add second part of oxammonium hydrochloride (0.0213g, 0.307mmol), continue heating 7 hours.Then vacuum is removed volatile matter, and resistates is purified (Luna 5u C 18/MeCN-H with preparation HPLC ₂o-NH ₄oAc), obtain foam, it is used to purified by flash chromatography (SiO again ₂/ 5%MeOH-CH ₂cl ₂).By the colourless wax of gained from CH ₃cN-H ₂freeze-drying in O, obtains title compound (0.0344g, 22%), is colorless solid.

¹h NMR (400MHz, DMSO-d ₆) δ 12.18-12.22 (m, 1H), 11.80 (s, 1H), 11.75 (s, 1h), 8.03-8.06 (m, 1H), 7.77 (apparent d, J=8.1Hz, 2H), 7.62-7.73 (m, 4H), 7.50 (dd, J=2.0, 5.5Hz, 1H), 7.24-7.29 (m, 2H), 5.69 (s, 1H), 5.06-5.11 (m, 2H), 4.14 (t, J=8.6Hz, 1H), 4.06 (do not resolve dd, J=8.0, 8.6Hz, 1H), 3.78-3.90 (m, 3H), 3.53 (s, 3H), 3.01 (br s, 2H), 2.10-2.19 (m, 3H), 1.90-2.04 (m, 5H), 0.81-0.96 (m, 12H).

LCMS: for C ₄₀h ₄₉n ₁₁o ₅analytical calculation value: 763; Measured value: 764 (M+H) ⁺.

The preparation of ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(cyano group (dimethyl) amidino groups)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane (cj-17)

By (S)-1-((S)-2-(5-(4 '-(2-((S)-1-((S)-2-((Z/E)-(cyanoimino) (phenoxy group) methylamino-)-3-methylbutyryl base) pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) pyrrolidin-1-yl)-3-methyl isophthalic acid-oxo fourth-2-aminocarbamic acid methyl esters (cj-14) (0.115g; 0.198mmol) and the solution of dimethylamine hydrochloride (0.0257g, 0.315mmol) and iPrOH (5ml) at 90 ℃, heat 12 hours.Add second part of dimethylamine hydrochloride (0.0257g, 0.315mmol), continue heating 48 hours.Then vacuum is removed volatile matter, and resistates is purified (Luna 5u C18/MeCN-H with preparation HPLC ₂o-NH ₄oAc) after, with flash chromatography repurity (SiO ₂/ 5%MeOH-CH ₂cl ₂).By the colourless wax of gained from CH ₃cN-H ₂freeze-drying in O, obtains title compound (0.0318g, 21%), is colorless solid.

¹h NMR (400MHz, DMSO-d ₆) δ 12.22 (m, 0.6H), 11.81 (s, 1H), 11.75 (s, 1H), 12.17-12.22 (m, 0.5H), 11.99-12.04 (m, 0.5H), 11.75-11.81 (m, 1H), 7.76-7.79 (m, 3H), 7.62-7.73 (m, 5H), 7.50 (t, J=2.0Hz, 1H), 7.23-7.29 (m, 1H), 6.64 (d, J=8.1Hz, 1H), 5.06-5.08 (m, 2H), 4.47 (t, J=8.1Hz, 2H), 4.06 (do not resolve dd, J=8.0, 8.6Hz, 1H), 3.84-3.90 (m, 2H), 3.76-3.82 (m, 3H), 3.53 (s, 3H), 3.00 (s, 6H), 2.11-2.20 (m, 3H), 1.90-2.04 (m, 5H), 0.97 (d, J=6.5Hz, 3H), 0.89-0.91 (m, 6H), 0.84 (d, J=6.5Hz, 3H).

LCMS: for C ₄₂h ₅₃n ₁₁o ₄analytical calculation value: 775; Measured value: 776 (M+H) ⁺

Embodiment cj-20

The preparation of ((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-3-pyridyl-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane (cj-20)

In DMF (2ml) solution of (S)-3-methyl isophthalic acid-oxo-1-((S)-2-(5-(4 '-(2-((S)-pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) pyrrolidin-1-yl) fourth-2-aminocarbamic acid methyl esters (cj-13) (0.060g, 0.103mmol), add iPr ₂nEt (0.18ml, 1.02mmol), (S)-3-methyl-2-(pyridin-3-yl is amino) butyric acid (Cap-88) (0.040g, 0.206mmol) and HATU (0.078g, 0.205mmol).Reaction mixture was at room temperature stirred after 1.5 hours, directly with preparation HPLC, purify (Luna 5uC18/MeCN-H ₂o-NH ₄oAc).Flash chromatography repurity (SiO for gained solid ₂/ 0-10%MeOH-CH ₂cl ₂), by products therefrom from CH ₃cN-H ₂freeze-drying in O, obtains title compound (0.044g, 56%), is solid. ¹H NMR(400MHz，DMSO-d ₆)δ12.19(s，1H)，11.76(s，1H)，8.07(d，J＝2.6Hz，1H)，7.62-7.85(m，8H)，7.49-7.51(m，2H)，7.24-7.29(m，1H)，6.99-7.06(m，2H)，6.46-6.49(m，0.5H)，5.97-5.99(m，0.5H)，5.71(d，J＝9.0Hz，1H)，5.55(d，J＝10.6Hz，1H)，5.22-5.44(m，1H)，5.03-5.09(m，2H)，4.04-4.13(m，2H)，3.78-3.90(m，3H)，3.66-3.71(m，1H)，3.53(s，3H)，2.03-2.19(m，2H)，1.84-2.01(m，4H)，0.81-1.01(m，12H)。

LCMS: for C ₄₃h ₅₁n ₉o ₄analytical calculation value: 757; Measured value: 758 (M+H) ⁺.

(S) preparation of-3-methyl isophthalic acid-oxo-1-((S)-2-(5-(4 '-(2-((S)-pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) pyrrolidin-1-yl) fourth-2-aminocarbamic acid methyl esters (cj-12)

Synthetic by intermediate-28d and Cap-51 according to embodiment 28e, use subsequently TFA/CH ₂cl ₂slough Boc, with MCX resin formation free alkali.

¹H NMR(400MHz，MeOH-d ₄)δ7.79-7.82(m，3H)，7.65-7.75(m，5H)，7.48(s，1H)，7.32(s，1H)，5.19(dd，J＝5.5，5.7Hz，1H)，4.75(t，J＝7.8Hz，1H)，4.25(d，J＝7.3Hz，1H)，3.88-4.04(m，2H)，3.67(s，3H)，3.35-3.51(m，3H)，2.43-2.51(m，1H)，2.02-2.38(m，7H)，0.97(d，J＝6.5Hz，3H)，0.92(d，J＝6.9Hz，3H)。

LCMS: for C ₃₃h ₃₉n ₇o ₃analytical calculation value: 581; Measured value: 582 (M+H) ⁺.

(S) preparation of-1-oxo-1-((S)-2-(5-(4 '-(2-((S)-pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) pyrrolidin-1-yl) third-2-aminocarbamic acid methyl esters (cj-22)

As synthetic by intermediate-28d and Cap-52 in embodiment 28e, use subsequently TFA/CH ₂cl ₂slough Boc, with MCX resin formation free alkali.

¹h NMR (400MHz, MeOH-d ₄) δ 7.68-7.79 (m, 4H), 7.59-7.65 (m, 4H), 7.44 (d, J=6.6Hz, 1H), 7.37 (s, 0.3H), 7.27 (s, 0.7H), 5.18 (dd, J=4.0,7.6Hz, 1H), 4.74 (t, J=8.0Hz, 1H), 4.46 (dd, J=6.8,13.9Hz, 1H), 3.84 (do not resolve dd, J=6.1,6.5Hz, 1H), 3.62 (s, 3H), 3.54 (s, 1H), 3.32-3.46 (m, 3H), 2.40-2.46 (m, 1H), 2.26-2.39 (m, 2H), 2.14-2.24 (m, 2H), 2.01-2.12 (m, 2H), 0.32 (d, J=7.1Hz, 3H).

LCMS: for C ₃₁h ₃₅n ₇o ₃analytical calculation value: 553; Measured value: 554 (M+H) ⁺.

The preparation of (2S, 3R)-3-methoxyl group-1-oxo-1-((S)-2-(5-(4 '-(2-((S)-pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) pyrrolidin-1-yl) fourth-2-aminocarbamic acid methyl esters (cj-23)

As synthetic by intermediate-28d and Cap-86 in embodiment 28e, use subsequently TFA/CH ₂cl ₂slough Boc, with MCX resin formation free alkali.

¹H NMR(400MHz，MeOH-d ₄)δ7.72(m，4H)，7.64-7.69(m，4H)，7.48(d，J＝4.1Hz，1H)，7.38(s，0.3H)，7.33(s，0.7H)，5.51-5.54(m，0.2H)，5.22(dd，J＝4.9，7.6Hz，0.8H)，4.76(t，J＝8.0Hz，1H)，4.48(d，J＝5.1Hz，0.8H)，4.35-4.36(m，0.2H)，3.90-3.99(m，1H)，3.68(s，3H)，3.54(s，1H)，3.35-3.48(m，4H)，3.29(s，3H)，2.42-2.50(m，1H)，2.30-2.37(m，2H)，2.19-2.26(m，2H)，2.05-2.15(m，2H)，1.19(d，J＝6.1Hz，3H)。

LCMS: for C ₃₃h ₃₉n ₇o ₄analytical calculation value: 597; Measured value: 598 (M+H) ⁺.

(R) preparation of-2-(diethylin)-2-phenyl-1-((S)-2-(5-(4 '-(2-((S)-pyrrolidin-2-yl)-1H-imidazoles-5-yl) biphenyl-4-yl)-1H-imidazoles-2-yl) pyrrolidin-1-yl) ethyl ketone (cj-24)

As synthetic by intermediate-28d and Cap-2 in embodiment 28e, use subsequently TFA/CH ₂cl ₂slough Boc, with MCX resin formation free alkali.

¹H NMR(400MHz，MeOH-d ₄)δ7.59-7.82(m，10H)，7.36-7.51(m，4H)，7.01-7.15(m，1H)，5.09-5.13(m，2H)，4.77(t，J＝8.5Hz，1H)，4.03-4.05(m，1H)，3.67-3.93(m，1H)，3.35-3.47(m，2H)，3.18-3.23(m，1H)，2.91-3.07(m，2H)，2.70-2.84(m，2H)，2.34-2.60(m，2H)，1.97-2.24(m，5H)，1.07-1.17(m，6H)。

LCMS: for C ₃₈h ₄₃n ₇o analytical calculation value: 613; Measured value: 614 (M+H) ⁺.

According to the method for embodiment 28, by 28d, start to prepare following compounds.In table, provide end group (cap), to appended on 28d.If do not provide end group (cap) numbering, corresponding carboxylic acid is commercially available.

Embodiment cj-111 to embodiment cj-113.

For embodiment cj-111 to embodiment cj-113, under the similar condition for embodiment 28 steps d, (just do not use K ₂cO ₃), the compound of embodiment cj-105 to embodiment cj-107 is carried out to hydrogenation.

The preparation of embodiment cj-103, cj-114 and cj-115

According to method described in embodiment 28 step e, by intermediate cj-12 and Cap-122 coupling, prepare intermediate cj-124.LCMS: for C ₆₀h ₆₃n ₉o ₈analytical calculation value: 1037; Measured value: 520 (1/2M+H) ⁺.This is equivalent to the molion with twice electric charge.

Embodiment cj-103

At room temperature, intermediate cj-124 (83.0mg, 0.08mmol) is dissolved in after DMF (5ml), adds piperidines (1ml).Within 2 hours, final vacuum is removed volatile matter, and resistates is purified (YMC-Pack C-18,30 * 100mm, CH with preparation HPLC ₃cN-H ₂o-TFA), obtain the tfa salt (87.0mg, 94%) of amine.LCMS: for C ₄₅h ₅₃n ₉o ₆analytical calculation value: 815; Measured value: 816 (M+H) ⁺.

Embodiment cj-114 to embodiment cj-115

Embodiment cj-114, R=Ac

Embodiment cj-115, R=CONHEt

Be similar under the condition of embodiment 25, the product that derives from embodiment cj-103 carries out acidylate with diacetyl oxide or ethyl isocyanate as shown in flow process.

Embodiment cj-114, LCMS: for C ₄₇h ₅₅n ₉o ₇analytical calculation value: 857; Measured value: 858 (M+H) ⁺.

Embodiment cj-115, LCMS: for C ₄₈h ₅₈n ₁₀o ₇analytical calculation value: 886; Measured value: 887 (M+H) ⁺.

Employing is similar to the method for embodiment 1, and by intermediate, 1e prepares the following example.As shown in Table, if do not provide end group (cap) numbering, carboxylic acid is commercially available to additional end group (cap).

Embodiment cj-142

By the CH with 40%TFA ₂cl ₂solution-treated, products therefrom Preparation Example cj-142 in embodiment cj-140.Mixture was at room temperature stirred after 3 hours, vacuum concentration, resistates is purified (YMC-Pack, C1830 * 100mm, CH with preparation HPLC ₃cN-H ₂o-TFA).

Embodiment cj-156

According to for method shown in Cap-51, by the compound carbamyl that makes to prepare in embodiment-cj-142, carry out the compound of Preparation Example-cj-156.

JG part

Method G:HPLC-Phenomenex Gemini C-184.6 * 150mm, gradient 10-80%B, in 35 minutes, 1 minute residence time, A=5% acetonitrile, 95% water, 10mM ammonium acetate, B=95% acetonitrile, 5% water, 10mM ammonium acetate.

Method H:HPLC-Phenomenex Gemini C-184.6 * 150mm, gradient 10-80%B, in 25 minutes, 1 minute residence time, A=5% acetonitrile, 95% water, 10mM ammonium acetate, B=95% acetonitrile, 5% water, 10mM ammonium acetate.

Method I:HPLC-Waters-X-Bridge C-184.6 * 150mm, gradient 10-70%B, in 30 minutes, 1 minute residence time, A=5% acetonitrile, 95% water, 10mM ammonium acetate, B=95% acetonitrile, 5% water, 10mM ammonium acetate.

Step a:

By (3S, 3 ' S, 5S, 5 ' S)-5,5 '-(5,5 '-(biphenyl-4,4 '-bis-bases) two (1H-imidazoles-5,2-bis-bases)) solid of two (3-hydroxyl pyrrolidine-1-t-butyl formate) (1.40g, 2.13mmol) is added to the 14.0ml CH of two (2-methoxy ethyl) amino sulfur trifluorides (0.87ml, 4.69mmol) ₂cl ₂in solution (being cooled to-78 ℃).Reactant is stirred after 2 hours at-78 ℃, be warming up to room temperature and stir 2 hours.Reactant is poured in saturated sodium bicarbonate solution, stirred, until stop bubbling.Separated each layer, water layer CH ₂cl ₂washing once.The organism salt water washing merging, dry (MgSO ₄), concentrated after filtering, obtain yellow oil.This oily matter CH ₂cl ₂grind with pentane, obtain (3R, 3 ' R, 5S, 5 ' S)-5,5 '-(5,5 '-(biphenyl-4,4 '-bis-bases) two (1H-imidazoles-5,2-bis-bases)) two (3-fluoropyrrolidine-1-t-butyl formate) JG-1 (0.98g, 71%, tawny solid).

¹H NMR(500MHz，DMSO-d ₆)δppm 12.10(2H，m)7.60-7.82(8H，m)7.35(2H，m)5.45(1H，s)5.35(1H，s)4.85-4.90(2H，m)3.69-3.79(4H，m)2.53-2.61(2H，m)2.28-2.37(2H，m)1.40(8H，s)1.12(10H，s)。

LCMS-Phenomenex C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.1%TFA, B=90% methyl alcohol 10% water 0.1%TFA, (t _r=3.04 minutes).For C ₃₆h ₄₂f ₂n ₆o ₄analytical calculation value: 660.70; Measured value: 661.68 (M+H) ⁺.

Step b:

To (3R, 3 ' R, 5S, 5 ' S)-5,5 '-(5,5 '-(biphenyl-4,4 '-bis-bases) two (1H-imidazoles-5,2-bis-bases)) in the 4ml dioxane solution of two (3-hydroxyl pyrrolidine-1-t-butyl formate) (0.098g, 1.48mmol), add 2.0ml 4.0M HCl dioxane solution.Reactant was at room temperature stirred after 2 hours to concentrating under reduced pressure.Gained tawny solid, through vacuum-drying, obtains 4,4 '-bis-(2-((2S, 4S)-4-fluoropyrrolidine-2-yl)-1H-imidazoles-5-yl) biphenyl four hydrochloride JG-2 (0.89g, yield 100%).Without being further purified.

¹H NMR(500MHz，DMSO-d ₆)δppm 9.05(2H，s)，8.18(2H，s)，8.00-8.09(4H，m)7.89(4H，d，J＝7.63Hz)5.71(1H，s)5.61(1H，s)5.24-5.33(2H，m)3.92(2H，d，J＝10.68Hz)3.63-3.71(2H，m)2.79-2.89(2H，m)。

LCMS-Phenomenex C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.1%TFA, B=90% methyl alcohol 10% water 0.1%TFA, (t _r=2.12 minutes).For C ₂₆h ₂₆f ₂n ₆analytical calculation value: 460.53; Measured value: 461.37 (M+H) ⁺.

Step c:

To 4,4 '-bis-(2-((2S, 4R)-4-fluoropyrrolidine-2-yl)-1H-imidazoles-5-yl) biphenyl four hydrochloride (0.060g, 0.10mmol), (S)-2-(methoxycarbonyl is amino) propionic acid (0.031g, 0.21mmol) and HATU (0.081g, 0.21mmol) and in the stirred solution of 3ml DMF add diisopropylethylamine (0.11ml, 0..61mmol).Reactant is at room temperature stirred and spend the night after (16 hours), concentrating under reduced pressure.Crude product is purified with anti-phase preparation HPLC, then by Waters MCX extraction cartridge purifying, obtains (2S, 2 ' S)-1,1 '-((3R, 3 ' R, 5S, 5 ' S)-5,5 '-(5,5 '-(biphenyl-4,4 '-bis-bases) two (1H-imidazoles-5,2-bis-bases)) two (3-fluoropyrrolidine-5,1-bis-bases)) two (1-oxo propane-2,1-bis-bases) two (Urethylane) JG-3 (0.0097g, 7.5%, free alkali).

¹H NMR(500MHz，DMSO-d ₆)δppm 11.91(2H，m)，7.76-7.84(3H，m)，7.64-7.84(5H，m)，7.48-7.58(2H，m)，5.55(1H，s)，5.11(1H，s)，4.29-4.38(2H，m)，4.13(2H，d，J＝12.51Hz)，3.89-3.98(2H，m)，3.53(6H，s)，2.54-2.64(4H，m)，1.21(6H，s)。

LCMS-Luna C-183.0 * 50mm, gradient 0-100%B, in 7.0 minutes, 1 minute residence time, A=5% acetonitrile, 95% water, 10mM ammonium acetate, B=95% acetonitrile, 5% water, 10mM ammonium acetate, (t _r=2.40 minutes).

Nominal/LRMS-is for C ₃₆h ₄₀f ₂n ₈o ₆calculated value: 718.30; Measured value: 719.24 (M+H) ⁺.

Accurately/HRMS-is for C ₃₆h ₄₁f ₂n ₈o ₆calculated value: 719.3117; Measured value: 719.3114 (M+H) ⁺.

As embodiment 28 step a, with oxyproline, replace proline(Pro) and synthesize JG-18.

¹H NMR(500MHz，DMSO-d ₆)δppm 7.89(2H，t，J＝8.39Hz)7.74(2H，t，J＝8.24Hz)7.28-7.37(5H，m)5.01-5.08(3H，m)4.27-4.57(4H，m)3.44-3.53(1H，m)3.37(1H，d，J＝10.99Hz)2.12(1H，d，J＝11.60Hz)1.93(1H，dd，J＝12.05Hz，6.56Hz)。

LCMS-Phenomenex C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.1%TFA, B=90% methyl alcohol 10% water 0.1%TFA moving phase, t _r=3.62 minutes, for C ₂₁h ₂₁brN ₂o ₅analytical calculation value: 461.32; Measured value: 462.64 (M+H) ⁺.

As embodiment 28 step b, by the synthetic JG-19 of JG-18.

LCMS-Luna C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=5% acetonitrile, 95% water, 10mm ammonium acetate, B=95% acetonitrile, 5% water, 10mm ammonium acetate, t _r=1.88 minutes, for C ₂₁h ₂₀bN ₃o ₃analytical calculation value: 441.07; Measured value: 442.22 (M+H) ⁺.

By (2S, 4R)-2-(5-(4-bromophenyl)-1H-imidazoles-2-yl)-4-hydroxyl pyrrolidine-1-benzyl formate (1.5g, solid 3.4mmol) is added to the 15ml CH of two (2-methoxy ethyl) amino sulfur trifluorides (0.98ml, 5.1mmol) ₂cl ₂in solution (being cooled to-78 ℃).Reactant is stirred after 2 hours at-78 ℃, be warming up to room temperature, then stir 2 hours.Reactant is poured in saturated sodium bicarbonate solution, stirred, until stop bubbling.Separated each layer, water layer CH ₂cl ₂washing once.The organism salt water washing merging, dry (MgSO ₄), concentrated after filtering, obtain yellow oil.This oily matter CH ₂cl ₂grind with pentane, obtain (2S, 4S)-2-(5-(4-bromophenyl)-1H-imidazoles-2-yl)-4-fluoropyrrolidine-1-benzyl formate JG-20 (0.96g, 62%, yellow solid).

¹H NMR(500MHz，DMSO-d ₆)δppm 7.70(2H，d，J＝7.02Hz)7.48-7.55(3H，m)7.41-7.35(3H，m)7.19-7.11(2H，m)5.15-5.02(3H，m)3.84-3.78(2H，m)3.33(2H，s)2.53-2.61(1H，m)2.33-2.42(1H，m)。

LCMS-Luna C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=5% acetonitrile, 95% water, 10mm ammonium acetate, B=95% acetonitrile, 5% water, 10mm ammonium acetate, t _r=2.10 minutes, for C ₂₁h ₁₉br ₁f ₁n ₃o ₂analytical calculation value: 443.06; Measured value: 444.05 (M+H) ⁺.

By (2S, ((4-(4 for 5-for 4R)-4-hydroxyl-2-, 4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) phenyl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate 1-2c (1.5g, solid 3.3mmol) is added to the 15mlCH of two (2-methoxy ethyl) amino sulfur trifluorides (0.91ml, 5.0mmol) ₂cl ₂in solution (being cooled to-78 ℃).Reactant is stirred after 2 hours at-78 ℃, be warming up to room temperature, then stir 2 hours.Reactant is poured in saturated sodium bicarbonate solution, stirred, until stop bubbling.Separated each layer, water layer CH ₂cl ₂washing once.The organism salt water washing merging, dry (MgSO ₄), concentrated after filtering, obtain brown oil.This oily matter is processed (5%MeOH/CH with silica gel chromatography ₂cl ₂), obtain 4-(2-((2S, 4S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-yl)-1H-imidazoles-5-yl) phenyl-boron dihydroxide (0.46g, 37%, tawny solid).

LCMS-Luna C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=5% acetonitrile, 95% water, 10mm ammonium acetate, B=95% acetonitrile, 5% water, 10mm ammonium acetate, t _r=1.46 minutes, for C ₁₈h ₂₃b ₁f ₁n ₃o ₄analytical calculation value: 375.18; Measured value: 376.12 (M+H) ⁺.

Described in embodiment 28 step c, by JG-20 and the synthetic JG-22 of JG-21.

LCMS-Luna C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=5% acetonitrile, 95% water, 10mm ammonium acetate, B=95% acetonitrile, 5% water, 10mm ammonium acetate, t _r=2.27 minutes, for C ₃₉h ₄₀f ₂n ₆o ₄analytical calculation value: 694.31; Measured value: 695.35 (M+H) ⁺.

Described in embodiment 28 steps d, by the synthetic JG-23 of JG-22.

LCMS-Phenomenex C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=10% methyl alcohol 90% water 0.1%TFA, B=90% methyl alcohol 10% water 0.1%TFA moving phase, t _r=2.62 minutes, for C ₃₁h ₃₄f ₂n ₆o ₂analytical calculation value: 560.27; Measured value: 561.52 (M+H) ⁺.

Described in embodiment 28 step e, by JG-22 and the synthetic JG-24 of Cap-2.

LCMS-Luna C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=5% acetonitrile, 95% water, 10mm ammonium acetate, B=95% acetonitrile, 5% water, 10mm ammonium acetate, t _r=2.30 minutes, for C ₄₁h ₄₅f ₂n ₇o ₃analytical calculation value: 721.36; Measured value: 722.42 (M+H) ⁺.

Described in embodiment LS14 step b, by the synthetic JG-25 of methanol solution of JG-24 and HCl.

JG-25

LCMS-Luna C-183.0 * 50mm, gradient 0-100%B, in 4.0 minutes, 1 minute residence time, A=5% acetonitrile, 95% water, 10mm ammonium acetate, B=95% acetonitrile, 5% water, 10mm ammonium acetate, t _r=1.98 minutes, for C ₃₆h ₃₇f ₂n ₇o ₁analytical calculation value: 621.30; Measured value: 622.48 (M+H) ⁺.

The LC condition of OL part:

Condition 1: solvent orange 2 A: 5% acetonitrile/95% water/10mmol ammonium acetate; Solvent B:95% acetonitrile/5% water/10mmol ammonium acetate; Post: Phenomenex GEMINI 5u C184.6 * 5.0mm; Wavelength: 220nm; Flow velocity: 4ml/ minute; 0%B～100%B, in 3 minutes, 1 minute residence time.

Condition 2: solvent orange 2 A: 5% acetonitrile/95% water/10mmol ammonium acetate; Solvent B:95% acetonitrile/5% water/10mmol ammonium acetate; Post: Phenomenex GEMINI 5u C184.6 * 5.0mm; Wavelength: 220nm; Flow velocity: 4ml/ minute; 0%B～100%B, in 2 minutes, 1 minute residence time.

Condition 3: solvent orange 2 A: 5% acetonitrile/95% water/10mmol ammonium acetate; Solvent B:95% acetonitrile/5% water/10mmol ammonium acetate; Post: Phenomenex GEMINI 5u C184.6 * 5.0mm; Wavelength: 220nm; Flow velocity: 4ml/ minute; 0%B～100%B, in 4 minutes, 1 minute residence time.

Condition 4: solvent orange 2 A: 10%MeOH/90% water/0.1%TFA; Solvent B:90%MeOH/10% water/0.1%TFA; Post: Phenomenex 10u C183.0 * 5.0mm; Wavelength: 220nm; Flow velocity: 4ml/ minute; 0%B～100%B, in 4 minutes, 1 minute residence time.

Condition 5: solvent orange 2 A: 5% acetonitrile/95% water/10mmol ammonium acetate; Solvent B:95% acetonitrile/5% water/10mmol ammonium acetate; Post: Phenomenex GEMINI 5u C184.6 * 5.0mm; Wavelength: 220nm; Flow velocity: 4ml/ minute; 0%B～100%B, in 9 minutes, 1 minute residence time.

Condition 6: solvent orange 2 A: 10%MeOH/90% water/0.2%H ₃pO ₄; Solvent B:90%MeOH/10% water/0.2%H ₃pO ₄; Post: Phenomenex 5u C-184.6 * 50mm; Wavelength: 220nm; Flow velocity: 1.5ml/ minute; 0%B～100%B, in 14 minutes, 3 minute residence time.

Condition 7: solvent orange 2 A: 10%MeOH/90% water/0.1%TFA; Solvent B:90%MeOH/10% water/0.1%TFA; Post: Phenomenex 10u C183.0 * 5.0mm; Wavelength: 220nm; Flow velocity: 4ml/ minute; 0%B～100%B, in 3 minutes, 1 minute residence time.

Condition 8: solvent orange 2 A: 10%MeOH/90% water/0.1%TFA; Solvent B:90%MeOH/10% water/0.1%TFA; Post: Phenomenex 10u C183.0 * 5.0mm; Wavelength: 220nm; Flow velocity: 4ml/ minute; 0%B～100%B, in 2 minutes, 1 minute residence time.

Experimental section (Cap):

Step a: dimethylaminoethyl chloride (0.92ml, 10mmol) is slowly added to (S)-2-amino-benzyl 3-methylbutyrate hydrochloride (2.44g; 10mmol) and in THF (50ml) solution of Hunig alkali (3.67ml, 21mmol).Gained white suspension is at room temperature stirred and spend the night after (16 hours), concentrating under reduced pressure.Resistates is distributed between ethyl acetate and water.Organic layer salt water washing, dry (MgSO ₄), after filtration, concentrating under reduced pressure.Gained is purified by flash chromatography (use ethyl acetate: hexane (1: 1) wash-out) for yellow oil.The flow point of collecting, after vacuum concentration, obtains 2.35g (85%) intermediate Cap OL-1, is transparent oily matter. ¹H NMR(300MHz，DMSO-d ₆)δppm 0.84(d，J＝6.95Hz，3H)0.89(d，J＝6.59Hz，3H)1.98-2.15(m，1H)2.80(s，6H)5.01-5.09(m，J＝12.44Hz，1H)5.13(d，J＝12.44Hz，1H)6.22(d，J＝8.05Hz，1H)7.26-7.42(m，5H)。LC (condition 1): RT=1.76 minute; MS: for [M+H] ⁺c ₁₆h ₂₂n ₂o ₃analytical calculation value: 279.17; Measured value: 279.03.

Step b: to intermediate Cap OL-1 (2.35g; In 50ml MeOH solution 8.45mmol), add Pd/C (10%; 200mg), gained black suspension N ₂purge (3 times) and be placed on 1 atmospheric H ₂under.Mixture is at room temperature stirred and spent the night, through primitive fiber filter (microfiber filter), remove by filter catalyzer.Then gained clear solution, through concentrating under reduced pressure, obtains 1.43g (89%) Cap OL-2, is white foam shape thing, without being further purified just, can use. ¹H NMR(500MHz，DMSO-d ₆)δppm 0.87(d，J＝4.27Hz，3H)0.88(d，J＝3.97Hz，3H)1.93-2.11(m，1H)2.80(s，6H)3.90(dd，J＝8.39，6.87Hz，1H)5.93(d，J＝8.54Hz，1H)12.36(s，1H)。LC (condition 1): RT=0.33 minute; MS: for [M+H] ⁺c ₈h ₁₇n ₂o ₃analytical calculation value: 1898.12; Measured value: 189.04.

According to method described in Cap OL-2, by (S)-2-alanine benzyl ester hydrochloride, prepare Cap OL-3. ¹H NMR(500MHz，DMSO-d ₆)δppm 1.27(d，J＝7.32Hz，3H)2.80(s，6H)4.06(qt，1H)6.36(d，J＝7.32Hz，1H)12.27(s，1H)。LC (condition 1): RT=0.15 minute; MS: for [M+H] ⁺c ₆h ₁₃n ₂o ₃analytical calculation value: 161.09; Measured value: 161.00.

According to method described in Cap-47, by (S)-2-amino-3 Methylbutanoic acid tert-butyl ester hydrochloride and chloroformic acid 2-fluorine ethyl ester, prepare Cap OL-4. ¹H NMR(500MHz，DMSO-d ₆)δppm 0.87(t，J＝6.71Hz，6H)1.97-2.10(m，1H)3.83(dd，J＝8.39，5.95Hz，1H)4.14-4.18(m，1H)4.20-4.25(m，1H)4.50-4.54(m，1H)4.59-4.65(m，1H)7.51(d，J＝8.54Hz，1H)12.54(s，1H)。

According to method described in Cap-51, by (S)-diethyl L-Ala and methyl-chloroformate, prepare Cap OL-5. ¹H NMR(500MHz，DMSO-d ₆)δppm 0.72-0.89(m，6H)1.15-1.38(m，4H)1.54-1.66(m，1H)3.46-3.63(m，3H)4.09(dd，J＝8.85，5.19Hz，1H)7.24(d，J＝8.85Hz，1H)12.55(s，1H)。LC (condition 2): RT=0.66 minute; MS: for [M+H] ⁺c ₉h ₁₈nO ₄analytical calculation value: 204.12; Measured value: 204.02.

New embodiment:

According to the similar fashion of Preparation Example 1, adopt suitable end group (Cap), by 1e, prepare following analogue.

Embodiment OL-7

((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-4; the fluoro-1-of 4-bis-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-4, the fluoro-1-pyrrolidyl of 4-bis-) carbonyl)-2-methyl-propyl) Urethylane

According to the similar fashion of Preparation Example 1, use Cap-51 as coupling mating partner, by 1-2e-3 Preparation Example OL-7. ¹H NMR(500MHz，DMSO-d ₆)δppm 0.80(dd，J＝6.41，2.44Hz，12H)1.87-1.98(m，2H)2.79-2.91(m，2H)3.01-3.13(m，2H)3.54(s，6H)3.98(t，J＝7.93Hz，2H)4.22-4.37(m，2H)4.52(t，J＝14.19Hz，2H)5.31(t，J＝8.39Hz，2H)7.50(d，J＝7.93Hz，2H)7.82-7.87(m，4H)7.88-7.97(m，6H)8.08(s，2H)。LC (condition 6): 7.64 minutes; MS: for [M+H] ⁺c ₄₀h ₄₇f ₄n ₈o ₆analytical calculation value: 811.35; Measured value: 811.46.HRMS: for (M+H) ⁺c ₄₀h ₄₇f ₄n ₈o ₆analytical calculation value: 811.3549; Measured value: 811.3553.

According to the similar fashion of Preparation Example 1, adopt suitable end group (Cap), by 1-2e-3, prepare following analogue.

According to the similar fashion of Preparation Example 1, adopt suitable end group (Cap), by 1-3e, prepare following analogue.

Embodiment OL-19

((1S)-1-(((2R, 3S)-3-hydroxyl-2-(4-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane

Step a: by the similar fashion of intermediate 1a, prepare intermediate OL-15, wherein with N-Boc-L-proline(Pro) replace N-Boc-trans-3-hydroxyl-L-PROLINE. ¹H NMR(500MHz，DMSO-d ₆)δppm 1.34/1.4)(2br s，9H)1.65-1.77(m，1H)1.83-1.95(m，1H)3.33-3.42(m，1H)3.43-3.51(m，1H)3.96-4.07(m，1H)4.16(s，1H)4.44-4.65(m，2H)5.22-5.28(m，1H)7.74(d，J＝8.54Hz，2H)7.86-7.94(m，2H)8.15-8.32(m，1H)。LC (condition 4): RT=3.33 minute; MS: for [2M+Na] ⁺c ₃₆h ₄₆br ₂n ₄naO ₁₀analytical calculation value: 877.57; Measured value: 877.11.

Step b: press the similar fashion of intermediate 1b, prepare intermediate OL-16 by intermediate OL-15. ¹H NMR(500MHz，DMSO-d ₆)δppm 1.16/1.39(2br s，9H)1.71-1.81(m，J＝6.10Hz，1H)2.01-2.17(m，1H)3.37-3.50(m，1H)3.50-3.62(m，1H)4.15(s，1H)4.49-4.70(m，1H)5.36(dd，J＝6.71，3.66Hz，1H)7.44-7.62(m，3H)7.68(d，J＝7.02Hz，2H)11.96/11.99/12.26/12.30(m，1H)。LC (condition 8): RT=1.87 minute; MS: for [M+H] ⁺c ₁₈h ₂₃brN ₃o ₃analytical calculation value: 408.08; Measured value: 408.09.

Step c: according to the similar fashion of preparation 1d, by making intermediate OL-16 and 1c coupling, prepare intermediate OL-17. ¹H NMR(500MHz，DMSO-d ₆)δppm1.09-1.49(m，18H)1.71-2.04(m，4H)2.06-2.28(m，2H)3.33-3.40(m，1H)3.41-3.65(m，3H)4.18(s，1H)4.52-4.69(m，1H)4.70-4.88(m，1H)5.38(s，1H)6.64-7.35(m，1H)7.39-7.96(m，9H)11.71-12.0/12.10-12.36(m，2H)。LC (condition 2): RT=1.36 minute; MS: for [M+H] ⁺c ₃₆h ₄₅n ₆o ₅analytical calculation value: 641.77; Measured value: 641.39.

Steps d: the similar fashion according to preparation 1-1e, with HCl, make intermediate OL-17 deprotection, prepare intermediate OL-18. ¹H NMR(500MHz，DMSO-d ₆)δppm1.92-2.07(m，2H)2.14-2.25(m，1H)2.35-2.44(m，1H)3.15(s，4H)3.32-3.41(m，J＝7.02，7.02，7.02Hz，1H)3.41-3.51(m，J＝7.32Hz，2H)3.54-3.66(m，1H)4.68(d，J＝4.27Hz，1H)4.78-4.89(m，J＝4.88Hz，1H)5.04(s，1H)6.89/7.73(2d，J＝8.70Hz，1H)7.89(dd，J＝8.24，4.58Hz，4H)7.96-8.07(m，4H)8.15(d，J＝23.19Hz，2H)9.62-10.12(m，2H)10.21-10.74(m，2H)。LC (condition 8): RT=1.30 minute; MS: for [M+H] ⁺c ₂₆h ₂₉n ₆o analytical calculation value: 441.24; Measured value: 441.18.

Step e: according to the similar fashion of Preparation Example 1, by making intermediate OL-18 and Cap-51 coupling, carry out Preparation Example OL-19. ¹H NMR(500MHz，DMSO-d ₆)δppm 0.78(d，J＝6.41Hz，6H)0.83(d，J＝6.71Hz，6H)1.92-2.12(m，5H)2.12-2.21(m，1H)2.31(dd，J＝12.21，5.80Hz，1H)2.35-2.43(m，1H)3.54(d，J＝4.27Hz，6H)3.78-3.89(m，3H)3.91-4.02(m，1H)4.07-4.19(m，2H)4.36-4.50(m，1H)4.81(d，J＝3.66Hz，1H)5.13(t，J＝7.17Hz，1H)5.79(s，1H)7.34(dd，J＝11.29，8.85Hz，2H)7.83-7.90(m，4H)7.90-8.01(m，4H)8.12(s，2H)。[noting: the signal of imidazoles NH is too wide so that cannot deterministic displacement study].LC (condition 4): RT=2.76 minute; MS: for [M+H] ⁺c ₄₀h ₅₁n ₈o ₇analytical calculation value: 755.39; Measured value: 755.38.HRMS: for (M+H) ⁺c ₄₀h ₅₁n ₈o ₇analytical calculation value: 755.3881; Measured value: 755.3873.

According to the similar fashion of Preparation Example 1, adopt Cap-52, by intermediate OL-18, prepare following analogue.

According to the similar fashion of preparation OL-19, but adopting N-Boc-cis-3-hydroxyl-l-proline is raw material, prepares following analogue.

J part

Condition 1:LCMS condition: Phenomenex-Luna 4.6 * 50mm S10,0-100%B, in 3 minutes, 4 minutes stand-by times, 4ml/ minute, 220nm, A:10%MeOH-90%H ₂o-0.1%TFA; B:90%MeOH-10%H ₂o-0.1%TFA.

Condition 2:LCMS condition: Phenomenex-Luna 4.6 * 50mm S10,0-100%B, in 2 minutes, 3 minutes stand-by times, 4ml/ minute, 220nm, A:10%MeOH-90%H ₂o-0.1%TFA; B:90%MeOH-10%H ₂o-0.1%TFA.

Embodiment J2.

Tetramethyleneimine-1-t-butyl formate 2-formic acid (2S)-(1-(4-bromophenyl)-3-oxyethyl group-1,3-dioxo third-2-base ester)

3-(4-bromophenyl)-3-oxo ethyl propionate (15g, 55mmol) is dissolved in to CH ₂cl ₂(600ml), add the NBS (9.8g, 55mmol) of fresh recrystallization, stirred solution 18 hours.Reaction mixture NaHCO ₃dry (MgSO after solution, salt water washing ₄), concentrated after filtering, obtain resistates, without purifying.By the bromo-3-of 2-(4-bromophenyl)-3-oxo ethyl propionate (16.5g, 48mmol) be dissolved in acetonitrile (450ml) with N-Boc-L-proline(Pro) (10g, 48mmol), add Hunig alkali (16ml, 95mmol), stirred solution 18 hours.By rotary evaporation, remove desolventizing, resistates is dissolved in to ethyl acetate, with 0.1N HCl and salt water washing. ¹HNMR(300MHz，DMSO-d ₆)δ7.95(d，J＝8.4Hz，2H)，7.79(d，J＝8.4Hz，2H)，6.68-6.65(m，1H)，4.39-4.30(m，1H)，4.21-4.12(m，2H)，2.27-2.21(m，1H)，2.0-1.95(m，1H)，1.90-1.76(m，2H)，1.39(s，2H)，1.31(s，9H)，1.11(t，J＝7.3Hz，3H)。

LRMS: for C ₂₁h ₂₆brNO ₇analytical calculation value: 484.09; Measured value: 410.08 (M+H) ⁺.

Embodiment J5

(S)-5-(4-bromophenyl)-2-(1-(tertbutyloxycarbonyl) pyrrolidin-2-yl)-1H-imidazoles-4-ethyl formate

In 1L pressure bottle, pack tetramethyleneimine-1-t-butyl formate 2-formic acid (2S)-2-(1-(4-bromophenyl)-3-oxyethyl group-1,3-dioxo third-2-base ester) J2 (7g, 35mmol) and 11g NH into ₄the 125ml xylene solution of OAc heats reactant 3.5 hours at 140 ℃.After cooling, solution is distributed between ethyl acetate and water.Concentrated organic layer, is added to gained resistates in Biotage40m silica gel cylinder, and the ethyl acetate/hexane wash-out with gradient 20-100%, obtains 3g (45%). ¹H NMR(300MHz，CDCl ₃)δ12.75(br.s，7.82)，(br.s，2H)，7.50(d，J＝8.4Hz，2H)，4.96-4.92(m，1H)，4.23(q，J＝6.6Hz，2H)，3.68-3.50(m，1H)，3.40-3.32(m，1H)，2.19-2.15(m，1H)，1.99-1.89(m，3H)，1.48/1.13(s，9H)，1.23(t，J＝7.3Hz，3H)。LRMS: for C ₂₁h ₂₆brN ₃o ₄analytical calculation value: 464.12; Measured value: 464.15 and 466.15 (M+H) ⁺.

Embodiment J7

(S)-2-(5-(4-bromophenyl)-4-(methylamino formyl radical)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate

By (S)-5-(4-bromophenyl)-2-(1-(tertbutyloxycarbonyl) pyrrolidin-2-yl)-1H-imidazoles-4-ethyl formate (1g, 2.1mmol) be dissolved in the MeOH solution (35ml) of 2M methylamine, in pressurized vessel, in 70 ℃, heat 48 hours.Reaction mixture, after concentrated, is added to resistates in Biotage25m silica gel cylinder, and the ethyl acetate/hexane wash-out with gradient 10-100%, obtains 556mg (57%). ¹H NMR(300MHz，DMSO-d ₆)δ12.5(br.s，1H)，7.86-7.82(m，1H)，7.77(d，J＝8.4Hz，2H)，7.61(d，J＝8.7Hz，2H)，4.83-4.70(m，1H)，3.69-3.52(br.s，1H)，3.42-3.32(m，1H)，2.71(d，4.8Hz，3H)，2.30-1.78(m，4H)，1.19-1.14(m，9H)。

LRMS: for C ₂₀h ₂₆brN ₄o ₃analytical calculation value: 449.12; Measured value: 449.15 and 451.14 (M+H) ⁺.

Embodiment J11.a

To number J9 (1.1g, 1.58mmol) and be dissolved in ethanol (60ml), add 28% ammonium hydroxide solution,stronger (10ml), reactant will be heated 48 hours in 75 ℃ in pressurized vessel.By rotary evaporation, remove after desolventizing, resistates is dissolved in to ethyl acetate, water, salt water washing.After concentrated, be added to 25M Biotage cylinder, with 10%-100% ethyl acetate/CH ₂cl ₂carry out gradient elution, obtain J11.a 90mg (8.5%), reclaim and obtain raw material J9696mg (63%).

Embodiment J32.a

(S)-2-(5-(4-bromophenyl)-4-(trifluoromethyl)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate

By 3-(4-bromophenyl)-3-(2,2-dimethyl hydrazono-)-1,1,1-trifluoropropyl-2-ketone (2.0g, 6.2mmol) is suspended in 5N sulfuric acid (60ml), heats 6 hours at 45 ℃.Temperature is risen to 85 ℃ and reach 2 hours, when cooling, form throw out.This product is separated by filtration, and obtains 1-(4-bromophenyl)-3,3,3-trifluoropropyl-1, and 2-diketone 1.6g (92%), is yellow solid.This diketone (1.6g, 5.7mmol) is dissolved in to methyl alcohol (30ml), adds after N-(tertbutyloxycarbonyl)-L-dried meat ammonium aldehyde (1g, 5.0mmol), add 28% solution of ammonium hydroxide (10ml).Reactant is at room temperature stirred 18 hours, be poured on methylene dichloride (200ml) upper, wash with water, use MgSO ₄dry.After filtering and concentrating, be added in 40M Biotage cylinder, by 5%-30% ethyl acetate/hexane, carry out gradient elution, obtain J32.a 1.3g (50%). ¹H NMR(300MHz，DMSO-d ₆)δ12.88(br.s，1H)，7.72(d，J＝8.4Hz，2H)，7.39(d，J＝8.0Hz，2H)，4.84-4.70(m，1H)，3.57-3.49(m，1H)，3.39-3.29(m，1H)，2.31-2.20(m，1H)，1.98-1.78(m，3H)，1.39/1.13(m，9H)。LRMS: for C ₁₉h ₂₀brF ₃n ₃o ₂analytical calculation value: 458.07; Measured value: 458.06 and 460.06 (M-H) ^-.HRMS: for C ₁₉h ₂₂brF ₃n ₃o ₂analytical calculation value: 460.0847; Measured value: 460.0866 and 462.0840 (M+H) ⁺.

D part

* LCMS condition: Phenomenex-Luna 4.6 * 50mm S10,0-100%B, in 3 minutes, 4 minutes stand-by times, 4ml/ minute, 220nm, A:10%MeOH-90%H ₂o-0.1%TFA; B:90%MeOH-10%H ₂o-0.1%TFA.

Embodiment D5.

(S)-2-(5-(the bromo-2-fluorophenyl of 4-)-1H-imidazoles-2-yl) tetramethyleneimine-1-t-butyl formate

Bromine (0.54ml, 10.6mmol) is added drop-wise to the bromo-2-fluoro acetophenone of 4-(in 2.30g, 10.6mmol) diox (80ml) and tetrahydrofuran (THF) (80ml) solution (cooling (0 ℃)).Mixture is stirred after 1 hour at 0 ℃, be warming up to room temperature and reach 15 hours.Mixture dilutes by ethyl acetate, uses saturated NaHCO ₃after solution, 5% hypo solution and salt water washing, dry (Na ₂sO ₄).Isolate the bromo-1-of 2-(the bromo-2-fluorophenyl of 4-) ethyl ketone (D1), be colourless membranoid substance, it solidifies while further concentrating under high vacuum.This solid is dissolved in to anhydrous acetonitrile (50ml), with N-Boc-L-proline(Pro) (2.28g, 10.6mmol) and diisopropylethylamine (1.85ml, 10.6mmol), processes.At room temperature stir after 3 hours, solvent removed in vacuo, is assigned in ethyl acetate and water resistates.0.1N hydrochloric acid, saturated NaHCO for organic phase ₃after solution and salt water washing, dry (Na ₂sO ₄), concentrated after filtering.This resistates is dissolved in to dimethylbenzene (50ml), and uses solid NH ₄oAc (4.1g, 53.0mmol) processes.Mixture after 2 hours, is made it to be cooled to envrionment temperature in 140 ℃ of heating in heavy wall, screw-topped flask, with ethyl acetate dilution, use saturated NaHCO ₃after solution and salt water washing, dry (Na ₂sO ₄) rear concentrated.Resistates Biotage ^tMflash chromatography on silica gel method purifying (65M post, with 1800ml 16%B pre-equilibration, then with 450ml 16%B to 16%B, 2199ml 16%B to 50%B and 2199ml50%B to 100%B, carry out gradient elution successively), obtain title compound (D5) (3.61g, 83%), be brown/caramel colour oily matter.Small part (40mg) title compound further purifies with preparation HPLC that (20%B to 100%B, in 14 minutes, wherein B is 10mM NH ₄oAc (is dissolved in 10: 90H ₂o/CAN), A is 10mM NH ₄oAc (is dissolved in 95: 5H ₂o/CAN), adopt Phenomenex-Gemini 30 * 100mm S10 post, flow velocity 40ml/ minute), obtain pure title compound (31.8mg), be white solid.

¹h NMR (500MHz, DMSO-d ₆) δ 12.13-11.95 (m, 1H), 7.94 (br s, 1H), 7.54 (d, J=10.7Hz, 1H), 7.42 (d, J=7.9Hz, 1H), 7.36-7.34 (m, 1H), 4.86-4.77 (2m, 1H), 3.54 (m, 1H), 3.38-3.32 (m, 1H), 2.28-2.14 (2m, 1H), 2.05-1.78 (2m, 3H), 1.39 and 1.14 (2s, 9H).

HPLC Phenomenex LUNA C-184.6 * 50mm, 0-100%B, in 3 minutes, 1 minute residence time.A=90% water, 10% methyl alcohol, 0.1%TFA, B=10% water, 90% methyl alcohol, 0.1%TFA, RT=2.27 minute, homogeneity index 95%.

LRMS: for C ₁₈h ₂₂brFN ₃o ₂analytical calculation value: 410.09 and 412.09; Measured value: 410.08 and 412.08 (M+H) ⁺.

HRMS: for C ₁₈h ₂₂brFN ₃o ₂analytical calculation value: 410.0879; Measured value: 410.0893 (M+H) ⁺.

Embodiment M1-M27

Adopt method described in embodiment 1, by 1e and corresponding sour Preparation Example M1-M27.Product is made into tfa salt, except as otherwise noted.LC condition is as follows:

Condition 1

Post=Phenomenex-Luna 3.0 * 50mm S10

Start %B=0

Final %B=100

Gradient time=2 minute

Stand-by time=3 minute

Flow velocity=4ml/ minute

Wavelength=220nm

10% methyl alcohol/90%H of solvent orange 2 A=0.1%TFA ₂o

90% methyl alcohol/10%H of solvent B=0.1%TFA ₂o

Condition 2

Post=Phenomenex-Luna 4.6 * 50mm S10

Start %B=0

Final %B=100

Gradient time=2 minute

Stand-by time=3 minute

Flow velocity=5ml/ minute

Wavelength=220nm

10% methyl alcohol/90%H of solvent orange 2 A=0.1%TFA ₂o

90% methyl alcohol/10%H of solvent B=0.1%TFA ₂o

Condition 3

Post=HPLC XTERRA C 183.0 * 50mm S7

Start %B=0

Final %B=100

Gradient time=3 minute

Stand-by time=4 minute

Flow velocity=4ml/ minute

Wavelength=220nm

10% methyl alcohol/90%H of solvent orange 2 A=0.1%TFA ₂o

90% methyl alcohol/10%H of solvent B=0.1%TFA ₂o

Condition M1

Post: Luna 4.6 * 50mm S10

Start %B=0

Final %B=100

Gradient time=3 minute

Stand-by time=4 minute

Flow velocity=4ml/ minute

Solvent orange 2 A :=95%H ₂o: 5%CH ₃cN, 10mm ammonium acetate

Solvent B:=5%H ₂o: 95%CH ₃cN; 10mm ammonium acetate

Embodiment M28

((1S)-1-(((2R)-2-(5-(4 '-(2-((2R)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane

Embodiment M28, step a

Bromide M28a, according to method described in its enantiomorph 28b, is prepared by D-PROLINE.

Embodiment M28, step b

According to method described in intermediate 1c, by bromide M28a, prepare boric acid ester M28b.LC:RT=1.57 minute (condition 1); LC/MS: for [M+H] ⁺c ₂₇h ₃₃bN ₃o ₄analytical calculation value: 474.26; Measured value: 474.24.

Embodiment M28, step c

According to method described in intermediate 1d, by bromide M28a and boric acid ester M28b, prepare biphenyl M28c.LC:RT=1.43 minute (condition 1); LC/MS: for [M+H] ⁺c ₄₂h ₄₁n ₆o ₄analytical calculation value: 693.32; Measured value: 693.38.

Embodiment M28, steps d

According to method described in intermediate 28d, by carbamate M28c, prepare tetramethyleneimine M28d. ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 11.83 (br s, 2H), 7.80 (d, J=8.3,4H), 7.66 (d, J=8.3,4H), 7.46 (br s, 2H), 4.16 (apparent t, J=7.2,2H), 3.00-2.94 (m, 2H), 2.88-2.82 (m, 2H), 2.10-2.01 (m, 2H), 1.94-1.85 (m, 2H), 1.82-1.66 (m, 4H).[note: the region between 3.2-2.6ppm, there is a wide background signal, be considered to the signal of tetramethyleneimine NH].LC:RT=1.02 minute (condition 1); LC/MS: for [M+H] ⁺c ₂₆h ₂₉n ₆analytical calculation value: 425.25; Measured value: 425.27.

Embodiment M28

According to method described in embodiment 1, by intermediate M28d and Cap-51 Preparation Example M28, be tfa salt.LC:RT=1.33 minute (condition 1); Homogeneity index 96%; LC/MS: for [M+H] ⁺c ₄₀h ₅₁n ₈o ₆analytical calculation value: 739.32; Measured value: 739.43; HRMS: for [M+H] ⁺c ₄₀h ₅₁n ₈o ₆analytical calculation value: 739.3932; Measured value: 739.3907.

Embodiment M28-1

According to method described in embodiment 1, by the tfa salt of the Cap-51 Preparation Example M28-1 of intermediate M28d and racemic form, be the mixture of 3 kinds of steric isomers.When carrying out sample analysis under the following conditions, the retention time of observing three peaks is 21.74 minutes, 22.62 minutes and 23.40 minutes, and demonstrates correct molecular weight:

Waters Acquity HPLC, has Micromass ZQ MS (electron spray(ES) probe) and Waters 2996PDA and detects (UV under 315nm detects).

Post: Acquity UPLC; BEH C18; 1.7 μ m; 100 * 2.1mm ID; (at approximately 30 ℃)

Mobile phase A: water, 25mM ammonium acetate (pH=5)

Mobile phase B: acetonitrile

Flow velocity: 0.50ml/ minute

10-50%B 0-35.0 minute

50-98%B 35.0-45.0 minute

Keep 98%B 45.0-48.0 minute

98%B～100%B 48.0-48.5 minute

Keep 100%B 48.5-50.0 minute

Embodiment M28-2

((1S)-1-(((2S)-2-(5-(4 '-(2-((2R)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane

Embodiment M28-2, step a

According to method described in intermediate 1d, by boric acid ester M28b and bromide 28b, prepare carbamate M28-2a. ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 12.25/12.01/11.93 (three br s, 2H), 7.86-6.98 (m, 20H), 5.13-4.88 (m, 6H), 3.63 (m, 2H), 3.47 (m, 2H), 2.35-1.84 (M, 8H).LC:RT=1.46 minute (condition 1); LC/MS: for [M+H] ⁺c ₄₂h ₄₁n ₆o ₄analytical calculation value: 693.32; Measured value: 693.34.

Embodiment M28-2, step b

According to method described in intermediate 28d, by carbamate M28-2a, prepare tetramethyleneimine M28-2b. ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 11.84 (br s, 2H), 7.80 (d, J=8.3,4H), 7.66 (d, J=8.3,4H), 7.46 (br s, 2H), 4.87 (m, 0.05H), 4.16 (apparent t, J=7.2,1.95H), 3.00-2.94 (m, 2H), 2.88-2.82 (m, 2H), 2.10-2.01 (m, 2H), 1.94-1.85 (m, 2H), 1.82-1.66 (m, 4H).[note: the region between～3.1-2.6ppm, there is a wide background signal, be considered to the signal of tetramethyleneimine NH].LC:RT=0.96 minute (condition 1); LC/MS: for [M+H] ⁺c ₂₆h ₂₉n ₆analytical calculation value: 425.25; Measured value: 425.28.

Embodiment M28-2

According to method described in embodiment 1, by intermediate M28-2b and Cap-51 Preparation Example M28-2, be its tfa salt.LC:RT=1.96 minute (condition 2); Homogeneity index 98%; LC/MS: for [M+H] ⁺c ₄₀h ₅₁n ₈o ₆analytical calculation value: 739.39; Measured value: 739.47.

Embodiment M28-3

According to method described in embodiment 1, by the tfa salt of the Cap-51 Preparation Example M28-3 of intermediate M28-2b and racemic form, be the mixture of 4 kinds of steric isomers.When carrying out sample analysis under LC/MS condition described in embodiment M28-1, the retention time of observing three peaks is 21.28 minutes, 22.19 minutes and 23.01 minutes, and shows correct molecular weight.

Embodiment M29

(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2R)-2,1-tetramethyleneimine two bases ((1R)-1-cyclopropyl-2-oxo-2,1-ethane two bases))) two (Urethylanes)

According to method described in embodiment 1, by intermediate M28d and Cap-54a Preparation Example M29, be its tfa salt.LC:RT=1.21 minute (condition 1); Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₄₀h ₄₇n ₈o ₆analytical calculation value: 735.36; Measured value: 735.42; HRMS: for [M+H] ⁺c ₄₀h ₄₇n ₈o ₆analytical calculation value: 735.3619; Measured value: 735.3598.

Embodiment M30-M62

Same procedure described in employing embodiment 28, by CJ-24 and corresponding end group (cap) Preparation Example M30-M62, is tfa salt.

Embodiment M63-M66

Adopt method described in embodiment 28, by 28f and corresponding sour Preparation Example M63-M66x.Product is made into tfa salt, except as otherwise noted.

Embodiment M67-M91

Adopt method described in embodiment 28, by 28d and corresponding sour Preparation Example M67-M91y.Final product is made into tfa salt, except as otherwise noted.

Embodiment M92-M103

Adopt method described in embodiment 28, by 28d and corresponding sour Preparation Example M92-M103.Final product is made into tfa salt, except as otherwise noted.

Embodiment M104

((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(3-hydroxyl-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane

Embodiment M104, step a

According to for the synthesis of method described in tetramethyleneimine 28f, by intermediate 28d and Cap-51, prepare tetramethyleneimine M104a.

Embodiment M104

HATU (96.3mg, 0.253mmol) is added to tetramethyleneimine M104a (150mg, 0.217mmol), (S)-2-(t-butoxycarbonyl amino)-HMB (65.8mg, 0.282mmol) and i-Pr ₂in DMF (5.0ml) solution of EtN (180 μ l, 1.03mmol), reaction mixture is stirred 35 minutes under envrionment conditions.Vacuum is removed volatile component, and resistates is purified (MeOH/H with reversed-phase HPLC ₂o/TFA) after, vacuum concentration flow point.Gained resistates 25%TFA/CH ₂cl ₂(6.0ml) process, and stir 3.25 hours.Vacuum is removed after volatile component, and resistates is through free alkalization (MCX; MeOH washing; 2.0M NH ₃/ MeOH wash-out), obtain embodiment M104 (107mg, canescence foam).LC (condition 2): RT=1.03 minute; Homogeneity index > 95%; LC/MS: for [M+H] ⁺c ₃₈h ₄₉n ₈o ₅analytical calculation value: 697.38; Measured value: 697.28.

Embodiment M105

((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-3-hydroxyl-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane

Methyl-chloroformate (20 μ l, 0.258mmol) is added to embodiment M104 (82.9mg, 0.119mmol) and i-Pr ₂in THF (2.0ml) solution of EtN (50 μ l, 0.287mmol), and stir 65 minutes.Then mixture uses 2.0M NH ₃/ MeOH (3ml) processes, and stirs 2.75 hours, and vacuum is removed volatile component.Gained resistates is purified (MeOH/H with reversed-phase HPLC ₂o/TFA), obtain the tfa salt (64.1mg, white foam shape thing) of embodiment M105.LC (condition 2): RT=1.17 minute; Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₄₀h ₅₁n ₈o ₇analytical calculation value: 755.39; Measured value: 755.25.

Embodiment M106

((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S, 3R)-4-hydroxyl-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane

HATU (69mg, 0.181mmol) is added to tetramethyleneimine M104a (101mg, 0.173mmol), Cap-80b (55.9mg ,～0.183mmol) and i-Pr ₂in DMF (3.0ml) solution of EtN (90 μ l, 0.515mmol), reaction mixture is stirred 70 minutes under envrionment conditions.Vacuum is removed after volatile component, and resistates is purified (H with reversed-phase HPLC ₂o/MeOH/TFA), reclaim and obtain main signal flow point.The flow point of collecting is under envrionment conditions after standing several hours, and vacuum is removed volatile component, and to be sloughed first completely silica-based for coupling product when the time comes.Products therefrom carries out reversed-phase HPLC purifying (ACN/H ₂o/NH ₄oAc), obtain embodiment M106 (32.2mg, canescence foam).LC (condition 2): RT=1.19 minute; Homogeneity index > 95%; LC/MS: for [M+H] ⁺c ₄₀h ₅₁n ₈o ₇analytical calculation value: 755.39; Measured value: 755.85.

Embodiment M107

((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S, 3S)-4-hydroxyl-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane

Method described in synthetic according to embodiment M106, by tetramethyleneimine M104a and Cap-80a Preparation Example M107.LC (condition 2): RT=1.20 minute; Homogeneity index～95%; LC/MS: for [M+H] ⁺c ₄₀h ₅₁n ₈o ₇analytical calculation value: 755.39; Measured value: 755.78.

Embodiment M108

((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-L-valyl-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane

HATU (70.1mg, 0.184mmol) is added to tetramethyleneimine M104a (100.7mg, 0.173mmol), (L)-Boc-α-amino-isovaleric acid (49.6mg, 0.228mmol) and i-Pr ₂in DMF (3.0ml) solution of EtN (70 μ l, 0.40mmol), reaction mixture is stirred 65 minutes under envrionment conditions.Vacuum is removed after volatile component, and resistates is purified (60-100%EtOAc/ hexane) with Biotage, obtains 116.6mg coupling product.

Above-mentioned product (112mg) is used 25%TFA/CH ₂cl ₂(2ml) after processing, reaction mixture is stirred 6 hours.Vacuum is removed after volatile component, (the MeOH washing of MCX resin for crude product; 2.0M NH ₃/ MeOH wash-out) in conjunction with reversed-phase HPLC (H ₂o/MeOH/TFA) carry out purifying, obtain the tfa salt (98.5mg, white foam shape thing) of embodiment M108.LC (condition 2): RT=1.14 minute; Homogeneity index > 98%; LC/MS: for [M+H] ⁺c ₃₈h ₄₉n ₈o ₄analytical calculation value: 681.39; Measured value: 681.36.HRMS: for [M+H] ⁺c ₃₈h ₄₉n ₈o ₄calculated value: 681.3877; Measured value: 681.3865.

Embodiment M109 (R=Bn) and embodiment M110 (R=Me)

M109:(3S)-3-((methoxycarbonyl) amino)-4-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-4-ketobutyric acid benzyl ester

M110:(3S)-3-((methoxycarbonyl) amino)-4-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-4-ketobutyric acid methyl esters

HATU (109mg, 0.287mmol) is added to tetramethyleneimine M104a (151mg, 0.260mmol), Cap-68 (109mg, 387mmol) and i-Pr ₂in DMF (1.5ml) solution of EtN (100 μ l, 0.574mmol), reaction mixture is stirred 3 hours under envrionment conditions.Vacuum is removed after volatile component, (the MeOH washing of MCX resin for crude product; 2.0MNH ₃/ MeOH wash-out) in conjunction with reversed-phase HPLC (H ₂o/MeOH/TFA) carry out purifying, obtain the tfa salt (88.0mg) of embodiment M109 and the tfa salt (90.2mg) of embodiment M110.Embodiment M109:LC (condition 2): RT=2.16; Homogeneity index 97%; LC/MS: for [M+H] ⁺c ₄₆h ₅₃n ₈o ₈analytical calculation value: 845.40; Measured value: 845.51.HRMS: for [M+H] ⁺c ₄₆h ₅₃n ₈o ₈calculated value: 845.3986; Measured value: 845.3983.Embodiment M110:LC (condition 2): RT=1.92; Homogeneity index 97%; LC/MS: for [M+H] ⁺c ₄₀h ₄₉n ₈o ₄analytical calculation value: 769.47; Measured value: 769.46.HRMS: for [M+H] ⁺c ₄₀h ₄₉n ₈o ₄calculated value: 769.3673; Measured value: 769.3682.

Embodiment M111

(3S)-3-((methoxycarbonyl) amino)-4-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-4-ketobutyric acid

At H ₂under air bag, embodiment M109 (69.7mg, 0.082mmol) and 10%Pd/C (10mg) are at room temperature stirred 1.5 hours with the mixture of methyl alcohol (5ml).Reactant is through diatomite filtration final vacuum is concentrated, and products therefrom is purified (H with reversed-phase HPLC ₂o/MeOH/TFA), obtain the tfa salt (54.0mg, canescence foam) of embodiment M111.LC (condition 2): RT=1.18; Homogeneity index 99%; LC/MS: for [M+H] ⁺c ₃₉h ₄₇n ₈o ₈analytical calculation value: 755.35; Measured value: 755.32.HRMS: for [M+H] ⁺c ₃₉h ₄₇n ₈o ₈calculated value: 755.3517; Measured value: 755.3525.

Embodiment M112

((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-4-(4-methyl isophthalic acid-piperazinyl)-4-oxobutanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane

HATU (30.6mg, 0.080mmol) is added to embodiment M111 (55.3mg, 0.0733mmol), N methyl piperazine (11.0mg, 0.11mmol) and i-Pr ₂in DMF (1.5ml) solution of EtN (25 μ l, 0.14mmol), reaction mixture is stirred 1.5 hours under envrionment conditions.All volatile components after vacuum is removed, MCX resin-bonded reversed-phase HPLC (H for resistates ₂o/MeOH/TFA) carry out purifying, obtain the tfa salt (51.4mg, canescence foam) of embodiment M112.LC (condition 2): RT=1.75; Homogeneity index 91%; LC/MS: for [M+H] ⁺c ₄₄h ₅₇n ₁₀o ₇analytical calculation value: 837.44; Measured value: 837.59.HRMS: for [M+H] ⁺c ₄₄h ₅₇n ₁₀o ₇calculated value: 837.4412; Measured value: 837.4453.

Embodiment M113

((1S)-3-(dimethylamino)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-3-oxopropyl) Urethylane

According to method described in embodiment M112, by embodiment M111 and Me ₂n.HCl Preparation Example M118.LC (condition 2): RT=1.89; Homogeneity index 99%.LC/MS: for [M+H] ⁺c ₄₁h ₅₂n ₉o ₇analytical calculation value: 782.40; Measured value: 782.47.HRMS: for [M+H] ⁺c ₄₁h ₅₂n ₉o ₇calculated value: 782.3990; Measured value: 782.4008.

Embodiment M114

4,4 '-bis-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-2-diphenic acid

Embodiment M114, step a

DMF (20ml) is added to KHCO ₃in the mixture of the bromo-5-iodo-benzoic acid of (1.84g, 18.4mmol) and 2-(4.99g, 15.3mmol), gained mixture is stirred 15 minutes.In 5 minutes, drip bromotoluene (2.4ml, 20.2mmol), and under envrionment conditions, continue to stir～20 hours.Vacuum is removed after most of volatile component, makes resistates at CH ₂cl ₂(50ml) and between water (50ml) distribute organic layer water (50ml) washing, dry (MgSO ₄), concentrated after filtering.Gained is purified by flash chromatography (7%EtOAc/ hexane) for crude product, obtains ester M114a (6.01g, viscosity colorless oil). ¹H NMR(DMSO-d ₆，δ＝2.5ppm，400MHz)：δ8.07(d，J＝2.0，1H)，7.81(dd，J＝8.4，2.1，1H)，7.53(d，J＝8.4，1H)，7.48(m，2H)，7.43-7.34(m，3H)，5.34(s，2H)。LC (condition 1): RT=2.1 minute; LC/MS: for [M+Na] ⁺c ₁₄h ₁₀brINaO ₂analytical calculation value: 438.88; Measured value: 438.83.

Embodiment M114, step b-d

Adopt for the three step schemes by the iodo-2-toluene of the bromo-4-of 1-synthetic bromide compound 121c, ester M114a is refined into ester M114d.M114d: ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 12.04/11.97 (br s, 1H), 8.12 (d, J=2.0,0.92H), 7.99 (apparent br s, 0.08H), 7.81 (dd, J=8.3,2.0,0.92H), 7.74-7.62 (m, 2.08H), 7.50 (apparent br d, J=7.0,2H), 7.44-7.35 (m, 3H), 5.38 (s, 2H), 4.79 (m, 1H), 3.52 (apparent br s, 1H), 3.36 (m, 1H), 2.24-1.79 (m, 4H), 1.39/5.11 (two s, 9H).LC (condition 1): RT=1.66 minute; LC/MS: for [M+H] ⁺c ₂₆h ₂₉brN ₃o ₄analytical calculation value: 526.13; Measured value: 526.16.

Embodiment M114, step e

According to the preparation method of dimer 1d, by bromide M114d and boric acid ester 1c, prepare ester M114e. ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 12.18/12.00/11.91/11.83 (four br s, 2H), 8.11-7.03 (m, 14H), 5.10 (s, 2H), 4.85-4.78 (m, 2H), 3.55 (apparent br s, 2H), 3.37 (m, 2H), 2.29-1.80 (m, 8H), 1.41/1.16 (two s, 18H).LC (condition 1): RT=1.54 minute; LC/MS: for [M+H] ⁺c ₄₄h ₅₁n ₆o ₆analytical calculation value: 759.39; Measured value: 759.63.

Embodiment M114, step f

By benzyl ester M114e (1.005g, 1.325mmol) and 10%Pd/C (236mg) with the mixture of MeOH (20ml) at H ₂under air bag, stir 5 hours.Then reaction mixture uses MeOH and the CH of 1: 1 ₂cl ₂mixture process, through diatomite ( -521) pad filters, and filtrate, after rotary evaporation, obtains sour M114f (840mg), and it is carried composition Ph by Suzuki coupling step ₃pO pollutes. ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 12.17/11.98/11.89/11.81 (four apparent br s, 2H), 8.04-7.31 (m, 9H), 4.85-4.78 (m, 2H), 3.55 (apparent br s, 2H) ,～3.37 (m, 2H, with water signal overlap) 2.27-1.84 (m, 8H), 1.41/1.16 (two s, 18H).LC (condition 1): RT=1.37 minute; LC/MS: for [M+H] ⁺c ₃₇h ₄₅n ₆o ₆analytical calculation value: 669.34; Measured value: 669.53.

Embodiment M114, step g

Successively by 4N HCl/ diox (8.0ml) and CH ₂cl ₂(2.0ml) be added in carbamate M114f (417mg, 0.623mmol), by mixture vigorous stirring, after 5.5 hours, vacuum is removed volatile component, obtains HCl (.4x) salt (487mg) of tetramethyleneimine M114g, and it is by Ph ₃pO contaminating impurity. ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz) and D ₂after O exchange: δ 8.23 (d, J=1.7,1H), 8.09-8.04 (m, 3H), 7.92 (d, J=8.3,2H), 7.53 (d, J=8.1,1H), 7.48 (d, J=8.3,2H), 5.00 (apparent br t, J=8.3,1H), 4.90 (apparent br t, J=8.4,1H), 3.6-3.3 (m, 4H), 2.5-1.99 (m, 8H).LC (condition 1): RT=0.92 minute; LC/MS: for [M+H] ⁺c ₂₇h ₂₉n ₆o ₂analytical calculation value: 469.24; Measured value: 469.31.

Embodiment M114

HATU (79.9mg, 0.21mmol) is added to tetramethyleneimine M114g.4HCl (80mg, 0.13mmol), Cap-51 (92.4mg, 0.527mmol) and i-Pr ₂in DMF (3.0ml) solution of EtN (160 μ l, 0.919mmol), reaction mixture is stirred 2 hours under envrionment conditions.Vacuum is removed after volatile component, (the MeOH washing of MCX for resistates; 2.0M NH ₃/ MeOH wash-out) in conjunction with reversed-phase HPLC (CH ₃cN/H ₂o/NH ₄oAc) carry out purifying, obtain the acetate of embodiment M114.LC (condition 1): RT=1.20 minute; Homogeneity index > 98%.LC/MS: for [M+H] ⁺c ₄₁h ₅₁n ₈o ₈analytical calculation value: 783.38; Measured value: 783.34.HRMS: for [M+H] ⁺c ₄₁h ₅₁n ₈o ₈calculated value: 783.3830; Measured value: 783.3793.

Embodiment M115-M116

Adopt same procedure described in embodiment M114, by the acid with suitable, replace Cap-51, carry out Preparation Example M115-M116.According to the character of HPLC purification step moving phase, product is separated into acetate or tfa salt.

Embodiment M118

((1S)-1-(((2S)-2-(5-(2 '-formamyl-4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane

Embodiment M118, step a

By Et ₃n (300 μ l, 2.15mmol) is added to sour M114f (198.3mg, 0.297mmol), HOBt (94.2mg, 0.697mmol), EDCI (0.66mmol), NH ₄in the mixture of Cl (101mg, 1.89mmol) and DMF (8.0ml), under envrionment conditions, stir 17 hours.Reaction mixture is after 0.45 μ m filter filters, and vacuum is removed volatile component, makes resistates at CH ₂cl ₂and distribute between water.Concentrated organic layer, gained crude product is purified (MeOH/H with reversed-phase HPLC ₂o/TFA).

Above-mentioned product 25%TFA/CH ₂cl ₂(4.0ml) after processing, reaction mixture is stirred 2.5 hours under envrionment conditions.Vacuum is removed volatile component, and resistates is through free alkalization (MCX; MeOH washing; 2.0M NH ₃/ MeOH wash-out), obtain acid amides M118a (67.2mg). ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 11.83 (br s, 2H), 7.81-7.80 (m, 2H), 7.73 (d, J=8.3,2H), 7.65 (br s, 1H), 7.52 (br S, 1H), 7.44 (br s, 1H), 7.41 (d, J=8.3,2H), 7.36 (d, J=8.3,1H), 7.31 (br s, 1H), 4.16 (apparent t, J=7.2,2H), 3.00-2.94 (m, 2H), 2.88-2.82 (m, 2H), 2.10-2.01 (m, 2H), 1.94-1.85 (m, 2H), 1.83-1.66 (m, 4H).LC (condition 1): RT=0.89 minute; Homogeneity index > 95.LC/MS: for [M+H] ⁺c ₂₇h ₃₀n ₇o analytical calculation value: 468.25; Measured value: 468.24.

Embodiment M118

According to method described in embodiment 1, by the tfa salt of intermediate M118a and Cap-51 Preparation Example M118.LC (condition 1): RT=1.16 minute; Homogeneity index 97%.LC/MS: for [M+H] ⁺c ₄₁h ₅₂n ₉o ₇analytical calculation value: 782.40; Measured value: 782.40.HRMS: for [M+H] ⁺c ₄₁h ₅₂n ₉o ₇analytical calculation value: 782.3990; Measured value: 782.3979.

Embodiment M119

((1S)-1-(((2S)-2-(5-(2-(hydroxymethyl)-4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane

Embodiment M119, step a

By DIBAL-H (8.0ml 1.0M/CH ₂cl ₂, 8.0mmol) be added drop-wise to the water-cooled CH of ice of benzyl ester M114e (1.216g, 1.60mmol) ₂cl ₂(20ml), in solution, reaction mixture was stirred after 1 hour, then add DIBAL-H (0.5ml 1.0M/CH ₂cl ₂, 0.5mmol), and continue to stir～2.5 hours.Excessive saturated NH for reactant ₄the quencher of Cl solution, after mixture dilute with water, uses CH ₂cl ₂extraction (3 times).Organic phase drying (the MgSO merging ₄), filter final vacuum concentrated.Gained crude product is purified (100g silica gel with Biotage; 2-6%MeOH/EtOAc), obtain alcohol M119a (610mg, canescence foam). ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 12.23 (br s, 0.19H), 12.17 (br s, 0.19H), 11.89 (br s, 0.81H), 11.82 (br s, 0.81H), 7.97 (s, 0.81H), 7.84 (s, 0.19H), 7.78 (d, J=8.1,1.62H), 7.69-7.20 (m, 6.38H), 5.21-5.15 (m, 1H), 4.86-4.78 (m, 2H), 4.49-4.45 (m, 2H) ,～3.54 (m, 2H), 3.40-3.34 (m, 2H), 2.30-1.80 (m, 8H), 1.41/1.17 (two s, 18H).LC (condition 1): RT=1.36 minute.LC/MS: for [M+H] ⁺c ₃₇h ₄₇n ₆o ₅analytical calculation value: 655.36; Measured value: 655.34.

Embodiment M119, step b

By 25%TFA/CH ₂cl ₂(3.0ml) be added in carbamate M119a (105mg, 0.160mmol), mixture is stirred 4.5 hours under envrionment conditions.Vacuum is removed after volatile component, and resistates is through free alkalization (MCX; MeOH washing; 2.0M NH ₃/ MeOH wash-out), obtain tetramethyleneimine M119b, it is polluted by the trifluoroacetylation derivative of its zone of ignorance chemical structure.This sample is dissolved in to MeOH (1.5ml), uses 1.0M NaOH/H ₂after O (300 μ l, 0.3mmol) processes, mixture is stirred 2.75 hours.Then carried out (the MeOH washing of MCX purifying; 2.0M NH ₃/ MeOH wash-out), obtain M119b (63.8mg, white solid membranoid substance). ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 11.82 (br s, 2H), 7.96 (s, 1H), 7.77 (d, J=8.0,2H), 7.66 (d, J=8.0,1H), 7.46 (br s, 1H), 7.42 (br s, 1H), 7.36 (d, J=8.0,2H), 7.21 (d, J=8.0,1H), 5.16 (apparent br s, 1H), 4.46 (s, 2H), 4.16 (apparent t, J=7.1,2H), 3.00-2.82 (two m, 4H; There is a wide background signal in tetramethyleneimine NH region in not being included in integration), 2.10-2.01 (m, 2H), 1.94-1.85 (m, 2H), 1.83-1.67 (m, 4H).LC (condition 1): RT=0.78 minute.LC/MS: for [M+H] ⁺c ₂₇h ₃₁n ₆o analytical calculation value: 455.26; Measured value: 455.27.

Embodiment M119

According to method described in embodiment 1, just purification step is used and has ACN/H ₂o/NH ₄the reversed-phase HPLC of OAC solvent systems, by M119b and Cap-51 Preparation Example M119.LC (condition 1): RT=1.15 minute; Homogeneity index 98%.LC/MS: for [M+H] ⁺c ₄₁h ₅₃n ₈o ₇analytical calculation value: 769.40; Measured value: 769.40.HRMS: for [M+H] ⁺c ₄₁h ₅₃n ₈o ₇analytical calculation value: 769.4037; Measured value: 769.4023.

Embodiment M120

((1S)-1-(((2S)-2-(5-(2-((dimethylamino) methyl)-4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane

Embodiment M120, step a

By CH ₂cl ₂(6.0ml) be added to alcohol M119a (501mg, 0.765mmol), TPAP (29.1,0.083mmol) and in the mixture of 4-methylmorpholine N-oxide compound (135.8mg, 1.159mmol), by gained heterogeneous mixture vigorous stirring 14.5 hours under envrionment conditions.Add again TPAP (11.0mg, 0.031mmol) and 4-methylmorpholine N-oxide compound (39mg, 0.33mmol), and continue again to stir 24 hours.Mixture is through diatomite filter, filtrate is after rotary evaporation, and gained crude product is purified (2%MeOH/EtOAc) with Biotage, obtains aldehyde M120a (195.6mg, viscous yellow oil).LC (condition 1): RT=1.37 minute.LC/MS: for [M+H] ⁺c ₃₇h ₄₅n ₆o ₅analytical calculation value: 653.35; Measured value: 653.40.

Embodiment M120, step b

By NaCNBH ₃(33mg, 0.50mmo1) disposable aldehyde M120a (195.6mg, 0.30mmol) and Me of being added to ₂nH (200 μ l 40% solution/H ₂o), in MeOH (3.0ml) solution, reaction mixture is stirred 4 hours.Vacuum is removed after volatile component, and (sample adds by silica gel sieve mesh purified by flash chromatography for resistates; 3-15%MeOH/CH ₂cl ₂), obtain amine M120b (120mg, canescence foam).LC (condition 1): RT=1.32 minute.LC/MS: for [M+H] ⁺c ₃₉h ₅₂n ₇o ₄analytical calculation value: 682.41; Measured value: 682.42.

Embodiment M120, step c

Employing is prepared scheme described in 1e by 1d, makes carbamate M120b change into M120c. ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 11.82 (br s, 2H), 7.87 (s, 1H), 7.77 (d, J=8.0,2H), 7.65 (d, J=7.8,1H), 7.45/7.43 (two overlapping br s, 2H), 7.37 (d, J=7.8,2H), 7.21 (d, J=7.8,1H), 4.87 (m, 0.1H), 4.17 (m, 1.90H) ,～3.3 (Me ₂nCH ₂signal and the signal overlap of water), 3.01-2.94 (m, 2H), 2.89-2.83 (m, 2H), 2.10 (s, 6H), 2.10-2.01 (m, 2H), 1.94-1.85 (m, 2H), 1.81-1.67 (m, 4H).LC (condition 1): RT=0.79 minute.LC/MS: for [M+H] ⁺c ₂₉h ₃₆n ₇analytical calculation value: 482.30; Measured value: 482.35.

Embodiment M120

According to method described in embodiment 1, by the tfa salt of tetramethyleneimine M120c and Cap-51 Preparation Example M120.LC (condition 1): RT=1.06 minute; Homogeneity index 96%.LC/MS: for [M+H] ⁺c ₄₃h ₅₈n ₉o ₆analytical calculation value: 796.45; Measured value: 796.48.HRMS: for [M+H] ⁺c ₄₃h ₅₈n ₉o ₆analytical calculation value: 796.4510; Measured value: 796.4515.

Embodiment M121

((2-((dimethylamino) methyl)-4,4 '-biphenyl, two bases) two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (Urethylanes)

According to method described in embodiment 1, by the tfa salt of M120c and Cap-4 Preparation Example M121.LC (condition 1): RT=1.15 minute; Homogeneity index > 98%.LC/MS: for [M+H] ⁺c ₄₉h ₅₄n ₉o ₆analytical calculation value: 796.45; Measured value: 864.46.HRMS: for [M+H] ⁺c ₄₉h ₅₄n ₉o ₆analytical calculation value: 864.4197; Measured value: 864.4222.

Embodiment M122

((1S)-1-(((1S; 3S; 5S)-3-(5-(4 '-(2-((1S; 3S, 5S)-2-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-azabicyclic [3.1.0] oneself-3-yl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-2-azabicyclic [3.1.0] oneself-2-yl) carbonyl)-2-methyl-propyl) Urethylane

Embodiment M122, step a

By diisopropylethylamine (1.81ml; 10.4mmol) be slowly added to (1S; 3S; 5S)-2-(tertbutyloxycarbonyl)-2-azabicyclic [3.1.0] hexane-3-formic acid (2.36g; 10.4mmol) with (2-4 ' (2-acetyl bromide) biphenyl-4-yl)-2-oxoethyl) bromine (2.0g; in acetonitrile 5.05mmol) (20ml) solution, reaction mixture is stirred 16 hours under envrionment conditions.Solvent, after evaporation, distributes resistates between ethyl acetate and water (1: 1, each 40ml).The saturated NaHCO of organic layer ₃(2 * 10ml), salt water washing, dry (Na ₂sO ₄), filter final vacuum concentrated, obtain keto ester M122a (3.58g), be the amber oily thing of viscosity, while preserving in refrigerator, solidify. ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 8.20 (m, 4H), 7.97 (d, J=8.5,4H), 5.71-5.48 (m, 4H), 4.69 (m, 2H), 3.44 (m, 2H), 3.3 (m, 2H), 2.76-2.67 (m, 2H), 2.27 (m, 2H), 1.60 (m, 2H), 1.44/1.38 (two s, 18H), 0.78 (m, 2H), 0.70 (m, 2H).LC (condition 1): RT=1.70 minute; LC/MS: the ion that does not obtain molecule.

Embodiment M122, step b

Ammonium acetate (2.89g, 37.5mmol) is added in toluene (20ml) solution of keto ester M122a (2.58g, 3.75mmol), gained mixture is heated 4.5 hours at 120 ℃, the water azeotropic simultaneously forming with Dean-Stark device.Reaction mixture is cooled to after room temperature, and vacuum is removed volatile component.By saturated NaHCO ₃solution (10ml) is added in solid, and mixture was stirred after 30 minutes, and solid after filtration, after vacuum-drying, carries out Biotage purifying (28-100%EtOAc/ hexane), obtains imidazoles M122b (0.6g, light yellow solid).LC (condition 1): RT=1.52 minute; LC/MS: for [M+H] ⁺c ₃₈h ₄₅n ₆o ₄analytical calculation value: 649.35; Measured value: 649.78.

Embodiment M122, step c

By the dioxane solution of 4N HCl (5ml) be added to carbamate M122b (0.8g, 1.2mmol) in the water-cooled diox of ice (16ml) solution, remove after ice-water bath, mixture is stirred 4 hours under envrionment conditions.The bulk solid during reaction forming crushes with spatula.Vacuum is removed after volatile component, obtains tetramethyleneimine M122c (.4HCl) (0.73g, yellow solid). ¹h NMR (DMSO-d ₆, δ=2.5ppm, 400MHz): δ 7.90 (d, J=8.3,4H), 7.84 (br s, 2H), 7.79 (d, J=8.3,4H), 5.24 (m, 2H), 3.38 (m, 2H), 2.71 (m, 2H),～2.50 (2H, overlapping with solvents signals), 1.93 (m, 2H), 1.38 (m, 2H), 0.96 (m, 2H).LC (condition 1): RT=1.03 minute; LC/MS: for [M+H] ⁺c ₂₈h ₂₉n ₆analytical calculation value: 449.25; Measured value: 449.59.

Embodiment M122

According to method described in embodiment 1, by the tfa salt of M122c and Cap-51 Preparation Example M122.LC (condition 1): RT=1.34 minute; LC/MS: for [M+H] ⁺c ₄₂h ₅₁n ₈o ₆analytical calculation value: 763.39; Measured value: 763.73.

Embodiment M123-M130

Embodiment M123-M130 is prepared according to method described in embodiment M122.Embodiment M123-M129 is made into tfa salt, and embodiment M130 is made into free alkali.

Embodiment M131

((1S)-1-(((1R; 3R; 5R)-3-(5-(4 '-(2-((1R; 3R, 5R)-2-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-azabicyclic [3.1.0] oneself-3-yl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-2-azabicyclic [3.1.0] oneself-2-yl) carbonyl)-2-methyl-propyl) Urethylane

Embodiment M131 according to method described in its diastereomer embodiment M122 by (1R, 3S, 5R)-2-(tertbutyloxycarbonyl)-2-azabicyclic [3.1.0] hexane-3-formic acid starts preparation, (1R, 3S, 5R)-2-(tertbutyloxycarbonyl)-2-azabicyclic [3.1.0] hexane-3-formic acid itself adopts the synthetic (Hanessian etc. of document scheme, Angew.Chem., Int.Ed.Engl.1997,36,1881-1884).LC (condition I): RT=1.273 minute; LC/MS: for [M+H] ⁺c ₄₂h ₅₀n ₈o ₆analytical calculation value: 763.39; Measured value: 763.94.

Biologic activity

In present disclosure, applied HCV replicon experiment, and by common all PCT/US2006/022197 and O ' Boyle etc., Antimicrob Agents Chemother.2005 April; 49 (4): method described in 1346-53 is prepared, carried out and verify.

With HCV 1b-377-neo replicon cell test series of compounds as herein described and due to due to the Y2065H sudden change in NS5A to the cell of compd A resistance (referring to application PCT/US2006/022197).After measured, low more than 10 times to the inhibition specific activity wild-type cell of compd A resistant cell of the compound of surveying, show relevant mechanism of action between these two kinds of series of compounds.Therefore, the compound of present disclosure can effectively suppress the function of HCVNS5A albumen, and we think present disclosure compound with first to file PCT/US2006/022197 and jointly the described compound in all WO/O4014852 effective equally aspect drug combination.In addition, the compound of present disclosure can be effectively for HCV 1b genotype.It should be understood that, the compound of present disclosure can suppress the Multi-genotype of HCV.Table 2 represents that present disclosure representative compound is for the genotypic EC of HCV 1b ₅₀value.In one embodiment, the compound of present disclosure has activity for genotype 1a, 1b, 2a, 2b, 3a, 4a and 5a.EC for HCV 1b ₅₀scope is as follows: A=1-10 μ M; B=100-999nM; C=1-99nM; D=10-999pM.

The compound of present disclosure can by except NS5A suppresses or the mechanism that is different from NS5A inhibition suppress HCV.In one embodiment, the compound of present disclosure suppresses HCV replicon, and in another embodiment, the compound of present disclosure suppresses NS5A.

Table 2

Embodiment	Scope
		1	D
24-4e	C
		24-4f	B
24-4g	A
		25-1	D
25-2	D
		25-3	D
25-4	D
		25-5	D
25-6	C
		25-7	C
25-8	D
		24-4h	D
120-9	D
		120	D
120-5	C
		120-6	C
120-7	D
		120-8	C
103-3	D
		103-4	D
103-1	D
		103-2	D
103-5	D
		103-6	C
103-8	D
		103-7	D
151 isomer 1	C
		151 isomer 2	B
152j-9	C
		152j-10	C
152j-1	C
		152j-2	D
153c-5	C
		153c-6	C
153c-2	C
		153c-1	C
152j-7	C
		152j-8	D
153c-3	A
		153c-4	A
152j-11	D
		152j-12	D
152j-15	D
		152j-28	D
152j-13	C
		152j-14	C
152j-19	D
		152j-16	D

Embodiment	Scope
		152j-3	D
152j-20	C
		152j-17	D
152j-18	D
		152j-3	D
152j-5	D
		152j-6	D
152l-2	D
		152l-1	D
152j-24	D
		152j-23	D
153c-7	C
		152j-22	D
24-18-2	D
		24-18-1	D
24-18-4	D
		24-18-5	D
24-18-6	D
		24-18-3	D
152j-21	D
		152l-3	D
131.1-2	D
		131.1-1	D
24-4a	D
		120-1	D
120-2	D
		120-3	D
120-4	D
		24-10	D
24-9	D
		24-8	D
24-11	C
		24-12	C
11	C
		24-16	D
24-18	D
		24-17	D
24-15	C
		24-13	B
24-14	C
		24-4b	C
24-4c	D
		24-4d	D
148	C
		149	D
150	C
		24-5	D
24-6	D
		24-7	D

Embodiment	Scope
		24-1	D
24-2	D
		24-3	D
28-1	D
		28-2	D
28-3	D
		28-4	D
28-5	D
		84-1	D
84-2	D
		84-3	D
84-4	D
		84-7	C
84-10	C
		84-12	D
84-14	C
		84-15	C
84-17	D
		84-18	C
84-19	C
		84-20	C
84-24	D
		84-26	D
84-27	D
		84-28	D
84-32	D
		84-33	D
84-34	C
		84-35	D
84-36	D
		84-38	D
84-39	D
		84-40	D
84-44	D
		84-46	D
84-47	D
		84-48	D
84-49	D
		84-50	D
84-51	D
		84-52	D
84-53	D
		84-54	D
84-55	D
		84-56	D
84-57	D
		84-58	D
84-59	D
		84-60	D

Embodiment	Scope
		84-61	D
84-62	D
		84-63	D
84-64	D
		84-65	C-D
84-66	C-D
		84-67	D
84-68	C
		84-69	D
84-70	C
		84-71	C
84-72	C
		84-73	C
84-74	D
		84-75	C
84-76	D
		84-77	D
84-78	D
		84-79	D
84-80	D
		84-81	D
84-82	D
		84-83	D
84-84	D
		84-85	D
84-86	D
		84-87	D
94-1	D
		94-2	C
94-3	D
		94-6	C-D
94-9	D
		94-10	D
94-12	C
		94-13	D
94-17	D
		94-19	D
94-20	C
		94-24	D
94-25	D
		94-26	D
94-27	C
		94-30	D
94-32	C
		94-33	C
94-34	C
		94-36	D
94-37	C
		94-38	D
94-42	D

Embodiment	Scope
		94-44	D
94-45	D
		94-46	D
94-47	D
		94-48	D
94-49	D
		94-50	D
94-51	D
		94-52	D
94-53	D
		94-54	D
94-55	D
		94-56	D
107-1	D
		107-2	D
107-3	D
		107-4	D
107-5	D
		107-6	D
107-7	D
		107-8	D
107-9	D
		107-10	D
107-11	D
		107-12	D
107-13	D
		107-14	D
107-15	D
		107-16	D
107-17	D
		107-18	D
107-19	D
		107-20	D
107-21	D
		107-22	D
107-23	D
		107-24	D
107-25	D
		107-26	D
107-27	D
		107-28	D
107-29	D
		107-30	D
107-31	D
		107-32	D
107-33	D
		107-34	D
107-35	D
		107-36	D
107-37	D

Embodiment	Scope
		107-38	D
107-39	D
		107-40	D
107-41	D
		107-42	D
107-43	D
		107-44	D
2	D
		3	D
4	D
		5	C
6	C
		7	D
8	D
		24-23	D
9	C
		10	C
11	C
		12	C
13	C
		14	B
15	C
		16	C
17	D
		18	D
19	D
		20	C
21	D
		22	D
23	D
		24	C
25	D
		26	C
27	C
		28	C
29	D
		30	C
31	D
		32	C
33	D
		34	D
35	D
		36	D
37	D
		38	D
39	D
		40	D
41	D
		42	D
43	D

44	D
		45	D
46	D
		47	D
48	D
		49	D
50	B
		51	D
52	D
		53	D
54	D
		55	D
56	D
		57	D
58	D
		59	D
60	D
		61	D
62	D
		63	D
64	D
		65	C
67	D
		68	D
69	D
		70	C
71	D
		72	C
73	D
		74	D
75	D
		76	D
77	D

78	D
		79	D
80	D
		81	D
82	D
		83	D
84	D
		85	D
86	D
		87	D
88	D
		89	D
90	D
		91	D
92	D
		93	D
94	D
		95	D
96	D
		97	D
98	D
		99	D
100	D
		101	D
102	D
		103	D
104	D
		105	D
106	D
		107	D
108	D
		109	C
110	D
		111	D

112	D
		113	D
114	D
		115	D
116	D
		117	D
118	D
		119	D
120	D
		121	D
122	D
		123	D
124	D
		125	D
126	D
		127	D
128	D
		129	D
130	D
		131	D
132	D
		133	C
134	D
		135	D
136	D
		138	D
139	D
		140	D
141	D
		142	C
143	D
		144	D
145	D

146	D
		147	D
LS2	C
		LS3	C
LS4	C
		LS16	C
LS6	B
		LS11	A
LS14	D
		LS20	D
LS21	D
		LS22	D
LS23	D
		LS24	D
LS25	D
		LS26	D

LS27D’mer 1	D
		LS27D’mer 2	D
LS36	D
		LS37	D
F5	D
		F6	D
F7	D
		F8	D
F14	D
		F15	D
F16	D
		F17	D
F20	B
		F21	B

F22	B
		F25	D
F26	C
		F27	C
F28	C
		F29	C
F30	C
		F32	B
F33	B
		F34	C
F35	B
		F37	B
F38	D
		F39 diastereomer	D

F41	D
		F43	D
F48	D
		F49	C
F51	D
		F52	D
F53	D
		F54	D
F55	D
		F56	D
F57	D
		F58	D
F60	D
		F61	C
F62	C
		F63	D
F64	C
		F65	B
F66	C
		F67	C
F69	B
		F70	B
F71	D
		cj-48	B
cj-49	C
		cj-50	D
cj-51	D
		cj-52	D
cj-53	D
		cj-54	D
cj-55	D
		cj-56	D
cj-57	D
		cj-58	D
cj-59	D
		cj-60	D
cj-61	D
		cj-62	D
cj-63	D
		cj-64	D
cj-65	D
		cj-66	D
cj-67	D
		cj-68	D
cj-69	D
		cj-70	D
cj-71	D
		cj-72	D
cj-73	D
		cj-74	C
cj-75	D

cj-76	D
		cj-77	D
cj-78	D
		cj-79	D
cj-80	D
		cj-81	D
cj-82	D
		cj-83	D
cj-84	D
		cj-85	D
cj-86	D
		cj-87	D
cj-88	D
		cj-89	D
cj-90	D
		cj-91	D
cj-92	C
		cj-93	D
cj-94	D
		cj-95	D
cj-96	D
		cj-97	D
cj-98	D
		cj-99	D
cj-100	D
		cj-101	D
cj-102	D
		cj-103	D
cj-104	D
		cj-105	D
cj-106	D
		cj-107	D
cj-108	D
		cj-109	D
cj-110	D
		cj-111	D
cj-112	D
		cj-113	D
cj-114	D
		cj-115	D
cj-116	D
		cj-117	D
cj-118	D
		cj-119	D
cj-120	D
		cj-121	D
cj-122	D
		cj-45	D
cj-41	D
		cj-47	C
cj-43	D

cj-44	D
		cj-40	D
cj-46	D
		cj-42	D
cj-36	D
		cj-37	D
cj-38	D
		cj-39	D
cj-32	D
		cj-33	D
cj-34	D
		cj-35	C
cj-136	D
		cj-137	C
cj-138	A
		cj-139	C
cj-140	B
		cj-141	A
cj-142	A
		cj-143	A
cj-144	D
		cj-145	C
cj-146	B
		cj-147	C
cj-148	C
		cj-149	C
cj-150	C
		cj-151	C
cj-152	C
		cj-153	D
cj-154	D
		cj-155	C
cj-156	D
		cj-126	D
cj-127	C
		cj-128	D
cj-129	D
		cj-130	D
cj-131	C
		cj-132	B
cj-133	C
		cj-134	C
cj-135	C
		cj-125	C
cj-15c	D
		cj-20c	D
cj-20b	D
		cj-20a	D
cj-17	D
		cj-16	D
cj-20d	D

cj-20	D
		cj-15a	D
cj-15	D
		cj-15d	D
cj-11n	C
		cj-11o	C
cj-11p	D
		cj-11m	C
cj-11h	D
		cj-11i	D
cj-11j	D
		cj-11k	D
cj-11e	A
		cj-11f	C
cj-11g	C
		cj-11d	D
cj-11b	D
		cj-11	D
cj-11a	D
		cj-11c	D
JG-3	D
		JG-4	C
JG-5	D
		JG-6	C
JG-7	D
		JG-8	D
JG-9	D
		JG-10	C
JG-12	D
		JG-13	C
JG-14	D
		JG-15	D
JG-16	D
		JG-17	D
OL-1	D
		OL-2	D
OL-3	C
		OL-4	D

OL-5	D
		OL-6	D
OL-7	D
		OL-8	D
OL-9	D
		OL-10	D
OL-11	D
		OL-12	D
OL-13	D
		OL-19	D
OL-20	C
		OL-21	D
D73	D
		D74	D
D75	D
		D76	D
D77	D
		J16	D
J17	D
		J18	D
J19	D
		J20	D
J21	D
		J22	D
J23	D
		J24	D
J25	D
		J26	D
J27	D
		J28	C
J29	D
		J30	C
J31	D
		J37	D
J38	D
		J39	D
J40	D
		J41	D
J42	D
		J42.a	D
J45	D
		J46	D
J47	D
		J48	D
J49	D
		J50	D
J51	C
		D33	D
D34	D
		D35	D
D36	D

D37	D
		D38	D
D39	D
		D40	D
D41	D
		D42	D
D43	D
		D44	D
D45	D
		D46	D
D47	D
		D48	D
D49	D
		D50	D
D51	D
		D52	D
D53	D
		D54	D
D55	D
		D56	D
D57	D
		D58	D
D59	D
		D60	D
D61	D
		D62	D
D63	D
		D64	D
D65	D
		D66	D
D67	D
		D68	D
D69	D
		D70	D
M1	＞A
		M2	C
M3	C
		M4	B
M5	A
		M6	A
M7	＞A
		M8	A
M9	B
		M10	＞A
M11	C
		M12	C
M13	B
		M14	B
M15	B
		M16	A
M17	B

M18	A
		M19	＞A
M21	C
		M22	A
M23	C
		M24	C
M25	C
		M26	B
M27	C
		M28	A
M28-2	B
		M29	＞A
M30	C
		M31	C
M32	B
		M33	C
M34	C
		M35	C
M36	C
		M37	C
M38	C
		M39	C
M40	C
		M41	C
M42	C
		M43	C
M44	B
		M45	C
M46	C
		M47	C
M48	C
		M49	C
M50	C
		M51	C
M52	C
		M53	C
M54	C
		M55	C
M56	C
		M57	C

M58	C
		M59	C
M60	C
		M61	C
M62	C
		M63	C
M64	C
		M65	C
M66a	B
		M66b	B
M66x	C
		M67a	B
M67b	B
		M68	B
M69	B
		M70	C
M71	C
		M72	C
M73	B
		M74	C
M75	C
		M76	C
M77	C
		M78	C
M79	C
		M80	C
M81	B
		M82	C
M83	C
		M84	C
M85	C
		M86	C
M87	C
		M88	C
M89	C
		M90	A
M91	C
		M91x	C
M91y	B
		M92	A

M93	C
		M94	C
M95	C
		M96	B
M97	C
		M98	C
M99	C
		M100	C
M101	B
		M102	C
M103	B
		M104	B
M105	C
		M106	C
M107	C
		M108	C
M109	C
		M110	C
M111	A
		M112	C
M113	C
		M114	＞A
M115	＞A
		M116	＞A
M117	＞A
		M118	＞A
M119	B
		M120	B
M121	B
		M122	C
M123	A
		M124	C
M125	C
		M126	C
M127	C
		M128	C
M129	A
		M130	C

It will be apparent to one skilled in the art that present disclosure is not limited to above stated specification embodiment, and can be embodied in other specific form and don't depart from its essential characteristics.Therefore, expect that each embodiment is considered in all respects illustrative and nonrestrictive, should be with reference to appended claims, rather than previous embodiment, therefore, in the implication of appended claims equivalents and all changes in scope, be all included in herein.

The compound of present disclosure can by except NS5A suppresses or the mechanism that is different from NS5A inhibition suppress HCV.In one embodiment, the compound of present disclosure suppresses HCV replicon, and in another embodiment, the compound of present disclosure suppresses NS5A.The compound of present disclosure can suppress the Multi-genotype of HCV.

Claims

1. the compound of a following formula (I) or its pharmacy acceptable salt:

Wherein:

M and n are 0,1 or 2 independently;

Q and s are 0,1,2,3 or 4 independently;

U and v are 0,1,2 or 3 independently;

X is selected from O, S, S (O), SO ₂, CH ₂, CHR ⁵and C (R ⁵) ₂;

Y is selected from O, S, S (O), SO ₂, CH ₂, CHR ⁶and C (R ⁶) ₂;

R ³and R ⁴independently be selected from separately hydrogen and R ⁹-C (O)-and R ⁹-C (S)-;

R ⁷and R ⁸independently be selected from separately hydrogen, alkoxy carbonyl, alkyl, alkoxy aryl carbonyl R, carboxyl, haloalkyl, (NR ^ar ^b) carbonyl and trialkylsilkl alkoxyalkyl; And

Each R ⁹independently be selected from alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkoxy carbonyl alkyl, alkyl, alkyl-carbonyl alkyl, aryl, aryl alkenyl, alkoxy aryl, arylalkyl, aryloxy alkyl, cycloalkyl, cycloalkyl thiazolinyl, cycloalkylalkyl, cycloalkyl oxy alkyl, haloalkyl, heterocyclic radical, heterocyclic radical thiazolinyl, heterocyclic radical alkoxyl group, heterocyclic radical alkyl, heterocyclyloxy base alkyl, hydroxyalkyl ,-NR ^cr ^d, (NR ^cr ^d) thiazolinyl, (NR ^cr ^d) alkyl and (NR ^cr ^d) carbonyl;

Wherein term " alkyl " refers to the group derived from the straight or branched stable hydrocarbon that contains 1-6 carbon atom;

Term " aryl " refers to phenyl or bicyclic condensed ring system, and wherein this bicyclic condensed ring system is by forming with 4-6 unit's aromatics or non-aromatic carbocyclic fused phenyl;

Term " heterocyclic radical " refers to and contains 1,2,3 or 44,5,6 or 7 ring that are independently selected from nitrogen, oxygen and sulfur heteroatom, and term " heterocyclic radical " also comprises bicyclic groups, heterocyclic ring and another monocyclic heterocycles base or 4-6 unit aromatics or non-aromatic carbocyclic fused wherein; And bridge joint bicyclic groups

Term " alkoxyl group " refers to that alkyl is connected with parent molecular moiety by Sauerstoffatom;

Term " thiazolinyl " refers to the straight or branched group of 2-6 the carbon atom that contains at least one carbon-to-carbon double bond;

Term " aryloxy " refers to that aryl is connected with parent molecular moiety by Sauerstoffatom;

Term " cycloalkyl " refers to have 3-7 carbon atom and the heteroatomic saturated mono cyclic hydrocarbon of zero ring system;

Term " alkene oxygen base " refers to that thiazolinyl is connected with parent molecular moiety by Sauerstoffatom;

Term " NR ^ar ^b" refer to R ^aand R ^btwo groups are connected with parent molecular moiety by nitrogen-atoms, wherein R ^aand R ^bindependently be selected from hydrogen, thiazolinyl and alkyl;

Term " NR ^cr ^d" refer to R ^cand R ^dtwo groups are connected with parent molecular moiety by nitrogen-atoms, R wherein ^cand R ^dindependently be selected from hydrogen, allyloxycarbonyl, alkoxyalkyl carbonyl, alkoxy carbonyl, alkyl, alkyl-carbonyl, alkyl sulphonyl, aryl, aryl-alkoxy carbonyl, arylalkyl, aromatic yl alkyl carbonyl, aryl carbonyl, aryloxycarbonyl, aryl sulfonyl, cycloalkyl, naphthene sulfamide base, formyl radical, halo alkoxy carbonyl, heterocyclic radical, heterocyclic radical alkoxy carbonyl, heterocyclic radical alkyl, heterocyclic radical alkyl-carbonyl, heterocyclic radical carbonyl, heterocyclyloxy base carbonyl, hydroxyalkyl carbonyl, (NR ^er ^f) alkyl, (NR ^er ^f) alkyl-carbonyl, (NR ^er ^f) carbonyl, (NR ^er ^f) alkylsulfonyl ,-C (NCN) OR ' and-C (NCN) NR ^xr ^y, wherein R ' is selected from alkyl and unsubstituted phenyl, and wherein the moieties in arylalkyl, aromatic yl alkyl carbonyl, heterocyclic radical alkyl and heterocyclic radical alkyl-carbonyl also optionally by one-NR ^er ^fgroup replaces, and aryl wherein, aryl moiety in aryl-alkoxy carbonyl, arylalkyl, aromatic yl alkyl carbonyl, aryl carbonyl, aryloxycarbonyl and aryl sulfonyl, heterocyclic radical, and the heterocyclic radical in heterocyclic radical alkoxy carbonyl, heterocyclic radical alkyl, heterocyclic radical alkyl-carbonyl, heterocyclic radical carbonyl and heterocyclyloxy base carbonyl is partly also optionally independently selected from following substituting group by 1,2 or 3 and replaces: alkoxyl group, alkyl, cyano group, halogen, halogenated alkoxy, haloalkyl and nitro,

Term " NR ^er ^f" refer to R ^eand R ^ftwo groups are connected with parent molecular moiety by nitrogen-atoms; R wherein ^eand R ^findependently be selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted cycloalkylalkyl, unsubstituted heterocyclic radical, unsubstituted heterocyclic radical alkyl, (NR ^xr ^y) alkyl and (NR ^xr ^y) carbonyl; With

Term " NR ^xr ^y" refer to R ^xand R ^ytwo groups are connected with parent molecular moiety by nitrogen-atoms; R wherein ^xand R ^yindependently be selected from hydrogen, alkoxy carbonyl, alkyl, alkyl-carbonyl, unsubstituted aryl, unsubstituted aryl-alkoxy carbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclic radical and (NR ^{x '}r ^{y '}) carbonyl, wherein R ^{x '}and R ^{y '}independently be selected from hydrogen and alkyl.

2. the compound of claim 1 or its pharmacy acceptable salt, wherein m and n respectively do for oneself 1.

3. the compound of claim 1 or its pharmacy acceptable salt, wherein:

U and v are 0,1 or 2 independently of one another; And

Each R ¹with each R ²independently be selected from alkoxyl group, alkoxyalkyl, alkyl, aryl alkane R base carbonyl, carboxyl, formyl radical, halogen, haloalkyl, hydroxyalkyl, (NR ^ar ^b) alkyl and (NR ^ar ^b) carbonyl.

4. the compound of claim 1 or its pharmacy acceptable salt, wherein:

U and v are 0 or 1 independently of one another; And

When existing, R ¹and/or R ²for halogen.

5. the compound of claim 4 or its pharmacy acceptable salt, wherein halogen is fluorine.

6. the compound of claim 1 or its pharmacy acceptable salt, wherein at least one in X and Y is S.

7. the compound of claim 6 or its pharmacy acceptable salt, wherein X and the Y S that respectively does for oneself.

8. the compound of claim 1 or its pharmacy acceptable salt, wherein X is selected from CHR ⁵and C (R ⁵) ₂; Y is selected from CH ₂, CHR ⁶and C (R ⁶) ₂.

9. the compound of claim 1 or its pharmacy acceptable salt, wherein R ⁷and R ⁸independently be selected from hydrogen, alkoxy carbonyl, alkyl, aryl-alkoxy carbonyl, carboxyl, haloalkyl and (NR ^ar ^b) carbonyl.

10. the compound of claim 9 or its pharmacy acceptable salt, wherein R ⁷and R ⁸the hydrogen of respectively doing for oneself.

The compound of 11. claims 1 or its pharmacy acceptable salt, wherein:

Q and s are 0,1 or 2 independently; And

The compound of 12. claims 1 or its pharmacy acceptable salt, wherein:

Q and s are 0 or 1 independently; And

When existing, R ⁵and/or R ⁶for halogen.

The compound of 13. claims 12 or its pharmacy acceptable salt, wherein halogen is fluorine.

The compound of 14. claims 1 or its pharmacy acceptable salt, wherein R ³and R ⁴in at least one be hydrogen.

The compound of 15. claims 1 or its pharmacy acceptable salt, wherein R ³and R ⁴r respectively does for oneself ⁹-C (O)-.

The compound of 16. claims 15 or its pharmacy acceptable salt, wherein each R ⁹independently be selected from alkoxyl group, alkoxyalkyl, alkyl, alkyl-carbonyl alkyl, aryl, aryl alkenyl, alkoxy aryl, arylalkyl, aryloxy alkyl, cycloalkyl, cycloalkylalkyl, cycloalkyl oxy alkyl, heterocyclic radical, heterocyclic radical alkyl, hydroxyalkyl ,-NR ^cr ^d, (NR ^cr ^d) thiazolinyl, (NR ^cr ^d) alkyl and (NR ^cr ^d) carbonyl.

The compound of 17. 1 kinds of following formulas (II) or its pharmacy acceptable salt:

Wherein:

Q and s are 0,1 or 2 independently;

U and v are 0,1 or 2 independently;

X is selected from S, CH ₂, CHR ⁵and C (R ⁵) ₂;

Y is selected from S, CH ₂, CHR ⁶and C (R ⁶) ₂;

Each R ⁹independently be selected from alkoxyl group, alkoxyalkyl, alkyl, alkyl-carbonyl alkyl, aryl, aryl alkenyl, alkoxy aryl, arylalkyl, aryloxy alkyl, cycloalkyl, cycloalkylalkyl, cycloalkyl oxy alkyl, heterocyclic radical, heterocyclic radical alkyl, hydroxyalkyl ,-NR ^cr ^d, (NR ^cr ^d) thiazolinyl, (NR ^cr ^d) alkyl and (NR ^cr ^d) carbonyl;

Wherein term " alkyl ", " alkoxyl group ", " aryl ", " aryloxy ", " thiazolinyl ", " alkene oxygen base ", " cycloalkyl ", " heterocyclic radical ", " NR ^ar ^b", " NR ^cr ^d", " NR ^er ^f" and " NR ^xr ^y" as defined in claim 1.

The compound of 18. 1 kinds of following formulas (III) or its pharmacy acceptable salt:

Wherein:

Q and s are 0,1 or 2 independently;

U and v are 0 or 1 independently;

X is selected from CH ₂, CHR ⁵and C (R ⁵) ₂;

Y is selected from CH ₂, CHR ⁶and C (R ⁶) ₂;

When existing, R ¹and/or R ²for halogen, wherein halogen is fluorine;

R ³and R ⁴r respectively does for oneself ⁹-C (O)-;

When existing, R ⁵and/or R ⁶for halogen, wherein halogen is fluorine; And

19. 1 kinds of compounds, are selected from:

(1) (2S, 2 ' S)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases)) two (1-pyrrolidinecarboxylic acid tert-butyl esters);

(2) (2S)-2-(4-(3 '-(2-((2S)-1-(tertbutyloxycarbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-3-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester;

(3) 5,5 '-(4,4 '-biphenyl, two bases) two (2-((2S)-2-pyrrolidyl)-1H-imidazoles);

(4) 2-((2S)-2-pyrrolidyl)-4-(3 '-(2-((2S)-2-pyrrolidyl)-1H-imidazoles-5-yl)-3-xenyl)-1H-imidazoles;

(5) (1R, 1 ' R)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amines);

(6) (1R, 1 ' R)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (2-oxo-1-phenylethyl alcohols);

(7) (2S, 2 ' S)-1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (1-oxo-2-phenyl-2-propyl alcohol);

(8) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (Urethylanes);

(9) (1S, 1 ' S)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amines);

(10) 5,5 '-(4,4 '-biphenyl, two bases) two (2-((2S)-1-benzoyl-2-pyrrolidyl)-1H-imidazoles);

(11) 5,5 '-(4,4 '-biphenyl, two bases) two (2-((2S)-1-(phenylacetyl)-2-pyrrolidyl)-1H-imidazoles);

(12) 5,5 '-(4,4 '-biphenyl, two bases) two (2-((2S)-1-((2R)-2-methoxyl group-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles);

(13) (2R, 2 ' R)-1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (1-oxo-3-phenyl-2-propyl alcohol);

(14) 5,5 '-(4,4 '-biphenyl, two bases) two (2-((2S)-1-propionyl-2-pyrrolidyl)-1H-imidazoles);

(15) 5,5 '-(4,4 '-biphenyl, two bases) two (2-((2S)-1-(cyclopropyl carbonyl)-2-pyrrolidyl)-1H-imidazoles);

(16) 5,5 '-(4,4 '-biphenyl, two bases) two (2-((2S)-1-(cyclopropyl ethanoyl)-2-pyrrolidyl)-1H-imidazoles);

(17) 5,5 '-(4,4 '-biphenyl, two bases) two (2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles);

(18) 2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-2-oxo ethamine);

(19) (2R, 2 ' R)-1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (1-oxo-2-propyl alcohol);

(20) (2R, 2 ' R)-1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (3-methyl isophthalic acid-oxo-2-butanols);

(21) 5,5 '-(4,4 '-biphenyl, two bases) two (2-((2S)-1-((2R)-2-phenyl-2-(1-pyrrolidyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles);

(22) 4,4 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) dimorpholine;

(23) 5,5 '-(4,4 '-biphenyl, two bases) two (2-((2S)-1-((the fluoro-1-pyrrolidyl of (3S)-3-) (phenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles);

(24) 5,5 '-(4,4 '-biphenyl, two bases) two (2-((2S)-1-((the fluoro-1-pyrrolidyl of (3S)-3-) (phenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles);

(25) (1R, 1 ' R)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-diethyl-2-oxo-1-phenyl-ethyl amines);

(26) (1R, 1 ' R)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N-ethyl-N-methyl-2-oxo-1-phenyl-ethyl amines);

(27) N, N '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) diformamide;

(28) 1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two base carbonyls)) two ring propyl alcohol;

(29) 1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two piperidines;

(30) 1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (4-methyl-4-piperidine alcohols);

(31) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-1-(2-chloro-phenyl-)-2-oxo-2,1-ethane two bases))) two (Urethylanes);

(32) N ', N " '-(4,4 '-biphenyl, two bases two (1H-imidazoles-4,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (1,1-dimethyl ureas);

(33) N ', N " '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (1-MUs);

(34) N ', N " '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (1-ethyl carbamides);

(35) N ', N " '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (1-cyclopentyl ureas);

(36) 2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N-benzyl-N-methyl-2-oxo ethamine);

(37) (2S, 2 ' S)-1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N-benzyl-N-methyl isophthalic acid-oxo-2-propylamine);

(38) 1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N-benzyl-N, 3-dimethyl-1-oxo-2-butylamine);

(39) 1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases (2-oxo-1-phenyl-2,1-ethane two bases))) two (4-piperidine alcohols);

(40) 1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases ((2S, 4S)-4-fluoro-2,1-tetramethyleneimine two bases) ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two piperidines;

(41) (1R, 1 ' R)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases ((2S, 4S)-4-fluoro-2,1-tetramethyleneimine two bases))) two (N, N-diethyl-2-oxo-1-phenyl-ethyl amines);

(42) (1R, 1 ' R)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases ((2S, 4S)-4-fluoro-2,1-tetramethyleneimine two bases))) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amines);

(43) 1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-4,2-bis-bases ((2S)-4,4-bis-is fluoro-2,1-tetramethyleneimine two bases) ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two piperidines;

(44) (4,4 '-biphenyl, two bases two (1H-imidazoles-4,2-bis-bases ((2S)-4,4-bis-is fluoro-2,1-tetramethyleneimine two bases) ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (Urethylanes);

(45) 1-((1R)-2-((2S)-2-(4-(4 '-(2-((2S)-4, the fluoro-1-of 4-bis-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) piperidines;

(46) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases ((2S, 4R)-4-hydroxyl-2,1-tetramethyleneimine two bases) ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (Urethylanes);

(47) (3R, 5S, 3 ' R, 5 ' S)-5,5 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases)) two (1-((2R)-2-hydroxyl-2-phenylacetyl)-3-pyrrolidinols);

(48) N, N " (4,4 '-biphenyl, two bases two (1H-imidazoles-5; 2-bis-bases ((2S; 4R)-4-hydroxyl-2,1-tetramethyleneimine two bases) ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (3-MUs);

(49) N ', N " '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5; 2-bis-bases ((2S; 4R)-4-hydroxyl-2,1-tetramethyleneimine two bases) ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (1-ethyl carbamides);

(50) N1, N " '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5; 2-bis-bases ((2S; 4R)-4-hydroxyl-2,1-tetramethyleneimine two bases) ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (1-cyclopentyl ureas);

(51) (3S, 5S, 3 ' S, 5 ' S)-5,5 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases)) two (1-((2R)-2-(dimethylamino)-2-phenylacetyl)-3-pyrrolidinols);

(52) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases ((2S, 4S)-4-hydroxyl-2,1-tetramethyleneimine two bases) ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (Urethylanes);

(53) (3S, 5S, 3 ' S, 5 ' S)-5,5 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases)) two (1-((2R)-2-hydroxyl-2-phenylacetyl)-3-pyrrolidinols);

(54) N, N '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) diethylamide;

(55) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (t-butyl carbamates);

(56) (2R, 2 ' R)-N, N '-(4, two (1H-imidazoles-5 of 4 '-biphenyl, two bases, 2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (tetrahydrochysene-2-furoylamides);

(57) N, N '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (1-methyl isophthalic acid H-imidazoles-5-methane amides);

(58) (2S, 2 ' S)-N, N '-(4, two (1H-imidazoles-5 of 4 '-biphenyl, two bases, 2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (1-methyl-2-pyrrolidine formamides);

(59) N, N '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (2-(3-pyridyl) ethanamides);

(60) N, N '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (2-(dimethylamino) ethanamides);

(61) N, N '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (4-morpholine methane amides);

(62) N, N '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (4-methyl isophthalic acid-piperazine carboxamides);

(63) N, N " (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (3-(3-pyridyl) ureas);

(64) ((1R)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(65) (2R, 2 ' R)-1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (3-methyl isophthalic acid-oxo-2-butylamine);

(66) N-((1R)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-acetylaminohydroxyphenylarsonic acid 3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) ethanamide;

(67) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(68) (2S, 2 ' S)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases)) (the 1-pyrrolidinecarboxylic acid tert-butyl ester) (1-pyrrolidinecarboxylic acid benzyl ester);

(69) (2S)-2-(5-(4 '-(2-((2S)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester;

(70) (2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester;

(71) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(72) (1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(73) 1-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) piperidines;

(74) ((1R)-1-(2-chloro-phenyl-)-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(75) (1R)-1-(2-chloro-phenyl-)-N, N-dimethyl-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(76) (1R)-1-(2-fluorophenyl)-N, N-dimethyl-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(77) (1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(78) 1-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) piperidines;

(79) ((1R)-1-(2-chloro-phenyl-)-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(80) (1R)-1-(2-chloro-phenyl-)-N, N-dimethyl-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(81) (1R)-1-(2-fluorophenyl)-N, N-dimethyl-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(82) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((4-methyl isophthalic acid-piperazinyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(83) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-glycyl-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(84) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(tertbutyloxycarbonyl) glycyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(85) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(86) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-ethanoyl-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(87) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-propionyl-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(88) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(cyclopropyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(89) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(cyclopropyl ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(90) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-hydroxyl propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(91) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(92) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-dimethyl glycyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(93) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(94) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(4-morpholinyl ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(95) (2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(96) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-ethanoyl glycyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(97) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(98) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-hydroxyl-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(99) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((1-methyl-4-piperidyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(100) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(tetrahydrochysene-2H-pyrans-4-base carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(101) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(2-pyridyl ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(102) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(3-pyridyl ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(103) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(4-pyridyl ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(104) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((1-methyl isophthalic acid H-imidazoles-5-yl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(105) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(formyl-dimethylamino)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(106) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1-methyl D-prolyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(107) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1-methyl-L-prolyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(108) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-ethanoyl-D-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(109) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-ethanoyl-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(110) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(methoxyl group ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(111) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-maloyl group)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(112) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((4-methyl isophthalic acid-piperazinyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(113) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1-pyrrolidyl ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(114) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(115) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((1-hydroxyl cyclopropyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(116) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1H-imidazoles-5-base ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(117) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((1-methyl isophthalic acid H-imidazol-4 yl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(118) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1H-imidazoles-2-base carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(119) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((4-hydroxyl-piperidino) (phenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(120) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1H-TETRAZOLE-5-base ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(121) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(2-pyridyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(122) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(3-pyridyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(123) ((1R)-2-((2S)-2-(5-(4 '-(2-(the different nicotinoyl-2-of (2S)-1-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(124) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(the fluoro-1-methyl-L-of (4R)-4-prolyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(125) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1,3- azoles-2-base carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(126) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1,3- azoles-5-base carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(127) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((dimethylamino) (oxo) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(128) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(tetrahydrochysene-3-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(129) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(130) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-dimethyl-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(131) (2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid methyl esters;

(132) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(4-morpholinyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(133) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(the fluoro-L-prolyl of (4S)-4-)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(134) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-L-prolyl-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(135) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(the fluoro-L-prolyl of 4,4-bis-)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(136) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(the fluoro-L-prolyl of (4R)-4-)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(137) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((1S, 3S, 5S)-2-azabicyclic [3.1.0] oneself-3-base carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(138) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-L-alanyl-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(139) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(140) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-(2-fluorophenyl)-2-hydroxyl propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(141) ((1R)-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-(5-oxo-D-prolyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-styroyl) Urethylane;

(142) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(4-hydroxy-4-methyl-piperidino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(143) (4R)-4-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1,3-thiazoles alkane-3-t-butyl formate;

(144) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((1-((tertbutyloxycarbonyl) amino) cyclopentyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(145) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-benzoyl glycyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(146) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(4-(4-methyl isophthalic acid-piperazinyl) benzoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(147) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((5-phenyl-2-thienyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(148) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((4-phenyl-1,2,3-thiadiazoles-5-yl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(149) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2-phenyl-1,3-thiazoles-4-yl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(150) 4-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-4-methyl isophthalic acid-piperidine acid tert-butyl ester;

(151) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(4-(dimethylamino) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(152) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((3-hydroxy phenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(153) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-dimethyl-β-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(154) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(4-(methylol) benzoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(155) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(((3R)-1-benzyl-3-pyrrolidyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(156) (2S)-2-(2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl)-1-pyrrolidinecarboxylic acid tert-butyl ester;

(157) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((5-methyl isophthalic acid H-pyrazole-3-yl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(158) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(((3S)-7-hydroxyl-1,2,3,4-tetrahydrochysene-3-isoquinolyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(159) (2R)-2-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1-piperidine acid tert-butyl ester;

(160) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-((((5-phenyl-4-is different for (2S)-1-for 2- azoles base) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(161) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(((1R, 3S)-3-((tertbutyloxycarbonyl) amino) cyclopentyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(162) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(3-(piperidino) propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(163) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(2-benzoyl benzoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(164) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2-methoxyphenoxy) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(165) 3-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1-azetidine t-butyl formate;

(166) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(((3S)-1-benzyl-3-pyrrolidyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(167) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(3-(1-pyrrolidyl) benzoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(168) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(2-((tertbutyloxycarbonyl) amino) benzoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(169) (3R)-3-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1-piperidine acid tert-butyl ester;

(170) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((1-(trifluoromethyl) cyclopropyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(171) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(4-(dimethylamino) benzoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(172) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(3-benzoyl benzoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(173) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((cis-4-((tertbutyloxycarbonyl) amino) cyclohexyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(174) 4-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1-piperidine acid tert-butyl ester;

(175) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((cis-4-((tertbutyloxycarbonyl) amino) cyclohexyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(176) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(phenylbenzene ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(177) ((1R)-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-(4-oxo pentanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-styroyl) Urethylane;

(178) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(2-fluoro benzoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(179) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(2-xenyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(180) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(2-benzyl benzoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(181) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2E)-3-(4-(dimethylamino) phenyl)-2-acryl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(182) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1,3-thiazoles-4-base carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(183) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((((1R, 2S, 5R)-2-sec.-propyl-5-methylcyclohexyl) oxygen base) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(184) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((dimethylamino) (2-thienyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(185) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((dimethylamino) (3-thienyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(186) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((dimethylamino) (2-methyl isophthalic acid, 3-thiazole-4-yl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(187) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1,2-benzisoxa azoles-3-base (dimethylamino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(188) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1-thionaphthene-3-base (dimethylamino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(189) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((dimethylamino) (1-naphthyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(190) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((dimethylamino) (3-quinolyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(191) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((dimethylamino) (2-methyl isophthalic acid, 3-benzothiazole-5-yl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(192) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((dimethylamino) (3-(trifluoromethyl) phenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(193) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((dimethylamino) (2-(trifluoromethyl) phenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(194) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2-chloro-phenyl-) (dimethylamino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(195) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((3-chloro-phenyl-) (dimethylamino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(196) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((4-chloro-phenyl-) (dimethylamino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(197) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((dimethylamino) (2-fluorophenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(198) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((dimethylamino) (3-fluorophenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(199) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((dimethylamino) (2-pyridyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(200) ((1R)-2-((2S)-2-(4-(4 '-(2-((2S)-1-((dimethylamino) (3-pyridyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(201) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((4-p-methoxy-phenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(202) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((3-p-methoxy-phenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(203) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2-p-methoxy-phenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(204) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2-chloro-phenyl-) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(205) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((3-chloro-phenyl-) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(206) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((4-chloro-phenyl-) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(207) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2-aminomethyl phenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(208) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((4-aminomethyl phenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(209) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((3-aminomethyl phenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(210) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2-methyl isophthalic acid, 3-thiazole-4-yl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(211) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(3-thienyl ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(212) ((1R)-2-((2S)-2-(5-(4 '-((((3-methyl-5-is different for (2S)-1-for 2- azoles base) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(213) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(cyclohexyl ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(214) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(215) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((1-phenycyclopropyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(216) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((1-(4-chloro-phenyl-) cyclopropyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(217) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(2-(4-chloro-phenyl-)-2-methylpropionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(218) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-methoxyl group-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(219) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-3, the fluoro-2-methoxyl group-2-of 3,3-tri-phenyl propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(220) acetic acid (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-phenyl chlorocarbonate;

(221) acetic acid (1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-phenyl chlorocarbonate;

(222) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2-(4-morpholinyl methyl) phenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(223) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2-(piperidino methyl) phenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(224) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2-(1-pyrrolidyl methyl) phenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(225) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2-((dimethylamino) methyl) phenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(226) (1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(3-pyridyl ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(227) (1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(228) (1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(229) (1R)-N, N-dimethyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((1-methyl isophthalic acid H-imidazol-4 yl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-phenyl-ethyl amine;

(230) (1R)-N, N-dimethyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(4-morpholinyl)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-phenyl-ethyl amine;

(231) (1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(1-pyrrolidyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(232) (2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(233) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(234) (1R)-N, N-dimethyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(4-morpholinyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-phenyl-ethyl amine;

(235) (1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1-pyrrolidyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(236) (2S)-1-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-(2-fluorophenyl)-1-oxo-2-propyl alcohol;

(237) (5R)-5-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-Pyrrolidone;

(238) 1-((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl)-4-methyl-4-piperidine alcohols;

(239) (4R)-4-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1,3-thiazoles alkane-3-t-butyl formate;

(240) (1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclopentyl) t-butyl carbamate;

(241) N-(2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) benzamide;

(242) (1R)-N, N-dimethyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(4-(4-methyl isophthalic acid-piperazinyl) benzoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-phenyl-ethyl amine;

(243) (1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((5-phenyl-2-thienyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(244) (1R)-N, N-dimethyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(4-(4-morpholinyl) benzoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-phenyl-ethyl amine;

(245) (1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((4-phenyl-1,2,3-thiadiazoles-5-yl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(246) (1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2-phenyl-1,3-thiazoles-4-yl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(247) 4-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-4-methyl isophthalic acid-piperidine acid tert-butyl ester;

(248) 3-(2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) phenol;

(249) 3-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-3-oxo-1-propylamine;

(250) (4-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) phenyl) methyl alcohol;

(251) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1H-indol-3-yl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(252) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(((3R)-1-benzyl-3-pyrrolidyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(253) (2S)-2-(2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl)-1-pyrrolidinecarboxylic acid tert-butyl ester;

(254) (1R)-N, N-dimethyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((5-methyl isophthalic acid H-pyrazole-3-yl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-phenyl-ethyl amine;

(255) (2R)-2-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1-piperidine acid tert-butyl ester;

(256) ((1S, 3R)-3-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-

Pyrrolidyl) carbonyl) cyclopentyl) t-butyl carbamate;

(257) (1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(3-(piperidino) propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(258) (2-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) phenyl) (phenyl) ketone;

(259) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2-methoxyphenoxy) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(260) 3-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1-azetidine t-butyl formate;

(261) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(((3S)-1-benzyl-3-pyrrolidyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(262) (1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(3-(1-pyrrolidyl) benzoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(263) (2-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) phenyl) t-butyl carbamate;

(264) (3R)-3-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1-piperidine acid tert-butyl ester;

(265) (1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((1-(trifluoromethyl) cyclopropyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(266) 4-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-DMA;

(267) (3-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) phenyl) (phenyl) ketone;

(268) (cis-4-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclohexyl) t-butyl carbamate;

(269) 4-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1-piperidine acid tert-butyl ester;

(270) (cis-4-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclohexyl) t-butyl carbamate;

(271) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(phenylbenzene ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(272) 5-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-5-oxo-2 pentanone;

(273) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(2-fluoro benzoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(274) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(2-xenyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(275) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(2-benzyl benzoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(276) 4-((1E)-3-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-3-oxo-1-propylene-1-yl)-DMA;

(277) (1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1,3-thiazoles-4-base carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(278) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((((1R, 2S, 5R)-2-sec.-propyl-5-methylcyclohexyl) oxygen base) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(279) 1-(6-chloro-3-pyridyl base)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo ethamine;

(280) 2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-(3-pyridyl) ethamine;

(281) 2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-(2-pyridyl) ethamine;

(282) (1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(2-thienyl ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(283) (1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(3-thienyl ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(284) (1R)-N, N-dimethyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1-naphthalene ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-phenyl-ethyl amine;

(285) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1H-imidazoles-5-base ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(286) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2-fluorophenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(287) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((3-fluorophenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(288) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((4-fluorophenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(289) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1-thionaphthene-3-base ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(290) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1,2-benzisoxa azoles-3-base ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(291) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1H-indol-3-yl ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(292) 2-((2S)-1-((2R)-2-phenyl-2-(1-pyrrolidyl) ethanoyl)-2-pyrrolidyl)-5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles;

(293) 4-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(1-pyrrolidyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) morpholine;

(294) 1-(2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(1-pyrrolidyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-4-piperidine alcohols;

(295) 1-methyl-4-(2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(1-pyrrolidyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) piperazine;

(296) (1R)-N, N-diethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(1-pyrrolidyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(297) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(1-pyrrolidyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(298) ((1S)-1-methyl-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(1-pyrrolidyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(299) (2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(1-pyrrolidyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(300) (2S)-N, N-dimethyl-1-oxo-1-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(1-pyrrolidyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-propylamine;

(301) 1-(2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-4-Phenylpiperidine;

(302) 1-(2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-4-Phenylpiperidine;

(303) 1-methyl-4-(2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) piperazine;

(304) 1-methyl-4-(2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) piperazine;

(305) 4-(2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-1-piperazinecarboxylic acid benzyl ester;

(306) 4-(2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-1-piperazinecarboxylic acid benzyl ester;

(307) 1-(2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) piperazine;

(308) 4-(2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-2-piperazinones;

(309) 1-methyl-3-((1R)-2-oxo-1-phenyl-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) urea;

(310) 1-ethyl-3-((1R)-2-oxo-1-phenyl-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) urea;

(311) 1-cyclopentyl-3-((1R)-2-oxo-1-phenyl-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) urea;

(312) 1,1-dimethyl-3-((1R)-2-oxo-1-phenyl-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) urea;

(313) 1-methyl-4-(2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) piperazine;

(314) 4-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) morpholine;

(315) (1R)-N, N-diethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(316) (1R)-N-ethyl-N-methyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(317) acetic acid (1S)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl ester;

(318) 4-methyl isophthalic acid-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-4-piperidine alcohols;

(319) 1-((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(2-fluoro benzoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) piperidines;

(320) N, N-dimethyl-4-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) aniline;

(321) 5-oxo-5-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2 pentanone;

(322) 1-((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(phenylbenzene ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) piperidines;

(323) 1-(3-oxo-3-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) propyl group) piperidines;

(324) 1-((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2-methoxyphenoxy) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) piperidines;

(325) 4-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1-piperidine acid tert-butyl ester;

(326) 4-(4-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) phenyl) morpholine;

(327) 1-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1,3-thiazoles-4-base carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) piperidines;

(328) 3-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1-azetidine t-butyl formate;

(329) (cis-4-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclohexyl) t-butyl carbamate;

(330) 4-methyl-4-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1-piperidine acid tert-butyl ester;

(331) 1-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((1-(trifluoromethyl) cyclopropyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) piperidines;

(332) 1-((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((5-methyl isophthalic acid H-pyrazole-3-yl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) piperidines;

(333) 1-((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(((3R)-1-benzyl-3-pyrrolidyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) piperidines;

(334) 1-((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(((3S)-1-benzyl-3-pyrrolidyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) piperidines;

(335) 1-((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-methoxyl group-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) piperidines;

(336) 1-((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-methoxyl group-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) piperidines;

(337) acetic acid (1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl ester;

(338) 1-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((1-phenycyclopropyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) piperidines;

(339) N, N-dimethyl-1-(2-(2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) phenyl) methylamine;

(340) 1-((1R)-2-((2S)-2-(5-(4 '-((((3-methyl-5-is different for (2S)-1-for 2- azoles base) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) piperidines;

(341) 1-((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2-methyl isophthalic acid, 3-thiazole-4-yl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) piperidines;

(342) 4-(2-(2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) benzyl) morpholine;

(343) 1-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2-(1-pyrrolidyl methyl) phenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) piperidines;

(344) 1-((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2-fluorophenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) piperidines;

(345) 1-((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-ethanoyl-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) piperidines;

(346) 1-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(2-thienyl ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) piperidines;

(347) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-(2-fluorophenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(348) (1R)-1-(2-fluorophenyl)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-methoxyl group-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo ethamine;

(349) acetic acid (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-(2-fluorophenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-phenyl chlorocarbonate;

(350) (1R)-1-(2-fluorophenyl)-N, N-dimethyl-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-((1-phenycyclopropyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(351) (1R)-1-(2-chloro-phenyl-)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo ethamine;

(352) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(2-chloro-phenyl-)-2-(dimethylamino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(353) (1R)-1-(2-chloro-phenyl-)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-methoxyl group-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo ethamine;

(354) (1R)-1-(2-chloro-phenyl-)-N, N-dimethyl-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(355) ((1R)-1-(2-chloro-phenyl-)-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(356) ((1R)-1-(2-chloro-phenyl-)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(357) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(2-chloro-phenyl-)-2-((methoxycarbonyl) amino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(358) ((1R)-1-(2-chloro-phenyl-)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(4-hydroxy-4-methyl-piperidino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(359) ((1R)-1-(2-chloro-phenyl-)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-methoxyl group-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(360) ((1R)-1-(2-chloro-phenyl-)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(2-chloro-phenyl-)-2-(dimethylamino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(361) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(ethylamino formyl radical)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(362) (2S, 2 ' S)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases)) two (1-pyrrolidinecarboxylic acid benzyl esters);

(363) (2S)-2-(5-(4 '-(2-((2S)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid benzyl ester;

(364) (2R)-N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) tetrahydrochysene-2-furoylamide;

(365) (1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(366) (2R)-N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) tetrahydrochysene-2-furoylamide;

(367) N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-4-morpholine methane amide;

(368) (2S)-N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) tetrahydrochysene-2-furoylamide;

(369) 1-methyl-N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-L-prolineamide;

(370) 1-methyl-N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-4-piperidyl urea;

(371) N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) tetrahydrochysene-2H-pyrans-4-methane amide;

(372) the fluoro-1-methyl-N-of (4R)-4-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-L-prolineamide;

(373) 4-methyl-N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-1-piperazine carboxamides;

(374) N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) ethanamide;

(375) (2R)-N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) tetrahydrochysene-2-furoylamide;

(376) N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-4-morpholine methane amide;

(377) 1-methyl-N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-1H-imidazoles-5-methane amide;

(378) 1-methyl-N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-L-prolineamide;

(379) N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-2-(3-pyridyl) ethanamide;

(380) N ², N ²-dimethyl-N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) G-NH2;

(381) 1-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-3-(3-pyridyl) urea;

(382) (1R, 1 ' R)-2,2 '-((2,2 '-dimethyl-4,4 '-biphenyl, two bases) two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amines);

(383) ((2,2 '-dimethyl-4,4 '-biphenyl, two bases) two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (Urethylanes);

(384) (1R, 1 ' R)-2,2 '-((2-methyl-4,4 '-biphenyl, two bases) two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amines);

(385) ((2-methyl-4,4 '-biphenyl, two bases) two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (Urethylanes);

(386) (1R, 1 ' R)-2,2 '-((2-methyl-4,4 '-biphenyl, two bases) two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (2-oxo-1-phenylethyl alcohols);

(387) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-2 '-methyl-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(388) ((1R)-2-((2S)-2-(5-(2 ' methyl-4 '-(2-((2S)-1-(3-pyridyl ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(389) ((1R)-2-((2S)-2-(5-(2 '-methyl-4 '-(2-((2S)-1-((2S)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(390) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-2,2 '-dimethyl-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(391) (1R, 1 ' R)-2,2 '-((2-(trifluoromethyl)-4,4 '-biphenyl, two bases) two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amines);

(392) (1R, 1 ' R)-2,2 '-((2-(trifluoromethyl)-4,4 '-biphenyl, two bases) two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amines);

(393) 5,5 '-(2-(trifluoromethyl)-4,4 '-biphenyl two bases) two (2-((2S)-1-((2R)-2-phenyl-2-(1-pyrrolidyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles);

(394) (1R, 1 ' R)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (4R)-1,3-thiazoles alkane-4,3-bis-bases)) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amines);

(395) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (4R)-1,3-thiazoles alkane-4,3-bis-bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (Urethylanes);

(396) (4R, 4 ' R)-4,4 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases)) two (3-((2R)-tetrahydrochysene-2-furyl carbonyl)-1,3-thiazoles alkane);

(397) (1R, 1 ' R)-2,2 '-(4,4 '-biphenyl, two bases two ((1-methyl isophthalic acid H-imidazoles-4,2-bis-bases) (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amines);

(398) (1S, 1 ' S)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (1-cyclohexyl-2-oxo ethanol);

(399) (2S, 2 ' S)-1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (4-methyl isophthalic acid-oxo-2-amylalcohols);

(400) (2S, 2 ' S)-1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (3-methyl isophthalic acid-oxo-2-butanols);

(401) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-(((3-butene-1-Ji oxygen base) carbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) carboxylamine 3-butene-1-Ji ester;

(402) ((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-methyl glycyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(403) (2S, 2 ' S)-1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N-methyl isophthalic acid-oxo-2-propylamine);

(404) (4S, 4 ' S)-4,4 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two base carbonyls)) two (1,3-oxazas oneself-2-ketone);

(405) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(tetrahydrochysene-2H-pyrans-4-yl) ethyl) Urethylane;

(406) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-ethyl glycinamide aminoacyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(407) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-benzyl glycyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(408) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-isobutyl-glycyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(409) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-sec-butyl glycyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(410) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-sec.-propyl glycyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(411) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-di-isopropyl glycyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(412) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-(3-oxetanyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(413) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-2-(3-oxetanyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(414) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-2-methyl isophthalic acid-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(415) ((1S, 2R)-2-methoxyl group-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-Threonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-2-methyl isophthalic acid-pyrrolidyl) carbonyl) propyl group) Urethylane;

(416) ((1R)-2-((2R)-2-(5-(4 '-(2-((2S, 5R)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-5-phenyl-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(417) rel-(1R)-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl) octahydro-1H-indoles-2-yl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(418) rel-((1R)-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl) octahydro-1H-indoles-2-yl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(419) (1R)-N-ethyl-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-2-(ethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-phenyl-ethyl amine;

(420) (1R)-N-methyl-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-2-(methylamino-)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-phenyl-ethyl amine;

(421) N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(the third amino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl)-1-propylamine;

(422) N-((1R)-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-2-(fourth is amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl)-1-butylamine;

(423) ((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-((ethoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) urethanum;

(424) ((1S)-1-methyl-2-oxo-2-((2S)-2-(4-(4 '-(2-((2S)-1-(N-(the third oxygen carbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) carboxylamine propyl ester;

(425) ((1S)-2-((2S)-2-(4-(4 '-(2-((2S)-1-(N-(butoxy carbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) butyl carbamate;

(426) (2S)-2-hydroxy-n-((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-((2S)-2-hydroxy-3-methyl butyryl radicals)-L-alanyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl)-3-methylbutyryl amine;

(427) ((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-((ethoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) urethanum;

(428) ((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-((isopropyl oxygen carbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) carbamic acid isopropyl ester;

(429) (2S)-1-((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-hydroxyl propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-oxo-2-propyl alcohol;

(430) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((tertbutyloxycarbonyl) (methyl) amino)-4-methylpent acyl group)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-3-methyl butyl) methyl carbamic acid tert-butyl ester;

(431) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((tertbutyloxycarbonyl) (methyl) amino)-3-methylpent acyl group)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl butyl) methyl carbamic acid tert-butyl ester;

(432) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((tertbutyloxycarbonyl) (methyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) methyl carbamic acid tert-butyl ester;

(433) ((1S, 2R)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-(the other isoleucyl of N-(tertbutyloxycarbonyl)-N-methyl-L-)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl butyl) methyl carbamic acid tert-butyl ester;

(434) (2S)-N, 4-dimethyl-1-((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-4-methyl-2-(methylamino-) pentanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-oxo-2-amylamine;

(435) (2S)-N, 3-dimethyl-1-((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-3-methyl-2-(methylamino-) pentanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-oxo-2-amylamine;

(436) (2S)-N, 3-dimethyl-1-((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-3-methyl-2-(methylamino-) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-oxo-2-butylamine;

(437) (2S, 3R)-N, 3-dimethyl-1-((2S)-2-(4-(4 '-(2-((2S)-1-((2S, 3R)-3-methyl-2-(methylamino-) pentanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-oxo-2-amylamine;

(438) ((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-2,3-dimethyl butyrate acyl group)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1,2-dimethyl propyl) Urethylane;

(439) ((1S)-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-2-(tetrahydrochysene-2H-pyrans-4-yl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(tetrahydrochysene-2H-pyrans-4-yl) ethyl) Urethylane;

(440) (2-((2S)-2-(4-(4 '-(2-((2S)-1-(((methoxycarbonyl) amino) (tetrahydrochysene-2H-pyrans-4-yl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(tetrahydrochysene-2H-pyrans-4-yl) ethyl) Urethylane;

(441) ((1S)-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-2-(ethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(442) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1,2-dimethyl propyl) Urethylane;

(443) ((1S)-2-methyl isophthalic acid-(((2S)-2-(4-(4 '-(2-((2S)-1-(N-(tetrahydrochysene-2H-pyrans-4-yl)-L-alanyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(444) ((1S)-2-methyl isophthalic acid-(((2S)-2-(4-(4 '-(2-((2S)-1-(N-(tetrahydrochysene-2H-pyrans-4-yl)-L-is valyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(445) ((1S)-2-methyl isophthalic acid-(((2S)-2-(4-(4 '-(2-((2S)-1-(N-(tetrahydrochysene-2H-pyrans-4-yl) glycyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(446) ((1S)-2-methyl isophthalic acid-(((2S)-2-(4-(4 '-(2-((2S)-1-(N-(tetrahydrochysene-2H-pyrans-4-yl)-D-is valyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(447) ((1S)-2-methyl isophthalic acid-(((2S)-2-(4-(4 '-(2-((2S)-1-(N-(tetrahydrochysene-2H-pyrans-4-yl)-D-alanyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(448) ((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) carboxylamine (3S)-tetrahydrochysene-3-furans ester;

(449) ((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) carboxylamine tetrahydrochysene-2H-pyrans-4-base ester;

(450) ((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) carboxylamine (3R)-tetrahydrochysene-3-furans ester;

(451) ((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-(tetrahydrochysene-2H-pyrans-4-yl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(452) ((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-2-(tetrahydrochysene-2H-pyrans-4-yl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(453) N-((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-acetylaminohydroxyphenylarsonic acid 3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) ethanamide;

(454) N-((1S)-2-methyl isophthalic acid-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-3-methyl-2-(propionyl is amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) propionic acid amide;

(455) 2-methoxyl group-N-((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-((methoxyl group ethanoyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) ethanamide;

(456) 1-methyl-3-((1S)-2-methyl isophthalic acid-(((2S)-2-(4-(4 '-(2-((2S)-1-(N-(methylamino formyl radical)-L-is valyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) urea;

(457) 1-ethyl-3-((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-((ethylamino formyl radical) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) urea;

(458) N-((1S)-2-methyl isophthalic acid-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-3-methyl-2-((methyl sulphonyl) amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) amsacrine;

(459) N-((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-((ethylsulfonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) ethane sulphonamide;

(460) N-((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-((cyclopropyl alkylsulfonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) cyclopropane sulphonamide;

(461) N-((1S)-1-methyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methyl sulphonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) amsacrine;

(462) ((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-2-pyrimidyl-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(463) ((1S)-1-methyl-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-2-pyrimidyl-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(464) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-2-pyrimidyl-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(465) N-((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl)-2-PYRIMITHAMINE;

(466) ((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(1-methyl-4,5-dihydro-1H-imidazoles-2-yl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(467) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(4,5-dihydro-1H-imidazoles-2-yl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(468) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(4,5-dihydro-1H-imidazoles-2-yl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(469) N-((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl)-4,5-dihydro-1H-imidazoles-2-amine;

(470) ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-2-pyrimidyl-D-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(471) ((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-2-pyrimidyl-D-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(472) ((1S)-1-methyl-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-2-pyrimidyl-D-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(473) N-((1R)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl)-2-PYRIMITHAMINE;

(474) ((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(1-methyl-4,5-dihydro-1H-imidazoles-2-yl)-D-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(475) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(4,5-dihydro-1H-imidazoles-2-yl)-D-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(476) ((1S)-1-cyclopropyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(4,5-dihydro-1H-imidazoles-2-yl)-D-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(477) N-((1R)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl)-4,5-dihydro-1H-imidazoles-2-amine;

(478) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(5-amino-1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(479) ((1S)-1-(((2S)-2-(5-(4 '-(((N-(4 for (2S)-1-for 2-, 5-dihydro-1,3-thiazoles-2-yl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(480) ((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-4-pyrimidyl-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(481) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(5-amino-1,2,4- diazole-3-yl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(482) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(cyano group (dimethyl) amidino groups)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(483) ((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-3-pyridyl-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(484) ((1S)-1-methyl-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-3-pyridyl-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(485) ((1S, 2R)-2-methoxyl group-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-3-pyridyl-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(486) N-((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl)-3-pyridine amine;

(487) ((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-5-pyrimidyl-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(488) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(1H-1,2,3-triazole-4-yl methyl) ethyl) Urethylane;

(489) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(1H-1,2,3-triazole-4-yl methyl) ethyl) Urethylane;

(490) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-(1H-1,2,3-triazole-4-yl) propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(491) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S, 3R)-3-methoxyl group-2-((methoxycarbonyl) amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(1H-1,2,3-triazole-4-yl methyl) ethyl) Urethylane;

(492) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(1H-pyrazol-1-yl methyl) ethyl) Urethylane;

(493) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(1H-pyrazol-1-yl methyl) ethyl) Urethylane;

(494) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-(1H-pyrazol-1-yl) propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(495) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-Threonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(1H-pyrazol-1-yl methyl) ethyl) Urethylane;

(496) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-((1-methyl isophthalic acid H-imidazol-4 yl) methyl)-2-oxoethyl) Urethylane;

(497) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-((1-methyl isophthalic acid H-imidazol-4 yl) methyl)-2-oxoethyl) Urethylane;

(498) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-(1-methyl isophthalic acid H-imidazol-4 yl) propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(499) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S, 3R)-3-methoxyl group-2-((methoxycarbonyl) amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-((1-methyl isophthalic acid H-imidazol-4 yl) methyl)-2-oxoethyl) Urethylane;

(500) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-((1-methyl isophthalic acid H-imidazoles-5-yl) methyl)-2-oxoethyl) Urethylane;

(501) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-((1-methyl isophthalic acid H-imidazoles-5-yl) methyl)-2-oxoethyl) Urethylane;

(502) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-(1-methyl isophthalic acid H-imidazoles-5-yl) propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(503) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S, 3R)-3-methoxyl group-2-((methoxycarbonyl) amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-((1-methyl isophthalic acid H-imidazoles-5-yl) methyl)-2-oxoethyl) Urethylane;

(504) ((1S)-1-methyl-2-oxo-2-((2S)-2-(5-(4 '-(2-((2S)-1-(((2S)-4-oxo-2-azetidinyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane;

(505) (2S)-2-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1-azetidine methyl-formiate;

(506) (2S)-2-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1-azetidine methyl-formiate;

(507) ((1S)-3-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-3-oxopropyl) Urethylane;

(508) ((1R)-3-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-sec.-propyl-3-oxopropyl) Urethylane;

(509) ((1S)-1-benzyl-3-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-3-oxopropyl) Urethylane;

(510) ((1R)-3-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-3-oxo-1-(2-thienyl methyl) propyl group) Urethylane;

(511) ((1R)-3-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-3-oxo-1-(3-thienyl methyl) propyl group) Urethylane;

(512) ((1S)-3-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-3-oxo-1-(2-thienyl methyl) propyl group) Urethylane;

(513) ((1S, 3R)-3-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclopentyl) Urethylane;

(514) ((1R)-1-benzyl-3-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-3-oxopropyl) Urethylane;

(515) ((1R)-3-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-(2-luorobenzyl)-3-oxopropyl) Urethylane;

(516) ((1R, 3S)-3-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclopentyl) Urethylane;

(517) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(((1R, 3S)-3-((methoxycarbonyl) amino) cyclopentyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(518) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(((1S, 3R)-3-((methoxycarbonyl) amino) cyclopentyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(519) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(((1R, 3S)-3-((methoxycarbonyl) amino) cyclopentyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(520) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(((1S, 3R)-3-((methoxycarbonyl) amino) cyclopentyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(521) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-(2-pyridyl) propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(522) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(2-pyridylmethyl) ethyl) Urethylane;

(523) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S, 3R)-3-methoxyl group-2-((methoxycarbonyl) amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(2-pyridylmethyl) ethyl) Urethylane;

(524) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(2-pyridylmethyl) ethyl) Urethylane;

(525) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((cis-4-((methoxycarbonyl) amino) cyclohexyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(526) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((trans-4-((methoxycarbonyl) amino) cyclohexyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(527) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((cis-4-(diethylin) cyclohexyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(528) ((1S, 2R)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((cis-4-(diethylin) cyclohexyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methoxy-propyl) Urethylane;

(529) cis-4-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-N, N-diethyl cyclohexylamine;

(530) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((cis-4-(diethylin) cyclohexyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(531) ((1S)-1-((1-benzyl-1H-imidazol-4 yl) methyl)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S, 3R)-3-methoxyl group-2-((methoxycarbonyl) amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(532) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-3-(1-benzyl-1H-imidazol-4 yl)-2-((methoxycarbonyl) amino) propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(533) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-3-(1-benzyl-1H-imidazol-4 yl)-2-((methoxycarbonyl) amino) propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(534) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S, 3R)-3-methoxyl group-2-((methoxycarbonyl) amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(1,3-thiazoles-4-ylmethyl) ethyl) Urethylane;

(535) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-(1,3-thiazoles-4-yl) propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(536) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(1,3-thiazoles-4-ylmethyl) ethyl) Urethylane;

(537) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(1,3-thiazoles-4-ylmethyl) ethyl) Urethylane;

(538) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S, 3R)-3-methoxyl group-2-((methoxycarbonyl) amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(3-pyridylmethyl) ethyl) Urethylane;

(539) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(3-pyridylmethyl) ethyl) Urethylane;

(540) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(3-pyridylmethyl) ethyl) Urethylane;

(541) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(3-pyridylmethyl) ethyl) Urethylane;

(542) ((1R, 3S)-3-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-3-methoxyl group-2-((methoxycarbonyl) amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclopentyl) Urethylane;

(543) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S, 3R)-3-methoxyl group-2-((methoxycarbonyl) amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(4-pyridylmethyl) ethyl) Urethylane;

(544) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(4-pyridylmethyl) ethyl) Urethylane;

(545) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(4-pyridylmethyl) ethyl) Urethylane;

(546) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(4-pyridylmethyl) ethyl) Urethylane;

(547) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(O-(hydroxyl (methoxyl group) phosphoryl)-N-(methoxycarbonyl)-L-tyrosyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(548) ((1S, 2R)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(O-(hydroxyl (methoxyl group) phosphoryl)-N-(methoxycarbonyl)-L-tyrosyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methoxy-propyl) Urethylane;

(549) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(((1S, 2R)-2-((methoxycarbonyl) amino) cyclohexyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(550) ((1R, 2S)-2-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclohexyl) Urethylane;

(551) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(((1S, 2R)-2-((methoxycarbonyl) amino) cyclohexyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(552) ((1R, 2S)-2-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclohexyl) Urethylane;

(553) ((1R, 2S)-2-(((2S)-2-(5-(4 '-(2-((2S)-1-((cis-4-(diethylin) cyclohexyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclohexyl) Urethylane;

(554) ((1R, 2S)-2-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-acetylaminohydroxyphenylarsonic acid 2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclohexyl) Urethylane;

(555) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-3-(1H-indol-3-yl)-2-((methoxycarbonyl) amino) propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(556) ((1S)-1-(1H-indol-3-yl methyl)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S, 3R)-3-methoxyl group-2-((methoxycarbonyl) amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(557) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-(1H-indol-3-yl methyl)-2-oxoethyl) Urethylane;

(558) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-3-(1H-indol-3-yl)-2-((methoxycarbonyl) amino) propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(559) ((1S)-1-(4-(amino methyl) benzyl)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(560) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(O-benzyl-N-(methoxycarbonyl)-L-tyrosyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(561) ((1S, 2R)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(O-benzyl-N-(methoxycarbonyl)-L-tyrosyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methoxy-propyl) Urethylane;

(562) ((1S)-1-(4-(benzyloxy) benzyl)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(563) ((1S)-1-(4-(benzyloxy) benzyl)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(564) ((1R, 2R)-2-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclopentyl) Urethylane;

(565) ((1R, 2R)-2-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclopentyl) Urethylane;

(566) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(((1R, 2R)-2-((methoxycarbonyl) amino) cyclopentyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(567) ((1S)-1-(4-hydroxybenzyl)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(568) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-(4-hydroxybenzyl)-2-oxoethyl) Urethylane;

(569) ((1S)-1-(4-hydroxybenzyl)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(570) ((1S)-1-(4-(acetylamino methyl) benzyl)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(571) ((1S)-1-(4-(((ethylamino formyl radical) amino) methyl) benzyl)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(572) ((1S, 2S)-2-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclopentyl) Urethylane;

(573) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(((1S, 2S)-2-((methoxycarbonyl) amino) cyclopentyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(574) ((1S, 2S)-2-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclopentyl) Urethylane;

(575) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-homoseryl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(576) ((1S)-3-methoxyl group-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(577) ((1S, 2R)-2-methoxyl group-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-homoseryl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(578) ((1S, 2S)-2-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-homoseryl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclopentyl) Urethylane;

(579) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-(1H-1,2,3-triazole-4-yl) propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(1H-1,2,3-triazole-4-yl methyl) ethyl) Urethylane;

(580) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((2S)-4-oxo-4,2-butane two bases))) two (Urethylanes);

(581) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((3R)-4-methyl isophthalic acid-oxo-1,3-pentane two bases))) two (Urethylanes);

(582) ((1R)-3-((2S)-2-(5-(4 '-(2-(1-((3R)-3-((methoxycarbonyl) amino)-3-phenyl propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-3-oxo-1-phenyl propyl) Urethylane;

(583) ((1S)-3-((2S)-2-(5-(4 '-(2-(1-((3S)-3-((methoxycarbonyl) amino)-3-phenyl propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-3-oxo-1-phenyl propyl) Urethylane;

(584) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-(2-pyridyl) propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(2-pyridylmethyl) ethyl) Urethylane;

(585) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-3-(1H-imidazol-4 yl)-2-((methoxycarbonyl) amino) propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-(1H-imidazol-4 yl methyl)-2-oxoethyl) Urethylane;

(586) (6S, 6 ' S)-6,6 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two base carbonyls)) two (dihydro-2,4 (1H, 3H)-pyrimidine diones);

(587) (4S, 5R, 4 ' S, 5 ' R)-4,4 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two base carbonyls)) two (5-methyl isophthalic acid, 3- azoles alkane-2-ketone);

(588) N-(3-((2S)-2-(5-(4 '-(2-((2S)-1-(3-kharophen propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-3-oxopropyl) ethanamide;

(589) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((3R)-1-oxo-5-phenyl-1,3-pentane two bases))) two (Urethylanes);

(590) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((2R)-4-oxo-1-(2-thienyl)-4,2-butane two bases))) two (Urethylanes);

(591) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((2R)-4-oxo-1-(3-thienyl)-4,2-butane two bases))) two (Urethylanes);

(592) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((2S)-4-oxo-1-(2-thienyl)-4,2-butane two bases))) two (Urethylanes);

(593) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two base carbonyls (1R, 2R)-2,1-hexanaphthene two bases)) two (Urethylanes);

(594) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((2S)-4-(dimethylamino)-1-oxo-1,2-butane two bases))) two (t-butyl carbamates);

(595) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two base carbonyls (1R, 2S)-2,1-hexanaphthene two bases)) two (Urethylanes);

(596) (3S, 3 ' S)-4,4 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N～1～, N～1～-dimethyl-4-oxo-1,3-butanediamine);

(597) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((2R)-4-oxo-1-phenyl-4,2-butane two bases))) two (Urethylanes);

(598) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two base carbonyls (1R, 3S)-3,1-pentamethylene two bases)) two (Urethylanes);

(599) ((1R)-1-benzyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-3-phenyl propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(600) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((2S)-4-(dimethylamino)-1-oxo-1,2-butane two bases))) two (Urethylanes);

(601) (2R, 2 ' R)-1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-1-oxo-3-phenyl-2-propylamine);

(602) ((1S)-1-benzyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-phenyl propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(603) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two base carbonyls (1R, 3S)-3,1-pentamethylene two bases)) two (Urethylanes);

(604) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two base carbonyl cis-4,1-hexanaphthene two bases)) two (Urethylanes);

(605) (4,4 '-biphenyl, two bases two (1-tetramethyleneimine two base carbonyls are trans-4,1-hexanaphthene two bases for 1H-imidazoles-5,2-bis-bases (2S)-2)) two (Urethylanes);

(606) ((cis)-4,4 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two base carbonyls)) two (N, N-diethyl cyclohexylamines);

(607) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-(1,3-thiazole-4-yl) propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-(1,3-thiazoles-4-ylmethyl) ethyl) Urethylane;

(608) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-3-(1-benzyl-1H-imidazol-4 yl)-2-((methoxycarbonyl) amino) propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-((1-benzyl-1H-imidazol-4 yl) methyl)-2-oxoethyl) Urethylane;

(609) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two base carbonyls (1S, 2S)-2,1-pentamethylene two bases)) two (Urethylanes);

(610) ((1S)-3-methoxyl group-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-homoseryl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(611) ((1S)-2-((2S, the fluoro-2-of 4R)-4-(5-(4 '-(2-(the fluoro-1-of (2S, 4R)-4-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(612) ((1S)-2-((2S, 4R)-4-hydroxyl-2-(5-(4 '-(2-((2S, 4R)-4-hydroxyl-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(613) ((1S)-1-(((2S, 4R)-4-hydroxyl-2-(5-(4 '-(2-((2S, 4R)-4-hydroxyl-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(614) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases ((2S, 4R)-4-hydroxyl-2,1-tetramethyleneimine two bases) ((1S)-1-cyclopropyl-2-oxo-2,1-ethane two bases))) two (Urethylanes);

(615) (3S, 5S, 3 ' S, 5 ' S)-5,5 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases)) two (1-((2R)-2-(diethylin)-2-phenylacetyl)-3-pyrrolidinols);

(616) ((1S)-2-((2S, 4S)-4-hydroxyl-2-(5-(4 '-(2-((2S, 4S)-4-hydroxyl-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(617) ((1S)-1-(((2S, 4S)-4-hydroxyl-2-(5-(4 '-(2-((2S, 4S)-4-hydroxyl-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(618) ((1S)-1-(((2S, the fluoro-2-of 4S)-4-(5-(4 '-(2-(the fluoro-1-of (2S, 4S)-4-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(619) ((1S)-1-(((2S, the fluoro-2-of 4R)-4-(5-(4 '-(2-(the fluoro-1-of (2S, 4R)-4-((2S)-2-((methoxycarbonyl) amino)-4-methylpent acyl group)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-3-methyl butyl) Urethylane;

(620) ((1S)-2-((2S, the fluoro-2-of 4S)-4-(5-(4 '-(2-(the fluoro-1-of (2S, 4S)-4-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(621) ((1S)-2-((2S, 4S)-2-(5-(4 '-(2-(the fluoro-2-pyrrolidyl of (2S, 4S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-4-)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl) fluoro-1-pyrrolidyl of-4-)-1-methyl-2-oxoethyl) Urethylane;

(622) ((1S)-1-(((2S, 4S)-2-(5-(4 '-(2-(the fluoro-2-pyrrolidyl of (2S, 4S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-4-)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl) fluoro-1-pyrrolidyl of-4-) carbonyl)-2-methyl-propyl) Urethylane;

(623) ((1S)-1-(((2S, the fluoro-2-of 4R)-4-(5-(4 '-(2-(the fluoro-1-of (2S, 4R)-4-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(624) (1R, 1 ' R)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases ((2S, 4R)-4-fluoro-2,1-tetramethyleneimine two bases))) two (N, N-diethyl-2-oxo-1-phenyl-ethyl amines);

(625) 3-((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-((formyl-dimethylamino) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl)-1,1-dimethyl urea;

(626) 3-((1S)-2-((2S)-2-(4-(4 '-(2-((2S)-1-(N-(formyl-dimethylamino)-L-alanyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl)-1,1-dimethyl urea;

(627) ((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-(((2-fluorine oxyethyl group) carbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) carboxylamine 2-fluorine ethyl ester;

(628) ((1S)-2-ethyl-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-3-ethyl-2-((methoxycarbonyl) amino) pentanoyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) butyl) Urethylane;

(629) 1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-4,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((2S)-3-methyl isophthalic acid-oxo-1,2-butane two bases))) two (tetrahydrochysene-2 (1H)-pyrimidones);

(630) ((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-4-methylpent acyl group)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-3-methyl butyl) Urethylane;

(631) ((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-4, the fluoro-1-of 4-bis-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-4, the fluoro-1-pyrrolidyl of 4-bis-) carbonyl)-2-methyl-propyl) Urethylane;

(632) (1R, 1 ' R)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-4,2-bis-bases ((2S)-4,4-bis-is fluoro-2,1-tetramethyleneimine two bases))) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amines);

(633) (1R, 1 ' R)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-4,2-bis-bases ((2S)-4,4-bis-is fluoro-2,1-tetramethyleneimine two bases))) two (N, N-diethyl-2-oxo-1-phenyl-ethyl amines);

(634) ((1S, 2R)-1-(((2S)-2-(4-(4 '-(2-((2S)-4, the fluoro-1-of 4-bis-(N-(methoxycarbonyl)-O-methyl-L-Threonyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-4, the fluoro-1-pyrrolidyl of 4-bis-) carbonyl)-2-methoxy-propyl) Urethylane;

(635) ((1S)-2-((2S)-2-(4-(4 '-(2-((2S)-4, the fluoro-1-of 4-bis-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-4, the fluoro-1-pyrrolidyl of 4-bis-)-1-methyl-2-oxoethyl) Urethylane;

(636) ((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-4, the fluoro-1-of 4-bis-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(637) racemize-(1R)-2-((2S)-2-(4-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-4, the fluoro-2-pyrrolidyl of 4-bis-)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-diethyl-2-oxo-1-phenyl-ethyl amine;

(638) ((1S)-1-(((2R, 3S)-3-hydroxyl-2-(4-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(639) ((1S)-2-((2S)-2-(4-(4 '-(2-((2R, 3S)-3-hydroxyl-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(640) ((1S)-1-(((2R)-3-hydroxyl-2-(4-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(641) 2-((2S)-1-(tertbutyloxycarbonyl)-2-pyrrolidyl)-5-(4 '-(2-((2S)-1-(tertbutyloxycarbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-4-methyl-formiate;

(642) 2-((2S)-1-(tertbutyloxycarbonyl)-2-pyrrolidyl)-5-(4 '-(2-((2S)-1-(tertbutyloxycarbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-4-ethyl formate;

(643) 2-((2S)-1-(tertbutyloxycarbonyl)-2-pyrrolidyl)-5-(4 '-(2-((2S)-1-(tertbutyloxycarbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-4-benzyl formate;

(644) (2S)-2-(5-(4 '-(2-((2S)-1-(tertbutyloxycarbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-4-(methylamino formyl radical)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester;

(645) 2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-4-methyl-formiate;

(646) 2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-4-methyl-formiate;

(647) 2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-4-methyl-formiate;

(648) 2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-4-ethyl formate;

(649) 2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-4-ethyl formate;

(650) 2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-4-benzyl formate;

(651) 2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-4-benzyl formate;

(652) 2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-4-benzyl formate;

(653) 2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-4-benzyl formate;

(654) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-4-(methylamino formyl radical)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(655) 2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-N-methyl isophthalic acid H-imidazoles-4-methane amide;

(656) N-methyl-2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-4-methane amide;

(657) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-4-(methylamino formyl radical)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(658) ((1R)-2-((2S)-2-(4-formamyl-5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(659) 2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-5-

(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-4-formic acid;

(660) 2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-5-(4 '-(2-((2S)-1-((2R)-2-phenyl-2-(piperidino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-4-formic acid;

(661) (2S)-2-(5-(4 '-(2-((2S)-1-(tertbutyloxycarbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl) 4-(trifluoromethyl)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester;

(662) (2S)-2-(5-(4 '-(2-((2S)-1-((benzyloxy) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-4-(trifluoromethyl)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester;

(663) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-4-(trifluoromethyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(664) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-4-(trifluoromethyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(665) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-4-(trifluoromethyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(666) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-4-(trifluoromethyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-diethyl-2-oxo-1-phenyl-ethyl amine;

(667) ((1S)-1-cyclopropyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-cyclopropyl-2-((methoxycarbonyl) amino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-4-(trifluoromethyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(668) ((1S, 2R)-2-methoxyl group-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-Threonyl)-2-pyrrolidyl)-4-(trifluoromethyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(669) (2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-4-(trifluoromethyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid benzyl ester;

(670) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-4-(trifluoromethyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(671) (2S)-2-(4-(4 '-(2-((2S)-1-(tertbutyloxycarbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-methoxyl group-3-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester;

(672) (2S, 2 ' S)-2,2 '-((fluoro-4, the 4 '-biphenyl of 3-two bases) two (1H-imidazoles-4,2-bis-bases)) two (1-pyrrolidinecarboxylic acid tert-butyl esters);

(673) (2S)-2-(4-(4 '-(2-((2S)-1-(tertbutyloxycarbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-2, the fluoro-4-xenyl of 5-bis-)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester;

(674) (2S, 2 ' S)-2,2 '-((3,3 '-bis-fluoro-4,4 '-biphenyl two bases) two (1H-imidazoles-5,2-bis-bases)) two (1-pyrrolidinecarboxylic acid tert-butyl esters);

(675) (2S)-2-(4-(4 '-(2-((2S)-1-((benzyloxy) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl) fluoro-4-xenyl of-3-)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester;

(676) (2S)-2-(4-(4 '-(2-((2S)-1-((benzyloxy) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-3,3 '-bis-fluoro-4-xenyls)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester;

(677) (2S)-2-(5-(fluoro-4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl of 3-)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester;

(678) (2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl) fluoro-4-xenyl of-3-)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester;

(679) (2S)-2-(5-(fluoro-4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl of 3-)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester;

(680) (2S)-2-(5-(3,3 '-bis-fluoro-4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester;

(681) (2S)-2-(5-(3,3 '-bis-fluoro-4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester;

(682) (2S)-2-(5-(fluoro-4 '-(2-((2S)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl of 3-)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester triacetate;

(683) (2S)-2-(5-(3,3 '-bis-fluoro-4 '-(2-((2S)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidinecarboxylic acid tert-butyl ester;

(684) ((1R)-2-((2S)-2-(5-(3 '-fluoro-4 '-(2-((2S)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(685) ((1S)-1-(((2S)-2-(5-(3 '-fluoro-4 '-(2-((2S)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(686) (1R)-N, N-diethyl-2-((2S)-2-(5-(3 '-fluoro-4 '-(2-((2S)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-phenyl-ethyl amine;

(687) ((1S)-1-(((2S)-2-(5-(3,3 '-bis-fluoro-4 '-(2-((2S)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(688) ((1R)-2-((2S)-2-(5-(3,3 '-bis-fluoro-4 '-(2-((2S)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(689) 5,5 '-(4-methoxyl group-3,4 '-biphenyl, two bases) two (2-((2S)-2-pyrrolidyl)-1H-imidazoles);

(690) 5,5 '-(fluoro-4, the 4 '-biphenyl of 3-two bases) two (2-((2S)-2-pyrrolidyl)-1H-imidazoles) tetraacetate;

(691) 5,5 '-(fluoro-4, the 4 '-biphenyl of 2,5-bis-two bases) two (2-((2S)-2-pyrrolidyl)-1H-imidazoles);

(692) (1R, 1 ' R)-2,2 '-((4-methoxyl group-3,4 '-biphenyl, two bases) two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amines);

(693) ((4-methoxyl group-3,4 '-biphenyl, two bases) two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (Urethylanes);

(694) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl) fluoro-4-xenyl of-3-)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(695) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl) fluoro-4-xenyl of-3-)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(696) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl) fluoro-4-xenyl of-3-)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(697) ((1R)-2-((2S)-2-(5-(3 '-fluoro-4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(698) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-3 '-fluoro-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(699) ((1S)-1-(((2S)-2-(5-(3 '-fluoro-4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(700) ((1S)-1-(((2S)-2-(5-(3 '-fluoro-4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(701) ((1S, 2R)-1-(((2S)-2-(5-(fluoro-4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl of 3-)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methoxy-propyl) Urethylane;

(702) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-diethyl-D-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-3 '-fluoro-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(703) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-3 '-fluoro-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(704) ((1S)-2-((2S)-2-(5-(3 '-fluoro-4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(705) ((fluoro-4, the 4 '-biphenyl of 3-two bases) two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (Urethylanes);

(706) (1R, 1 ' R)-2,2 '-((fluoro-4, the 4 '-biphenyl of 3-two bases) two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-diethyl-2-oxo-1-phenyl-ethyl amines);

(707) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-diethyl-D-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-3 '-fluoro-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(708) ((1S)-1-cyclopropyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl) fluoro-4-xenyl of-3-)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(709) ((1S)-1-cyclopropyl-2-((2S)-2-(5-(fluoro-4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl of 3-)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(710) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-diethyl-D-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-3 '-fluoro-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(711) ((1S)-2-((2S)-2-(5-(2 ', 5 '-bis-fluoro-4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyls)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(712) ((2, fluoro-4, the 4 '-biphenyl of 5-bis-two bases) two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (Urethylanes);

(713) (1R, 1 ' R)-2,2 '-((fluoro-4, the 4 '-biphenyl of 2,5-bis-two bases) two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-diethyl-2-oxo-1-phenyl-ethyl amines);

(714) ((1S)-1-cyclopropyl-2-((2S)-2-(5-(3,3 '-bis-fluoro-4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(715) ((1S, 2R)-1-(((2S)-2-(5-(3,3 '-bis-fluoro-4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methoxy-propyl) Urethylane;

(716) ((1S)-1-(((2S)-2-(5-(3,3 '-bis-fluoro-4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(717) ((1S)-1-(((2S)-2-(5-(3,3 '-bis-fluoro-4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(718) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-diethyl-D-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-3,3 '-bis-fluoro-4-xenyls)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(719) ((1S)-1-(((2S)-2-(5-(3,3 '-bis-fluoro-4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(720) ((1S)-2-((2S)-2-(5-(3,3 '-bis-fluoro-4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(721) ((1R)-2-((2S)-2-(5-(3,3 '-bis-fluoro-4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(722) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-diethyl-D-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-3,3 '-bis-fluoro-4-xenyls)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(723) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-3,3 '-bis-fluoro-4-xenyls)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(724) ((1S, 2R)-1-(((2S)-2-(5-(3,3 '-bis-fluoro-4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methoxy-propyl) Urethylane two (trifluoroacetate);

(725) ((1S)-1-cyclopropyl-2-((2S)-2-(5-(3,3 '-bis-fluoro-4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(726) 7,7 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases (2-oxo-1-phenyl-2,1-ethane two bases))) two (7-azabicyclic [2.2.1] heptane);

(727) 7,7 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases (2-oxo-1-phenyl-2,1-ethane two bases))) two (7-azabicyclic [2.2.1] heptane);

(728) N, N '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (N-ethyl cyclopropylamines);

(729) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(ethoxycarbonyl)-D-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) urethanum;

(730) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(ethoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) urethanum;

(731) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two base carbonyl-1,1-cyclopropane two bases)) two (Urethylanes);

(732) (2-((2S)-2-(5-(4 '-(2-((2S)-1-(2-((methoxycarbonyl) amino)-2-methylpropionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1,1-dimethyl-2-oxoethyl) Urethylane;

(733) (2R, 2 ' R)-1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-1-oxo-2-propylamine);

(734) (2R, 2 ' R)-1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-diethyl-1-oxo-2-propylamine);

(735) (2R, 2 ' R)-1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-diethyl-3-methyl isophthalic acid-oxo-2-butylamine);

(736) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) (methyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) methylene dicarbamate;

(737) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1S)-2-oxo-1-phenyl-2,1-ethane two bases))) two (Urethylanes);

(738) N, N '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((2R)-1-oxo-1,2-propane two bases))) two (N-propyl group-1-propylamine);

(739) ((1S)-2-hydroxyl-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-3-hydroxyl-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(740) ((1S, 2R)-2-hydroxyl-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S, 3R)-3-hydroxyl-2-((methoxycarbonyl) amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(741) ((1S, 2S)-2-hydroxyl-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S, 3S)-3-hydroxyl-2-((methoxycarbonyl) amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(742) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(743) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-D-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(744) (2S, 2 ' S)-1,1 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-1-oxo-2-propylamine);

(745) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((2R)-1-oxo-1,2-butane two bases))) two (Urethylanes);

(746) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((2S)-1-oxo-1,2-butane two bases))) two (Urethylanes);

(747) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-1-cyclopropyl-2-oxo-2,1-ethane two bases))) two (Urethylanes);

(748) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1S)-1-cyclopropyl-2-oxo-2,1-ethane two bases))) two (Urethylanes);

(749) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3,3-dimethyl butyrate acyl group)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2,2-dimethyl propyl) Urethylane;

(750) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((4S)-5-oxo-1-amylene-5,4-bis-bases))) two (Urethylanes);

(751) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-seryl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-(methoxymethyl)-2-oxoethyl) Urethylane;

(752) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino) pentanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) butyl) Urethylane;

(753) ((1S)-1-(((2R)-2-(5-(4 '-(2-((2R)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(754) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2R)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(755) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2R)-2,1-tetramethyleneimine two bases ((1R)-1-cyclopropyl-2-oxo-2,1-ethane two bases))) two (Urethylanes);

(756) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) urethanum;

(757) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) urethanum;

(758) (5S)-5-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-Pyrrolidone;

(759) (1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclopropyl) Urethylane;

(760) (2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1,1-dimethyl-2-oxoethyl) Urethylane;

(761) (2R)-1-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-diethyl-1-oxo-2-propylamine;

(762) (2S)-1-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-diethyl-1-oxo-2-propylamine;

(763) (1R)-N, N-diethyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1,3- azoles-2-base carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-phenyl-ethyl amine;

(764) (1R)-N, N-diethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(3-pyridyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine;

(765) (2R)-1-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-oxo-2-propyl alcohol;

(766) (2S)-1-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-oxo-2-propyl alcohol;

(767) (1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclobutyl) Urethylane;

(768) (1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) cyclopentyl) Urethylane;

(769) N-((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl) 4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl)-N-propyl group-1-propylamine;

(770) (4S)-4-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-1,3- azoles alkane-2-ketone;

(771) (2R)-1-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-diethyl-3-methyl isophthalic acid-oxo-2-butylamine;

(772) N-((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl)-N-propyl group-1-propylamine;

(773) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(774) (1R)-N, N-diethyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(4-morpholinyl)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-phenyl-ethyl amine;

(775) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(776) (2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(777) (1R)-N, N-diethyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(4-morpholinyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-phenyl-ethyl amine;

(778) (1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-N, N-dimethyl-2-oxo-1-phenyl-ethyl amine;

(779) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(780) ((1R)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(781) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(782) ((1R)-1-cyclopropyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(783) ((1S)-1-cyclopropyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(784) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(785) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2,2-dimethyl propyl) Urethylane;

(786) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-3-butene-1-yl) Urethylane;

(787) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-(methoxymethyl)-2-oxoethyl) Urethylane;

(788) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) butyl) Urethylane;

(789) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-diethyl-D-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(790) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-dipropyl-D-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(791) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1H-imidazoles-5-base carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(792) M66a:((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(4-(diethylin)-2-((methoxycarbonyl) amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(793) ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane;

(794) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(4-(diethylin)-2-((methoxycarbonyl) amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(795) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-3-(4-morpholinyl) propyl group) Urethylane;

(796) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-diethyl-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(797) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-diethyl-D-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(798) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-(methoxymethyl)-2-oxoethyl) Urethylane;

(799) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3,3-dimethyl butyrate acyl group)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(800) (2-((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(801) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(802) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) butyl) Urethylane;

(803) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-3-butene-1-yl) Urethylane;

(804) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-cyclopropyl-2-((methoxycarbonyl) amino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(805) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(ethyl (methyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(806) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-diethyl-D-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(807) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(808) ((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-(3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(809) ((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-((4-methyl isophthalic acid-piperazinyl) carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(810) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-dipropyl-D-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(811) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-dipropyl-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(812) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(813) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-(diethylin) butyryl radicals)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(814) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(1H-imidazol-4 yl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(815) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-diethyl-O-methyl-L-seryl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(816) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N ², N ²-diethyl-D-Asn acyl group)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(817) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2R)-1-((2R)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(818) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-diethyl-O-methyl D-seryl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(819) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-diethyl-3-methyl D-valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(820) ((1S)-3-amino-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-3-oxopropyl) Urethylane;

(821) ((1S)-1-methyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(1,3- azoles-2-base carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(822) ((1S)-1-cyclopropyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxoethyl) Urethylane;

(823) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino) propionyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) butyl) Urethylane;

(824) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2,2-dimethyl propyl) Urethylane;

(825) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-diethyl-D-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(826) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(7-azabicyclic [2.2.1] heptan-7-base (phenyl) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(827) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-hydroxyl-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(828) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(ethyl (methyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(829) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-(methoxymethyl)-2-oxoethyl) Urethylane;

(830) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-diethyl-D-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(831) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-dipropyl-D-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(832) ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N, N-dipropyl-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane;

(833) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-(3-hydroxyl-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(834) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-3-hydroxyl-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(835) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S, 3R)-4-hydroxyl-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(836) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S, 3S)-4-hydroxyl-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(837) ((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-L-valyl-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane;

(838) (3S)-3-((methoxycarbonyl) amino)-4-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-4-ketobutyric acid benzyl ester;-

(839) (3S)-3-((methoxycarbonyl) amino)-4-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-4-ketobutyric acid methyl esters;

(840) (3S)-3-((methoxycarbonyl) amino)-4-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-4-ketobutyric acid;

(841) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-4-(4-methyl isophthalic acid-piperazinyl)-4-oxobutanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(842) ((1S)-3-(dimethylamino)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-3-oxopropyl) Urethylane;

(843) 4,4 '-bis-(2-((2S)-1-(N-(methoxycarbonyl)-L-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-2-diphenic acid;

(844) 4,4 '-bis-(2-((2S)-1-((2R)-2-cyclopropyl-2-((methoxycarbonyl) amino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-2-diphenic acid;

(845) 4,4 '-bis-(2-((2S)-1-((2S)-2-cyclopropyl-2-((methoxycarbonyl) amino) ethanoyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-2-diphenic acid;

(846) 4,4 '-bis-(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-2-diphenic acid;

(847) ((1S)-1-(((2S)-2-(5-(2 '-formamyl-4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(848) ((1S)-1-(((2S)-2-(5-(2-methylol)-4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(849) ((1S)-1-(((2S)-2-(5-(2-((dimethylamino) methyl)-4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane;

(850) ((2-((dimethylamino) methyl)-4,4 '-biphenyl, two bases) two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (Urethylanes);

(851) ((1S)-1-(((1S, 3S, 5S)-3-(5-(4 '-(2-((1S, 3S, 5S)-2-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-azabicyclic [3.1.0] oneself-3-yl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-2-azabicyclic [3.1.0] oneself-2-yl) carbonyl)-2-methyl-propyl) Urethylane;

(852) ((1R)-1-(((1S, 3S, 5S)-3-(5-(4 '-(2-((1S, 3S, 5S)-2-((2R)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-azabicyclic [3.1.0] oneself-3-yl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-2-azabicyclic [3.1.0] oneself-2-yl) carbonyl)-2-methyl-propyl) Urethylane;

(853) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-base (1S, 3S, 5S)-2-azabicyclic [3.1.0] hexane-3,2-bis-bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (Urethylanes);

(854) ((1S)-2-hydroxyl-1-(((1S, 3S, 5S)-3-(5-(4 '-(2-((1S, 3S, 5S)-2-((2S)-3-hydroxyl-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-azabicyclic [3.1.0] oneself-3-yl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-2-azabicyclic [3.1.0] oneself-2-yl) carbonyl)-2-methyl-propyl) Urethylane;

(855) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (1S, 3S, 5S)-2-azabicyclic [3.1.0] hexane-3,2-bis-bases ((2S)-1-oxo-1,2-butane two bases))) two (Urethylanes);

(856) (4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-base (1S, 3S, 5S)-2-azabicyclic [3.1.0] hexane-3,2-bis-bases ((1S)-1-cyclopropyl-2-oxo-2,1-ethane two bases))) two (Urethylanes);

(857) ((1S)-1-(((1S, 3S, 5S)-3-(5-(4 '-(2-((1S, 3S, 5S)-2-((2S)-2-((methoxycarbonyl) amino)-3,3-dimethyl butyrate acyl group)-2-azabicyclic [3.1.0] oneself-3-yl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-2-azabicyclic [3.1.0] oneself-2-yl) carbonyl)-2,2-dimethyl propyl) Urethylane;

(858) (2-((1S, 3S, 5S)-3-(5-(4 '-(2-((1S, 3S, 5S)-2-(((methoxycarbonyl) amino) ethanoyl)-2-azabicyclic [3.1.0] oneself-3-yl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-2-azabicyclic [3.1.0] oneself-2-yl)-2-oxoethyl) Urethylane;

(859) ((1S)-2-((1S, 3S, 5S)-3-(5-(4 '-(2-((1S, 3S, 5S)-2-(N-(methoxycarbonyl)-L-alanyl)-2-azabicyclic [3.10] oneself-3-yl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-2-azabicyclic [3.1.0] oneself-2-yl)-1-methyl-2-oxoethyl) Urethylane; With

(860) ((1S)-1-(((1R, 3R, 5R)-3-(5-(4 '-(2-((1R, 3R, 5R)-2-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-azabicyclic [3.1.0] oneself-3-yl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-2-azabicyclic [3.1.0] oneself-2-yl) carbonyl)-2-methyl-propyl) Urethylane;

Or its pharmacy acceptable salt.

20. 1 kinds of compounds, are selected from:

Or its pharmacy acceptable salt.

21. 1 kinds of compounds, are selected from:

(12) ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3,3-dimethyl butyrate acyl group)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2,2-dimethyl propyl) Urethylane;

Or its pharmacy acceptable salt.

The pharmacy acceptable salt of the compound of 22. claims 21, wherein salt is dihydrochloride.

23. 1 kinds of compounds, described compound is ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2-methyl-propyl) Urethylane or its pharmacy acceptable salt.

24. 1 kinds of compounds, described compound is (1R, 1 ' R)-2,2 '-(4,4 '-biphenyl, two bases two (1H-imidazoles-5,2-bis-bases (2S)-2,1-tetramethyleneimine two bases)) two (N, N-dimethyl-2-oxo-1-phenyl-ethyl amines) or its pharmacy acceptable salt.

25. 1 kinds of compounds, described compound is ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(diethylin)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane or its pharmacy acceptable salt.

26. 1 kinds of compounds; described compound is ((1S)-1-(((2S)-2-(4-(4 '-(2-((2S)-4; the fluoro-1-of 4-bis-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-pyrrolidyl)-1H-imidazol-4 yl)-4-xenyl)-1H-imidazoles-2-yl)-4, the fluoro-1-pyrrolidyl of 4-bis-) carbonyl)-2-methyl-propyl) Urethylane or its pharmacy acceptable salt.

27. 1 kinds of compounds; described compound is ((1S)-1-(((1R; 3R; 5R)-3-(5-(4 '-(2-((1R; 3R, 5R)-2-((2S)-2-((methoxycarbonyl) amino)-3-methylbutyryl base)-2-azabicyclic [3.1.0] oneself-3-yl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-2-azabicyclic [3.1.0] oneself-2-yl) carbonyl)-2-methyl-propyl) Urethylane or its pharmacy acceptable salt.

28. 1 kinds of compounds, described compound is ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethyl) Urethylane or its pharmacy acceptable salt.

29. 1 kinds of compounds, described compound is ((1S)-2-methyl isophthalic acid-(((2S)-2-(5-(4 '-(2-((2S)-1-(N-2-pyrimidyl-D-is valyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl) propyl group) Urethylane or its pharmacy acceptable salt.

30. 1 kinds of compounds, described compound is ((1R)-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-2-oxo-1-styroyl) Urethylane or its pharmacy acceptable salt.

31. 1 kinds of compounds, described compound is (4, two (1H-imidazoles-5 of 4 '-biphenyl, two bases, 2-bis-bases (2S)-2,1-tetramethyleneimine two bases ((1R)-2-oxo-1-phenyl-2,1-ethane two bases))) two (Urethylanes) or its pharmacy acceptable salt.

32. 1 kinds of compounds, described compound is (1R)-N, N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4 '-(2-((2S)-1-((2R)-tetrahydrochysene-2-furyl carbonyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) ethamine or its pharmacy acceptable salt.

33. 1 kinds of compounds, described compound is ((1S)-2-((2S)-2-(5-(4 '-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl)-1-methyl-2-oxoethyl) Urethylane or its pharmacy acceptable salt.

34. 1 kinds of compounds; described compound is ((1S)-1-(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3; 3-dimethyl butyrate acyl group)-2-pyrrolidyl)-1H-imidazoles-5-yl)-4-xenyl)-1H-imidazoles-2-yl)-1-pyrrolidyl) carbonyl)-2,2-dimethyl propyl) Urethylane or its pharmacy acceptable salt.

35. 1 kinds of compositions, the compound that described composition comprises claim 1 or its pharmacy acceptable salt and pharmaceutically acceptable carrier.

The composition of 36. claims 35, described composition also comprises one or both other compounds with anti-HCV activity.

The composition of 37. claims 36, wherein at least one other compound is Interferon, rabbit or ribavirin.

The composition of 38. claims 37, wherein Interferon, rabbit is selected from interferon alpha 2B, glycol interferon alpha, interferon alfacon-1, interferon alpha 2A and lymphocytoblast interferon-tau.

39. the composition of claim 36, wherein at least one other compound is selected from interleukin-22, interleukin 6, interleukin 12, promotion and produces compound that 1 type helper T cell replys, RNA interfering, sense-rna, miaow quinoline not moral, ribavirin, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine and Rimantadine.

40. the composition of claim 36, the function that wherein at least one other compound effectively suppresses to be selected from following target infects with treatment HCV: HCV metalloprotease, HCV serine protease, HCV polysaccharase, HCV helicase, HCV NS4B albumen, HCV enter, HCV assembles, HCV discharges, HCV NS5A albumen and IMPDH.

Purposes in the medicine that the compound of 41. claims 1 or its pharmacy acceptable salt infect at the HCV for the preparation for the treatment of patient, comprises compound or its pharmacy acceptable salt of the claim 1 that gives patient treatment significant quantity.

The purposes of 42. claims 41, before being also included in the compound or its pharmacy acceptable salt that gives claim 1, give other compound that one or both have anti-HCV activity afterwards or simultaneously.

The purposes of 43. claims 42, wherein at least one other compound is Interferon, rabbit or ribavirin.

The purposes of 44. claims 43, wherein Interferon, rabbit is selected from interferon alpha 2B, glycol interferon alpha, interferon alfacon-1, interferon alpha 2A and lymphocytoblast interferon-tau.

45. the purposes of claim 42, wherein at least one other compound is selected from interleukin-22, interleukin 6, interleukin 12, promotion and produces compound that 1 type helper T cell replys, RNA interfering, sense-rna, miaow quinoline not moral, ribavirin, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine and Rimantadine.

46. the purposes of claim 42, the function that wherein at least one other compound effectively suppresses to be selected from following target infects with treatment HCV: HCV metalloprotease, HCV serine protease, HCV polysaccharase, HCV helicase, HCV NS4B albumen, HCV enter, HCV assembles, HCV discharges, HCV NS5A albumen and IMPDH.