CN101242816B

CN101242816B - Hcv inhibitors

Info

Publication number: CN101242816B
Application number: CN2006800296080A
Authority: CN
Inventors: M·格瑞普; J·O·林克; C·文卡特拉马尼
Original assignee: Virobay Inc
Current assignee: Virobay Inc
Priority date: 2005-06-30
Filing date: 2006-06-29
Publication date: 2012-10-31
Anticipated expiration: 2026-06-29
Also published as: CN101242816A; TW200744625A; ZA200711069B; TWI449711B

Abstract

The present invention is directed to compounds that are antiviral agents. Specifically the compounds of the present invention inhibit replication of HCV and are therefore useful in treating hepatitis C infections. The present invention is also directed to pharmaceutical compositions comprising these compounds and processes for preparing them.

Description

The HCV inhibitor

The cross reference of related application

The application requires the rights and interests of the U.S. Provisional Application serial number 60/695,767 of submission on June 30th, 2005, and its content is included this paper by reference in.

Under federal funding research or exploitation, accomplish the rights statement of invention

Do not have

Relate to " sequence table ", form or the computer program tabulation adnexa submitted to compact disk

Do not have

Background of invention

Invention field

Thereby the present invention relates to suppress HCV and duplicate the chemical compound that can be used for treating hepatitis C.The invention still further relates to the pharmaceutical composition that contains these chemical compounds and their method for preparing.

The state of the art

Hepatitis C virus (HCV) is an a kind of sense single stranded rna virus, it be non-first type, non-hepatitis B in the world wide main diseases because of.How the National People's Congress that is infected by HCV can suffer from chronic hepatopathy.This chronic hepatitis C infection can make the patient be in again to suffer from liver cirrhosis, hepatocarcinoma and cause in the excessive risk of serious hepatopathy such as dead final hepatopathy.At present, hepatitis C infection is through independent or treat with the injectable interferons of ribavirin combination or the interferon (PEG-Intron

and Pegasys

) of Pegylation.Yet these therapies can cause such as serious adverse such as retinopathy, thyroiditis, acute pancreatitis, depressions.Therefore, need the oral drugs that safe treatment hepatitis C infects.The present invention has satisfied this demand and related needs.

Summary of the invention

Aspect first, the present invention relates to the chemical compound of a kind of formula (I), or its pharmaceutically acceptable salt:

In the formula:

E is-COCONR ⁵R ⁶,-COCF ₂CONR ⁵R ⁶,-COCF ₂C (O) OR ⁵,-COCOR ⁷,-COCF ₂R ⁸,-COR ⁹,-COCOOR ¹⁰,-CONR ¹¹R ¹²Or-B (OR ¹³) ₂, R wherein ⁵, R ⁶, R ⁷, R ⁹, R ¹⁰, R ¹¹, R ¹²With each R ¹³Independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical alkyl, and R ⁸Be halogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical alkyl; Wherein, the aliphatic among the E, alicyclic and aromatic group can be chosen wantonly by following group and replace: 1,2 or 3 R ^aIndependently be selected from hydroxyl, alkoxyl, halogenated alkoxy, aryloxy group, heteroaryloxy, alkylthio group, aryl sulfo-, heteroaryl sulfo-, amino, mono-substituted amino, disubstituted amino, alkyl sulphonyl, aryl sulfonyl, carboxyl, alkoxy carbonyl, thiazolinyl oxygen base carbonyl, alkynyloxy base carbonyl, alkenyl amino carbonyl, acyl amino, amino carbonyl, halogen or cyanic acid; In addition; Wherein, R ^aIn aromatic series or alicyclic ring can choose wantonly by 1,2 or 3 substituent group that independently is selected from down group and replace: alkyl, alkoxyl, halogen, haloalkyl, halogenated alkoxy, carboxyl or carboxyalkyl; And randomly, R ⁵And R ⁶And R ¹¹And R ¹²Can be combined to form 5-7 unit ring with they bonded nitrogen-atoms;

R ¹Be alkyl, haloalkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical alkyl, wherein, R ¹In aliphatic, alicyclic and aromatic group can choose wantonly by following group and replace: 1 or 2 R ^bIndependently be selected from hydroxyl, alkoxyl, aryloxy group, heteroaryloxy, alkylthio group, aryl sulfo-, heteroaryl sulfo-, amino, mono-substituted amino, disubstituted amino, alkyl sulphonyl, aryl sulfonyl, carboxyl, alkoxy carbonyl, acyl amino, amino carbonyl, halogen or cyanic acid; In addition; Wherein, R ^bIn aromatic series or alicyclic ring can choose wantonly by 1,2 or 3 substituent group that independently is selected from down group and replace: alkyl, alkoxyl, halogen, haloalkyl, halogenated alkoxy, cyanic acid, carboxyl or carboxyalkyl;

X is-O-,-NR ¹⁴-,-S-,-SO-or-SO ₂-;

R ³Be alkyl, haloalkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical alkyl, wherein, R ³In aliphatic, alicyclic and aromatic group can choose wantonly by 1 or 2 R that independently is selected from down group ^cReplace: hydroxyl, alkoxyl, halogenated alkoxy, aryloxy group, heteroaryloxy, alkylthio group, aryl sulfo-, heteroaryl sulfo-, amino, mono-substituted amino, disubstituted amino, alkyl sulphonyl, aryl sulfonyl, carboxyl, alkoxy carbonyl, acyl amino, amino carbonyl, halogen or cyanic acid; In addition; Wherein, R ^cIn aromatic series or alicyclic ring can choose wantonly by 1,2 or 3 substituent group that independently is selected from down group and replace: alkyl, alkoxyl, halogen, haloalkyl, halogenated alkoxy, carboxyl or carboxyalkyl;

Y is-C (O) NH-,-OC (O) NH-,-NR ¹⁴-C (O) NH-or-NR ¹⁴C (O) O-.For each X and Y, each R ¹⁴When existing, independently be selected from hydrogen, optional by halogen, hydroxyl, alkoxyl, amino, mono-substituted amino, the substituted alkyl of disubstituted amino and optional by halogen and the substituted aryl of alkyl, heteroaryl or heterocyclic radical;

R ²Be heteroaryl or-CO-(condensed heterocycle base) ring, wherein, heteroaryl and condensed heterocycle basic ring can be chosen wantonly by 1,2,3 or 4 and independently be selected from down the R that organizes ^dReplace: hydrogen, alkyl, cycloalkyl; Thiazolinyl, alkynyl, alkylthio group, hydroxyl, alkoxyl, halogen, haloalkyl, halogenated alkoxy, carboxyl, carboxyalkyl, hydroxy alkyl, alkoxyalkyl, aminoalkyl, alkyl sulphonyl, alkyl-carbonyl, aryl, aralkyl, aryl sulfonyl, aryl carbonyl, aryloxycarbonyl, amino-sulfonyl, amino carbonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heteroaryl carbonyl, heteroaryloxy carbonyl, heterocyclic radical, heterocyclic radical alkyl, heterocyclic radical sulfonyl, heterocyclic radical carbonyl, heterocyclyloxy base carbonyl, amino, mono-substituted amino or disubstituted amino; Perhaps, as two R ^dWhen being positioned on the adjacent carbon atom they can with they bonded carbon atom form contain 1 or 2 hetero atom that is selected from nitrogen, oxygen, sulfur or-SO ₂-4,5 or 6 yuan of heterocyclic rings, wherein this heterocyclic ring can be chosen wantonly by 1 or 2 alkyl and replace; In addition, wherein, R ^dIn aromatic series or alicyclic ring can choose wantonly by 1,2 or 3 R that independently is selected from down group ^eReplace: alkyl, alkyl-carbonyl-amino, alkoxycarbonyl amino, cycloalkyl, cycloalkyl-alkyl, cyclo alkoxy carbonyl amino, cycloalkyl-alkyl oxygen base carbonylamino, nitro, alkoxyl, cycloalkyl oxy, aryloxy group, heteroaryloxy, halogen, haloalkyl, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl, amino, mono-substituted amino, disubstituted amino, acyl amino or urea groups; Wherein, R ^eIn cycloalkyl and cycloalkyl-alkyl can choose wantonly by 1,2 or 3 alkyl and replace; With

R ⁴Be:

(i) alkyl, prerequisite be, Y is-OC (O) NH-,-NR ¹⁴-C (O) NH-or-NR ¹⁴C (O) O-, and work as R ²At least one R when being heteroaryl ^dNot hydrogen;

(ii) cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical alkyl, prerequisite is R ²In heteroaryl and condensed heterocycle basic ring replaced by at least one heteroaryl ring; Perhaps

(iii) alkyl, prerequisite be, when Y be-C (O) NH-or-SO ₂R during NH- ²In heteroaryl and condensed heterocycle basic ring replaced by at least one heteroaryl ring;

Wherein, R ⁴In aromatic series or alicyclic ring can choose wantonly by 1,2 or 3 R that independently is selected from down group ^fReplace: alkyl, alkoxyl, halogen, haloalkyl, halogenated alkoxy, cyanic acid, carboxyl, carboxyalkyl, hydroxy alkyl, alkoxyalkyl, aminoalkyl, alkyl sulphonyl, alkyl-carbonyl, aryl, aralkyl, aryl sulfonyl, aryl carbonyl, aryloxycarbonyl, amino-sulfonyl, amino carbonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heteroaryl carbonyl, heteroaryloxy carbonyl, heterocyclic radical, heterocyclic radical alkyl, heterocyclic radical sulfonyl, heterocyclic radical carbonyl, heterocyclyloxy base carbonyl, mono-substituted amino or disubstituted amino; Wherein, R ^fIn aromatic series or alicyclic ring can choose wantonly by 1,2 or 3 substituent group that independently is selected from down group and replace: alkyl, alkoxyl, halogen, haloalkyl, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl, mono-substituted amino, disubstituted amino or acyl amino.

For clarity sake, it is pointed out that Y group and R ⁴The junction point of group is following: R ⁴C (O) NH-, R ⁴OC (O) NH-, R ⁴NR ¹⁴-C (O) NH-or R ⁴NR ¹⁴C (O) O-.

Aspect second, the present invention relates to a kind of pharmaceutical composition, wherein contain chemical compound or its pharmaceutically acceptable salt with the mutually blended formulas of one or more pharmaceutically acceptable excipient (I).

Aspect the 3rd; The present invention relates to a kind of method of treating the hepatitis C of animal; This method comprises and gives said animal a kind of pharmaceutical composition, contains chemical compound or its pharmaceutically acceptable salt with the formula (I) of the mutually blended treatment effective dose of one or more pharmaceutically acceptable excipient in this pharmaceutical composition.

Aspect the 4th, the present invention relates to the method for preparing of the chemical compound of formula (I).

The accompanying drawing summary

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Detailed Description Of The Invention

Definition

Except as otherwise noted, the following term that uses in this description and claims has carried out definition and has had following implication according to the application's purpose.

" alicyclic " refers to that becoming the non-aromatic ring structure of sealing with carbon atom arrangement is the part of characteristic, for example, and middle as indicated cycloalkyl and the heterocyclic ring that defines.

Alkyl, the alkenyl or alkynyl of definition during " aliphatic " refers to as indicated.

Except as otherwise noted, itself represents the saturated aliphatic groups of the straight or branched that contains 1-8 carbon atom " alkyl ", and for example, alkyl comprises methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl, isobutyl group, the tert-butyl group etc.

" alkyl-carbonyl-amino " refers to-NHC (O) R group that wherein R is like the defined alkyl of preceding text, for example, and methyl carbonylamino, ethyl carbonylamino etc.

Except as otherwise noted, " alkylidene " refers to contain the divalent group of representative examples of saturated aliphatic of the straight or branched of 1-6 carbon atom, for example, and methylene (CH ₂-), ethylene (CH ₂CH ₂-), trimethylene (CH ₂CH ₂CH ₂-), tetramethylene (CH ₂CH ₂CH ₂CH ₂-), 2-methyl tetramethylene (CH ₂CH (CH ₃) CH ₂CH ₂-), pentamethylene (CH ₂CH ₂CH ₂CH ₂CH ₂-) etc.

" thiazolinyl " refers to contain straight chain univalence hydrocarbyl or the side chain univalence hydrocarbyl of 3-6 carbon atom of 2-6 carbon atom of 1 or 2 two key; For example, vinyl, acrylic (comprising all isomeric forms), 1-methylpropenyl, cyclobutenyl (comprising all isomeric forms) or pentenyl (comprising all isomeric forms) etc.

" thiazolinyl oxygen base carbonyl " refers to-C (O) OR group, and wherein R is like the defined thiazolinyl of preceding text, for example, and 3-propylene-1-base oxygen base carbonyl etc.

" alkenyl amino carbonyl " refers to-C (O) NHR group, and wherein R is like the defined thiazolinyl of preceding text, for example, and 3-propylene-1-base amino carbonyl etc.

" alkynyl " refers to contain the straight chain univalence hydrocarbyl of 1 or 2 triple-linked 2-6 carbon atom or the side chain univalence hydrocarbyl of 3-6 carbon atom; For example, acetenyl, propinyl (comprising all isomeric forms), 1-methyl-prop alkynyl, butynyl (comprising all isomeric forms) or pentynyl (comprising all isomeric forms) etc.

" alkynyloxy base carbonyl " refers to-C (O) OR group, and wherein R is like the defined alkynyl of preceding text, for example, and 3-propine-1-base oxygen base carbonyl etc.

" alkylthio group " refers to-the SR group, and wherein R is the middle as indicated alkyl that defines, for example, and methyl mercapto, ethylmercapto group, rosickyite base or butylthio etc.

" alkyl sulphonyl " refers to-SO ₂The R group, wherein R is the middle as indicated alkyl that defines, for example, methyl sulphonyl, ethylsulfonyl etc.

" alkoxyl " refers to-the OR group, and wherein R is like the defined alkyl of preceding text, for example, and methoxyl group, ethyoxyl etc.

" alkoxycarbonyl amino " refers to-NHC (O) OR group that wherein R is like the defined alkyl of preceding text, for example, and methoxycarbonyl amino, ethoxy carbonyl amino etc.

" alkoxyalkyl " refers to by at least one like the defined alkoxyl of preceding text, the straight chain univalence hydrocarbyl of preferred 1 or 2 the substituted 1-6 of alkoxyl carbon atom or the side chain univalence hydrocarbyl of 3-6 carbon atom; For example; 2-methoxyl group-ethyl, 1-, 2-or 3-methoxy-propyl, 2-ethoxyethyl group etc.

" alkoxy carbonyl " refers to-C (O) OR group that wherein R is like the defined alkyl of preceding text, for example, and methoxycarbonyl, ethoxy carbonyl etc.

" amino " refers to-NH ₂Group.

" alkyl amino " refer to-the NHR group, wherein R be as indicated in the alkyl of definition, for example, methylamino, ethylamino, n-pro-pyl is amino, isopropyl is amino, normal-butyl is amino, isobutylamino, tert-butyl group amino etc.

" aminoalkyl " refers to by at least 1, the straight chain univalence hydrocarbyl of the substituted 1-6 of preferred 1 or 2 a-NRR ' carbon atom or the side chain univalence hydrocarbyl of 3-6 carbon atom; Wherein R is hydrogen, alkyl, acyl group, hydroxy alkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl or heterocyclic radical alkyl; R ' is hydrogen, alkyl, hydroxy alkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical alkyl, cycloalkyl, cycloalkyl-alkyl, amino carbonyl or amino-sulfonyl; Above-mentioned group is middle as indicated to be defined; For example; Amino methyl, methylamino ethyl, dimethyl aminoethyl, 1,3-diaminourea propyl group, acetyl-amino propyl group etc.

" acyl group " refers to-the COR group; Wherein R is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl or the heterocyclic radical of middle definition as indicated; For example, formoxyl, acetyl group, trifluoroacetyl group, benzoyl, piperazine-1-base carbonyl etc.This group is called as alkyl-carbonyl in this application when R is alkyl.This group is called as aryl carbonyl in this application when R is aryl.This group is called as the heteroaryl carbonyl in this application when R is heteroaryl.This group is called as the heterocyclic radical carbonyl in this application when R is heterocyclic radical.

" acyl amino " refers to-NRCOR ' group; Wherein R is a hydrogen or alkyl; R ' is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl or heterocyclic radical; Above-mentioned group is middle as indicated to be defined, for example, and formoxyl, acetyl group, trifluoroacetyl group, benzoyl, piperazine-1-base carbonyl etc.

" amino carbonyl " refers to-CONRR ' group, and wherein R and R ' independently are selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl or heterocyclic radical alkyl, perhaps R and R ' with they bonded nitrogen-atoms form as indicated in the heterocyclic amino group of definition.

" amino-sulfonyl " refers to-SO ₂NRR ' group, wherein R and R ' independently are selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl or heterocyclic radical alkyl, perhaps R and R ' with they bonded nitrogen-atoms form as indicated in the heterocyclic amino group of definition.

" animal " comprises people, non-human mammal (for example, Canis familiaris L., cat, rabbit, cattle, horse, sheep, goat, pig, deer etc.) and nonmammalian (for example, birds etc.).

" aromatic series " refers to that it is the part that the sum of sp2 hydridization and pi-electron equals 4n+2 that wherein composed atom constitutes all atoms in unsaturated loop systems, the loop systems.

" aryl " refers to contain the monocycle or the fused bicyclic of 6-10 ring carbon atom, and wherein each ring is aromatic ring, for example, and phenyl or naphthyl.

" aryloxy group " refers to-the O-R group, and wherein R is like the defined aryl of preceding text, for example, and phenoxy group, naphthoxy etc.

" aryloxycarbonyl " refers to-C (O) OR group that wherein R is like the defined aryl of preceding text, for example, and phenyl oxygen base carbonyl, naphthyl oxygen base carbonyl etc.

" aralkyl " refers to-(alkylidene)-R group, and wherein R is like the defined aryl of preceding text, for example, and benzyl, phenethyl etc.

" aryl sulfo-" refers to-the SR group, and wherein R is the middle as indicated aryl that defines, for example, and thiophenyl or naphthalene sulfenyl.

" aryl sulfonyl " refers to-SO ₂The R group, wherein R is the middle as indicated aryl that defines, for example, phenyl sulfonyl or naphthyl sulfonyl.

" carboxyl " refers to-C (O) OH group.

" carboxyalkyl " refer to by at least 1, preferred 1 or 2-C (O) OH group substituted as indicated in defined alkyl, for example, carboxyl methyl, carboxy ethyl, 1-, 2-or 3-carboxyl propyl group etc.

" cycloalkyl " refers to contain the saturated monocycle of unit price of 3-8 ring carbon atom, for example, and cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc.

" cycloalkyl-alkyl " refers to-(alkylidene)-R group, and wherein R is like the defined cycloalkyl of preceding text, for example, and cyclopropyl methyl, cyclobutyl ethyl, cyclobutylmethyl etc.

" cycloalkyl oxy " refers to-the OR group, and wherein R is like the defined cycloalkyl of preceding text, for example, and cyclopropyl oxygen base, cyclopentyloxy, cyclohexyl oxygen base etc.

" cycloalkyl oxy carbonylamino " refers to-NHC (O) OR group, and wherein R is like the defined cycloalkyl of preceding text, for example, and cyclopropyl oxygen base carbonylamino, cyclopentyloxy carbonylamino etc.

" cycloalkyl-alkyl oxygen base carbonylamino " refers to-NHC (O) OR group, and wherein R is like the defined cycloalkyl-alkyl of preceding text, for example, and cyclopropyl methyl oxygen base carbonylamino, cyclopentyl-methyl oxygen base carbonylamino etc.

" disease " specifically comprises any non-health status of animal or its part, and comprises the non-health status that causes that possibly caused by medical science that puts on this animal or veterinary treatment or therefore unexpected, i.e. " side effect " of this treatment.

" dialkyl amido " refers to group-NRR ', and wherein R and R ' are independent is the middle as indicated alkyl that defines, for example, and dimethylamino, diethylamino, N, N-methyl-propyl amino or N, N-Methylethyl amino etc.

" disubstituted amino " refers to group-NRR '; Wherein R and R ' independently are selected from alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy alkyl, alkoxyalkyl, aminoalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl; Above-mentioned group is middle as indicated to be defined, for example, and dimethylamino, diethylamino, N; N-methyl-propyl amino or N, N-Methylethyl amino, aminomethyl phenyl amino etc.Dialkyl amido is a subclass of two substituted-aminos.

" condensed heterocycle base " refer to literary composition in defined aryl or heteroaryl ring condensed as indicated in defined heterocyclic radical group, for example, 2,3-xylylenimine-1-base, 1,2,3,4-tetrahydroisoquinoline-1-base etc.

" halogen " refers to fluorine, chlorine, bromine or iodine.

" haloalkyl " refers to by one or more, preferably 1-7 " halogen " atom is substituted like the defined alkyl of preceding text, and " halogen " defines in this application.Haloalkyl comprises single haloalkyl, dihalo alkyl, tri haloalkyl, whole haloalkyl etc., for example, and chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluor ethyl, 2,2,2-three fluoro-1,1-Dichloroethyl etc.

" halogenated alkoxy " refers to-the OR group, and wherein R is like the defined haloalkyl of preceding text, for example, and trifluoromethoxy, 2,2,2-trifluoro ethoxy, difluoro-methoxy etc.

" heteroaryl " representes to have the aromatic series monocycle or the dicyclo part of 5-10 annular atoms as the part of a group or group, one or more arranged wherein, preferred 1,2 or 3 annular atoms is selected from nitrogen, oxygen or sulfur, and remaining annular atoms is a carbon.Representational heteroaryl ring includes but not limited to: pyrrole radicals, furyl, thienyl 、 oxazolyl 、 isoxazolyl, thiazolyl, imidazole radicals, triazolyl, tetrazole radical, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, indyl, benzofuranyl, benzo thiophenyl, benzimidazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, pyrazolyl etc.

" heteroaryloxy " refers to-the O-R group, and wherein R is assorted like the defined aryl of preceding text, for example, and furyl oxygen base, pyridine radicals oxygen base, indyl oxygen base etc.

" heteroaryloxy carbonyl " refers to-C (O) O-R group, and wherein R is assorted like the defined aryl of preceding text, for example, and pyridine radicals oxygen base carbonyl, pyrimidine radicals oxygen base carbonyl etc.

" heteroarylalkyl " refers to-(alkylidene)-R group, and wherein R is assorted like the defined aryl of preceding text, for example, and pyridylmethyl, 1-or 2-furyl ethyl, imidazolyl methyl etc.

" heteroarylalkyl oxygen base carbonyl " refers to-C (O) O-R group, and wherein R is like the defined heteroarylalkyl of preceding text, for example, and pyridylmethyl oxygen base carbonyl, Pyrimidylmethyl oxygen base carbonyl etc.

" heteroaryl sulfo-" refer to-the SR group, wherein R be as indicated in the heteroaryl of definition, for example, pyridylthio, furyl sulfo-, thienyl sulfur generation etc.

" heteroarylsulfonyl " refers to-SO ₂The R group, wherein R is the middle as indicated heteroaryl that defines, for example, pyridyl sulfonyl, thienyl sulphonyl base etc.

" heterocyclic radical " refers to contain the undersaturated monocycle of saturated or part or the bicyclic radicals of 4,5,6 or 7 carboatomic ring atoms; Wherein, one or more, preferred 1,2 or 3 ring carbon atom is selected from following hetero atom and substituted :-N=,-N-,-O-,-S-,-SO-or-S (O) ₂-, in addition, wherein 1 or 2 ring carbon atom is optional (CO-) alternative by ketone group.This heterocyclic ring can be chosen cycloalkyl, aryl or the heteroaryl ring that condenses definition in as indicated wantonly.Representational example includes but not limited to: imidazolidinyl, morpholinyl, thio-morpholinyl, thiomorpholine generation-1-oxide, thiomorpholine are for-1; 1-dioxide, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydrochysene sulfo-pyranose, 1-oxo-tetrahydrochysene sulfo-pyranose, 1; 1-dioxo tetrathio-pyranose, indolinyl, piperazinyl, piperidyl, pyrrolidinyl, pyrrolinyl, quininuclidinyl, 3,4-dihydro-isoquinoline base, indolinyl etc.Be called as " heterocyclic amino group " in the text when heterocyclic radical contains at least 1 azo-cycle atomic time, it is a subclass like the defined heterocyclic radical of preceding text.

" heterocyclic radical alkyl " refers to-(alkylidene)-R group, and wherein R is like the defined heterocyclic radical of preceding text, for example, and pyrrolidinyl methyl, tetrahydrofuran base ethyl, pyridylmethyl piperidino methyl etc.

" heterocyclyloxy base carbonyl " refers to-C (O) OR group, and wherein R is like the defined heterocyclic radical of preceding text, for example, and piperidyl oxygen base carbonyl, tetrahydrofuran oxygen base carbonyl etc.

" heterocyclic radical sulfonyl " refers to-SO ₂The R group, wherein R is the middle as indicated heterocyclic radical that defines, for example, piperidines-1-base sulfonyl, pyrrolidine-1-base sulfonyl etc.

" hydroxyl " refers to-the OH group.

" hydroxy alkyl " refers to by the straight chain univalence hydrocarbyl of 1 or 2 the substituted 1-6 of hydroxyl carbon atom or the side chain univalence hydrocarbyl of 3-6 carbon atom, and prerequisite is, if two hydroxyls then they do not appear on the identical carbon atoms simultaneously.Representational example includes but not limited to: hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methyl-propyl, 2-hydroxybutyl, 3-hydroxybutyl; 4-hydroxybutyl, 2; 3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxy butyl, 3,4-dihydroxy butyl and 2-(hydroxymethyl)-3-hydroxypropyl; Preferred 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(hydroxymethyl)-2-hydroxyethyl.

" isomer " expression has the same molecular formula but bonded character of atom or order are different or atoms in space is arranged the chemical compound of different formulas (I).The isomer that the atom spatial arrangements is different is called " stereoisomer ".Do not become the stereoisomer of mirror image to be called as " diastereomer " each other, and be in can not synergetic mirror image stereoisomer be called as " enantiomer ", perhaps be also referred to as " optical isomer " sometimes.Carbon atom in conjunction with four different substituents is called as " chiral centre ".There is the chemical compound with a chiral centre of the enantiomeric form of two kinds of opposite chiralitys to be called as " racemic mixture ".Chemical compound with 1 above chiral centre has 2 ^N-1Individual enantiomer is right, and wherein n is the number of chiral centre.Chemical compound with 1 above chiral centre can exist or exist with the mixture of the diastereomer that is called as " mixture of diastereomers " with one diastereomer.When having 1 chiral centre, absolute configuration that can this chiral centre characterizes stereoisomer.Absolute configuration is meant the substituent spatial arrangements that is connected in this chiral centre.Enantiomer can characterize with their absolute configuration of chiral centre, and describes with R-and the S-ordering rule of Cahn, Ingold and Prelog.The convention of spatial chemistry name, the method for confirming spatial chemistry and difference stereoisomer be well known in the art (for example; Referring to " Advanced Organic Chemistry (senior organic chemistry) ", the 4th edition, March; Jerry; John Wiley Publishing Company (John Wiley&Sons), New York, 1992).Should be understood that the application is used for title and the example of chemical compound of description formula (I) and implies and comprise all possible stereoisomer.

" mono-substituted amino " refers to group-NHR; Wherein R is selected from: alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy alkyl, alkoxyalkyl, aminoalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl; Above-mentioned group is middle as indicated to be defined; For example, methylamino, ethylamino, propyl group amino, phenyl amino, benzylamino etc.

" choose wantonly " or " randomly, and " or " possibility " refer to that incident or the situation described subsequently may or maybe not can occur, and this description comprises example and incident wherein or the absent variable example of situation that wherein incident or situation occur.For example, phrase " wherein, R ^aIn aromatic ring can choose wantonly by 1 or 2 substituent group that independently is selected from alkyl replace " refer to that this aromatic ring possibly replaced or possibly do not replaced by alkyl by alkyl, these situation all are included within the scope of the present invention.

The present invention also comprises the N-oxide derivative of the chemical compound of formula (I).The N-oxide derivative refer to wherein nitrogen-atoms be in the state of oxidation (be N → O), for example pyridine N-oxides, and chemical compound with formula (I) of required pharmacological activity.

" pathology " of disease refer to intrinsic propesties, the cause of disease and the development of disease, and the 26S Proteasome Structure and Function that this lysis causes changes.

" pharmaceutically acceptable " refers to can be used for pharmaceutical compositions, and it is safety non-toxic normally, and aspect biology or other, is not undesirable, and is veterinary use and human medicine purposes are acceptable.

" pharmaceutically acceptable salt " refers to the salt of chemical compound pharmaceutically acceptable and that have the formula (I) of required pharmacological activity, " pharmaceutically acceptable " such as preceding text definition.This salt comprises the acid-addition salts that is formed by mineral acid or organic acid; Said mineral acid example hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc.; Said organic acid such as acetic acid, propanoic acid, caproic acid, enanthic acid, Pentamethylene. propanoic acid, glycolic, acetone acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, Fumaric acid, tartaric acid, citric acid, benzoic acid, neighbour-(4-hydroxy benzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, 1; 2-ethionic acid, 2-hydroxyl-ethyl sulfonic acid, benzenesulfonic acid, right-chlorobenzenesulfonic acid, 2-LOMAR PWA EINECS 246-676-2, right-toluenesulfonic acid, camphorsulfonic acid, 4-methyl bicyclic [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4 '-di-2-ethylhexylphosphine oxide (3-hydroxyl-2-alkene-1-carboxylic acid), 3-phenylpropionic acid, trimethylace tonitric, tributyl acetic acid, lauryl sulfonic acid, gluconic acid, glutamic acid, carbonaphthoic acid, salicylic acid, stearic acid, muconic acid etc.

Pharmaceutically acceptable salt also comprises base addition salts, when the acid proton that exists can react with inorganic or organic base, can form base addition salts.Acceptable inorganic base comprises sodium hydroxide, sodium carbonate, potassium hydroxide, aluminium hydroxide and calcium hydroxide.Acceptable organic base comprises ethanolamine, diethanolamine, triethanolamine, tromethane, N-NMG etc.

The present invention also comprises the prodrug of the chemical compound of formula (I).Prodrug refers to can transform in vivo through metabolic approach (for example through hydrolysis) chemical compound of the chemical compound of an accepted way of doing sth (I).For example, the ester of chemical compound that contains the formula (I) of hydroxyl can change into parent molecule in vivo through hydrolysis.Perhaps, the ester of chemical compound that contains the formula (I) of carboxyl can change into parent molecule in vivo through hydrolysis.The ester of the chemical compound of the suitable formula that contains hydroxyl (I) has; For example, acetas, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionic ester, succinate, fumarate, maleate, methylene-two-β b-carbonaphthoic acid ester, Radix Gentianae acid esters, isethionic acid ester, two-right-tolyl tartrate, methanesulfonates, esilate, benzene sulfonate, right-tosylate, cyclohexyl sulfamate and quinate.The ester of the chemical compound of the suitable formula that contains carboxyl (I) has, and for example, Li Wenbai (Leinweber), F.J. be at " drug metabolism investigation " (Drug Metab.Res.), those that describe in the 1987,18,379th page.The ester of the chemical compound of be particularly useful one type formula (I) that contains hydroxyl can be formed by acid moieties, and said acid moieties is selected from Ban Jiade (Bundgaard) etc. at " Jian Shi medical chemistry " (J.Med.Chem.), and 1989; 32; Those that describe in the 2503-2507 page or leaf, and comprise substituted (amino methyl)-benzoate, for example; Dialkyl amido-methyl benzoic acid ester; Two alkyl wherein can link together and/or interrupted (morpholino-methyl) benzoate of more specifically saying so, for example 3-or 4-(morpholino methyl)-benzoate by oxygen atom or the nitrogen-atoms that is optionally substituted such as alkylating nitrogen-atoms; And (4-alkyl piperazine-1-yl) benzoate, for example 3-or 4-(4-alkyl piperazine-1-yl) benzoate.Should be understood that the application is used for title and the example of chemical compound of description formula (I) and implies and comprise its all possible prodrug.

" derivant of protection " refers to that one or more reaction site are by the derivant of the chemical compound of the formula (I) of being protected base to seal.The derivant of the protection of the chemical compound of formula (I) can be used for the chemical compound of preparation formula (I), and perhaps they itself promptly are the protease S of active mass inhibitor.The comprehensive list of suitable protection base can be at " the protection base in the organic synthesis " (Protective Groups in Organic Synthesis) of T.W. Green (T.W.Greene); The third edition; John Wiley Publishing Company (John Wiley&Sons) finds in 1999.Should be understood that the application is used for title and the example of chemical compound of description formula (I) and implies the derivant that comprises its all possible protection.

" treatment effective dose " refers to a kind of dosage, when this dosage being given animal with the treatment disease, is enough to treat this disease.

" treatment " refers to any instructions about how to take medicine of The compounds of this invention, comprising:

(1) disease takes place in the prevention animal, and said animal possibly contact disease but also not experience or demonstrate this sick pathology or symptomatology,

(2) suppressing the disease of animal, said animal is experiencing or is demonstrating ill pathology or symptomatology (that is, stoping pathology and/or semeiologic further developing), or

(3) alleviate the disease of animal, said animal is experiencing or is demonstrating ill pathology or symptomatology (that is, reversing pathology and/or symptomatology).

" urea groups " refers to group-NHCONRR ', and wherein R is a hydrogen or alkyl, and R ' is hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl.

Preferred implementation

In the wide region of in summary of the invention, listing, the chemical compound of some formula (I) is preferred.For example:

A. the chemical compound of one group of preferred formula (I) is, wherein:

E is-COCONHR ⁶, R wherein ⁶Be hydrogen, alkyl, cycloalkyl, aralkyl or heteroarylalkyl, wherein, aromatic ring can be chosen wantonly by 1 or 2 halogen and replace, preferably, and R ⁶Be cyclopropyl ,-CH (CH ₃) R, wherein R is phenyl, 4-chlorphenyl, 2,4-Dichlorobenzene base, 2,4 difluorobenzene base, 3,4-Dichlorobenzene base, 3,4-difluorophenyl or pyridin-4-yl.Preferably, R ⁶It is cyclopropyl.

B. another chemical compound of organizing preferred formula (I) is, wherein:

E is-COCOOR ¹⁰, R wherein ¹⁰Such as in the summary of the invention part definition.Preferably, R ¹⁰Be-CH ₂C ≡ CH ,-CH ₂CH=CH ₂, n-pro-pyl, 2,2-dimethyl propyl, carboxyl methyl, methoxycarbonyl methyl, tert-butoxycarbonyl methyl ,-CH ₂C (O) OCH ₂C ≡ CH ,-CH ₂C (O) OCH ₂CH=CH ₂,-CH ₂C (O) O (CH ₂) ₂CH ₃,-CH ₂C (O) NH ₂,-CH ₂C (O) NHCH ₃,-CH ₂C (O) N (CH ₃) ₂,-CH ₂C (O) NHCH ₂CH=CH ₂Or 2-phenethyl.

(a) in above-mentioned preferred group A and B and the group that is more preferably that wherein comprised, the one group of chemical compound that is more preferably is, wherein:

X is-O-;

R ¹Be optional alkoxy, alkylthio group or the substituted alkyl of alkyl sulphonyl, thiazolinyl, alkynyl, cycloalkyl or cycloalkyl-alkyl, preferable methyl, ethyl, n-pro-pyl, normal-butyl, n-pentyl, third-2-thiazolinyl, propine-2-base, 1-Methylethyl, 1-methyl-propyl, 2-methyl-propyl, 3-methyl butyl, cyclopropyl, methoxy, 2-methoxy ethyl, methyl methyl mercapto, sulfonyloxy methyl ylmethyl or cyclobutylmethyl.More preferably be cyclobutylmethyl, ethyl, n-pro-pyl or normal-butyl; With

R ³Being alkyl, cycloalkyl or aryl, more preferably is 1-Methylethyl, 1-methyl-propyl, the tert-butyl group, cyclopropyl, phenyl or cyclohexyl.Preferably, R ³Be the tert-butyl group or cyclohexyl.

(1) in group (A), (B), A (a) and B (a) and the group that is more preferably that wherein comprised, the one group of chemical compound that is more preferably is, wherein:

Y is-OC (O) NH-; R ²Be optional by 1,2,3 or 4 R that independently is selected from down group ^dSubstituted heteroaryl: hydrogen, alkyl, cycloalkyl, alkynyl, alkylthio group, hydroxyl, alkoxyl, halogen, haloalkyl, halogenated alkoxy, carboxyl, carboxyalkyl, hydroxy alkyl, alkoxyalkyl, aminoalkyl, alkyl sulphonyl, alkyl-carbonyl, aryl, aralkyl, aryl sulfonyl, aryl carbonyl, aryloxycarbonyl, amino-sulfonyl, amino carbonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heteroaryl carbonyl, heteroaryloxy carbonyl, heterocyclic radical, heterocyclic radical alkyl, heterocyclic radical sulfonyl, heterocyclic radical carbonyl, heterocyclyloxy base carbonyl, amino, mono-substituted amino or disubstituted amino; Perhaps, as two R ^dWhen being positioned on the adjacent carbon atom they can with they bonded carbon atom form contain 1 or 2 hetero atom that is selected from nitrogen, oxygen, sulfur or-SO ₂-4,5 or 6 yuan of heterocyclic rings, wherein, this heterocyclic ring can be chosen wantonly by 1 or 2 alkyl and replace; In addition, wherein, R ^dIn aromatic series or alicyclic ring can choose wantonly by 1,2 or 3 R that independently is selected from down group ^eReplace: alkyl, alkoxycarbonyl amino, cycloalkyl, cycloalkyl-alkyl, cyclo alkoxy carbonyl amino, cycloalkyl-alkyl oxygen base carbonylamino, nitro, alkoxyl, cycloalkyl oxy, aryloxy group, heteroaryloxy, halogen, haloalkyl, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl, mono-substituted amino, disubstituted amino, acyl amino or urea groups; Wherein, R ^eIn cycloalkyl and cycloalkyl-alkyl can choose wantonly by 1,2 or 3 alkyl and replace; With

R ⁴Be alkyl, the preferred tertiary butyl methyl, prerequisite is at least one R ^dNot hydrogen.

(i) preferably, R ²Be the group shown in the formula (a):

In the formula:

R ^D1Be hydrogen, hydroxyl, alkoxyl, amino, alkyl amino, dialkyl amido, halogenated alkoxy or alkyl sulphonyl;

R ^dAnd R ^D2Independent is hydrogen, alkyl, halogen, alkoxyl, alkylthio group or alkyl sulphonyl; Or

R ^D1And R ^dPerhaps R ^D1And R ^D2Form 4-, 5-or 6-unit heterocyclic ring with their bonded carbon atoms, wherein 1 or 2 annular atoms can by O or-N-substitutes, wherein this heterocyclic ring can be chosen wantonly by 1 or 2 alkyl and replace;

R ^D3Be optional by the substituted aryl of following group, heteroaryl or heterocyclic radical: halogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxyl, cycloalkyloxy, nitro, alkyl-carbonyl-amino, cycloalkyl amino carbonyl, cycloalkyl alkyl carbonyl amino, alkoxycarbonyl amino, amino, alkyl amino, dialkyl amido, cycloalkyl amino, cycloalkyl alkyl amino or-NHCONRR '; Wherein R is a hydrogen or alkyl; R ' is hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl; Wherein, R ^D3In cycloalkyl and cycloalkyl-alkyl can choose wantonly by 1,2 or 3 alkyl and replace.

Preferably,

R ^D1Be hydrogen, hydroxyl, alkoxyl, amino, alkyl amino or dialkyl amido;

R ^dAnd R ^D2Independent is hydrogen, alkyl, halogen, alkoxyl, alkylthio group or alkyl sulphonyl; And R ^D3Be the group shown in the following formula:

Above-mentioned group can be chosen wantonly by following group and replace: halogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxyl, cycloalkyloxy, nitro, alkyl-carbonyl-amino, cycloalkyl amino carbonyl, cycloalkyl alkyl carbonyl amino, alkyl oxy carbonylamino, amino, alkyl amino, dialkyl amido, cycloalkyl amino, cycloalkyl alkyl amino or-NHCONRR '; Wherein R is a hydrogen or alkyl; R ' is hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl, and wherein cycloalkyl and cycloalkyl-alkyl can be chosen wantonly by 1,2 or 3 alkyl and replace.

More preferably, R ^D3Be the group shown in the following formula:

Or

Again preferably, R ^D3Be:

; Or

In another preferred implementation of Asia group (i), R ^D3Be cycloalkyl, be more preferably cyclopropyl, cyclobutyl or cyclopenta, again cyclopropyl preferably.All the other groups, R ^d, R ^D1And R ^D2Has the implication that provides for formula (a).

In above-mentioned preferred group, the one group of chemical compound that is more preferably is, wherein:

R ^D1Be that hydrogen, hydroxyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, methylamino, ethylamino, n-pro-pyl are amino, isopropyl is amino, dimethylamino, Methylethyl is amino, methyl (n-pro-pyl) is amino and methyl (isopropyl) amino; More preferably be hydrogen, hydroxyl; Methoxyl group or dimethylamino, methoxyl group preferably again.Perhaps, hydrogen preferably again;

R ^dAnd R ^D2Independent is hydrogen, fluorine, chlorine, methyl, acetenyl, methoxyl group, ethyoxyl, methyl mercapto or methyl sulphonyl.More preferably, R ^dBe hydrogen, acetenyl, fluorine, chlorine, methyl, methoxyl group, methyl mercapto or methyl sulphonyl, and R ^D2Be hydrogen.

More preferably, R ^D1Be methoxyl group, R ^dBe hydrogen or methyl, fluorine, chlorine or methoxyl group, and R ^D2Be hydrogen.

(ii) preferably, R ²Be the group shown in the following formula:

or

In the formula:

Z ^aAnd Z ^bIndependent be-O-or-NH-, wherein H can be substituted by R, preferably Z ^aAnd Z ^bBe-O-;

R is an alkyl, preferable methyl;

R ^D2Be hydrogen or methyl, preferred hydrogen; With

R ^D3Like preceding text is the definition of inferior group (i).

(iii) preferably, R ²Be the group shown in the following formula:

; Or

R is an alkyl, preferable methyl;

R ^dBe hydrogen or methyl, preferred hydrogen; With

R ^D3Like preceding text is the definition of inferior group (i).

(iv) preferably, R ²Be the group shown in the formula (b):

In the formula:

R ^D3Be hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl.

Preferably,

R ^D1Be hydrogen, hydroxyl, alkoxyl, amino, alkyl amino or dialkyl amido;

R ^dAnd R ^D2Independent is hydrogen, alkyl, halogen, alkoxyl, alkylthio group or alkyl sulphonyl; And

R ^D3Be hydrogen, alkyl or cycloalkyl.

R ^D1Be that hydrogen, hydroxyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, methylamino, ethylamino, n-pro-pyl are amino, isopropyl is amino, dimethylamino, Methylethyl is amino, methyl (n-pro-pyl) is amino and methyl (isopropyl) amino; More preferably be hydrogen, hydroxyl, methoxyl group, ethyoxyl or dimethylamino, methoxy or ethoxy preferably again; With

R ^dAnd R ^D2Independent is hydrogen, fluorine, chlorine, methyl, acetenyl, methoxyl group, ethyoxyl, methyl mercapto or methyl sulphonyl; More preferably, R ^dBe hydrogen, acetenyl, fluorine, chlorine, methyl, methoxyl group, methyl mercapto or methyl sulphonyl, and R ^D2Be hydrogen.

More preferably, R ^D1Be methoxy or ethoxy, R ^dBe hydrogen or methyl, fluorine, chlorine or methoxyl group, and R ^D2Be hydrogen.

In above-mentioned group (i)-(iii) and the group that is more preferably that wherein comprised, preferred one group of chemical compound is, wherein, and R ^D3Ring can be chosen wantonly by following group and replace: methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, 1-methyl-propyl, 2-methyl-propyl, the tert-butyl group, 2; 2-dimethyl propyl, 1; 2-dimethyl propyl, 1; 2; 2-trimethyl propyl group, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl and cyclohexyl methyl, said cycloalkyl and cycloalkyl-alkyl ring can be chosen wantonly by 1-3 substituent group that independently is selected from methyl or ethyl, preferable methyl and replace.

In above-mentioned group (i)-(iii) and the group that is more preferably that wherein comprised, preferred one group of chemical compound is, wherein, and R ^D3Ring can be chosen wantonly by following group and replace: amino, methylamino, ethylamino, amino, the 1-Methylethyl amino, 1 of propyl group; The 1-dimethyl ethyl is amino, the 2-methyl-propyl is amino, 1-methyl-propyl amino, 2; 2-dimethyl propyl amino, 1; 2-dimethyl propyl amino, 1; The 1-dimethyl propyl is amino, cyclopropyl is amino, cyclobutyl is amino, cyclopenta is amino, cyclohexyl is amino, the cyclopropyl methylamino, cyclobutylmethyl is amino, cyclopentyl-methyl is amino, cyclohexyl methyl is amino, methyl carbonylamino, ethyl carbonylamino, propyl group carbonylamino, 1-Methylethyl carbonylamino, 1; 1-dimethyl ethyl carbonylamino, 2-methyl-propyl carbonylamino, 1-methyl-propyl carbonylamino, 2; 2-dimethyl propyl carbonylamino, 1; 2-dimethyl propyl carbonylamino, 1; 1-dimethyl propyl carbonylamino, cyclopropyl carbonyl are amino, cyclobutyl carbonyl is amino, cyclopentylcarbonyl is amino, cyclohexyl-carbonyl is amino, cyclopropyl methyl carbonylamino, cyclobutylmethyl carbonylamino, cyclopentyl-methyl carbonylamino, cyclohexyl methyl carbonylamino, methoxycarbonyl is amino, ethoxy carbonyl is amino, propoxycarbonyl is amino, 1-methyl ethoxy carbonylamino, 1,1-dimethyl-ethoxy carbonyl amino, 2-methyl propoxyl group carbonylamino, 1-methyl propoxyl group carbonylamino, 2,2-dimethyl propoxyl group carbonylamino, 1; 2-dimethyl propoxyl group carbonylamino or 1,1-dimethyl propoxyl group-carbonylamino.

(2) in group (A), (B), A (a) and B (a) and the group that is more preferably that wherein comprised, the one group of chemical compound that is more preferably is, wherein:

Y is-NHC (O) NH-R ²Like the definition of preceding text in preferred implementation (1), comprise its preferred subgroup, and R ⁴Be alkyl, the preferred tertiary butyl.

(3) in group (A), (B), A (a) and B (a) and the group that is more preferably that wherein comprised, the one group of chemical compound that is more preferably is, wherein:

Y is-C (O) NH-R ²Like the definition of preceding text in preferred implementation (1), comprise its preferred subgroup, prerequisite is R ^D3Be heteroaryl ring, and R ⁴Such as in summary of the invention definition, preferred alkyl, the more preferably tert-butyl group.

(4) in group (A), (B), A (a) and B (a) and the group that is more preferably that wherein comprised, the one group of chemical compound that is more preferably is, wherein:

Y is-OC (O) NH-R ²Be-CO-(condensed heterocycle base), wherein, the condensed heterocycle base can be chosen wantonly by 1,2 or 3 R that independently is selected from down group ^dReplace: alkyl, alkoxyl, halogen, haloalkyl, halogenated alkoxy, carboxyl, carboxyalkyl, hydroxy alkyl, alkoxyalkyl, aminoalkyl, alkyl sulphonyl, alkyl-carbonyl, aryl, aralkyl, aryl sulfonyl, aryl carbonyl, aryloxycarbonyl, amino-sulfonyl, amino carbonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heteroaryl carbonyl, heteroaryloxy carbonyl, heterocyclic radical, heterocyclic radical alkyl, heterocyclic radical sulfonyl, heterocyclic radical carbonyl, heterocyclyloxy base carbonyl, mono-substituted amino or disubstituted amino; Wherein, R ^dIn aromatic series or alicyclic ring can choose wantonly by 1,2 or 3 R that independently is selected from down group ^eReplace: alkyl, alkoxyl, halogen, haloalkyl, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl, mono-substituted amino, disubstituted amino or acyl amino; And R ⁴It is alkyl.Preferably, R ²Be optional by 1,2 or 3 above-mentioned R ^dSubstituted 2,3-xylylenimine-1-base, 1,2,3,4-tetrahydroisoquinoline-1-base.

(5) in group (A), (B), A (a) and B (a) and the group that is more preferably that wherein comprised, the one group of chemical compound that is more preferably is, wherein:

Y is-NHC (O) NH-R ²Be-CO-(condensed heterocycle base), wherein, the condensed heterocycle base can be chosen wantonly by 1,2 or 3 R that independently is selected from down group ^dReplace: alkyl, alkoxyl, halogen, haloalkyl, halogenated alkoxy, carboxyl, carboxyalkyl, hydroxy alkyl, alkoxyalkyl, aminoalkyl, alkyl sulphonyl, alkyl-carbonyl, aryl, aralkyl, aryl sulfonyl, aryl carbonyl, aryloxycarbonyl, amino-sulfonyl, amino carbonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heteroaryl carbonyl, heteroaryloxy carbonyl, heterocyclic radical, heterocyclic radical alkyl, heterocyclic radical sulfonyl, heterocyclic radical carbonyl, heterocyclyloxy base carbonyl, mono-substituted amino or disubstituted amino; Wherein, R ^dIn aromatic series or alicyclic ring can choose wantonly by 1,2 or 3 R that independently is selected from down group ^eReplace: alkyl, alkoxyl, halogen, haloalkyl, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl, mono-substituted amino, disubstituted amino or acyl amino; And R ⁴It is alkyl.Preferably, R ²Be optional by 1,2 or 3 above-mentioned R ^dSubstituted 2,3-xylylenimine-1-base, 1,2,3,4-tetrahydroisoquinoline-1-base.

(C) another chemical compound of organizing preferred formula (I) is again, wherein, and R ²Be the group shown in the formula (a):

In the formula:

R ^D3Be optional by the substituted aryl of following radicals, heteroaryl, cycloalkyl or heterocyclic radical: halogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxyl, cycloalkyloxy, nitro, alkyl-carbonyl-amino, cycloalkyl amino carbonyl, cycloalkyl alkyl carbonyl amino, alkyl oxy carbonylamino, amino, alkyl amino, dialkyl amido or-NHCONRR '; Wherein R is a hydrogen or alkyl; R ' is hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl, and wherein cycloalkyl and cycloalkyl-alkyl can be chosen wantonly by 1,2 or 3 alkyl and replace.

(i) preferably,

R ^D1Be hydrogen, hydroxyl, alkoxyl, amino, alkyl amino or dialkyl amido;

or

Above-mentioned group can be chosen wantonly by following group and replace: halogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxyl, cycloalkyloxy, nitro, alkyl (amkyl) carbonylamino, cycloalkyl amino carbonyl, cycloalkyl alkyl carbonyl amino, alkyl oxy carbonylamino, amino, alkyl amino, dialkyl amido or-NHCONRR '; Wherein R is a hydrogen or alkyl; R ' is hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl, and wherein cycloalkyl and cycloalkyl-alkyl can be chosen wantonly by 1,2 or 3 alkyl and replace.

More preferably, R ^D3Be the group shown in the following formula:

Or

Above-mentioned group can be chosen wantonly by following group and replace: halogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxyl, cycloalkyloxy, nitro, alkyl-carbonyl-amino, cycloalkyl amino carbonyl, cycloalkyl alkyl carbonyl amino, alkyl oxy (alkyoxy) carbonylamino, amino, alkyl amino, dialkyl amido or-NHCONRR '; Wherein R is a hydrogen or alkyl; R ' is hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl, and wherein cycloalkyl and cycloalkyl-alkyl can be chosen wantonly by 1,2 or 3 alkyl and replace.

Again preferably, R ^D3Be:

; Or

Above-mentioned group can be chosen wantonly by following group and replace: halogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxyl, cycloalkyloxy, nitro, alkyl-carbonyl-amino, cycloalkyl amino carbonyl, cycloalkyl alkyl carbonyl amino, alkyl oxy carbonylamino, amino, alkyl amino, dialkyl amido or-NHCONRR '; Wherein R is a hydrogen or alkyl; R ' is hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl, and wherein cycloalkyl and cycloalkyl-alkyl can be chosen wantonly by 1,2 or 3 alkyl and replace.

R ^{D with}R ^D2Independent is fluorine, chlorine, methyl, acetenyl, methoxyl group, ethyoxyl, methyl mercapto or methyl sulphonyl.More preferably, R ^dBe hydrogen, acetenyl, fluorine, chlorine, methyl, methoxyl group, methyl mercapto or methyl sulphonyl, and R ^D2Be hydrogen.

(ii) preferably, R ²Be the group shown in the following formula:

or?

In the formula:

Z ^aAnd Z ^bIndependent be-O-or-NH-, wherein, H can be substituted by R, preferably-O-;

R is an alkyl, preferable methyl;

R ^D2Be hydrogen or methyl, preferred hydrogen; With

R ^D3Like preceding text is the definition of inferior group (i).

(iii) preferably, R ²Be the group shown in the following formula:

Z ^aAnd Z ^bIndependent be-O-or-NH-, wherein H can be substituted by R, preferably-O-;

R is an alkyl, preferable methyl;

R ^dBe hydrogen or methyl, preferred hydrogen; With

R ^D3Like preceding text is the definition of inferior group (i).

In above-mentioned group (i)-(iii) and the group that is more preferably that wherein comprised, preferred one group of chemical compound is, wherein, and R ^D3Ring can be chosen wantonly by following group and replace: methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, 1-methyl-propyl, 2-methyl-propyl, the tert-butyl group, 2; 2; Dimethyl propyl, 1; 2-dimethyl propyl, 1; 2,2-trimethyl propyl group, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl and cyclohexyl methyl, said cycloalkyl and cycloalkyl-alkyl ring can be chosen wantonly separately by 1-3 substituent group that independently is selected from methyl or ethyl, preferable methyl and replace.

(1) in above-mentioned preferred group (C) and the group that is more preferably that wherein comprised, one group of chemical compound that is more preferably is, wherein:

X is-O-:

R ¹Be optional alkoxy, alkylthio group or the substituted alkyl of alkyl sulphonyl, thiazolinyl, alkynyl or cycloalkyl-alkyl; Preferred alkyl or cycloalkyl-alkyl, preferable methyl, ethyl, n-pro-pyl, normal-butyl, n-pentyl, third-2-thiazolinyl, propine-2-base, 1-Methylethyl, 1-methyl-propyl, 2-methyl-propyl, 3-methyl butyl, cyclopropyl, methoxy, 2-methoxy ethyl, methyl methyl mercapto, sulfonyloxy methyl ylmethyl or cyclobutylmethyl.More preferably cyclobutylmethyl, ethyl or n-pro-pyl; With

R ³Be alkyl, aryl or cycloalkyl, preferably 1-Methylethyl, 1-methyl-propyl, the tert-butyl group, cyclopropyl, phenyl or cyclohexyl.Preferred R ³Be the tert-butyl group or cyclohexyl.

(a) in this group C and C (1) and the group that is more preferably that wherein comprised, preferred one group of chemical compound is, wherein:

(b) in this group C and C (1) and the group that is more preferably that wherein comprised, preferred one group of chemical compound is, wherein:

E is-COCOOR ¹⁰, R wherein ¹⁰Such as in summary of the invention definition.Preferably, R ¹⁰Be-CH ²C ≡ CH ,-CH ₂CH=CH ₂, n-pro-pyl, 2,2-dimethyl propyl, carboxyl methyl, methoxycarbonyl methyl, tert-butoxycarbonyl methyl ,-CH ₂C (O) OCH ₂C ≡ CH ,-CH ₂C (O) OCH ₂CH=CH ₂,-CH ₂C (O) O (CH ₂) ₂CH ₃,-CH ₂C (O) NH ₂,-CH ₂C (O) NHCH ₃,-CH ₂C (O) N (CH ₃) ₂,-CH ₂C (O) NHCH ₂CH=CH ₂Or 2-phenethyl.

(D) chemical compound of one group of preferred formula (I) is again, wherein, and R ²Be the group shown in the formula (b):

In the formula:

R ^D3Be hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl.

(i) preferably,

R ^D1Be hydrogen, hydroxyl, alkoxyl, amino, alkyl amino or dialkyl amido;

R ^dAnd R ^D2Independent is hydrogen, alkyl, halogen, alkoxyl, alkylthio group or alkyl sulphonyl; And R ^D3Be hydrogen, alkyl or cycloalkyl.

R ^dAnd R ^D2Independent is fluorine, chlorine, methyl, acetenyl, methoxyl group, ethyoxyl, methyl mercapto or methyl sulphonyl.More preferably, R ^dBe hydrogen, acetenyl, fluorine, chlorine, methyl, methoxyl group, methyl mercapto or methyl sulphonyl, and R ^D2Be hydrogen.

(1) in above-mentioned preferred group (D) and the group that is more preferably that wherein comprised, preferred one group of chemical compound is, wherein:

X is-O-;

R ¹Be optional alkoxy, alkylthio group or the substituted alkyl of alkyl sulphonyl, thiazolinyl, alkynyl or cycloalkyl-alkyl; Preferred alkyl or cycloalkyl-alkyl; Preferable methyl, ethyl, n-pro-pyl, normal-butyl, n-pentyl, third-2-thiazolinyl, propine-2-base, 1-Methylethyl, 1-methyl-propyl, 2-methyl-propyl, 3-methyl butyl, cyclopropyl, methoxy, 2-methoxy ethyl, methyl methyl mercapto, sulfonyloxy methyl ylmethyl or cyclobutylmethyl.More preferably cyclobutylmethyl, ethyl or n-pro-pyl; With

(a) in this group D and D (1) and the group that is more preferably that wherein comprised, one group preferably chemical compound be, wherein:

(b) in this group D and D (1) and the group that is more preferably that wherein comprised, one group preferably chemical compound be, wherein:

E is-COCOOR ¹⁰, R wherein ¹⁰Such as in summary of the invention definition.Preferably, R ¹⁰Be-CH ₂C ≡ CH ,-CH ₂CH=CH ₂, n-pro-pyl, 2,2-dimethyl propyl, carboxyl methyl, methoxycarbonyl methyl, tert-butoxycarbonyl methyl ,-CH ₂C (O) OCH ₂C ≡ CH ,-CH ₂C (O) OCH ₂CH=CH ₂,-CH ₂C (O) O (CH ₂) ₂CH ₃,-CH ₂C (O) NH ₂,-CH ₂C (O) NHCH ₃,-CH ₂C (O) N (CH ₃) ₂,-CH ₂C (O) NHCH ₂CH=CH ₂Or 2-phenethyl.

When it should be noted that the preferred implementation of above mentioning, listing, except as otherwise noted, comprise all combinations of particular group and preferred group.

General synthetic schemes

Chemical compound of the present invention can prepare through the method for describing in the reactions scheme.

Preparing used raw material of these chemical compounds and reagent can be from Ai Derui interest chemical company (the Aldrich Chemical Co. of supplier such as Milwaukee, the state of Wisconsin; Milwaukee; Wis.), Pasteur's chemical company of California torrance (Bachem, Torrance, Calif.) or (Sigma of Sigma company of St. Louis, the Missouri State; St.Louis; Mo.) locate to obtain, perhaps can adopt and be proficient in method known to those skilled in the art according to preparing below with reference to the process of listing in the document, said document is like " Fei Sheer and the Fei Sheer reagent that are used for organic synthesis " (Fieser and Fieser ' s Reagents for Organic Synthesis); 1-17 rolls up (John Wiley Publishing Company, 1991); (Luo De) Rodd " chemistry of carbon compound " (Chemistry ofCarbon Compounds), 1-5 volume and supplementary issue (Ai Er swell science and technology publishing house (Elsevier Science Publishers), 1989); " organic reaction " (Organic Reactions); 1-40 rolls up (John Wiley Publishing Company; 1991); " organic conversion is discussed entirely " (Comprehensive Organic Transformations) (VCH publishing house (VCHPublishers Inc.), 1989) of " the senior organic chemistry " of Ma Ce (March) (Advanced Organic Chemistry) (John Wiley Publishing Company, the 4th edition) and La Luoke (Larock).These schemes have only been given an example and can have been synthesized the Several Methods of The compounds of this invention, can make various modifications to these schemes, and are proficient in those skilled in the art and after reading the disclosure, can propose such modification.

The raw material and the intermediate of available if desired routine techniques separation and purification reaction, said technology includes but not limited to filtration, distillation, crystallization, chromatography etc.Can adopt the conventional method that comprises physical constant and spectroscopic data to characterize these materials.

Only if opposite explanation is arranged, described herein being reflected under the constant pressure carried out, and the temperature range of reaction is for-78 ℃ to about 150 ℃ approximately, and preferably from about 0 ℃ to about 125 ℃, most preferably in about room temperature (or ambient temperature), for example about 20 ℃ are carried out.

After the reactive functional groups that in end-product, needs that possibly need protection in the reaction described participate in unwanted reaction, these functional groups such as hydroxyl, amino, imino group, sulfo-or carboxyl to avoid them.Can use conventional protection base according to standard practices; For example can be referring to T.W. Green (T.W.Greene) and P.G.M. 5 " the protection base in the organic chemistry " (the Protective Groups in Organic Chemistry) of (P.G.M.Wuts) now; John Wiley Publishing Company, 1999.

The chemical compound of formula (I), wherein Y is-OC (O) NH-, E is-COCONR ⁵R ⁶, X, R ¹, R ², R ³And R ⁴Such as in the summary of the invention part definition, can prepare according to reactions scheme 1.

Reaction scheme 1

With the amino protecting group PG in the pyrrolidine compound of formula 1 ₁, like tert-butoxycarbonyl, benzyl oxygen base carbonyl etc., go protection, wherein PG is suitable carboxyl-protecting group, preferred alkyl, and X and R ²Such as in the summary of the invention part definition, thereby obtain the chemical compound of formula 2.The reaction condition that amino protecting group is adopted depends on the character that protection is basic, for example, if PG ₁Be tert-butoxycarbonyl, then in organic solvent such as diox, oxolane etc. with 1 and sour example hydrochloric acid handle and to be removed.The nitrogen-protecting group that other are suitable and add and remove their reaction condition can be at T.W. Green (Greene; T.W.) and P.G.M. 5 (Wuts, " the protection base in the organic chemistry " P.G.M.) (Protecting Groups in Organic Synthesis) now; John Wiley Publishing Company finds in 1999.The chemical compound of formula 1 can be used method preparation well known in the art.The some of them method is described in US 2003191067, US 6608027, US 6268207, US 6404397, US 6268207 and WO 2005/028501, and their content is included this paper by reference in full in.

Aminoacid with formula 3 under peptide (peptidic) coupling reaction condition is handled chemical compound 2, wherein R ³Such as in summary of the invention definition, thereby obtain the chemical compound of formula 4, wherein Y is-O-C (O) NH-, R ⁴It is alkyl.Usually there is suitable coupling agents when carrying out this reaction; Like hexafluorophosphoric acid BTA-1-base-oxygen base tripyrrole Wan Ji Phosphonium (PyBOP

), hexafluorophosphoric acid BTA-N; N, N ', N '-tetramethylurea (HBTU), hexafluorophosphoric acid 2-(7-azo BTA)-N; N; N ', N '-tetramethylurea (HATU), hydrochloric acid 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDC) or 1,3-dicyclohexyl-carbodiimide (DCC); And optional 1-hydroxyl-BTA (HOBT) and alkali such as N, N-diisopropylethylamine, triethylamine, the N-methylmorpholine etc. of existing.The reaction usually 20-30 ℃, preferably carry out at about 25 ℃.Suitable reaction dissolvent is inert organic solvents such as halogenated organic solvent (for example dichloromethane, chloroform etc.), acetonitrile, N, dinethylformamide, ether solvents such as oxolane 、 diox etc., perhaps their mixture.The aminoacid of formula 3 can be buied or with method well known in the art preparation through commerce.

Ester group in the chemical compound 4 (PG=alkyl) under aqueous alkaline hydrolysis condition hydrolysis to obtain the chemical compound of formula 5.This reaction usually in aqueous alcoholic such as methanol, ethanol etc. by completion such as cesium carbonate, Lithium hydrate, sodium hydroxide.

Under above-mentioned peptide coupling reaction condition, obtain the chemical compound of formula 7 with the Alpha-hydroxy aminocarboxylic amide-treated chemical compound 5 of formula 6.The chemical compound of formula 6 can be used method preparation well known in the art, and some of them are described in detail in following work embodiment, reference example A and B.Chemical compound 6 also can be from chemical compound 17 (scheme 3 below its synthetic being described in) preparation.In brief, behind due care amino, (for example make it become carbamic acid t-Boc ester), thereby the ester group of under the basic hydrolysis condition, removing chemical compound 17 form corresponding alpha-hydroxy acid.Under the coupling reaction condition, use formula NHR ⁵R ⁶Amine handle this acid, then amine protecting group carried out acid-catalyzed hydrolysis to obtain the chemical compound of formula 6.

Perhaps, can at first change into active acid derivant when carrying out above-mentioned coupling step,, make the alpha-alcohol ketone amide reaction of itself and formula 6 then like carboxylic acid halides, succinimide ester etc. with 5.The condition that this reaction is adopted depends on the character of active acid derivant.For example, if 5 acid chloride derivant, then be reflected at and exist suitable alkali (for example triethylamine, diisopropylethylamine, pyridine etc.) time to carry out.Suitable reaction dissolvent is a polar organic solvent, like acetonitrile, N, and dinethylformamide, dichloromethane, or its any suitable mixture.Obtain the chemical compound of formula (I) with the hydroxyl in suitable oxidant such as moral silk Martin (Dess Martin) high iodine alkane (Periodinane) oxidized compound 8.

The chemical compound of formula (I), wherein Y is-NHC (O) NH-, E is-COCONR ⁵R ⁶, X, R ¹, R ², R ³And R ⁴Such as in the summary of the invention part definition, can prepare according to reactions scheme 2.

Reaction scheme 2

Under the acid hydrolytic reaction condition, remove the amino-compound that Boc group in the chemical compound 4 obtains formula 9, this chemical compound and alkyl isocyanate reaction obtain the urea-based compound of formula 10.This is reflected at when having organic base such as triethylamine, pyridine etc. and in appropriate organic solvent such as dichloromethane etc., carries out.This urea-based compound also can be through prepared by other well known in the art, as makes chemical compound 9 and carbamoyl halide reaction.The description of pressing such scheme 1 then transforms chemical compound 10 chemical compound of an accepted way of doing sth (I).Similarly, available aryl-, heteroaryl-or aralkyl-isocyanates or carbamyl halogenide replace alkyl isocyanate to prepare wherein R ⁴It or not the chemical compound of the formula (I) of alkyl.

Similarly, can make chemical compound 9 under condition well known in the art respectively with acylating agent or formula R ⁴Y is to prepare wherein for COL reaction-CONH-or-SO ₂The chemical compound of the formula of NH-(I).

Perhaps, can protect base to go protection to obtain corresponding acid and from the chemical compound of chemical compound 4 preparation formulas (I) acid.Acid and 6 reactions of Alpha-hydroxy aminocarboxylic amide are removed Boc [alkyl OC (O)-] group in the products therefrom then, thereby are obtained the free amine group chemical compound.This amino-compound and alkyl isocyanate or carbamyl halide reaction obtain chemical compound 12, then by the above-mentioned chemical compound that hydroxyl oxidize is converted it into formula (I).

The chemical compound of formula (I), wherein E is-COCOOR ¹⁰, X, Y, R ¹, R ², R ³, R ⁴And R ¹⁰Such as in the summary of the invention part definition, can prepare according to reactions scheme 3.

Reaction scheme 3

Under condition well known in the art, use N, the amino-acid compound of the N-Boc-protection of O-DMA processing formula 13 obtains Wien primary (Weinreb) amide compound of formula 14.Can be under condition well known in the art prepare the chemical compound of formula 13 from commercially available aminoacid and tert-butoxycarbonyl acid anhydride.Also can adopt other suitable amino protecting groups.Can obtain the corresponding aldehyde shown in the formula 15 in appropriate organic solvent as handling chemical compound 14 with appropriate reductant like lithium aluminium hydride reduction in the oxolane etc.Handle chemical compound 15 with acetone cyanohydrin and obtain chemical compound 16, then at formula R ¹⁰Chemical compound 16 and carboxylic acid halides are reacted to obtain the α hydroxyl ester compounds of formula 17, wherein R ¹⁰Such as in summary of the invention definition.

Under aforementioned peptide coupling condition, with the compound treatment chemical compound 17 of formula 5, then the hydroxyl oxidize in the products therefrom is obtained the chemical compound of formula (I), wherein Y is-OC (O) NH-, R ⁴It is alkyl.As stated, can be with Y wherein-OC (O) NH-, R ⁴The chemical compound that is the formula (I) of alkyl changes into wherein Y and R ⁴Chemical compound like defined other formulas (I) in the summary of the invention part.

The chemical compound of formula (I), wherein E is-CONR ¹¹R ¹², X, Y, R ¹, R ², R ³, R ⁴, R ¹¹And R ¹²Such as in the summary of the invention part definition, can prepare according to reactions scheme 4.

Reaction scheme 4

Under above-mentioned coupling reaction condition, use formula NHR ¹¹R ¹²Amine handle the chemical compound that chemical compound 13 obtains formula 18.Under the acid hydrolytic reaction condition, remove the Boc group and obtain chemical compound 19, then by the above-mentioned chemical compound that converts it into formula (I).

The chemical compound of formula (I), wherein E is-COR ⁹, X, Y, R ¹, R ², R ³, R ⁴And R ⁹Such as in the summary of the invention part definition, can prepare according to reactions scheme 5.

Reaction scheme 5

Use formula R respectively ⁹Li or R ⁹The organolithium of MgX or RMgBr are handled the chemical compound of formula 15 to obtain the chemical compound of formula 20, wherein R ⁹Such as in summary of the invention definition.This reaction is being carried out in organic solvent such as oxolane etc. under as-78 ℃ than low reaction temperatures usually.Remove the Boc group and obtain chemical compound 21, make it under above-mentioned coupling reaction condition, react the chemical compound that obtains formula 22 with chemical compound 5.Then hydroxyl oxidize is obtained the chemical compound of formula (I), wherein Y is-OC (O) NH-, R ⁴It is alkyl.Can prepare wherein Y and R according to the method described above ⁴It is the chemical compound of the formula (I) of other groups of partly defining of detailed Description Of The Invention.

The chemical compound of formula (I), wherein E is-CHO, X, Y, R ¹, R ², R ³, R ⁴And R ⁸Such as in the summary of the invention part definition, can prepare according to reactions scheme 6.

Reaction scheme 6

Under the acid hydrolytic reaction condition, remove the amino protecting group in the chemical compound 23, make the chemical compound coupling of gained amino-compound and formula 5 obtain the chemical compound of formula 24 then.A or method B are with the chemical compound of chemical compound 24 conversion accepted way of doing sth (I) according to the method described above then, and wherein E is-CHO.

In method A, ester group hydrolysis under the basic hydrolysis condition obtains the chemical compound of formula 25, converts it into Wien primary (Weinreb) amide of formula 26 again.With the acylamino-in appropriate reductant such as the lithium aluminium hydride reduction 26, obtain the chemical compound of formula (I) then, wherein E is-CHO, Y is-OC (O) NH-.

Perhaps, the ester group in available appropriate reductant such as the lithium aluminium hydride reduction chemical compound 24 is to obtain the alcohol of corresponding formula 27, and the reuse oxidizer treatment obtains the chemical compound of formula (I), and wherein E is-CHO, and Y is-OC (O) NH-.Can preparing wherein as stated above, Y is the chemical compound of the formula (I) of other groups.

Can the chemical compound of formula (I) be changed into the chemical compound of other formulas (I).For example:

Can alkoxyl/benzyl oxy substituents be gone-alkylation/benzylization contains the chemical compound of the formula (I) of hydroxyl with preparation; The chemical compound that can hydrolysis of ester group be prepared those formulas that contain acid groups (I); In addition, the bromine atoms in the chemical compound of replaceable corresponding formula (I) is to prepare the chemical compound of those formulas that contain cyanic acid (I).Can cyan-hydrolysis be changed into the respective compound that contains carboxyl with the chemical compound of the formula (I) that will contain cyanic acid.Can carboxyl be changed into ester group then.

Free alkali form and the pharmaceutically acceptable inorganic or organic acid reaction that can make chemical compound shown in the formula (I) are to be prepared into pharmaceutically-acceptable acid addition with it.Free acid form and the reaction of pharmaceutically acceptable inorganic or organic base that perhaps, can make chemical compound shown in the formula (I) are to be prepared into it pharmaceutically acceptable base addition salts.Be fit to inorganic and the organic acid of the pharmaceutically acceptable salt of chemical compound shown in the preparation formula (I) and the definitional part that inorganic and organic base is listed in the application.Perhaps, the salt form useful raw materials of chemical compound or the salt of intermediate prepare shown in the formula (I).

The free acid of chemical compound or free alkali form shown in the formula (I) can be from corresponding base addition salts or acid-addition salts prepare.For example, available suitable alkali (for example ammonia, sodium hydroxide etc.) thus the chemical compound of handling the formula (I) of acid-addition salts form changes into corresponding free alkali.Available suitable acid (for example hydrochloric acid etc.) thus the chemical compound of handling the formula (I) of base addition salts form changes into corresponding free acid.

The N-oxide that can prepare chemical compound shown in the formula (I) through the known method of one of ordinary skill in the art.For example; Can be in the time of about 0 ℃ at suitable inert organic solvents (halogenated hydrocarbon for example; Like dichloromethane) in oxidant (for example, trifluoroperacetic acid, cross maleic acid (permaleic acid), benzylhydroperoxide, peracetic acid ,-chloroperoxybenzoic acid etc.) the not oxidised form of chemical compound shown in the processing formula (I) to be to prepare the N-oxide.The N-oxide that perhaps, can prepare chemical compound shown in the formula (I) from the N-oxide of suitable feedstock.

The chemical compound of the formula of non-oxidised form (I) can through in the time of 0-80 ℃ at suitable inert organic solvents (for example; Acetonitrile, ethanol 、 diox aqueous solution etc.) middle with the N-oxide preparation of Reducing agent (for example, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, Phosphorous chloride., tribromide etc.) processing from chemical compound shown in the formula (I).

The prodrug derivant of chemical compound shown in the formula (I) can be through the known method preparation of one of ordinary skill in the art (for example; Can be referring to Sony you (Saulnier) etc. for further understanding details; (1994); " biological organic and medical chemistry licence " (Bioorganic and Medicinal Chemistry Letters), the 4th volume, the 1985th page).For example, suitable prodrug can with the chemical compound of not deutero-formula (I) and suitable carbamylation agent (for example, 1,1-acyloxy alkyl-carbonyl chloride (1,1-acyloxyalkylcarbonochloridate), right-nitrophenyl carbonate etc.) reaction and preparing.

Can come the derivant of the protection of chemical compound shown in the preparation formula (I) through the known method of one of ordinary skill in the art.The detailed description that is applicable to the technology that forms the protection base and they are removed can be at " the protection base in the organic synthesis " Protecting Groups in of T.W. Green (T.W.Greene) Organic Synthesis; The third edition; John Wiley Publishing Company finds in 1999.

Chemical compound of the present invention can be used as solvate (for example hydrate) preparation or formation easily in process of the present invention.The hydrate of The compounds of this invention can be from the aqueous/ORGANIC SOLVENT MIXTURES that forms by organic solvents such as dioxin, oxolane or methanol recrystallization and preparation easily.

The chemical compound of formula (I) can be made with the diastereomer of different physical properties (for example, fusing point, boiling point, dissolubility, reactivity etc.), and can utilize these differences to separate easily.Diastereomer can be through chromatography, or preferably separate through the separation/disassemble technique based on dissolubility difference.Reclaim optically pure isomer through any racemic operational approach of its chiral centre that can not cause then.Be applicable to that the more detailed description that from the racemic mixture of chemical compound, splits the technology of stereoisomer can be at Jean Jacques Andre Collet; " enantiomorph, raceme and fractionation " (Enantiomers of SamuelH.Wilen; Racemates and Resolutions); John Wiley Publishing Company finds in (1981).

Pharmacology and application

Chemical compound of the present invention is a kind of hepatitis C virus (HCV) replication inhibitors, therefore can be used for treating hepatitis C infection.The inhibition activity of chemical compound shown in the formula (I) can be measured through the known method of one of ordinary skill in the art.The suitable external test method of measuring The compounds of this invention inhibition HCV replication capacity is listed in the following biological Examples 1.

Administration and pharmaceutical composition

Usually, will treat the chemical compound of the formula (I) of effective dose separately or with one or more therapeutic agents combinations through any useful and acceptable manner known in the art.The scope of treatment effective dose is very wide, and it depends on the age of severity of disease, object and usefulness and other factors healthy relatively, the chemical compound that adopts.For example, the scope of the treatment effective dose of chemical compound shown in the formula (I) can be generally about 100 μ g/kg/ days to about 10mg/kg/ days from about 10 micrograms/kg body weight (μ g/kg)/sky to about 100 mg/kg body weight (mg/kg)/sky.Therefore, for the human patients of 80kg, the scope of treatment effective dose can be from about 1mg/ days to about 8g/ days, usually from about 1mg/ days to about 800mg/ days.Usually, one of ordinary skill in the art can confirm to treat the treatment effective dose of chemical compound shown in the required formula of specified disease (I) on the basis of personal knowledge and teachings herein.

The chemical compound of formula (I) can give with pharmaceutical compositions through one of following approach: oral, general (for example, transdermal, intranasal or pass through suppository) or parenteral (for example intramuscular, intravenous or subcutaneous).The form of compositions can be tablet, pill, capsule, semisolid, powder, slow releasing preparation, solution, suspension, elixir, aerosol or any other suitable compositions, and contains the chemical compound and at least a pharmaceutically acceptable excipient of formula (I) usually.Acceptable excipient be nontoxic, auxiliary administration and can the therapeutic effect of active component not had a negative impact.This excipient can be solid, liquid, semisolid, then is the gaseous state excipient for aerosol composition perhaps, and normally those skilled in the art is obtainable for this.

The solid drugs excipient comprises starch, cellulose, Talcum, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, flour, Chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, exsiccant fibroin etc.Liquid and semisolid excipient can be selected from water, ethanol, glycerol, propylene glycol and various oil, comprising the oil (for example, Oleum Arachidis hypogaeae semen, Oleum Glycines, mineral oil, Semen Sesami wet goods) in oil, animal, plant or synthetic source.Preferred liquid-carrier, especially injection solution comprise water, saline, D/W and glycerol.

Compositions Chinese style (I) but the amount wide cut of chemical compound change, this depends on the size of preparation type, UD, known other factors of technical staff that excipient type elixir is proficient in the pharmaceutical science field.Usually, be used to treat compound compositions shown in the formula (I) of specified disease and will contain 0.01%w to 90%w, preferred 5%w to 50%w active component, and remainder is one or more excipient.Preferably give this pharmaceutical composition so that treatment continuously, perhaps can arbitrarily give one time unit dosage forms when needing relief of symptoms especially when thinking with unit dosage forms.The representational pharmaceutical preparation that contains chemical compound shown in the formula (I) is described below.

In some embodiments, can the chemical compound of formula (I) be needed patient with second antiviral agent treatment.The example of suitable antiviral agent is: interferon, like the interferon of Ai Nuo (Intron) A, Luo Fennuo (Roferon) A and Pegylation, like PEG-Ai Nuo (intron), Pei Jiasi (Pegasys); Ribavirin (Ribavirin), Wei rummy fixed (Viramidine), Levovirin (Levovirin); The HCV AG14361 is like penta Nuo Pixita shore (Valopicitabine), R1626 (Luo Shi (Roche)), HCV-796 (Fu Shi drugmaker (Viropharma)/Hui Shi (Wyeth)); And Bristol (toll) receptor stimulating agent such as ANA-975 (An Nadaisi company (Anadys)).The chemical compound of formula (I) can give or give separately with above-mentioned medicament combination.In addition, open the scheme at place according to the doctor, the chemical compound of formula (I) can give before or after second antiviral agent giving.

Embodiment

Through the further illustration of following examples the present invention, following examples preparation of chemical compound of formula according to the invention (I) of having given an example, but it is not constituted restriction.

Reference example A

Synthetic [1S-(cyclopropyl carbamyl hydroxymethyl) butyl] t-butyl carbamate

Step 1

Boc-NVa-OH (25g in dichloromethane (300mL); 0.115mo1), hydrochloric acid N; The O-dimethyl hydroxylamine (12.34g, 0.127mol), EDC (33.07g, 0.173mol), HOBt (22.9g; 0.15mol) mixture in slowly added while stirring in 30 minutes consuming time NMM (34.9g, 0.35mol).Reactant was at room temperature placed 2 hours, with 2000mL EtOAc dilution, used NaHCO then ₃, H ₂O and brine wash, and use MgSO ₄Dry.On rotary evaporator, remove and desolvate to obtain [1S-(methoxy carbamyl) butyl] t-butyl carbamate (20g) of colorless oil.

Step 2

Under-78 ℃, argon, (7.2g, (1M is dissolved in THF, 27.7mL) slowly to add LAH in anhydrous THF (100mL) solution 27.7mmol) at [1S-(methoxy carbamyl) butyl] t-butyl carbamate.After 2 hours, slowly add 1N HCl (20mL), make it rise to room temperature then with cessation reaction.Reactant mixture is with EtOAc (600mL) dilution, with 1N HCl, H ₂O and brine wash are also used MgSO ₄Dry.Removing desolvates obtains buttery (1S-formoxyl butyl) t-butyl carbamate (4.8g).

Step 3

Under 0 ℃, the cyclopropyl isonitrile (1.91g, 28.5mmol), (1S-formoxyl butyl) t-butyl carbamate (3.8g, add in dichloromethane 19mmol) (100mL) solution acetic acid (2.28g, 38mmol).Make reactant mixture rise to 25 ℃ and stirred 6 hours after add accomplishing.Reactant mixture is used saturated NaHCO then with EtOAc dilution (200mL) ₃Solution and saline (30mL) wash and use MgSO ₄Dry.Remove desolvate and from 50mL ethyl acetate and hexane (v/v=1/1) the thick product of crystallization, obtain the acetic acid 2-tert-butoxycarbonyl amino-1-cyclopropyl carbamyl pentyl ester (4.8g) of white solid.

Step 4

Under the room temperature, acetic acid 2-tert-butoxycarbonyl amino-1-cyclopropyl carbamyl-pentyl ester (4.8g, add in methanol 14.6mmol) (50mL) solution NaOH aqueous solution (1N, 22mL).After 2 hours, remove methanol and extract concentrate with ethyl acetate (300mL).Ethyl acetate layer is with brine wash and use MgSO ₄Dry.Except that after desolvating, the title compound (3.5g) of the thick product of crystallization from 100mL ethyl acetate and hexane (v/v=3/1) to obtain white solid.

Reference example B

Synthetic (1S-cyclobutylmethyl-2-cyclopropyl carbamyl-2-hydroxyethyl)-t-butyl carbamate

Step 1

30 minutes consuming time; Boc-L-cyclobutyl alanine .DIPA in dichloromethane (200mL) (10.33g, 30mmol), N, O-dimethyl hydroxylamine hydrochloride (3.22g; 33mmol), EDC (8.63g; 45mmol), HOBt (5.52g, slowly add while stirring in mixture 36mmol) NMM (9.11g, 90mmol).After 2 hours,, use NaHCO with EtOAc dilution (1000mL) reactant mixture ₃, H ₂O and brine wash are also used MgSO ₄Dry.Removing desolvates obtains [2-cyclobutyl-1S-(methoxy carbamyl) ethyl]-t-butyl carbamate (7.1g) of colorless oil.

Step 2

Under-78 ℃ of argon, [2-cyclobutyl-1S-(methoxy carbamyl) ethyl]-t-butyl carbamate (4.3g, slowly add in anhydrous THF (100mL) solution 15mmol) LAH (1M is dissolved in THF, 15mL, 15mmol).After 2 hours, slowly add 1N HCl (15mL), and after adding completion, make reactant mixture rise to room temperature with cessation reaction.Reactant mixture is with EtOAc dilution (500mL), with 1N HCl, H ₂O and brine wash are also used MgSO ₄Dry.Removing desolvates obtains buttery (2-cyclobutyl-1S-formoxyl ethyl) t-butyl carbamate (2.95g).

Step 3

Under 0 ℃, the cyclopropyl isonitrile (1.21g, 18mmol), (2-cyclobutyl-1S-formoxyl ethyl) t-butyl carbamate (2.95g, add in dichloromethane 13mmol) (20mL) solution acetic acid (1.56g, 26mmol).After add accomplishing, make reactant mixture rise to 25 ℃ and restir 4 hours.Reactant mixture dilutes, uses saturated NaHCO with 200mL EtOAc ₃Solution and brine wash are also used MgSO ₄Dry.Remove desolvate and from 50mL ethyl acetate and hexane (v/v=1/1) the thick product of crystallization to obtain the acetic acid 2S-tert-butoxycarbonyl amino-3-cyclobutyl-1-cyclopropyl carbamyl propyl ester (3.8g) of white solid.

Step 4

Under the room temperature, acetic acid 2S-tert-butoxycarbonyl amino-3-cyclobutyl-1-cyclopropyl carbamyl propyl ester (3.8g, add in methanol 10.7mmol) (50mL) solution NaOH aqueous solution (1N, 15mL).After 2 hours, remove methanol and use the ethyl acetate extraction concentrate.Ethyl acetate layer is with brine wash and use MgSO ₄Dry.Remove and desolvate and the title compound (2.9g) of crystalline residue from 100mL ethyl acetate and hexane (v/v=3/1) to obtain white solid.

Embodiment 1

Synthetic 1-[2S-(3-tert-butyl group urea groups)-3,3-dimethyl butyryl]-4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-23-carboxylic acid (1S-cyclopropyl amidoxalyl butyl) amide (7)

Step 1

In the time of 0 ℃; Commercially available uncle N--Boc-suitable-4S-hydroxyl-L-proline methyl ester (370mg; 1.51mmol) and 7-methoxyl group-2-pyrazol-1-yl-quinoline-4-alcohol (PCT application publication number WO 2000059929) (400mg; 1.66mmol) anhydrous THF (15mL) solution in add triphenylphosphine (594mg, 2.27mmol), then at N ₂Slow down adding DIAD (0.36mL, 1.81mmol).Make reactant mixture slowly rise to room temperature and stirred 18 hours.Concentrate this crude reaction mixture then and through the flash chromatography purification obtaining 4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-1, the 2-dicarboxylic acids 1-tert-butyl ester-2S-methyl ester (1), productive rate is 69%.

Step 2

At 4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-1, (200mg adds 4.0 M HCl De diox (3.0mL) solution to the 2-dicarboxylic acids 1-tert-butyl ester-2S-methyl ester in dichloromethane 0.43mmol) (1mL) solution.After 1 hour, reactant mixture is concentrated and dry 4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-2S-carboxylate methyl ester hydrochloride (2) to obtain white solid.

Step 3

At 4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine 2S-carboxylate methyl ester hydrochloride (67mg; 0.165mmol) dichloromethane/DMF (2.0mL; 1: 1) add in the solution uncle Boc-L--Leu-OH (38.1mg, 0.165mmol), HATU (69mg, 0.182mmol) and DIPEA (0.1mL; 0.5mmol), and at this mixture of stirring at room.After 16 hours, with the ethyl acetate diluted reaction mixture and with 1N HCl, saturated NaHCO ₃And brine wash.With the dry (MgSO of ethyl acetate layer ₄), filter and be evaporated to dried, thereby obtain 1-(2S-tert-butoxycarbonyl amino-3,3-dimethyl butyryl)-4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-2S-carboxylate methyl ester (3) with quantitative yield.

Step 4

Diox (3.0mL) solution that in dichloromethane (1mL) solution of rough 1-(2S-tert-butoxycarbonyl amino-3,3-dimethyl butyryl)-4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-2S-carboxylate methyl ester, adds 4.0 M HCl.After 1 hour; Reactant mixture is concentrated and dry 1-(2S-amino-3 to obtain white solid; 3-dimethyl butyryl)-and 4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-2S-carboxylate methyl ester hydrochlorate, this material need not to be further purified and just can be used for following step.

Step 5

(2S-amino-3 at 1-; 3-dimethyl butyryl)-add triethylamine (0.06mL in dichloromethane (3.0mL) solution of 4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-2S-carboxylate methyl ester hydrochlorate (0.165mmol); 0.413mmol) and tert-butyl isocyanate (0.02mL is 0.165mmol) and at the stirring at room reactant mixture.After 16 hours, with the dichloromethane diluted reaction mixture and with 1N HCl, saturated NaHCO ₃And brine wash.Then dichloromethane layer is evaporated to and does to obtain 1-[2S-(the 3-tert-butyl group-urea groups)-3,3-dimethyl-butyryl]-4R-(7-methoxyl group-2-pyrazol-1-yl quinolyl-4 oxygen base)-pyrrolidine-2S-carboxylate methyl ester (4).

Step 6

Handle 1-[2S-(the 3-tert-butyl group-urea groups)-3,3-dimethyl-butyryl]-4R-(7-methoxyl group-2-pyrazol-1-yl quinolyl-4 oxygen base)-pyrrolidine-2S-carboxylate methyl ester with methanol (6.0mL), THF (3.0mL) and 1N NaOH (6.mL).After the room temperature 1 hour, reactant mixture is concentrated, with 1N HCl acidify and use ethyl acetate extraction.The ethyl acetate layer that merges is then with brine wash and dry (MgSO ₄).Then ethyl acetate layer is filtered and is evaporated to and do to obtain 1-[2S-(the 3-tert-butyl group-urea groups)-3,3-dimethyl-butyryl]-4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-2S-carboxylic acid (5).

Step 7

(48mg 0.165mmol) is dissolved in dichloromethane (3.0mL) and add TFA (3.0mL) with [1S-(cyclopropyl carbamyl hydroxymethyl) butyl] t-butyl carbamate.After the stirring at room 1 hour, reactant mixture is evaporated to 3S-amino-2-hydroxycaproic acid cyclopropyl amide tfa salt of doing to obtain white solid.With 1-[2S-(3-tert-butyl group urea groups)-3; 3-dimethyl-butyryl]-(1: 1.6.0mL) solution joins 3S-amino-2-hydroxycaproic acid cyclopropyl amide tfa salt for the dichloromethane/DMF of 4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-2S-carboxylic acid; Add HATU (75mg then; 0.198mmol) and DIPEA (0.1mL, 0.7mmol).After the room temperature 24 hours, with the ethyl acetate diluted reaction mixture and with 1N HCl, NaHCO ₃And brine wash.With the dry (MgSO of ethyl acetate layer ₄), filter and be evaporated to dried.Then thick product is dissolved in anhydrous methylene chloride (10.0mL) and add the high iodine alkane of De Si-Martin (Dess-Martin) (112mg, 0.264mmol).After the stirring at room 2 hours, use 0.26MNa ₂S ₂O ₃Saturated NaHCO ₃The solution cessation reaction is also used ethyl acetate extraction.The ethyl acetate layer that merges is used saturated NaHCO then ₃And brine wash.Obtain title compound (7), the purity that HPLC records＞99% through the preparation HPLC purification.

1H NMR: (DMSO-d ₆) δ 8.76-8.70 (m, 2H); 8.22 (d, J=6.8Hz, 1H); 8.11 (d, J=9.6Hz, 1H); 7.87 (d, J=1.2 Hz, 1H); 7.45 (s, 1H); 7.27 (d, J=2.4Hz, 1H); 7.00-6.97 (dd, J=2.8 and 9.6Hz, 1H); 6.64-6.62 (m, 1H); 5.92 (brs, 1H); 5.49 (brs, 1H); 5.00-4.96 (m, 1H); 4.55-4.49 (m, 2H); 4.18 (d, J=5.6Hz, 1H); 3.90 (s, 3H); 3.91-3.82 (m, 1H); 3.54 (brs, 1H); 2.75-2.72 (m, 1H); 2.54-2.51 (m, 1H); 2.17-2.14 (m, 1H); 1.69-1.66 (m, 1H); 1.40-1.34 (m, 3H); 1.13 (m, 9H); 0.93 (m, 9H); 0.90-0.82 (m, 3H); 0.65-0.53 (m, 4H).MS(M ⁺+1)733。

Embodiment 2

Synthetic 1-[2S-(3-tert-butyl group urea groups)-3,3-dimethyl butyryl]-4R-(7-methoxyl group-2-pyrazol-1-yl quinolyl-4 oxygen base)-pyrrolidine-2-carboxylic acid (1S-cyclobutylmethyl-2-cyclopropyl carbamyl-2-oxoethyl) amide (9)

Step 1

(51mg 0.165mmol) is dissolved in dichloromethane (3.0mL) and add TFA (3.0mL) with (1S-cyclobutylmethyl-2-cyclopropyl carbamyl-2-hydroxyl-ethyl)-t-butyl carbamate.After the stirring at room 1 hour, reactant mixture is evaporated to 3S-amino-4-cyclobutyl-N-cyclopropyl-2-hydroxyl-butyramide tfa salt of doing to obtain white solid.With 1-[2S-(3-tert-butyl group urea groups)-3; 3-dimethyl-butyryl]-(1: 1.6.0mL) solution adds 3S-amino-4-cyclobutyl-N-cyclopropyl-2-hydroxyl-butyramide tfa salt for the dichloromethane/DMF of 4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-2S-carboxylic acid; Add HATU (75mg then; 0.198mmol) and DIPEA (0.1mL, 0.7mmol).After the room temperature 24 hours, with the ethyl acetate diluted reaction mixture and with 1N HCl, saturated NaHCO ₃And brine wash.With the dry (MgSO of ethyl acetate layer ₄), filter and be evaporated to dried.Then thick product is dissolved in anhydrous methylene chloride (10.0mL) and add the high iodine alkane of De Si-Martin (Dess-Martin) (112mg, 0.264mmol).After the stirring at room 2 hours, use 0.26M Na ₂S ₂O ₃Saturated NaHCO ₃The solution cessation reaction is also used ethyl acetate extraction.The ethyl acetate layer that merges is used saturated NaHCO then ₃And brine wash.Obtain title compound (9), the purity that HPLC records＞99% through the preparation HPLC purification.

¹H NMR: (DMSO-d ₆) δ 8.76-8.69 (m, 2H); 8.19 (d, J=8.0Hz, 1H); 8.10 (d, J=8.0Hz, 1H); 7.87-7.86 (m, 1H); 7.45 (s, 1H); 7.27 (d, J=2.8Hz, 1H); 7.00-6.97 (dd, J=2.8 and 9.6 Hz, 1H); 6.64-6.62 (m, 1H); 5.93 (brs, 1H); 5.48 (brs, 1H); 5.00-4.96 (m, 1H); 4.53-4.49 (m, 2H); 4.18 (d, J=9.2Hz, 1H); 3.90 (s, 3H); 3.91-3.82 (m, 1H); 3.42 (brs, 2H); 2.75-2.72 (m, 1H); 2.54-2.51 (m, 1H); 2.17-2.14 (m, 1H); 1.96-1.89 (m, 2H); 1.78-1.50 (m, 6H); 1.13 (m, 9H); 0.94 (m, 9H); 0.65-0.53 (m, 4H).MS(M ⁺+1)759。

Embodiment 3

Synthetic 1-[2S-(3-tert-butyl group urea groups)-3,3-dimethyl butyryl]-4R-(5-chloropyridine-2-base oxygen base)-pyrrolidine-2S-carboxylic acid (1S-cyclobutylmethyl-2-cyclopropyl carbamyl-2-oxoethyl)-amide (15)

Preparation 10, hydrochlorate

In the time of 23 ℃, commercially available t-Boc-(2S, 4R)-add potassium tert-butoxide (3mmol) with 15 minutes branch small lots in the DMSO solution of hydroxyproline (1mmol).Mixture was stirred 30 minutes at 23 ℃, be cooled to 0 ℃ then, 10 minutes branch small lots of reuse add 2,5-dichloropyridine (1.1mmol).Reactant mixture was stirred 16 hours at 23 ℃.The gained suspension is poured into 5% aqueous citric acid solution and extracted with EtOAc.The EtOAc layer that merges is with brine wash and dry (MgSO ₄).Organic moiety is filtered and concentrated to obtain white solid.This solid matter is dissolved in 4.0M HCl De diox (10mL) solution.After 1 hour, reactant mixture is concentrated also dry to obtain 4R-(5-chloropyridine-2-base oxygen base)-pyrrolidine-2S-carboxylate methyl ester hydrochlorate.

Step 1

At 4R-(5-chloropyridine-2-base oxygen base)-pyrrolidine-2S-carboxylate methyl ester hydrochlorate (242mg; 0.829mmol) dichloromethane/DMF (10mL; 1: 1) add in the solution uncle Boc-L--Leu-OH (192mg, 0.829 mmol), HATU (347mg, 0.912mmol) and DIPEA (0.37mL; 2.07mmol), and at the stirring at room reactant mixture.After 16 hours, also use saturated NaHCO with the ethyl acetate diluted reaction mixture ₃And brine wash.With the dry (MgSO of ethyl acetate layer ₄), filter and be evaporated to dried, thereby obtain 1-(2S-tert-butoxycarbonyl amino-3,3-dimethyl butyryl)-4-(5-chloro-pyridine-2-base oxygen base)-pyrrolidine-2S-carboxylate methyl ester (11) with quantitative yield.

Step 2

Handle 1-(2S-tert-butoxycarbonyl amino-3,3-dimethyl butyryl)-4R-(5-chloropyridine-2-base oxygen base)-pyrrolidine-2S-carboxylate methyl ester with methanol (5.0mL), THF (3.0mL) and 1N NaOH (5.0mL).After the room temperature 2 hours, reactant mixture is concentrated, with 1N HCl acidify and use ethyl acetate extraction.The ethyl acetate layer that merges is then with brine wash and dry (MgSO ₄).Then ethyl acetate layer is filtered and is evaporated to and do to obtain 1-(2S-tert-butoxycarbonyl amino-3,3-dimethyl-butyryl)-4R-(5-chloro-pyridine-2-base oxygen base)-pyrrolidine-2S-carboxylic acid (12).

Step 3

At (1S-cyclobutylmethyl-2-cyclopropyl carbamyl-2-hydroxyl-ethyl)-t-butyl carbamate (214mg, 0.83mmol) middle 4.0M HCl De diox (11.0mL) solution that adds.After 1 hour, reactant mixture is concentrated and dry 3S-amino-4-cyclobutyl-N-cyclopropyl-2-hydroxyl-butanamide hydrochloride to obtain white solid.In 3S-amino-4-cyclobutyl-N-cyclopropyl-2-hydroxyl-butyramide, add 1-(2S-tert-butoxycarbonyl amino-3; 3-dimethyl-butyryl)-dichloromethane/DMF (1: 1.10.0mL) solution, EDC (238mg of 4R-(5-chloro-pyridine-2-base oxygen base)-pyrrolidine-2S-carboxylic acid; 1.24mmol), HOBt (190mg; 1.24mmol) and NMM (0.6mL, 3.32mmol).After the room temperature 16 hours, also use saturated NaHCO with the ethyl acetate diluted reaction mixture ₃And brine wash, and dry (MgSO ₄).Then ethyl acetate layer is filtered, concentrates and through the flash chromatography purification to obtain { 1-[4R-(5-chloropyridine-2-base oxygen base)-2S-(1S-cyclobutylmethyl-2-cyclopropyl carbamyl-2-hydroxyethyl-carbamyl)-pyrrolidine-1-carbonyl]-2; 2-dimethyl-propyl group }-t-butyl carbamate (13), productive rate is 58%.

Step 4

At { 1-[4R-(5-chloropyridine-2-base oxygen base)-2S-(1S-cyclobutylmethyl-2-cyclopropyl carbamyl-2-hydroxyethyl-carbamyl)-pyrrolidine-1-carbonyl]-2; 2-dimethyl-propyl group }-(313mg adds 4.0M HCl De diox (3.0mL) solution to t-butyl carbamate in dichloromethane 0.482mmol) (2mL) solution.After 1 hour; Reactant mixture is concentrated and dry 1-(2S-amino-3,3-dimethyl butyryl)-4R-(5-chloropyridine-2-base oxygen base)-pyrrolidine-2-carboxylic acid (1-cyclobutyl-methyl-2-cyclopropyl carbamyl-2-hydroxyethyl)-amide hydrochloride to obtain white solid.

Step 5

(2S-amino-3 at 1-; 3-dimethyl butyryl)-4R-(5-chloropyridine-2-base oxygen base)-pyrrolidine-2-carboxylic acid (1-cyclobutyl-methyl-2-cyclopropyl carbamyl-2-hydroxyethyl)-amide hydrochloride (45mg; 0.077mmol) dichloromethane (3.0mL) solution in add triethylamine (0.02mL, 0.154mmol).After the room temperature 5 minutes, add tert-butyl isocyanate (0.01mL, 0.077mmol) and the stirring at room reactant mixture.After 16 hours, with the dichloromethane diluted reaction mixture and with 1N HCl, saturated NaHCO ₃And brine wash.Then dichloromethane layer is evaporated to and does to obtain 1-[2S-(the 3-tert-butyl group-urea groups)-3,3-dimethyl-butyryl]-4R-(5-chloropyridine-2-base oxygen base)-pyrrolidine-2S-carboxylic acid (1S-cyclobutylmethyl-2-cyclopropyl carbamyl-2-hydroxyethyl) amide (14).

Step 6

With 1-[2S-(the 3-tert-butyl group-urea groups)-3; 3-dimethyl-butyryl]-4R-(5-chloropyridine-2-base oxygen base)-pyrrolidine-2S-carboxylic acid (1S-cyclobutylmethyl-2-cyclopropyl carbamyl-2-hydroxyethyl) amide be dissolved in anhydrous methylene chloride (4.0mL) and add the high iodine alkane of De Si-Martin (Dess-Martin) (44mg, 0.103mmol).Stirring at room is used 0.26M Na after 2 hours ₂S ₂O ₃Saturated NaHCO ₃The solution cessation reaction is also used ethyl acetate extraction.The ethyl acetate layer that merges is used saturated NaHCO then ₃And brine wash.Obtain title compound (15), the purity that HPLC records＞90% through the preparation HPLC purification.

¹H?NMR：(DMSO)8.91-8.73(m，1H)；8.30-8.24(m，2H)；7.92-7.7.80(m，1H)；6.94-6.84(m，1H)；5.97(brs，1H)；5.50(s，1H)；5.00-4.95(m，1H)；4.54-4.52(m，1H)；4.17-3.88(m，3?H)；2.75-2.72(m，1H)；2.54-2.51(m，1H)；2.40-2.32(m，1H)；2.17-1.60(m，10H)；1.13(m，9H)；0.91(m，9?H)；0.67-0.58(m，4H)。MS(M ⁺+1)648。

Embodiment 4

Synthetic { 1S-[2S-(1S-cyclopropyl amidoxalyl butyl carbamyl)-4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-1-carbonyl]-2,2-dimethyl propyl }-t-butyl carbamate (16)

Description according to top embodiment 1 makes { 1S-[2R-(1S-cyclopropyl amino-oxalyl butyl carbamyl)-4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-1-carbonyl]-2,2-dimethyl propyl } t-butyl carbamate.MS：734(M+1)MS：734(M+1)。

Embodiment 5

Synthetic { 1S-[2S-(1S-cyclopropyl amidoxalyl butyl carbamyl)-4R-(7-methoxyl group-2-phenyl-quinolyl-4 oxygen base)-pyrrolidine-1-carbonyl]-2,2-dimethyl propyl }-t-butyl carbamate (17)

According to the description of top embodiment 4, but replace 7-methoxyl group-2-pyrazol-1-yl-quinoline-4-alcohol, make title compound with 7-methoxyl group-2-phenyl-quinoline-4-alcohol.MS：744(M+1)

Embodiment 6

Synthetic { 1S-[4R-(5-chloropyridine-2-base oxygen base)-2S-(1S-cyclopropyl amidoxalyl butyl-carbamyl)-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl group }-t-butyl carbamate (18)

Description according to top embodiment 4; But replace 4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-2S-carboxylate methyl ester hydrochloride with 4R-(5-chloropyridine-2-base oxygen base) pyrrolidine-2-carboxylate methyl ester hydrochloride, make title compound.MS：622(M+1)。

Embodiment 7

Synthetic { 1S-[4R-(5-chloropyridine-2-base oxygen base)-2S-(1S-cyclobutylmethyl-2-cyclopropyl carbamyl-2-oxo-ethylamino formyl)-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl group }-t-butyl carbamate (19)

Description according to top embodiment 4; But replace 4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-2S-carboxylate methyl ester hydrochloride with 4R-(5-chloro-pyridine-2-base oxygen base) pyrrolidine-2-carboxylate methyl ester hydrochloride; Use (1S-cyclobutylmethyl-2-cyclopropyl carbamyl-2-hydroxyethyl)-t-butyl carbamate to replace [1S-(cyclopropyl carbamyl hydroxymethyl) butyl] t-butyl carbamate simultaneously, make title compound.MS：648(M+1)

Embodiment 8

Synthetic 1-[2-(3-tert-butyl group urea groups)-3,3-dimethyl-butyryl]-4-(5-chloro-pyridine-2-base oxygen base)-pyrrolidine-2-carboxylic acid (1-cyclopropyl amidoxalyl-butyl)-amide (20)

According to the description of top embodiment 3, but replace (1S-cyclobutylmethyl-2-cyclopropyl carbamyl-2-hydroxyethyl)-t-butyl carbamate, make title compound with [1S-(cyclopropyl-carbamyl hydroxymethyl) butyl] t-butyl carbamate.MS：621(M+1)。

Embodiment 9

Synthetic 1-[2S-(the 3-tert-butyl group-urea groups)-3,3-dimethyl-butyryl]-4R-(6-methoxyl group-isoquinolyl-1 oxygen base)-pyrrolidine-2S-carboxylic acid (1S-cyclopropyl amidoxalyl-butyl)-amide (21)

Step 1

In the time of 0 ℃, the 3-methoxy cinnamic acid (5.3g, 29.7mmol) and triethylamine (8.3mL, dropwise add in acetone 59.4mmol) (35mL) solution ethyl chloroformate (4.3mL, 44.5mmol).0 ℃ of reaction is after 1 hour, dropwise adds Hydrazoic acid,sodium salt aqueous solution (3.1g, 47.5mmol, 16mL water) and reactant mixture was stirred 16 hours at 23 ℃.In mixture, add entry (50mL) and under vacuum, remove volatile material.The gained slurry is with toluene (3 * 25mL) extractions, and with the dry (MgSO of the organic layer that merges ₄).To pass through that exsiccant solution filters and dropwise add diphenyl methane (25mL) and tri-n-butylamine that (14.2mL is 59.4mmol) in the solution at 190 ℃.Toluene has just distilled when dripping.After adding, reaction temperature is risen to 210 ℃ kept 2 hours.After the cooling, through the product of filtration collecting precipitation, with hexane wash and dry to obtain 6-methoxyl group-2H-isoquinolin-1-ketone (1.7g, 9.7mmol, 33% productive rate) under vacuum.MS?m/z?176(M ⁺+H)。

Step 2

With 6-methoxyl group-2H-isoquinolin-1-ketone (900mgs, POCl 5.1mmol) ₃(4mL) suspension is 110 ℃ of heating 3 hours (the heating back obtains settled solution).After 3 hours, the concentrating under reduced pressure reactant mixture.Pour residue into frozen water (10mL), with 3N NaOH pH is transferred to 10 and use CHCl then ₃(3 * 25mL) extractions.The CHCl that merges ₃Layer is with brine wash and dry (MgSO ₄).Then organic layer is filtered, concentrates and through flash chromatography (50% ethyl acetate/hexane) purification to obtain the 1-chloro-6-methoxyl group-isoquinolin (720mgs, 3.7mmol, 73% productive rate) of white solid. ¹H?NMR(CD ₃OD)：8.23(d，1H，J＝8.8Hz)；8.11(d，1H，J＝6.0Hz)；7.69(d，1H，J＝6.0Hz)；7.37-7.33(m，2H)；3.97(s，3H)。MS?m/z?194(M ⁺+H)。

Step 3

In the time of 23 ℃, commercially available N-t-Boc-(2S, 4R)-DMSO (20mL) solution of hydroxyproline (684mg, 2.96 mmol) in 15 minutes branch small lots add potassium tert-butoxide (997mgs, 8.88mmol).Mixture was cooled to 0 ℃ in 30 minutes then 23 ℃ of stirrings.In the time of 0 ℃, and reuse branch small lot adding in 10 minutes 1-chloro-6-methoxyl group-isoquinolin (600mgs, 3.11mmol).Reactant mixture was stirred 16 hours at 23 ℃.Pour the gained suspension into 5% aqueous citric acid solution (100mL) also with EtOAc (3 * 50mL) extractions.The EtOAc layer that merges is with brine wash and dry (MgSO ₄).Then organic layer is filtered and concentrates with obtain white solid (2S, 4R)-(6-methoxyl group-isoquinolyl-1 oxygen base)-pyrrolidine-1, the 2-dicarboxylic acids 1-tert-butyl ester (1.04g, 2.68mmol, 91% productive rate).MSm/z?389(M ⁺+H)。This material need not to be further purified just and can be used for following step by crude product.

Step 4

At [1S-(cyclopropyl carbamyl-hydroxyl-methyl)-butyl]-t-butyl carbamate (100mg, 0.35mmol) middle 4.0M HCl De diox (10mL) solution that adds.After 1 hour, reactant mixture is concentrated also dry to obtain the hydrochlorate of corresponding white solid.DCM/DMF (8: 3.11.0mL) add (2S in the solution at above-mentioned amine hydrochlorate; 4R)-(6-methoxyl group-isoquinolyl-1 oxygen base)-pyrrolidine-1, the 2-dicarboxylic acids 1-tert-butyl ester (136mg, 0.35mmol), HATU (160mg; 0.42mmol) and DIPEA (0.2mL, 1.05mmol).Room temperature after 2 hours with ethyl acetate diluted reaction mixture and with 1N HCl (2x), NaHCO ₃(1x) and saline (1x) washing.With the dry (MgSO of ethyl acetate layer ₄), filter and be evaporated to and do to obtain 2S-[1S-(cyclopropyl carbamyl-hydroxyl-methyl)-butyl carbamyl]-4R-(6-methoxyl group-isoquinolyl-1 oxygen base)-pyrrolidine-1-carboxylic acid tert-butyl ester.

Step 5

In above-mentioned crude compound, add 4.0M HCl De diox (10mL) solution.After 1 hour, reactant mixture is concentrated also dry to obtain the hydrochlorate of corresponding white solid.The DCM/DMF of above-mentioned amine hydrochlorate (8: 3.11.0mL) add 2S-(the 3-tert-butyl group-urea groups)-3 in the solution, 3-dimethyl-butanoic acid (81.0mg, 0.35mmol), HATU (160mg, 0.42mmol) and DIPEA (0.2mL, 1.05mmol).After the room temperature 16 hours, with the ethyl acetate diluted reaction mixture and with 1N HCl (2x), NaHCO ₃(1x) and saline (1x) washing.With the dry (MgSO of ethyl acetate layer ₄), filter and be evaporated to dried.

Step 6

Then thick product is dissolved in anhydrous DCM (10.0mL) and add the high iodine alkane of De Si-Martin (Dess-Martin) (223mg, 0.525mmol).After the stirring at room 2 hours, use 0.26M Na ₂S ₂O ₃Saturated NaHCO ₃The solution cessation reaction is also with ethyl acetate extraction (3x).The ethyl acetate layer that merges is used saturated NaHCO then ₃(2x) and saline (1x) washing.Obtain 1-[2S-(the 3-tert-butyl group-urea groups)-3 through the preparation HPLC purification; 3-dimethyl-butyryl]-4R-(6-methoxyl group-isoquinolyl-1 oxygen base)-pyrrolidine-2S-carboxylic acid (1S-cyclopropyl amidoxalyl-butyl)-amide (21), the purity that HPLC records＞95%. ¹H?NMR.(DMSO-d ₆)8.74(d，1H，J＝4.8Hz)；8.28(d，1H，J＝7.2Hz)；8.15(d，1H，J＝9.2Hz)；7.97(d，1H，J＝6.0?z)；7.34-7.32(m，2H)；7.11-7.08(m，1H)；5.94(brs，1H)；5.72-5.70(m，1H)；5.04-5.00(m，1H)；4.58(t，1H，J＝8.4Hz)；4.34-4.22(m，2H)；3.91(s，3H)；3.90-3.86(m，1H)；2.79-2.74(m，1H)；2.54-2.51(m，1H)；2.18-2.11(m，1H)；1.77-1.70(m，1H)；1.48-1.38(m，3H)；1.15(m，9H)；0.91(m，9H)；0.90-0.86(m，3H)；0.69-0.56(m，4H)。MS?m/z?667(M ⁺+H)，689(M ⁺+Na)，665(M ⁺-H)。

Embodiment 10

Synthetic 1-[2S-(the 3-tert-butyl group-urea groups)-3,3-dimethyl-butyryl]-4R-(6-methoxyl group-isoquinolyl-1 oxygen base)-pyrrolidine-2S-carboxylic acid (2-cyclopropyl carbamyl-1S-cyclopropyl methyl-2-oxo-ethyl)-amide (23)

Step 1

At (S)-3-amino-4, N-two cyclopropyl-2-hydroxyl-butanamide hydrochloride (47mg, DCM/DMF 0.2mmol) (5: 1.5; 6.5mL) add (2S in the solution; 4R)-(6-methoxyl group-isoquinolyl-1 oxygen base)-pyrrolidine-1, the 2-dicarboxylic acids 1-tert-butyl ester (78mg, 0.2mmol), HATU (91mg; 0.4mmol) and DIPEA (0.1mL, 0.6mmol).After the room temperature 16 hours, with the ethyl acetate diluted reaction mixture and with 1N HCl (2x), NaHCO ₃(1x) and saline (1x) washing.With the dry (MgSO of ethyl acetate layer ₄), filter and be evaporated to and do to obtain 2S-(2-cyclopropyl carbamyl-1S-cyclopropyl methyl-2 (±)-hydroxyl-ethylamino formyl)-4R-(6-methoxyl group-isoquinolyl-1 oxygen base)-pyrrolidine-1-carboxylic acid tert-butyl ester (22).

Step 2

In above-mentioned crude compound, add 4.0M HCl De diox (5.0mL) solution.After 1 hour; Reactant mixture is concentrated also dry to obtain the hydrochlorate of corresponding white solid. at the DCM/DMF (7: 3.10.0mL) add 2S-(the 3-tert-butyl group-urea groups)-3 in the solution of above-mentioned amine hydrochlorate; 3-dimethyl-butanoic acid (46mg; 0.2mmol), HATU (91mg, 0.24mmol) and DIPEA (0.1mL, 0.6mmol).After the room temperature 3 hours, with the ethyl acetate diluted reaction mixture and with 1N HCl (2x), NaHCO ₃(1x) and saline (1x) washing.With the dry (MgSO of ethyl acetate layer ₄), filter and be evaporated to dried.

Step 3

Then thick product is dissolved in anhydrous DCM (8.0mL) and add the high iodine alkane of De Si-Martin (Dess-Martin) (127mg, 0.3mmol).After the stirring at room 2 hours, use 0.26M Na ₂S ₂O ₃Saturated NaHCO ₃The solution cessation reaction is also with ethyl acetate extraction (3x).The ethyl acetate layer that merges is used saturated NaHCO then ₃(2x) and saline (1x) washing.Obtain 1-[2S-(the 3-tert-butyl group-urea groups)-3 through the preparation HPLC purification; 3-dimethyl-butyryl]-4R-(6-methoxyl group-isoquinolyl-1 oxygen base)-pyrrolidine-2S-carboxylic acid (2-cyclopropyl carbamyl-1S-cyclopropyl methyl-2-oxo-ethyl)-amide (23), the purity that HPLC records＞95%.MS?m/z?679(M ⁺+H)，701(M ⁺+Na)，677(M ⁺-H)。

Embodiment 11

Synthetic 1-[2S-(the 3-tert-butyl group-urea groups)-3,3-dimethyl-butyryl]-4R-(6-ethyoxyl-isoquinolyl-1 oxygen base)-pyrrolidine-2-carboxylic acid (2-cyclopropyl carbamyl-1S-cyclopropyl methyl-2S-oxo-ethyl)-amide (26)

Step 1

In the time of 0 ℃, the 3-ethoxy-cinnamic acid (5.71g, 29.7mmol) and triethylamine (8.3mL, dropwise add in acetone 59.4mmol) (35mL) solution ethyl chloroformate (4.3mL, 44.5mmol).0 ℃ of reaction is after 1 hour, dropwise adds Hydrazoic acid,sodium salt aqueous solution (3.1g, 47.5mmol, 16mL water) and reactant mixture was stirred 16 hours at 23 ℃.In mixture, add entry (50mL) and under vacuum, remove volatile material.The gained slurry is with toluene (3 * 25mL) extractions, and with the dry (MgSO of the organic layer that merges ₄).To pass through that exsiccant solution filters and dropwise add diphenyl methane (25mL) and tri-n-butylamine that (14.2mL is 59.4mmol) in the solution at 190 ℃.Toluene has just distilled when dripping.After adding, reaction temperature is risen to 210 ℃ kept 2 hours.After the cooling, through the product of filtration collecting precipitation, with hexane wash and dry to obtain 6-ethyoxyl-2H-isoquinolin-1-ketone (1.92g, 10.2mmol, 34% productive rate) under vacuum.MS?m/z190(M ⁺+H)。

Step 2

With 6-ethyoxyl-2H-isoquinolin-1-ketone (896mg, POCl 4.74mmol) ₃(4mL) suspension is 110 ℃ of heating 3 hours (the heating back obtains settled solution).After 3 hours, the concentrating under reduced pressure reactant mixture.Pour residue into frozen water (10mL), with 3N NaOH pH is transferred to 10 and use CHCl then ₃(3 * 25mL) extractions.The CHCl that merges ₃Layer is with brine wash and dry (MgSO ₄).Then organic layer is filtered and concentrates to obtain the 1-chloro-6-ethyoxyl-isoquinolin (866mg, 4.18mmol, 88% productive rate, purity＞90%) of sepia solid, shaped.MS?m/z208(M ⁺+H)。

Step 3

In the time of 23 ℃, commercially available N-t-Boc-(2S, 4R)-hydroxyproline (531mg, in DMSO 2.30mmol) (20mL) solution with 15 minutes branch small lots add potassium tert-butoxide (774mg, 6.9mmol).Mixture was cooled to 0 ℃ in 30 minutes then 23 ℃ of stirrings.In the time of 0 ℃, and reuse branch small lot adding in 10 minutes 1-chloro-6-ethyoxyl-isoquinolin (500mgs, 2.41mmol).Reactant mixture was stirred 16 hours at 23 ℃.The gained suspension is poured in the water also with ether (2x) and ethyl acetate (2x) purging compound.The water-bearing layer with 1N HCl acidified aqueous solution to pH about 4 and extract with DCM (3x).The DCM layer that merges is with brine wash and dry (MgS0 ₄).Then organic layer is filtered and concentrates with obtain (2S, 4R)-(6-ethyoxyl-isoquinolyl-1 oxygen base)-pyrrolidine-1, the 2-dicarboxylic acids 1-tert-butyl ester (24) (weight=1.18g of crude product, purity＞90%).MS?m/z?403(M ⁺+H)，401(M ⁺-H)，303(M ⁺-Boc)。This material need not to be further purified just and can be used for following step by crude product.

Step 4

At (S)-3-amino-4, N-two cyclopropyl-2-hydroxyl-butanamide hydrochloride (66mgs, DCM/DMF 0.28mmol) (10: 3; 13mL) add (2S in the solution; 4R)-(6-ethyoxyl-isoquinolyl-1 oxygen base)-pyrrolidine-1, the 2-dicarboxylic acids 1-tert-butyl ester (114mgs, 0.28mmol), HATU (128mg; 0.34mmol) and DIPEA (0.15mL, 0.84mmol).After the room temperature 1 hour, with the ethyl acetate diluted reaction mixture and with 1N HCl (2x), NaHCO ₃(1x) and saline (1x) washing.With the dry (MgSO of ethyl acetate layer ₄), filter and be evaporated to and do to obtain 2S-(2-cyclopropyl carbamyl-1S-cyclopropyl methyl-2-hydroxyl-ethylamino formyl)-4R-(6-ethyoxyl-isoquinolyl-1 oxygen base)-pyrrolidine-1-carboxylic acid tert-butyl ester (25).

Step 5

In above-mentioned crude compound, add 4.0M HCl De diox (10mL) solution.After 1 hour, reactant mixture is concentrated also dry to obtain the hydrochlorate of corresponding white solid.The DCM/DMF of above-mentioned amine hydrochlorate (10: 3.13mL) add 2S-(the 3-tert-butyl group-urea groups)-3 in the solution, 3-dimethyl-butanoic acid (64mgs, 0.28mmol), HATU (128mg, 0.34mmol) and DIPEA (0.15mL, 0.84mmol).After the room temperature 1 hour, with the ethyl acetate diluted reaction mixture and with 1N HCl (2x), NaHCO ₃(1x) and saline (1x) washing.With the dry (MgSO of ethyl acetate layer ₄), filter and be evaporated to dried.

Step 6

Then thick product is dissolved in anhydrous DCM (10.0mL) and add the high iodine alkane of De Si-Martin (Dess-Martin) (154mgs, 0.364mmol).After the stirring at room 1 hour, use 0.26M Na ₂S ₂O ₃Saturated NaHCO ₃The solution cessation reaction is also with ethyl acetate extraction (3x).The EtOAc layer that merges is used saturated NaHCO then ₃(2x), saline (1x) washing and dry (MgSO ₄).Then organic layer is filtered, concentrates and through the 1-[2S-(the 3-tert-butyl group-urea groups)-3 of flash chromatography (65% ethyl acetate/hexane) purification to obtain white solid; 3-dimethyl-butyryl]-4R-(6-ethyoxyl-isoquinolyl-1 oxygen base)-pyrrolidine-2-carboxylic acid (2-cyclopropyl carbamyl-1S-cyclopropyl methyl-2S-oxo-ethyl)-amide (26) (80.7mg; 0.116mmol, 42% productive rate). ¹H?NMR：(DMSO)8.67(d，1H，J＝5.6Hz)；8.26(d，1H，J＝6.8Hz)；8.06(d，1H，J＝8.8Hz)；7.89(d，1H，J＝5.6Hz)；7.24-7.22(m，1H)；7.01-6.98(dd，1H，J＝2.4，8.8Hz)；5.90-5.85(m，2H)；5.65-5.62(m，1H)；5.06-5.01(m，1H)；4.53(t，1H，J＝8.0Hz)；4.26-4.23(m，1H)；4.16-4.08(m，3H)；3.84-3.80(m，1H)；2.69-2.65(m，1H)；2.11-2.04(m，1H)；1.64-1.57(m，1H)；1.35-1.29(m，3H)；1.15(m，9H)；0.91(m，9H)；0.89-0.81(m，3H)；0.61-0.48(m，4H)；0.36-0.27(m，2H)。MS?m/z?693(M ⁺+H)，715(M ⁺+Na)，691(M ⁺-H)。

Embodiment 12

Synthetic 1-[2S-(the 3-tert-butyl group-urea groups)-3,3-dimethyl-butyryl]-4R-(6-ethyoxyl-isoquinolyl-1 oxygen base)-pyrrolidine-2S-carboxylic acid (1S-cyclopropyl amidoxalyl-butyl)-amide (28)

Step 1

At [1S-(cyclopropyl carbamyl-hydroxyl-methyl)-butyl]-t-butyl carbamate (75mg, 0.26mmol) middle 4.0M HCl De diox (6.0mL) solution that adds.After 1 hour, reactant mixture is concentrated also dry to obtain the hydrochlorate of corresponding white solid.DCM/DMF (10: 3.13mL) add (2S in the solution at above-mentioned amine hydrochlorate; 4R)-(6-ethyoxyl-isoquinolyl-1 oxygen base)-pyrrolidine-1, the 2-dicarboxylic acids 1-tert-butyl ester (106mgs, 0.26mmol), HATU (119mg; 0.31mmol) and DIPEA (0.15mL, 0.78mmol).Room temperature after 1 hour with ethyl acetate diluted reaction mixture and with 1N HCl (2x), NaHCO ₃(1x) and saline (1x) washing.With the dry (MgSO of ethyl acetate layer ₄), filter and be evaporated to and do to obtain 2S-[1S-(cyclopropyl carbamyl-hydroxyl-methyl)-butyl carbamyl]-4R-(6-ethyoxyl-isoquinolyl-1 oxygen base)-pyrrolidine-1-carboxylic acid tert-butyl ester (27).

Step 2

In above-mentioned crude compound, add 4.0M HCl De diox (10mL) solution.After 1 hour, reactant mixture is concentrated also dry to obtain the hydrochlorate of corresponding white solid.The DCM/DMF of above-mentioned amine hydrochlorate (10: 3.13mL) add 2S-(the 3-tert-butyl group-urea groups)-3 in the solution, 3-dimethyl-butanoic acid (60mgs, 0.26mmol), HATU (128mg, 0.34mmol) and DIPEA (0.15mL, 0.84mmol).After the room temperature 1 hour, with the ethyl acetate diluted reaction mixture and with 1N HCl (2x), NaHCO ₃(1x) and saline (1x) washing.With the dry (MgSO of ethyl acetate layer ₄), filter and be evaporated to dried.

Step 3

Then thick product is dissolved in anhydrous DCM (10.0mL) and add the high iodine alkane of De Si-Martin (Dess-Martin) (143mgs, 0.338mmol).Stirring at room is used 0.26M Na after 1 hour ₂S ₂O ₃Saturated NaHCO ₃The solution cessation reaction is also with ethyl acetate extraction (3x).The ethyl acetate layer that merges is used saturated NaHCO then ₃(2x) and saline (1x) washing and dry (MgSO ₄).Then organic layer is filtered, concentrates and through the 1-[2S-(the 3-tert-butyl group-urea groups)-3 of flash chromatography (65% ethyl acetate/hexane) purification to obtain white solid; 3-dimethyl-butyryl]-4R-(6-ethyoxyl-isoquinolyl-1 oxygen base)-pyrrolidine-2S-carboxylic acid (1S-cyclopropyl amidoxalyl-butyl)-amide (28) (75.7mg; 0.11mmol, 43% productive rate). ¹H?NMR：(DMSO-d ₆)8.75(d，1H，J＝4.8Hz)；8.28(d，1H，J＝7.2Hz)；8.13(d，1H，J＝8.8Hz)；7.96(d，1H，J＝6.0Hz)；7.31-7.29(m，2H)；7.10-7.06(dd，1H，J＝2.4，9.2Hz)；5.94-5.92(m，2H)；5.72-5.70(m，1H)；5.04-5.00(m，1H)；4.58(t，1H，J＝7.6Hz)；4.34-4.30(m，1H)；4.23-4.17(m，3H)；3.90-3.86(m，1H)；2.79-2.74(m，1H)；2.54-2.51(m，1H)；2.18-2.11(m，1H)；1.77-1.70(m，1H)；1.48-1.38(m，3H)；1.15(m，9H)；0.91(m，9H)；0.89-0.86(m，3H)；0.69-0.59(m，4H)。MS?m/z?681(M ⁺+H)，703(M ⁺+Na)，679(M ⁺-H)。

Embodiment 13

Synthetic 1-[2S-(the 3-tert-butyl group-urea groups)-3,3-dimethyl-butyryl]-4R-(6-methoxyl group-isoquinolyl-1 oxygen base)-pyrrolidine-2S-carboxylic acid (1S-cyclopropyl amidoxalyl-amyl group)-amide (30)

Step 1

At (S)-3-amino-2-hydroxyl-enanthic acid cyclopropyl amide hydrochlorate (96mgs; 0.40mmol) DCM/DMF (10: 3,13mL) add in the solution (2S, 4R)-(6-methoxyl group-isoquinolyl-1 oxygen base)-pyrrolidine-1; The 2-dicarboxylic acids 1-tert-butyl ester (157mgs; 0.40mmol), HATU (200mg, 0.53mmol) and DIPEA (0.35mL, 2.0mmol).Room temperature after 1 hour with ethyl acetate diluted reaction mixture and with 1N HCl (2x), NaHCO ₃(1x) and saline (1x) washing.With the dry (MgSO of ethyl acetate layer ₄), filter and be evaporated to and do to obtain 2S-[1S-(cyclopropyl carbamyl-(±)-hydroxyl-methyl)-amyl group carbamyl]-4R-(6-methoxyl group-isoquinolyl-1 oxygen base)-pyrrolidine-1-carboxylic acid tert-butyl ester (29).MS?m/z?571(M ⁺+H)，593(M ⁺+Na)，569(M ⁺-H)，471(M ⁺-Boc)。

Step 2

In above-mentioned crude compound, add 4.0M HCl De diox (10mL) solution.After the room temperature 1 hour, reactant mixture is concentrated also dry to obtain the hydrochlorate of corresponding white solid.The DCM/DMF of above-mentioned amine hydrochlorate (10: 3.13mL) add 2S-(the 3-tert-butyl group-urea groups)-3 in the solution, 3-dimethyl-butanoic acid (93mgs, 0.40mmol), HATU (200mg, 0.53mmol) and DIPEA (0.35mL, 2.0mmol).Room temperature after 1 hour with ethyl acetate diluted reaction mixture and with 1N HCl (2x), NaHCO ₃(1x) and saline (1x) washing.With the dry (MgSO of ethyl acetate layer ₄), filter and be evaporated to dried.MS?m/z?683(M ⁺+H)，705(M ⁺+Na)，681(M ⁺-H)。

Step 3

Then thick product is dissolved in anhydrous DCM (10.0mL) and add the high iodine alkane of De Si-Martin (Dess-Martin) (223mgs, 0.53mmol).Stirring at room is used 0.26M Na after 2 hours ₂S ₂O ₃Saturated NaHCO ₃The solution cessation reaction is also with ethyl acetate extraction (3x).The ethyl acetate layer that merges is used saturated NaHCO then ₃(2x) and saline (1x) washing and dry (MgSO ₄).Then organic layer is filtered, concentrates and through the 1-[2S-(the 3-tert-butyl group-urea groups)-3 of flash chromatography (45% ethyl acetate/hexane) purification to obtain white solid; 3-dimethyl-butyryl]-4R-(6-methoxyl group-isoquinolyl-1 oxygen base)-pyrrolidine-2S-carboxylic acid (1S-cyclopropyl amidoxalyl-amyl group)-amide (30) (83.5mg; 0.12mmol, 31% productive rate). ¹H?NMR：(DMSO)8.74(d，1H，J＝4.8Hz)；8.27(d，1H，J＝7.2Hz)；8.15(d，1H，J＝9.2Hz)；7.97(d，1H，J＝6.0?Hz)；7.33-7.31(m，2H)；7.10-7.08(dd，1H，J＝2，8.8Hz)；5.96(s，1H)；5.94(d，1H，J＝9.6Hz)；5.71-5.69(m，1H)；5.02-4.98(m，1H)；4.60(t，1H，J＝8.4Hz)；4.34-4.22(m，1H)；4.23(d，1H，J＝9.2Hz)；3.91(s，3H)；3.90-3.87(m，1H)；2.78-2.73(m，1H)；2.54-2.51(m，1H)；2.17-2.11(m，1H)；1.77-1.72(m，1H)；1.43-1.33(m，5H)；1.20(m，9H)；0.95(m，9H)；0.88-0.85(m，5H)；0.69-0.58(m，4H)。MS?m/z?681(M ⁺+H)，703(M ⁺+Na)，680(M ⁺-H)。

Embodiment 14

Step 1

3-cyclopropyl-6-methoxyl group isoquinolin (32).In the time of-15 ℃ 2,2,6,6-tetramethyl piperidine (1.0g; 7.0mmol) THF (17mL) solution in dropwise add n-BuLi (1.6M be dissolved in hexane; 8.0mmol) with preparation tetramethyl piperidine lithium (Lithium tetramethylpiperidide).-15 ℃ of reactions dropwise added cyclohexyl (4-methoxyl group-2-methylbenzene methylene) amine (660mg after 15 minutes; 2.86mmol) THF (3mL) solution to obtain purple solution.Make reactant mixture rise to 0 ℃ with 20 minutes, then also at the THF (2mL) of 0 ℃ of disposable adding N-methyl-N-methoxyl group cyclopropane carboxamide (630mg:4.4mmol) solution.Reactant mixture was placed 30 minutes in room temperature, added saturated NH then ₄The Cl aqueous solution.With this solution of diethyl ether extraction and with organic facies with saturated NaCl solution washing, drying and vacuum concentration.

Residue is dissolved in dense NH ₄OH (15mL) also handles with acetic acid (1mL), is heated to backflow then.The mixture dilute with water, gained solution extracts with diethyl ether.Ether extract water and saturated NaCl solution washing, dry then and vacuum concentration.Chromatography (SiO ₂4: 1 hexanes/EtOAc) obtain 160mg (28%) title compound.Carry out this process with 1.5 gram imines and obtain 400mg (30%) title compound.

Step 2

1-chloro-3-cyclopropyl-6-methoxyl group-isoquinolin (34).3-cyclopropyl-6-methoxyl group isoquinolin (32) is dissolved in dichloromethane (8mL) and is cooled to 0 ℃.Between using-chlorine benzylhydroperoxide (mCPBA; 412mg; 2.4mmol) dichloromethane (8mL) this solution of solution-treated and with mixture stirring at room 2 hours.With dimethyl sulfide (100 μ L) cessation reaction and restir 15 minutes.Mixture is handled with saturated sodium bicarbonate aqueous solution (20mL) and each layer is separated.Water is used dichloromethane extraction, with the organic facies drying, vacuum concentration and the chromatography (SiO that merge ₂The CH of 10%MeOH ₂Cl ₂Solution) to obtain the N-oxide of 405mg (94%) 3-cyclopropyl-6-methoxyl group isoquinolin (33).

This N-oxide is dissolved in dichloromethane (5mL) and adds 1mL POCl ₃Mixture heated was refluxed 2 hours, cool off and pour in the ice.Use NH ₄The OH treatment mixture makes pH reach 8 also with ethyl acetate extraction gained solution.With organic facies with saturated NaCl solution washing, dry and vacuum concentration.Thick product is through chromatography (SiO ₂Hexane/EtOAc, 4: 1) purification to be to obtain 310mg (overall productivity is 66%) title compound.

Step 3

1-N-BOC-4-(3-cyclopropyl-6-methoxyl group isoquinolyl-1 oxygen base) pyrrolidine-2-carboxylic acid (37).Under the room temperature, with N-BOC-4-hydroxyl-L-proline (A; 192mg; 830 μ mol) be dissolved in DMSO (5mL), add potassium tert-butoxide (270mg then; 2.4mmol).With gained solution stirring at room 1.5 hours, add 1-chloro-3-cyclopropyl-6-methoxyl group isoquinolin (4 then; 192mg; 820 μ mol).The gained solution stirring is spent the night, with 15mL 5% aqueous citric acid solution dilution and use ethyl acetate extraction.Organic facies with saturated NaCl solution washing, dry and vacuum concentration to obtain the aryl ester of the rough N-BOC-4-hydroxyl of 375mg-L-proline (35).

The aryl ester that this is rough is dissolved in DMF (2mL), adds hexafluorophosphoric acid (O-7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethylurea (HATU; 380mg; 830 μ mol), add 3-(S)-amino-2-(RS)-hydroxycaproic acid-N-cyclopropyl carboxylic acid amides hydrochloride (36 then; 190mg; 830 μ mol) and N, N-diisopropylethylamine (DIPEA; 800 μ L).With gained mixture stirred overnight, dilute with water then.With the gained sedimentation and filtration, with water washing and dry to obtain 460mg (93%) title compound (37).

Step 4

(S)-and 1-[2-(3-tert-butyl group urea groups)-3,3-dimethyl butyryl]-4-is trans-(2-cyclopropyl-7-methoxy quinoline-4-base oxygen base) pyrrolidine-2-(S)-carboxylic acid (1-cyclopropyl amidoxalyl-butyl) acylamino hydrogen chloride (40).Chemical compound 37 is dissolved in 1 of 4N HCl, 4-diox (2mL) solution, stirring at room is 1 hour then.Be dissolved in DMF (2mL) with the reactant mixture vacuum concentration and with residue (chemical compound 38).Solution is with (S)-2-(3-tert-butyl group urea groups)-3,3-acid dimethyl (C; 100mg; 440 μ mol), HATU (200mg; 520 μ mol) and DIPEA (800mL) handle.The dilute with water reactant mixture also leaches gained deposition, with water washing and dry to obtain the corresponding 2-hydroxyl carboxylic acid amides 39 of 250mg (80%).This solid is dissolved in dichloromethane (20mL) also with 1,1,1-three (acetyl group oxygen base)-1,1-dihydro-1,2-benzoxazole (benziodoxol)-3-(1H)-ketone (D; 220mg; 660 μ mol) handle.With reactant mixture stirring at room 2 hours.Solution adds saturated Na then with diethyl ether (40 mL) dilution ₂S ₂O ₃Aqueous solution (10mL) and 10mL NaHCO ₃Aqueous solution (10mL).This two-phase mixture was stirred 10 minutes, separate each layer then.Organic facies is with saturated NaCl solution washing, dry and vacuum concentration.Residue is through chromatography (SiO ₂Hexane/EtOAc, 1: 1) purification, then from acetonitrile and the isolating material of 0.01%HCl aqueous solution lyophilizing to obtain the title compound (40) of 150mg (46%) hydrochloride form.Mass spectrum (M+Na) 705.

Embodiment 15

Step 1

4-acetyl group-6-methoxyl group is heterochromatic full-1,3-diketone (42).According to the method in the document (Ind.J.Chem. B joint, 1986,25B, 640-643), with 2-carboxyl methyl-4-methoxybenzoic acid (41; 1.0g; 4.8mmol) be dissolved in pyridine (1.4mL) and acetic anhydride (8.6mL; 9.3g; Mixture 91mmol) stirred 3 hours then, during have solid to form.This suspension is diluted, filters and use the diethyl ether washing leaching cake with diethyl ether.Productive rate: 905mg (81%) title compound.

Step 2

6-methoxyl group-3-methyl-2H-isoquinolin-1-ketone (43).With cyclic anhydride 42 (405mg; 1.73mmol) be dissolved in NH ₄The OH aqueous solution is reflux 1.5 hours then.Mixture is cooled to room temperature, solid is leached, dried overnight is to obtain 270mg (74%) title compound then.

Step 3

1-chloro-6-methoxyl group-3-methylisoquinolinium (44).Isoquinolin-1-ketone 43 is dissolved in POCl ₃(2.5mL) and reflux 1 hour.Under vacuum, remove excessive POCl ₃And residue is dissolved in CHCl ₃Gained solution is with 1N NaOH aqueous solution, water and saturated NaCl solution washing.Evaporation is desolvated and is obtained roughly 44, and this material can directly be used for following step.

Step 4

1-N-BOC-4-(6-methoxyl group-3-methylisoquinolinium-1-base oxygen base) pyrrolidine-2-carboxylic acid (45).Under the room temperature, with N-BOC-4-hydroxyl-L-proline (A; 281mg; 1.21mmol) be dissolved in DMSO (3mL), add potassium tert-butoxide (270mg then; 2.4mmol).With gained solution stirring at room 2 hours, be cooled to 0 ℃ then.In the cold soln of A and t-BuOK, dropwise add DMSO (3mL) solution of isoquinolin 14 then, make mixture rise to room temperature then.With this solution stirring 16 hours, add 0.2 equivalent A again and again mixture was stirred 1.5 hours.With 5% aqueous citric acid solution reactant mixture is acidified to pH=4.With this solution of ethyl acetate extraction, organic facies water and saturated NaCl solution washing.The vacuum concentration organic facies is to obtain title compound.

Step 5

1-N-BOC-2-[1-(cyclopropyl carbamyl hydroxymethyl) butyl carbamyl]-4-(6-methoxyl group-3-methyl-isoquinolyl-1 oxygen base) pyrrolidine (47).According to be that chemical compound 5 described same procedure are with chemical compound 45 (196mg; 487 μ mol) change into title compound.Pyrrolidine 47 (210mg; 77% productive rate) need not to be further purified the step that just can be used for subsequently.

Step 6

1-[2-(the 3-tert-butyl group-urea groups)-3,3-dimethyl-butyryl]-4-(7-methoxyl group-2-methylquinoline-4-base oxygen base)-pyrrolidine-2-carboxylic acid (1-cyclopropyl amidoxalyl butyl)-amide (50).Can according to the description of chemical compound 48 with chemical compound 47 (210mg; 368 μ mol) change into corresponding hydrochlorate.Employing is used with chemical compound 39 identical conditions hydrochlorate 48 is changed into tripeptides 49 with intermediate C and HATU then.At last can according to top changing into 40 identical processes with 39 and in dichloromethane, changing into title compound alpha-keto amide 50 with 49 of providing with D.Through chromatography (SiO ₂The hexane solution of 45% ethyl acetate) this thick product of purification obtains 85mg 50 (34%, from 17).Mass spectrum (M+) 680.

Embodiment 16

Synthetic 1-[2S-(the 3-tert-butyl group-urea groups)-3,3-dimethyl-butyryl]-4R-(7-methoxyl group-2-pyrazol-1-yl-quinoline-4-base oxygen base) pyrrolidine-2S-carboxylic acid (1S-cyclopropyl amidoxalyl-butyl)-amide (1):

The another kind of route of synthesis of chemical compound 7

Step 1

With 4-hydroxyl-7-methoxyl group-2-oxo-1,2-EEDQ (method uncle K. (Faber K.) etc., " Jian Shi heterocyclic chemistry " (J.Heterocyclic chem.), 1,985 22,1080) (5.0g, POCl 26.17mmol) ₃(25mL, 261.7mmol) suspension is 115 ℃ of heating 3 hours (the heating back obtains settled solution).After 3 hours, the concentrating under reduced pressure reactant mixture.Pour residue into frozen water (40mL), with 3N NaOH pH is transferred to 10 then, and use CHCl ₃(3x100mL) extraction.The CHCl that merges ₃Layer is with brine wash and dry (MgSO ₄).Then organic layer is filtered and concentrates to obtain 2 of brown solid shape, 4-two chloro-7-methoxy yl-quinolines (4.9g, 21.49mmol, 82% productive rate).MS?m/z?229(M ⁺+H)。

Step 2

Solid pyrazoles (3.2g, 47.36mmol, 3.0 equivalents) is heated to thawing at 80 ℃.Add solid 2 then, 4-two chloro-7-methoxy yl-quinolines (3.6g, 15.78mmol, 1.0 equivalents) and with mixture 115 ℃ the heating 3 hours.Then with mixture be cooled to room temperature and through flash chromatography (20% ethyl acetate/hexane) purification to obtain the 4-chloro-7-methoxyl group-2-pyrazol-1-yl-quinoline (2.3g, 8.88mmol, 56% productive rate) of white solid. ¹H?NMR(CDCl ₃)：8.77(d，1H，J＝2.8Hz)；8.18(s，1H)；8.10(d，1H，J＝9.2Hz)；7.79(s，1H)；7.38(d，1H，J＝2.8Hz)；7.23(dd，1H，J＝2.0，8.8Hz)；6.53-6.52(m，1H)；?3.98(s，3H)。MS?m/z?260(M ⁺+H)。

Step 3

In the time of 23 ℃, commercially available N-t-Boc-(2S, 4R)-hydroxyproline (1.53g, in DMSO 6.64mmol) (20mL) solution with 15 minutes branch small lots add potassium tert-butoxide (1.9g, 16.6mmol).With mixture 23 ℃ stirred 1.5 hours and then with 15 minutes branch small lot adding 4-chloro-7-methoxyl group-2-pyrazol-1-yl-quinoline (1.9g, 7.30mmol).Reactant mixture was stirred 16 hours at 23 ℃.The gained suspension is poured in the water (150mL) also with ethyl acetate (2 * 100mL) purging compounds.The water-bearing layer with 1N HCl acidified aqueous solution to pH about 4 and use CHCl ₃(3 * 100mL) extractions.The CHCl that merges ₃Layer is with brine wash and dry (MgSO ₄).Then organic layer is filtered and concentrates with obtain (2S, 4R)-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-1, the 2-dicarboxylic acids 1-tert-butyl ester (2.7g, 5.95mmol, 90% productive rate).MS?m/z?455(M ⁺+H)，453(M ⁺-H)，355(M ⁺-Boc)。This material need not to be further purified just and can be used for following step by crude product.

Step 4

At [1S-(cyclopropyl carbamyl-hydroxyl-methyl)-butyl]-t-butyl carbamate (1.05g, 3.67mmol) middle 4.0M HCl De diox (13mL) solution that adds.After 1 hour, reactant mixture is concentrated also dry to obtain the hydrochlorate of corresponding white solid.The DCM/DMF of above-mentioned amine hydrochlorate (3: 1,60mL) add in the solution (2S, 4R)-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-1; The 2-dicarboxylic acids 1-tert-butyl ester (1.66g; 3.67mmol), HATU (1.67g, 4.40mmol) and DIPEA (2.6mL, 14.08mmol).After the room temperature 1 hour, with ethyl acetate diluted reaction mixture (100mL) and with 1N HCl (2 * 50mL), NaHCO ₃(1 * 100mL) and saline (1x) washing.With the dry (MgSO of ethyl acetate layer ₄), filter and be evaporated to and do to obtain 2S-[1S-(cyclopropyl carbamyl-hydroxyl-methyl)-butyl carbamyl]-4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-1-carboxylic acid tert-butyl ester, it is the mixture of diastereomer.This material need not to be further purified just and can be used for following step by crude product.

Step 5

In above-claimed cpd, add 4.0M HCl De diox (15mL) solution.After 1 hour, reactant mixture is concentrated also dry to obtain the hydrochlorate of corresponding white solid.The DCM/DMF of above-mentioned amine hydrochlorate (3: 1,60mL) add 2S-(the 3-tert-butyl group-urea groups)-3 in the solution, 3-dimethyl-butanoic acid (848mg, 3.67mmol), HATU (1.67g, 4.40mmol) and DIPEA (2.6mL, 14.08mmol).After the room temperature 1 hour, with ethyl acetate diluted reaction mixture (100mL) and with 1N HCl (2 * 50mL), NaHCO ₃(1 * 100mL) and saline (1x) washing.With the dry (MgSO of ethyl acetate layer ₄), filter and be evaporated to dried.This material need not to be further purified just and can be used for following step by crude product.

Step 6

Then above-mentioned thick product is dissolved in anhydrous DCM (25mL) and add the high iodine alkane of De Si-Martin (Dess-Martin) (2.0g, 4.71mmol).Stirring at room is used 0.26M Na after 1 hour ₂S ₂O ₃Saturated NaHCO ₃The solution cessation reaction also extracts with DCM (3x).The DCM layer that merges is used saturated NaHCO then ₃(2x) and saline (1x) washing and dry (MgSO ₄).Then organic layer is filtered, concentrates and through the 1-[2S-(the 3-tert-butyl group-urea groups)-3 of flash chromatography (60% ethyl acetate/hexane) purification to obtain white solid; 3-dimethyl-butyryl]-4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base) pyrrolidine-2S-carboxylic acid (1S-cyclopropyl amidoxalyl-butyl)-amide (7) (1.6g; 2.18mmol, 60% productive rate). ¹H NMR: (DMSO-d ₆) 8.76-8.70 (m, 2 H); 8.22 (d, J=6.8Hz, 1H); 8.11 (d, J=9.6Hz, 1H); 7.87 (d, J=1.2Hz, 1H); 7.45 (s, 1H); 7.27 (d, J=2.4Hz, 1H); 7.00-6.97 (dd, J=2.8 and 9.6Hz, 1H); 6.64-6.62 (m, 1H); 5.92 (brs, 1H); 5.49 (brs, 1H); 5.00-4.96 (m, 1H); 4.55-4.49 (m, 2H); 4.18 (d, J=5.6Hz, 1H); (3.90 s, 3 H); 3.91-3.82 (m, 1H); 3.54 (brs, 1H); 2.75-2.72 (m, 1H); 2.54-2.51 (m, 1H); 2.17-2.14 (m, 1H); 1.69-1.66 (m, 1H); 1.40-1.34 (m, 3H); 1.13 (m, 9H); 0.93 (m, 9H); 0.90-0.82 (m, 3H); 0.65-0.53 (m, 4H).MS?m/z?733(M ⁺+H)，755(M ⁺+Na)，731(M ⁺-H)。

Biology embodiment

Embodiment 1

The test of HCV replicon

The test of HCV replicon is the cell culture system that HCV duplicates in a kind of analogue body, and it is for to duplicate a kind of system that provides in vitro study HCV.It with the viral RNA derived from the clone of total HCV genome sequence be transfected into half allow viral RNA to duplicate people Huh7 hepatocyte form (Luo Man V. (Lohmann V.); The promise F. of section (Korner F.); The plan J.-O. of section (Koch J.-O.), extra large Ruian U. (Herian U.), ferrum Germania L. (Theilmann L.) and Ba Teng plan lattice R. (Bartenschlager R.); 1999; " hepatoma cells is duplicating of the genomic HCV RNA of neutron " (Replication of subgenomic Hepatitis C virus RNAsin a hepatoma cell line). " science " (Science) 285,110-113, and Bu Laite K.J. (Blight K.J.); The card Hough A.A. of section (Kolykhalov A.A.) and this C.M. of Lay (Rice C.M.); 2000, " effective initiation that HCVRNA duplicates in the cell line " (Efficient initiation of HCV RNA Replication in cell culture). " science " (Science) 290,972-1974).Sub-gene group HCV rna gene group is contained in these cells transfected systems; Comprising: the HCV 5 ' NTR that 12 aminoacid of (1) and capsid coding region merge; (2) as the neomycin phosphotransferase gene (Neo) of selectable marker; (3) from the internal ribosome entry site (IRES) of encephalomyocarditis virus (EMCV), it can instruct the translation of HCV non-structural protein (NS2 or NS3 or NS5B), and (4) 3 ' NTR.It is spontaneous and duplicate HCV RNA constantly to contain the cell of replicon, and this can be through real-time qPCR quantitative measurement.Therefore, in the test based on cell, the replicon system helps the qualitative assessment antiviral activity through the variation of monitoring HCV rna replicon.

The cell (Huh7/Clone A) that contains the HCV replicon is maintained at clone A growth medium (DMEM culture medium [because of dimension Qu Gen company (Invitrogen)] wherein is added with 10% hyclone, 1% non essential amino acid and 1g/L G418) usually.Before treatment, test compounds is dissolved in dimethyl sulfoxine (DMSO) with preparation 200X stock solution, this stock solution is used to all dosage.

For carrying out the test of HCV replicon, the Huh7/CloneA cell in the culture bottle is used trypsin treatment, with 4 * 10 ⁴Cells/well is inoculated in the 1 mL Clone A growth medium that does not contain G418 in the 24 hole flat boards, and at the CO of humidity ₂(5%) in the incubator in 37 ℃ of overnight incubation.After the overnight incubation, the compound solution (every hole 5 μ l 200X chemical compound stock solutions) that in each hole, adds equal volume is so that the final concentration of DMSO is 0.5%.Add 5 μ l DMSO as untreated contrast in each three dull and stereotyped hole.Begin from initial stock solution, when carrying out 7 serial dilutions, measure the IC of chemical compound with three multiple holes ₅₀Flat board was cultivated 48 hours at 37 ℃.Cultivate the back harvesting, be transferred to 96 orifice plates, and extract total RNA with the middle process of describing of Rneasy 96 handbooks (just root company) that RNA separating kit (RNeasy 96, just root company (Qiagen)) is write according to manufacturer.

The method (molecular probe company (Molecular Probe)) that provides according to supplier through this Green of sieve (RiboGreen) test quantitatively is eluted in the dH that 130 μ l do not contain the RNA enzyme ₂RNA among the O.In brief, the every equal portions 5 μ l RNA samples of duplicate adding in 96 hole black microplates and 96 hole TaqMan optical flats.With this Green of sieve (RiboGreen) reagent of the RNA sample in the black microplate and 95 μ l dilution (be diluted at 1: 250 TE buffer) mixes and with fluorescence microplate reader at standard fluorescence element wavelength (excitation wave is about 480nm, and transmitted wave is about 520nm) time measuring samples fluorescence.Adopt ribosomal RNA (molecular probe company) as standard substance.

Adopt TaqMan quantitative PCR (RT-qPCR) to quantize the amount of HCV replicon rna in each sample.RT-qPCR is reflected on the ABI PRISM 7900 HT sequence detection systems (Applied Biosystems, Inc. (AppliedBiosystems)) and carries out, and reaction volume is 25 μ l.Contain the total RNA of 5 μ l (10-100 ng) in the reactant mixture, 1X TaqMan Buffer A (Applied Biosystems, Inc.), 5.5mM MgCl ₂, 1.2mM mixing dNTP, 0.625UAmpliTaq Gold (Applied Biosystems, Inc.), 5U MMLV reverse transcriptase (Pu Maige company (Promega)), 5U rRNasin (Pu Maige company), the various forwards of 300nM and reverse primer and 100nM TaqMan MGB probe.Primer and probe be designed to replicon in a part of neomycin resistance gene (neo) hybridization, its sequence is following: forward primer 5 '-GGCTACCTGCCCATTCGA-3 '; Reverse primer 5 '-CCGGCTTCCATCCGAGTAC-3 '; MGB probe 5 '-CCACCAAGCGAAACA-3 '.The RT step was carried out 30 minutes at 48 ℃, carried out 10 minutes at 95 ℃ then.The thermal cycle program comprises 95 ℃ of 15 seconds and 60 ℃ of 40 circulations of 1 minute.With sequence detection system (SDS) software analysis TaqMan initial data (Ct value), its arithmetic is converted to the amount of HCV rna gene group and is standardized into the total RNA in each sample.As contrast, the HCV replicon rna level of untreated cell is defined as 100% without the sample of compound treatment.The amount that the inhibition activity of chemical compound is defined as standardization HCV RNA in the treated sample accounts for the ratio of untreated control.The IC of employing standard 4 parameter curve nucleoid Model Calculation chemical compounds ₅₀

Detected chemical compound of the present invention and observed the IC that its inhibition HCV duplicates through above-mentioned test ₅₀＜100 micromoles.Chemical compound 3,6 and 7 suppresses the IC that HCV duplicates ₅₀＜50 micromoles; And the IC that chemical compound 1,2,5,8-13 and 15 inhibition HCV duplicate ₅₀＜10 micromoles.

Embodiment 1

The representational pharmaceutical preparation that contains chemical compound shown in the formula (I)

Oral formulations

The chemical compound 10-100mg of formula (I)

Citric acid monohydrate compound 105mg

Sodium hydroxide 18mg

Flavoring agent

Water is an amount of, to 100mL

Iv formulation

The chemical compound 0.1-10mg of formula (I)

Dextrose monohydrate is an amount of, extremely waits and oozes

Citric acid monohydrate compound 1.05mg

Sodium hydroxide 0.18mg

Water for injection is an amount of, to 1.0mL

Tablet formulation

The chemical compound 1% of formula (I)

Microcrystalline Cellulose 73%

Stearic acid 25%

Silica sol 1%

In order to clarify and to understand, describe foregoing invention to a certain extent in detail with embodiment by way of example.It will be apparent to those skilled in the art that and in the scope of accessory claim, to make a change and to modify for being proficient in.Therefore, should be understood that top description just for example and unrestricted.Therefore, scope of the present invention can not be decided according to top description, and should be with reference to following claim and the included full scope of equivalents of this claim and determine.

Claims

1. the chemical compound of formula (I) or its pharmaceutically acceptable salt or diastereomer:

In the formula,

E is-COCONR ⁵R ⁶, R wherein ⁵And R ⁶Independently be selected from hydrogen or C separately _3-8Cycloalkyl;

R ¹Be C _1-8Alkyl or C _3-8Cycloalkyl C _1-8Alkyl;

X is-O-;

R ³Be C _1-8Alkyl;

Y is-OC (O) NH-or-NR ¹⁴-C (O) NH-, wherein R ¹⁴Be hydrogen;

R ²Be randomly to be selected C by 1-2 _1-8Alkoxyl, halogen, C _1-8Alkyl, C _3-8The substituted quinolyl of the substituent group of cycloalkyl, phenyl and pyrazolyl, isoquinolyl or pyridine radicals; With

R ⁴Be C _1-8Alkyl.

2. chemical compound as claimed in claim 1, wherein, R ²Be the group shown in the formula (a):

In the formula:

R ^D1Be hydrogen or C _1-8Alkoxyl;

R ^dWith ^D2Independent is hydrogen, C _1-8Alkyl, halogen or C _1-8Alkoxyl;

R ^D3Be hydrogen, C _1-8Alkyl, C _3-8Cycloalkyl, phenyl or pyrazolyl.

3. chemical compound as claimed in claim 2, wherein, R ^D1Be hydrogen or C _1-8Alkoxyl; R ^dAnd R ^D2Independent is hydrogen, C _1-8Alkyl, halogen or C _1-8Alkoxyl; And R ^D3Be hydrogen, C _1-8Alkyl or C _3-8Cycloalkyl.

4. chemical compound as claimed in claim 2, wherein, R ^D1Be hydrogen, methoxyl group, ethyoxyl, positive propoxy or isopropoxy; R ^dAnd R ^D2Independent is fluorine, chlorine, methyl, acetenyl, methoxy or ethoxy.

5. chemical compound as claimed in claim 2, wherein, R ^D1Be hydrogen, methoxy or ethoxy; R ^dAnd R ^D2Independent is hydrogen, fluorine, chlorine or methyl.

6. chemical compound as claimed in claim 2, wherein, R ^D1It is methoxy or ethoxy; And R ^d, R ^D2And R ^D3The hydrogen of respectively doing for oneself.

7. chemical compound as claimed in claim 1, wherein, R ¹Be C _1-8Alkyl or C _3-8Cycloalkyl C _1-8Alkyl; And R ³Be 1-Methylethyl, 1-methyl-propyl or the tert-butyl group.

8. chemical compound as claimed in claim 1, wherein, R ¹Be cyclobutylmethyl, ethyl or n-pro-pyl; And R ³It is the tert-butyl group.

9. chemical compound as claimed in claim 1, wherein, E is-COCONHR ⁶, R wherein ⁶It is cyclopropyl.

10. chemical compound as claimed in claim 1, wherein, Y is-NHC (O) NH-R ⁴Be C _1-8Alkyl.

11. chemical compound as claimed in claim 1, wherein, Y is-OC (O) NH-R ⁴Be C _1-8Alkyl.

12. have the chemical compound of following structure, or its pharmaceutically acceptable salt:

13. have the chemical compound of following structure, or its pharmaceutically acceptable salt:

14. by the mixture of diastereomers of the chemical compound of following structure representative, or its pharmaceutically acceptable salt:

15. be selected from down the chemical compound of group:

1-[2S-(3-tert-butyl group urea groups)-3,3-dimethyl butyryl]-4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-2S-carboxylic acid (1S-cyclopropyl amidoxalyl butyl) amide;

1-[2S-(3-tert-butyl group urea groups)-3,3-dimethyl butyryl]-4R-(7-methoxyl group-2-pyrazol-1-yl quinolyl-4 oxygen base)-pyrrolidine-2S-carboxylic acid (1S-cyclobutylmethyl-2-cyclopropyl carbamyl-2-oxoethyl) amide;

{ 1S-[2S-(1S-cyclopropyl amidoxalyl butyl carbamyl)-4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-1-carbonyl]-2,2-dimethyl propyl }-t-butyl carbamate;

{ 1S-[2S-(1S-cyclopropyl amidoxalyl butyl carbamyl)-4R-(7-methoxyl group-2-phenyl-quinolyl-4 oxygen base)-pyrrolidine-1-carbonyl]-2,2-dimethyl propyl }-t-butyl carbamate;

(S)-and 1-[2-(3-tert-butyl group urea groups)-3,3-dimethyl butyryl]-4-is trans-(2-cyclopropyl-7-methoxy quinoline-4-base oxygen base) pyrrolidine-2-(S)-carboxylic acid (1-cyclopropyl amidoxalyl-butyl) acylamino hydrogen chloride; With

1-[2-(the 3-tert-butyl group-urea groups)-3,3-dimethyl-butyryl]-4-(7-methoxyl group-2-methylquinoline-4-base oxygen base)-pyrrolidine-2-carboxylic acid (1-cyclopropyl amidoxalyl butyl)-amide.

16. a pharmaceutical composition, it comprises like each described chemical compound among the claim 1-15 and one or more pharmaceutically acceptable excipient.

17. the purposes of each described chemical compound in the medicine that preparation treatment hepatitis C infection is used among the claim 1-15.

18. chemical compound as claimed in claim 1; It is 1-[2S-(3-tert-butyl group urea groups)-3,3-dimethyl butyryl]-4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-23-carboxylic acid (1-cyclopropyl amidoxalyl butyl) amide with and the mixture of any diastereomer or diastereomer; Or its pharmaceutically acceptable sulfate or sulfonate.

19. chemical compound as claimed in claim 1, it is 1-[2S-(3-tert-butyl group urea groups)-3,3-dimethyl butyryl]-4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-2S-carboxylic acid (1S-cyclopropyl amidoxalyl butyl) amide; Or its sulfate or metilsulfate.

20. chemical compound as claimed in claim 1, it is 1-[2S-(3-tert-butyl group urea groups)-3,3-dimethyl butyryl]-4R-(7-methoxyl group-2-pyrazol-1-yl-quinolyl-4 oxygen base)-pyrrolidine-2S-carboxylic acid (1R-cyclopropyl amidoxalyl butyl) amide; Or its sulfate or metilsulfate.

21. pharmaceutical composition as claimed in claim 16 also comprises second antiviral agent.

22. pharmaceutical composition as claimed in claim 21, wherein, said second antiviral agent is ribavirin or AG14361.

23. each the described chemical compound and second antiviral agent purposes in the medicine of preparation treatment HCV infection usefulness among the claim 1-15; Wherein, said second antiviral agent is selected from interferon, Pegylation or not interferon congener, ribavirin, HCV AG14361 and the toll receptor stimulating agent of Pegylation.