CN101103022B

CN101103022B - New carboxylic acid amide used as XA inhititor

Info

Publication number: CN101103022B
Application number: CN2005800129295A
Authority: CN
Inventors: 卡伊·格拉克; 罗兰·普福; 亨宁·普里普克; 沃尔夫冈·威尼恩; 安妮特·M·舒勒-梅茨; 乔格·达曼; 赫伯特·纳尔; 桑德拉·R·汉舒; 诺伯特·豪尔; 艾里斯·考夫曼-赫夫纳
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 2004-02-28
Filing date: 2005-02-22
Publication date: 2012-06-27
Anticipated expiration: 2025-02-22
Also published as: ES2371920T3; DE102004009835A1; CN101103022A; UA86616C2; ZA200604013B

Abstract

N-substituted 4-heterocyclyl-benzamide derivatives (I), their tautomers, enantiomers, diastereomers (and mixtures) and salts are new. - A = heterocyclic group; - R1 = hydrogen, fluoro, chloro, bromo, 1-3C alkyl (optionally (per)fluorinated), 2-3C alkenyl or alkynyl, nitro, amino, 1-3C alkoxy or mono-, di- or tri-fluoromethoxy; - R2 = hydrogen, chloro, bromo or 1-3C alkyl; - R3 = hydrogen or a substituent; - R4 = hydrogen or 1-3C alkyl, or R3 and R4together complete 3-7C cycloalkyl in which one methylene may be replaced by imino, 1-3C alkylimino, acylimino or sulfonylimino; - R5 = hydrogen or 1-3C alkyl; - B = fused heterocyclic group of formulae (Bi), (Bii) and (Biii); - n = 1 or 2; - R7 = hydrogen, 1-3C alkyl (optionally substituted by carboxy or 1-3C alkoxycarbonyl), hydroxy, 1-5C alkoxycarbonyl, amino or 1-3C alkylamino; - R8 = hydrogen, fluoro, chloro, bromo, iodo, 1-3C alkyl (optionally (per)fluorinated), 2-3C alkenyl or alkynyl, hydroxy, 1-3C alkoxy, trifluoromethoxy, amino, nitro or cyano. - The full definitions are given in theDEFINITIONS (Full Definitions) Field. - ACTIVITY - Thrombolytic; Anticoagulant; Antiulcer; Cerebroprotective; Cardiant; Cytostatic; Antiarthritic; Antirheumatic. - No biological data is given. - MECHANISM OF ACTION - (I) are inhibitors of factor Xa and/or related serine proteases (e.g. thrombin, urokinase, factors VIIa, IXa, XIa and XIIa).

Description

New carboxylic acid amide as the XA suppressor factor

Technical field under the invention

The invention relates to novel substituted carboxylic acid amide with following general formula

And the physiologically acceptable salt of tautomer, enantiomer, diastereomer, mixture and salt, particularly itself and inorganic or organic acid or alkali, it has the character of value.

Summary of the invention

The compound of top general formula I with and tautomer, enantiomer, diastereomer, mixture and salt; The physiologically acceptable salt of itself and inorganic or organic acid or alkali particularly; And steric isomer has the pharmacological properties of value, particularly antithrombotic acitivity and Xa factor suppresses active.

Therefore the application's case be about top general formula I compounds, its preparation, contain pharmaceutical composition, its preparation and the purposes of active compound on the pharmacology.

Embodiment

In the above-mentioned general formula of first embodiment, A represents the group of following general formula

Wherein

M represents numeral 1 or 2,

R ^6aRepresent hydrogen, fluorine, chlorine or bromine atom or C independently of one another _1-3-alkyl, hydroxyl, amino, C _1-3-alkylamino, two-(C _1-3Alkyl)-amino, aminocarboxyl, C _1-3-alkyl amino-carbonyl, two-(C _1-3-alkyl)-aminocarboxyl or C _1-3-alkyl-carbonyl-amino reaches

R ^6bCan be Wasserstoffatoms, C independently of one another _1-4-alkyl, C _1-4-alkyl-carbonyl, C _1-4-alkoxy carbonyl or C _1-3-alkyl sulphonyl, its restricted condition does

In above-mentioned substituted 5-to 7-member cyclic group A, the heteroatoms of randomly introducing as substituting group and another heteroatoms proper what a carbon atom of not being separated by, or

The group of following general formula

Wherein

M represents numeral 1 or 2,

X ¹Represention oxygen atom or methylene radical ,-NR ^6b-, carbonyl or alkylsulfonyl,

X ²Represention oxygen atom or-NR ^6bGroup,

X ³Represent methylene radical, carbonyl or alkylsulfonyl,

X ⁴Represent oxygen or sulphur atom ,-NR ^6bOr carbonyl,

X ⁵Represent carbonyl or alkylsulfonyl,

X ⁶Represention oxygen atom ,-NR ^6bOr methylene radical,

X ⁷Represent oxygen or sulphur atom or-NR ^6bGroup,

X ⁸Represent methylene radical or carbonyl,

X ⁹Representative-NR ^6bOr carbonyl,

X ¹⁰Represent sulfinyl or alkylsulfonyl, and

R ^6aRepresent hydrogen, fluorine, chlorine or bromine atom or C independently of one another _1-3-alkyl, hydroxyl, amino, C _1-3-alkylamino, two-(C _1-3-alkyl)-amino, aminocarboxyl, C _1-3-alkyl amino-carbonyl, two-(C _1-3-alkyl)-aminocarboxyl or C _1-3-alkyl-carbonyl-amino, and

In above-mentioned substituted 5-to 7-member cyclic group A, the heteroatoms of randomly introducing as substituting group and another heteroatoms proper what a carbon atom of not being separated by,

R ¹Represent hydrogen, fluorine, chlorine or bromine atom, C _1-3-alkyl (wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part), C _2-3-thiazolinyl, C _2-3-alkynyl, nitro, amino, C _1-3-alkoxyl group, list-, two-or trifluoromethoxy,

R ²Represent hydrogen, fluorine, chlorine or bromine atom or C _1-3-alkyl,

R ³Represent Wasserstoffatoms, C _2-3-thiazolinyl or C _2-3-alkynyl or straight or branched C _1-6-alkyl, wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part, and randomly by nitrile (nitrile), hydroxyl, C _1-5-alkoxyl group (wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part), allyloxy, alkynes propoxy-, benzyloxy, C _1-5-alkyl-carbonyl oxygen base, C _1-5-alkoxy-carbonyl oxy, carboxyl-C _1-3-alkoxyl group, C _1-5-alkoxy carbonyl-C _1-3-alkoxyl group, C _1-8-alkoxycarbonyl amino, sulfydryl, C _1-3-alkylthio, C _1-3-alkyl sulphinyl, C _1-3-alkyl sulphonyl, C _1-3-alkyl-carbonyl-amino-C _1-3-alkylthio, C _1-3-alkyl-carbonyl-amino-C _1-3-alkyl sulphinyl, C _1-3-alkyl-alkyl carbonylamino-C _1-3-alkyl sulphonyl, carboxyl, C _1-3-alkoxy carbonyl, allyloxy carbonyl, alkynes propoxycarbonyl, benzyloxycarbonyl, aminocarboxyl, C _1-3-alkyl amino-carbonyl, two-(C _1-3-alkyl)-aminocarboxyl, C _3-6-cycloalkylidene (cycloalkylene) imino-carbonyl, amino-sulfonyl, C _1-3-alkyl amino sulfonyl, two-(C _1-3-alkyl)-amino-sulfonyl, C _3-6-cycloalkylidene imino-alkylsulfonyl, amino, C _1-3-alkylamino, two-(C _1-3-alkyl)-amino, C _1-5-alkyl-carbonyl-amino, C _1-3-alkyl sulfonyl-amino, N-(C _1-3-alkyl sulphonyl)-C _1-3-alkylamino, C _3-6-cycloalkyl amino carbonyl, amino carbonyl amino, C _1-3-alkyl amino-carbonyl is amino, two-(C _1-3-alkyl)-amino carbonyl amino, 4-to 7-member cycloalkylidene imino-carbonylamino, benzyloxycarbonyl are amino, phenylcarbonyl group is amino or guanidino group replaces,

Carboxyl, aminocarboxyl, C _1-4-alkyl amino-carbonyl, C _3-6-cycloalkyl amino carbonyl, two-(C _1-3-alkyl)-aminocarboxyl, C _1-4-alkoxy carbonyl, C _4-6-cycloalkylidene imino-carbonyl,

Phenyl or heteroaryl, phenylcarbonyl group-C _1-3-alkyl, phenyl-C _1-3-alkyl or heteroaryl-C _1-3-alkyl, its randomly in phenyl or heteroaryl moieties by fluorine, chlorine or bromine atom, C _1-3-alkyl, amino, C _1-3-alkylamino, two-(C _1-3-alkyl)-amino, hydroxyl, C _1-4-alkoxyl group, list-, two-or trifluoromethoxy, benzyloxy, carboxyl-C _1-3-alkoxyl group, C _1-3-alkoxy carbonyl-C _1-3-alkoxyl group, aminocarboxyl-C _1-3-alkoxyl group, C _1-3-alkyl amino-carbonyl-C _1-3-alkoxyl group, two-(C _1-3-alkyl)-aminocarboxyl-C _1-3-alkoxyl group, 4-to 7-member cycloalkylidene imino-carbonyl-C _1-3-alkoxyl group, carboxyl, C _1-3-alkoxy carbonyl or C _1-3-alkoxycarbonyl amino list-or polysubstituted,

3-to 7-member naphthenic base, cycloalkylidene imino-, naphthenic base-C _1-3-alkyl or cycloalkylidene imino--C _1-3-alkyl, wherein the methylene radical in circular part can be by randomly by C _1-3-alkyl or C _1-3-alkyl-carbonyl is substituted-replacement of NH group or by the Sauerstoffatom replacement and wherein other adjacent to-NH-,-N (C _1-3-alkyl-carbonyl)-or-N (C _1-3-alkyl)-methylene radical of group can be by carbonyl or alkylsulfonyl replacement under various situation, its restricted condition be as in the cycloalkylidene imino-of aforementioned definitions two nitrogen-atoms of eliminating apart proper what a-CH ₂-group,

R ⁴Represent Wasserstoffatoms or C _1-3-alkyl or

R ³And R ⁴Represent C with its bonded carbon atom _3-7-naphthenic base, and

C _3-7A methylene radical of-naphthenic base can be by imino-, C _1-3-alkyl imino, acyl group imino-(acylimino) or alkylsulfonyl imino-(sulphonylimino) replacement,

R ⁵Represent Wasserstoffatoms or C _1-3-alkyl,

B represents the group of following formula

Wherein

N represents numeral 1 or 2,

R ⁷Represent Wasserstoffatoms or C _1-3-alkyl, hydroxyl, C _1-5-alkoxy carbonyl, carboxyl-C _1-3-alkyl, C _1-3-alkoxy carbonyl-C _1-3-alkyl, amino or C _1-3-alkylamino, and

R ⁸Represent hydrogen, fluorine, chlorine, bromine or iodine atom, C independently of one another _1-3-alkyl (wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part), C _2-3-thiazolinyl or C _2-3-alkynyl, hydroxyl, C _1-3-alkoxyl group, trifluoromethoxy, amino, nitro or itrile group,

And except as otherwise noted, the term of in the preamble definition, being mentioned " heteroaryl " means monocycle 5-or 6-person's heteroaryl, and

This 6-person's heteroaryl contains one, two or three nitrogen-atoms, and

This 5-person's heteroaryl contains randomly by C _1-3-alkyl, phenyl or phenyl-C _1-3The substituted imino-of-alkyl, oxygen or sulphur atom, or

Randomly by C _1-3-alkyl, phenyl, amino-C _2-3-alkyl, C _1-3-alkylamino-C _2-3-alkyl, two-(C _1-3-alkyl)-amino-C _2-3-alkyl, 4-to 7-member cycloalkylidene imino--C _1-3-alkyl or phenyl-C _1-3Substituted imino-of-alkyl or oxygen or sulphur atom and other nitrogen-atoms, or

Randomly by C _1-3-alkyl or phenyl-C _1-3The substituted imino-of-alkyl and two or three nitrogen-atoms,

In addition, randomly by fluorine, chlorine or bromine atom, C _1-3-alkyl, hydroxyl, C _1-3-alkoxyl group, amino, C _1-3-alkylamino, two-(C _1-3-alkyl)-amino or C _3-6The substituted phenyl ring of-cycloalkylidene imino-can be fused to above-mentioned bicyclic heteroaryl via two adjacent carbonss

And carry out bonding via heterocyclic moiety or the nitrogen-atoms or the carbon atom that condense on phenyl ring,

And be contained in alkyl and the alkoxyl group that have in the above-mentioned definition more than two carbon atoms, except as otherwise noted, for straight or branched, and in aforementioned dialkylated group for example the alkyl in the dialkyl amido can be identical or different,

And the methyl or the Wasserstoffatoms of ethyl that are contained in the front definition replace by fluorine atom whole or in part,

And tautomer, enantiomer, diastereomer, mixture and salt.

The instance of bicyclic heteroaryl is pyridyl, N-oxo-pyridyl, pyrazolyl, pyridazinyl, pyrimidyl, pyrazinyl, [1,2,3] triazinyl, [1,3,5] triazinyl, [1; 2,4] triazinyl, pyrryl, imidazolyl, [1,2,4] triazolyl, [1; 2,3] triazolyl, tetrazyl, furyl 、 isoxazolyl 、 oxazolyl, [1,2,3] oxadiazole bases, [1; 2,4] oxadiazole bases, furazan base, thienyl, thiazolyl, isothiazolyl, [1,2,3] thiadiazolyl group, [1; 2,4] thiadiazolyl group or [1,2,5] thiadiazolyl group.

The instance of bicyclic heteroaryl is benzimidazolyl-, benzofuryl, benzo [c] furyl, benzothienyl, benzo [c] thienyl, benzothiazolyl, benzo [c] isothiazolyl, benzo [d] isothiazolyl, benzoxazolyl, benzo [c] isoxazolyl, benzo [d] isoxazolyl, benzo [1; 2,5] oxadiazole bases, benzo [1,2; 5] thiadiazolyl group, benzo [1; 2,3] thiadiazolyl group, benzo [d] [1,2; 3] triazinyl, benzo [1; 2,4] triazinyl, benzotriazole base, cinnolines base, quinolyl, N-oxo-quinolyl, isoquinolyl, quinazolyl, N-oxo-quinazolyl, quinoxalinyl, phthalazinyl, indyl, pseudoindoyl or 1-oxa--2,3-diaza-indenyl.

The C that in the preamble definition, is mentioned _1-8The instance of-alkyl is methyl, ethyl, 1-propyl group, 2-propyl group, normal-butyl, sec.-butyl, the tertiary butyl, 1-amyl group, 2-amyl group, 3-amyl group, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl group, 2-octyl group, 3-octyl group or 4-octyl group.

The C that in the preamble definition, is mentioned _1-8The instance of-alkoxyl group is methoxyl group, oxyethyl group, 1-propoxy-, 2-propoxy-, n-butoxy, sec.-butoxy, tert.-butoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, neopentyl oxygen, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 1-oxygen in heptan base, 2-oxygen in heptan base, 3-oxygen in heptan base, 4-oxygen in heptan base, 1-octyloxy, 2-octyloxy, 3-octyloxy or 4-octyloxy.

The group that in body, can be transformed into carboxyl for example means the carboxyl with pure esterification, and wherein alcohol moiety is preferably C _1-6-alkanol, phenyl-C _1-3-alkanol, C _3-9-cycloalkanol, C _5-7-cyclenes alcohol, C _3-5-enol, phenyl-C _3-5-enol, C _3-5-alkynol or phenyl-C _3-5-alkynol, its restricted condition are that the key of Sauerstoffatom does not begin C from having two keys or triple-linked carbon atom _3-8-naphthenic base-C _1-3The alcohol of-alkanol or following formula

R ⁹-CO-O-(R ¹⁰CR ¹¹)-OH

Wherein

R ⁹Represent C _1-8-alkyl, C _5-7Naphthenic base, phenyl or phenyl-C _1-3-alkyl,

R ¹⁰Represent Wasserstoffatoms, C _1-3-alkyl, C _5-7-naphthenic base or phenyl reach

R ¹¹Represent Wasserstoffatoms or C _1-3-alkyl.

In body, can comprise C from the preferred group that carboxyl is sloughed _1-6-alkoxyl group such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, n-pentyloxy, positive hexyloxy or cyclohexyloxy or phenyl-C _1-3-alkoxyl group such as benzyloxy.

R wherein ³Those compounds that contain the general formula I of the group that in body, can change carboxyl into are R wherein ³The prodrug of those compounds that contains the general formula I of carboxyl.

Second embodiment of the present invention comprises those compounds of general formula I, wherein

A represents the group of following general formula

Wherein m represents numeral 1 or 2,

R ^6aRepresent hydrogen or fluorine atom, C independently of one another _1-3-alkyl, hydroxyl, amino, C _1-3-alkylamino, two-(C _1-3) alkyl-amino, aminocarboxyl, C _1-3-alkyl amino-carbonyl, two-(C _1-3-alkyl)-aminocarboxyl or C _1-3-alkyl-carbonyl-amino, and

The group of following general formula

Wherein

M represents numeral 1 or 2,

X ¹Represent methylene radical ,-NR ^6b-, carbonyl or alkylsulfonyl,

X ²Represention oxygen atom or-NR ^6bGroup,

X ³Represent methylene radical, carbonyl or alkylsulfonyl,

X ⁴Represent oxygen or sulphur atom ,-NR ^6bOr carbonyl,

X ⁵Represent carbonyl or alkylsulfonyl,

X ⁸Represent carbonyl,

X ⁹Represent carbonyl,

R ^6aRepresent hydrogen or fluorine atom, C independently of one another _1-3-alkyl, hydroxyl, amino, C _1-3-alkylamino, two-(C _1-3-alkyl)-amino, aminocarboxyl, C _1-3-alkyl amino-carbonyl, two-(C _1-3-alkyl)-aminocarboxyl or C _1-3-alkyl-carbonyl-amino, and

In above-mentioned substituted 5-to 7-member cyclic group A, the heteroatoms of introducing as substituting group and another heteroatoms proper what a carbon atom of not being separated by,

R ²Represent hydrogen, fluorine, chlorine or bromine atom or C _1-3-alkyl,

R ³Represent C _2-3-thiazolinyl or C _2-3The C of-alkynyl or straight or branched _1-6-alkyl, wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part, and randomly by nitrile (nitrile), hydroxyl, C _1-5-alkoxyl group (wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part), allyloxy, alkynes propoxy-, benzyloxy, C _1-5-alkyl-carbonyl oxygen base, C _1-5-alkoxy-carbonyl oxy, carboxyl-C _1-3-alkoxyl group, C _1-5-alkoxy carbonyl-C _1-3-alkoxyl group, C _1-8-alkoxycarbonyl amino, sulfydryl, C _1-3-alkylthio, C _1-3-alkyl sulphinyl, C _1-3-alkyl sulphonyl, C _1-3-alkyl-carbonyl-amino-C _1-3-alkylthio, C _1-3-alkyl-carbonyl-amino-C _1-3-alkyl sulphinyl, C _1-3Alkyl-carbonyl-amino-C _1-3-alkyl sulphonyl, carboxyl, C _1-3-alkoxy carbonyl, allyloxy carbonyl, alkynes propoxycarbonyl, benzyloxycarbonyl, aminocarboxyl, C _1-3-alkyl amino-carbonyl, two-(C _1-3-alkyl)-aminocarboxyl, C _3-6-cycloalkylidene imino-carbonyl, amino-sulfonyl, C _1-3-alkyl amino sulfonyl, two-(C _1-3-alkyl)-amino-sulfonyl, C _3-6-cycloalkylidene imino-alkylsulfonyl, amino, C _1-3-alkylamino, two-(C _1-3-alkyl)-amino, C _1-5-alkyl-carbonyl-amino, C _1-3-alkyl sulfonyl-amino, N-(C _1-3-alkyl sulphonyl)-C _1-3-alkylamino, C _3-6-cycloalkyl amino carbonyl, amino carbonyl amino, C _1-3-alkyl amino-carbonyl is amino, two-(C _1-3-alkyl)-amino carbonyl amino, 4-to 7-member cycloalkylidene imino-carbonylamino, benzyloxycarbonyl are amino, phenylcarbonyl group is amino or guanidino group replaces,

3-to 7-member naphthenic base, cycloalkylidene imino-, naphthenic base-C _1-3-alkyl or cycloalkylidene imino--C _1-3-alkyl, wherein the methylene radical in circular part can be by randomly by C _1-3-alkyl or C _1-3-alkyl-carbonyl is substituted-replacement of NH group or by the Sauerstoffatom replacement and wherein other adjacent to-NH-,-N (C _1-3-alkyl-carbonyl)-or-N (C _1-3-alkyl)-methylene of group based under the various situation by carbonyl or alkylsulfonyl replacement, its restricted condition be as in the cycloalkylidene imino-of aforementioned definitions two nitrogen-atoms of eliminating apart proper what a-CH ₂-group,

R ⁴Represent Wasserstoffatoms or C _1-3-alkyl,

R ⁵Represent Wasserstoffatoms or C _1-3-alkyl,

B represents the group of following formula

Wherein

N represents numeral 1 or 2,

R ⁷Represent Wasserstoffatoms, C _1-3-alkyl, hydroxyl, C _1-5-alkoxy carbonyl, carboxyl-C _1-3-alkyl, C _1-3-alkoxy carbonyl-C _1-3-alkyl, amino or C _1-3-alkylamino, and

This 6-person's heteroaryl contains one, two or three nitrogen-atoms, and

In addition, can be randomly by fluorine, chlorine or bromine atom, C _1-3-alkyl, hydroxyl, C _1-3-alkoxyl group, amino, C _1-3-alkylamino, two-(C _1-3-alkyl)-amino or C _3-6The substituted phenyl ring of-cycloalkylidene imino-is fused to above-mentioned bicyclic heteroaryl via two adjacent carbonss

And the methyl or the Wasserstoffatoms of ethyl that are contained in the front definition can replace by fluorine atom whole or in part,

And tautomer, enantiomer, diastereomer, mixture and salt.

The 3rd embodiment of the present invention comprises those compounds of general formula I, wherein

A represents the group of following general formula

Wherein m represents numeral 1 or 2,

In above-mentioned substituted 5-to 7-member group A, the heteroatoms of randomly introducing as substituting group and another heteroatoms proper what a carbon atom of not being separated by, or

The group of following general formula

Wherein

M represents numeral 1 or 2,

X ¹Represent methylene radical ,-NR ^6b-, carbonyl or alkylsulfonyl,

X ²Represention oxygen atom or-NR ^6bGroup,

X ³Represent methylene radical, carbonyl or alkylsulfonyl,

X ⁴Represent oxygen or sulphur atom or-NR ^6bGroup,

X ⁵Represent carbonyl or alkylsulfonyl,

R ¹Represent fluorine, chlorine or bromine atom, C _1-3-alkyl (wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part), nitro, C _1-3-alkoxyl group, list-, two-or trifluoromethoxy,

R ²Represent Wasserstoffatoms,

R ³Represent the C of straight or branched _1-6-alkyl, wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part, and randomly by nitrile, hydroxyl, benzyloxy, C _1-5-alkoxyl group (wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part), allyloxy, C _1-5-alkyl-carbonyl oxygen base, C _1-5-alkoxy-carbonyl oxy, carboxyl-C _1-3-alkoxyl group, C _1-5-alkoxy carbonyl-C _1-3-alkoxyl group, C _1-8-alkoxycarbonyl amino, C _1-3-alkylthio, C _1-3-alkyl sulphonyl, carboxyl, C _1-3Alkoxy carbonyl, C _1-3-alkyl amino-carbonyl, two-(C _1-3-alkyl)-aminocarboxyl, C _3-6-cycloalkylidene imino-carbonyl, amino carbonyl amino, C _1-3Amino or the two-(C of-alkyl amino-carbonyl _1-3-alkyl)-the amino carbonyl amino replacement,

Aminocarboxyl, C _1-4-alkyl amino-carbonyl, C _3-6-cycloalkyl amino carbonyl or two-(C _1-3-alkyl)-aminocarboxyl,

Phenyl or heteroaryl, phenyl-C _1-3-alkyl or heteroaryl-C _1-3-alkyl, its randomly in phenyl or heteroaryl moieties by fluorine, chlorine or bromine atom, C _1-3-alkyl, amino, C _1-3-alkylamino, two-(C _1-3-alkyl)-amino, hydroxyl, C _1-4-alkoxyl group, list-, two-or trifluoromethoxy, carboxyl, C _1-3-alkoxy carbonyl list-or polysubstituted,

3-to 7-member naphthenic base, wherein the methylene radical in circular part can be by randomly by C _1-3-alkyl or C _1-3-alkyl-carbonyl is substituted-NH-group replacement or by the Sauerstoffatom replacement,

R ⁴Represent Wasserstoffatoms,

R ⁵Represent Wasserstoffatoms,

B represents the group of following formula

Wherein

N represents numeral 1,

R ⁷Represent Wasserstoffatoms, and

R ⁸Represent hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, C _2-3-alkynyl or methoxyl group, wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part,

This 6-person's heteroaryl contains one, two or three nitrogen-atoms and reaches

This 5-person's heteroaryl contains randomly by C _1-3The substituted imino-of-alkyl, oxygen or sulphur atom, or

Randomly by C _1-3Substituted imino-of-alkyl or oxygen or sulphur atom and other nitrogen-atoms, or

Randomly by C _1-3The substituted imino-of-alkyl and two or three nitrogen-atoms,

And carry out bonding via nitrogen-atoms or carbon atom,

And tautomer, enantiomer, diastereomer, mixture and salt.

The 4th embodiment of the present invention comprises those compounds of general formula I, wherein

With A, R ¹, R ², R ⁴, R ⁵And B is as said under the 3rd embodiment and define, and

R ³Represent the C of straight or branched _1-6-alkyl, wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part, and randomly by nitrile, hydroxyl, benzyloxy, C _1-5-alkoxyl group (wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part), allyloxy, C _1-5-alkyl-carbonyl oxygen base, C _1-5-alkoxy-carbonyl oxy, carboxyl-C _1-3-alkoxyl group, C _1-5-alkoxy carbonyl-C _1-3-alkoxyl group, C _1-8-alkoxycarbonyl amino, C _1-3-alkylthio, C _1-3-alkyl sulphonyl, carboxyl, C _1-3-alkoxy carbonyl, C _1-3-alkyl amino-carbonyl, two-(C _1-3-alkyl)-aminocarboxyl, C _3-6-cycloalkylidene imino-carbonyl, amino carbonyl amino, C _1-3Amino or the two-(C of-alkyl amino-carbonyl _1-3-alkyl)-the amino carbonyl amino replacement,

And tautomer, enantiomer, diastereomer, mixture and salt.

The 5th embodiment of the present invention comprises those compounds of general formula I, wherein

R ³Represent phenyl or heteroaryl, phenyl-C _1-3-alkyl or heteroaryl-C _1-3-alkyl, its randomly in phenyl or heteroaryl moieties by fluorine, chlorine or bromine atom, C _1-3-alkyl, amino, C _1-3-alkylamino, two-(C _1-3-alkyl)-amino, hydroxyl, C _1-4-alkoxyl group, list-, two-or trifluoromethoxy, carboxyl or C _1-3-alkoxy carbonyl list-or polysubstituted,

This 5-person's heteroaryl contains randomly by C _1-3The substituted imino-of-alkyl, oxygen or sulphur atom or

And carry out bonding via nitrogen-atoms or carbon atom,

And tautomer, enantiomer, diastereomer, mixture and salt.

The 6th embodiment of the present invention comprises those compounds of general formula I, wherein

A represents the group of following general formula

Wherein m represents numeral 1 or 2,

R ^6aRepresent hydrogen or fluorine atom or C independently of one another _1-3-alkyl, and

R ^6bCan be Wasserstoffatoms or C _1-3-alkyl, its restricted condition does

The group of following general formula

Wherein

M represents numeral 1 or 2,

X ¹Represent methylene radical ,-NR ^6b-, carbonyl or alkylsulfonyl,

X ²Represention oxygen atom or-NR ^6bGroup,

X ³Represent methylene radical, carbonyl or alkylsulfonyl,

X ⁴Represent oxygen or sulphur atom or-NR ^6bGroup,

X ⁵Represent carbonyl or alkylsulfonyl,

R ^6bCan be Wasserstoffatoms or C independently of one another _1-3-alkyl, its restricted condition does

R ¹Represent chlorine or bromine atom, methyl or methoxy, wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part, or nitro,

R ²Represent Wasserstoffatoms,

R ³Represent the C of straight or branched _1-4-alkyl, wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part, and randomly by hydroxyl, C _1-4-alkoxyl group (wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part), C _1-3-alkylthio, C _1-3-alkyl sulphonyl, carboxyl or C _1-3Alkoxy carbonyl replaces,

Phenyl or heteroaryl, phenyl-C _1-3-alkyl or heteroaryl-C _1-3-alkyl, its randomly in phenyl or heteroaryl moieties by fluorine, chlorine or bromine atom, C _1-3-alkyl, amino, list-, two-or trifluoromethoxy, carboxyl or C _1-3-alkoxy carbonyl list-or polysubstituted,

R ⁴Represent Wasserstoffatoms,

R ⁵Represent Wasserstoffatoms, and

B represents the group of following formula

Wherein

N represents numeral 1,

R ⁷Represent Wasserstoffatoms, and

R ⁸Represent chlorine or bromine atom or ethynyl,

Randomly by C _1-3The substituted imino-of-alkyl and two or three nitrogen-atoms replace,

And carry out bonding via nitrogen-atoms or carbon atom,

And tautomer, enantiomer, diastereomer, mixture and salt.

The 7th embodiment of the present invention comprises those compounds of general formula I, wherein

With A, R ¹, R ², R ⁴, R ⁵And B is as said under the 6th embodiment and define, and

R ³Represent the C of straight or branched _1-4-alkyl, wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part, and randomly by hydroxyl, C _1-4-alkoxyl group (wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part), C _1-3-alkylthio, C _1-3-alkyl sulphonyl, carboxyl or C _1-3-alkoxy carbonyl replaces,

And tautomer, enantiomer, diastereomer, mixture and salt.

The 8th embodiment of the present invention comprises those compounds of general formula I, wherein

R ³Represent phenyl or heteroaryl, phenyl-C _1-3-alkyl or heteroaryl-C _1-3-alkyl, its randomly in phenyl or heteroaryl moieties by fluorine, chlorine or bromine atom, C _1-3-alkyl, C _1-4-alkoxyl group, list-, two-or trifluoromethoxy, carboxyl, C _1-3-alkoxy carbonyl list-or polysubstituted,

And carry out bonding via nitrogen-atoms or carbon atom,

And be contained in the alkyl that has in the above-mentioned definition more than two carbon atoms, except as otherwise noted, for straight or branched, and in aforementioned dialkylated group for example the alkyl in the dialkyl amido can be identical or different,

And tautomer, enantiomer, diastereomer, mixture and salt.

The 9th embodiment of the present invention comprises those compounds of general formula I, wherein

A represents the group of following formula

Wherein m represents numeral 1 or 2,

R ^6aRepresent hydrogen or fluorine atom or C independently of one another _1-3-alkyl, its restricted condition does

In above-mentioned substituted 5-to 7-member cyclic group A, the fluorine atom of introducing as substituting group and another heteroatoms proper what a carbon atom of not being separated by,

R ²Represent Wasserstoffatoms,

Furyl, thienyl, pyrryl, pyrazolyl, imidazolyl 、 oxazolyl 、 isoxazolyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridyl-C _1-2-alkyl or imidazolyl-C _1-2-alkyl, its randomly in heteroaryl moieties by one or two C _1-3-alkyl, C _1-3-alkoxyl group, carboxyl or C _1-3-alkoxyl group carboxyl substituted,

R ⁴Represent Wasserstoffatoms,

R ⁵Represent Wasserstoffatoms, and

B represents the group of following formula

Wherein

N represents numeral 1,

R ⁷Represent Wasserstoffatoms, and

R ⁸Represent chlorine or bromine atom or ethynyl,

And carry out bonding via nitrogen-atoms or carbon atom,

And tautomer, enantiomer, diastereomer, mixture and salt.

The of the present invention ten embodiment comprises those compounds of general formula I, wherein

With A, R ¹, R ², R ⁴, R ⁵And B is as said under the 9th embodiment and define, and

And tautomer, enantiomer, diastereomer, mixture and salt.

The 11 embodiment of the present invention comprises those compounds of general formula I, wherein

R ³Represent furyl, thienyl, pyrryl, pyrazolyl, imidazolyl 、 oxazolyl 、 isoxazolyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridyl-C _1-2-alkyl or imidazolyl-C _1-2-alkyl, its randomly in heteroaryl moieties by one or two C _1-3-alkyl (wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part), C _1-3-alkoxyl group (wherein Wasserstoffatoms can be replaced by fluorine atom whole or in part), carboxyl or C _1-3-alkoxy carbonyl replaces, and

And carry out bonding via nitrogen-atoms or carbon atom,

And tautomer, enantiomer, diastereomer, mixture and salt.

The 12 embodiment of the present invention comprises those compounds of the general formula I that is equivalent to embodiment 1,2,3,4,5,6,7 and 8, wherein radicals X ¹Represent methylene radical.

The 13 embodiment of the present invention comprises those compounds of the general formula I that is equivalent to embodiment 1,2,3,4,5,6,7 and 8, wherein radicals X ¹Represent carbonyl.

The 14 embodiment of the present invention comprises those compounds of the general formula I that is equivalent to embodiment 1,2,3,4,5,6,7,8,12 and 13, wherein radicals X ³Represent methylene radical.

The 15 embodiment of the present invention comprises those compounds of the general formula I that is equivalent to embodiment 1,2,3,4,5,6,7,8,12 and 13, wherein radicals X ³Represent carbonyl.

The 16 embodiment of the present invention comprises those compounds of the general formula I that is equivalent to embodiment 1,2,3,4,5,6,7,8,12,13,14 and 15, wherein radicals X ⁴Represention oxygen atom.

The 17 embodiment of the present invention comprises those compounds of the general formula I that is equivalent to embodiment 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15 and 16, and wherein group B is represented following groups

The 18 embodiment of the present invention comprises those compounds of the general formula I that is equivalent to embodiment 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15 and 16, and wherein group B is represented following groups

Nineteen embodiment of the present invention comprises those compounds of the general formula I that is equivalent to embodiment 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15 and 16, and wherein group B is represented following groups

The 20 embodiment of the present invention comprises those compounds of the general formula I that is equivalent to embodiment 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18 and 19, wherein radicals R ⁸Represent the chlorine atom.

The 21 embodiment of the present invention comprises those compounds of the general formula I that is equivalent to embodiment 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18 and 19, wherein radicals R ⁸Represent bromine atoms.

The 22 embodiment of the present invention comprises those compounds of the general formula I that is equivalent to embodiment 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18 and 19, wherein radicals R ⁸Represent ethynyl.

The 23 embodiment of the present invention comprises those compounds of the general formula I that is equivalent to embodiment 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 and 22, and it is equivalent to general formula I a

Now the preferred compound of following general formula I is recorded and narrated as embodiment:

(1) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-([1,4] Diazesuberane-1-yl)-BM,

(2) 4-(4-N-Boc-piperazine-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-trifluoromethyl-BM,

(3) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(piperazine-1-yl)-3-trifluoromethyl-BM,

(4) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-methoxyl group-ethyl]-4-(piperazine-1-yl)-3-trifluoromethyl-BM,

(5) 4-(4-N-ethanoyl-piperazine-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-trifluoromethyl-BM,

(6) 4-(azepan-2-ketone-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-BM,

(7) 4-(azepan-2-ketone-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-BM,

(8) 4-(azepan-2-ketone-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-hydroxyl-ethyl]-3-methyl-BM,

(9) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(pyrrolidin-2-one-1-yl)-BM,

(10) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(pyrrolidin-2-one-1-yl)-BM,

(11) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group]-3-methyl-4-(pyrrolidin-2-one-1-yl)-BM,

(12) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(4-N-methyl-[1,4] Diazesuberane-1-yl)-BM,

(13) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(2-methyl-tetramethyleneimine-1-yl)-BM,

(14) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-chloro-4-(morpholine-1-yl)-BM,

(15) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3,5-two fluoro-4-(morpholine-1-yl)-BM,

(16) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-trifluoromethyl-4-(morpholine-1-yl)-BM,

(17) 4-(azepan-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-trifluoromethyl-BM,

(18) 4-(azepan-1-yl)-3-chloro-N-[(] S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-BM,

(19) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(piperidines-1-yl)-BM,

(20) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-([1,4] oxaza heptane-4-yl)-BM,

(21) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(morpholine-3-ketone-4-yl)-3-trifluoromethyl-BM,

(22) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(23) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(24) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-hydroxyl-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(25) 4-(azepan-2-ketone-1-yl)-3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-BM,

(26) 4-(azepan-2-ketone-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-trifluoromethyl-BM,

(27) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(morpholine-3-ketone-4-yl)-BM,

(28) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(29) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(morpholine-3-ketone-4-yl)-BM,

(30) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(piperazine-1-yl)-BM,

(31) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(piperazine-2-ketone-1-yl)-BM,

(32) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(piperidines-2-ketone-1-yl)-BM,

(33) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(N-methyl-piperazine-1-yl)-3-trifluoromethyl-BM,

(34) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(35) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group]-4-(pyrrolidin-2-one-1-yl)-BM,

(36) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-phenyl-methyl]-4-(pyrrolidin-2-one-1-yl)-BM,

(37) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(3,5-lupetidine-1-yl)-BM,

(38) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(3,4-two dehydrogenations-piperidines-1-yl)-BM,

(39) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-([1,3] oxaza heptane-2-ketone-3-yl)-BM,

(40) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group]-4-(piperazine-1-yl)-3-trifluoromethyl-BM,

(41) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group]-4-(morpholine-3-ketone-4-yl)-3-nitro-BM,

(42) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(tetrahydrochysene pyridine pyridine-2-ketone-1-yl)-BM,

(43) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-([1,3] oxaza heptane-2-ketone-3-yl)-BM,

(44) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-([1,4] oxaza heptane-5-ketone-4-yl)-BM,

(45) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-([1,4] oxaza heptane-3-ketone-4-yl)-BM,

(46) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(piperidines-2-ketone-1-yl)-BM,

(47) N-[(1R)-1-(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-hydroxyl-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(48) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(1,1-dioxo-isothiazole-2-yl)-3-methyl-BM,

(49) N-[1-(5-chloro-1H-indoles-2-yl)-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(50) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-[2-(4-methyl-piperazine-1-base-methyl)-piperidines-1-yl]-BM,

(51) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-oxazolidine-2-ketone-3-yl)-BM,

(52) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(morpholine-3-ketone-4-yl)-BM,

(53) N-[(1R, 2S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(54) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(3,5-lupetidine-1-yl)-BM,

(55) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(thiomorpholine-3-ketone-4-yl)-BM,

(56) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(piperidines-2-ketone-1-yl)-BM,

(57) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-([1,3]-morpholine-2-ketone-3-yl)-BM,

(58) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-([1,3]-morpholine-2-ketone-3-yl)-BM,

(59) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(piperidines-2-ketone-1-yl)-3-trifluoromethyl-BM,

(60) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle hexane-2-yl)-3-methyl-BM,

(61) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(5,6-two dehydrogenations-azepan-2-ketone-1-yl)-BM,

(62) 4-(azepan-2-ketone-1-yl)-N-[(1S)-1-(5-chloro-6-fluoro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-BM,

(63) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(1,3-dioxo-thiomorpholine-4-yl)-3-methyl-BM,

(64) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(1,1,3-trioxy--thiomorpholine-4-yl)-BM,

(65) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(piperazine-1-yl)-BM,

(66) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(piperazine-2-ketone-1-yl)-BM,

(67) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-butyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(68) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-([1,3] oxaza heptane-2-ketone-3-yl)-3-trifluoromethyl-BM,

(69) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methoxyl group-4-(piperidines-2-ketone-1-yl)-BM,

(70) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methoxyl group-4-(piperidines-2-ketone-1-yl)-BM,

(71) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(1,1-dioxo-[1,2,6] sulphur diaza-cyclohexane-2-yl)-3-methyl-BM,

(72) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(1,1-dioxo-[1,2,6] sulphur diaza-cyclohexane-2-yl)-3-methyl-BM,

(73) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(1,1-dioxo-6-methyl-[1,2,6] sulphur diaza-cyclohexane-2-yl)-3-methyl-BM,

(74) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(1,1-dioxo-3-methyl-[1,2,6] sulphur diaza-cyclohexane-2-yl)-3-methyl-BM,

(75) N-[(1R)-1-(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(76) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-(1H-tetrazolium-5-yl)-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(77) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methoxyl group-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(78) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-thiene-3-yl--methyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(79) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methylthio group-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(80) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(81) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(morpholine-3-ketone-4-yl)-BM,

(82) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(3,6-dihydro-[1,2] oxazine-2-yl)-BM,

(83) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle hexane-2-yl)-BM,

(84) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle heptane-2-yl)-3-methyl-BM,

(85) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(piperidines-2-ketone-1-yl)-3-trifluoromethoxy-BM,

(86) 3-bromo-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(piperidines-2-ketone-1-yl)-BM,

(87) 3-bromo-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(piperidines-2-ketone-1-yl)-BM,

(88) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(furans-2-yl)-methyl]-3-methyl-4-(piperidines-2-ketone-1-yl)-BM,

(89) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-([1,2] morpholine-2-yl)-BM,

(90) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(5-oxo-[1,4] oxaza heptane-4-yl)-BM,

(91) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(4,4-dimethyl--2-oxo-imidazolidine-1-yl)-3-methyl-BM,

(92) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(4,4-dimethyl--2-oxo-imidazolidine-1-yl)-3-methyl-BM,

(93) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(4-methyl-2-oxo-oxazolidine-3-yl)-BM,

(94) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(4-methyl-2-oxo-oxazolidine-3-yl)-BM,

(95) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-phenyl-methyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(96) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(97) 3-bromo-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(morpholine-3-ketone-4-yl)-BM,

(98) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(7-oxo-[1,4] Diazesuberane-1-yl)-BM,

(99) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(thiophene-2-yl)-methyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(100) N-[(1R)-1-(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-hydroxyl-ethyl]-4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle hexane-2-yl)-3-methyl-BM,

(101) N-[(1R)-1-(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-hydroxyl-ethyl]-3-methyl-4-([1,3] oxaza heptane-2-ketone-3-yl)-BM,

(102) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(4-(4S)-methyl-2-oxo-oxazolidine-3-yl)-BM,

(103) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(4,4-dimethyl--2-oxo-oxazolidine-3-yl)-BM,

(104) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(4-(4R)-methyl-2-oxo-oxazolidine-3-yl)-BM,

(105) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(4-(4R)-ethyl-2-oxo-oxazolidine-3-yl)-BM,

(106) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-fluoro-4-(morpholine-3-ketone-4-yl)-BM,

(107) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(1H-pyrazole-3-yl)-methyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(108) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-cyanic acid-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(109) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-pyridin-3-yl-methyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(110) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(1H-1-methyl-pyrazole-3-yl)-methyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(111) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(5-methyl-morpholine-3-ketone-4-yl)-BM,

(112) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(3-dimethyl amine-tetramethyleneimine-1-yl)-BM,

(113) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(pyrazolidine-3-ketone-1-yl)-3-trifluoromethyl-BM,

(114) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(tetrahydrochysene-pyrimid-2-one-1-yl)-BM,

(115) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-chloro-4-([1,4] Diazesuberane-1-yl)-BM,

(116) 3-chloro-N-[1-(5-chloro-1H-indoles-2-yl)-2-methoxyl group-ethyl]-4-([1,4] Diazesuberane-1-yl)-BM,

(117) N-[1-(5-chloro-1H-indoles-2-yl)-2-methoxyl group-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(118) 3-bromo-N-[1-(5-chloro-1H-indoles-2-yl)-1-(furans-2-yl)-methyl]-4-([1,4] oxaza heptane-5-ketone-4-yl)-BM,

(119) N-[1-(5-bromo-1H-indoles-2-yl)-1-(1-methyl isophthalic acid H-pyrazole-3-yl)-methyl]-3-methyl-4-([1,3] oxaza heptane-2-ketone-3-yl)-BM,

(120) N-[1-(5-chloro-1H-indoles-2-yl)-3-(methyl-alkylsulfonyl)-propyl group]-3-methyl-4-(tetrahydropyrimidine-2-ketone-1-yl)-BM,

(121) N-[1-(5-chloro-1H-indoles-2-yl)-2-hydroxyl-ethyl]-3-methyl-4-(5-methyl-pyrrolidin-2-one-1-yl)-BM,

(122) N-[1-(5-chloro-1H-indoles-2-yl)-1-phenyl-methyl]-4-(piperazine-1-yl)-3-trifluoromethyl-BM,

(123) 4-(azepan-2-ketone-1-yl)-3-chloro-N-[1-(5-chloro-1H-indoles-2-yl)-3-(1H-tetrazolium-5-yl)-propyl group]-BM,

(124) N-[1-(5-bromo-1H-indoles-2-yl)-2-hydroxyl-ethyl]-4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle heptane-2-yl)-3-methyl-BM,

(125) 3-chloro-N-[1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-2-methoxyl group-ethyl]-4-(Diazesuberane-1-yl)-BM,

(126) 3-chloro-N-[1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-ethyl]-4-([1,4] oxaza heptane-5-ketone-4-yl)-BM,

(127) N-[(1S)-1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-3-methyl-butyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(128) N-[1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-2-methoxyl group-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(129) 3-bromo-N-[1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-(1H-pyrazole-3-yl)-methyl]-4-([1,4] oxaza heptane-5-ketone-4-yl)-BM,

(130) N-[1-(7-bromo-imidazo [1,2a] pyridine-2-yl)-2-hydroxyl-ethyl]-3-chloro-4-(4-methyl-piperazine-1-yl)-BM,

(131) N-[1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-2-hydroxyl-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(132) N-[1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-1-(furans-2-yl)-methyl]-4-(Diazesuberane-1-yl)-3-trifluoromethyl-BM,

(133) N-[1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-1-phenyl-methyl]-3-methyl-4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle heptane-2-yl)-BM,

(134) 3-chloro-N-[1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-2-methoxyl group-ethyl]-4-(morpholine-3-ketone-4-yl)-BM,

(135) 3-bromo-N-[1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-3-(methylthio group)-propyl group]-4-([1,4] oxaza heptane-3-ketone-4-yl)-BM,

(136) 3-chloro-N-[1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-2-hydroxyl-ethyl]-4-(piperazine-2-ketone-1-yl)-BM,

(137) N-[1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-2-methoxyl group-ethyl]-3-methyl-4-(piperidines-2-ketone-1-yl)-BM,

(138) N-[1-(7-bromo-imidazo [1,2a] pyridine-2-yl)-3-methoxyl group-propyl group]-3-chloro-4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle hexane-2-yl)-BM,

(139) N-[1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-2-trifluoromethoxy-ethyl]-3-methyl-4-([1,4] oxaza heptane-5-ketone-4-yl)-BM,

(140) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methyl-butyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(141) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-benzyloxy-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(142) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-benzyloxycarbonyl-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(143) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-hydroxycarbonyl group-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(144) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(pyrazine-2-yl)-methyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(145) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-oxazole-2-yl)-methyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(146) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(1H-imidazol-4 yl)-methyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(147) N-[1-(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-difluoro-methoxy-4-(morpholine-3-ketone-4-yl)-BM,

(148) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-methyl-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(149) N-[3-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-THF-3-yl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(150) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-(tetramethyleneimine-1-base-carbonyl-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(151) N-[1-(5-ethynyl-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(152) N-[1-(5-ethynyl-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(153) N-[1-(5-ethynyl-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(piperidines-2-ketone-1-yl)-BM,

(154) 3-bromo-N-[1-(5-ethynyl-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(morpholine-3-ketone-4-yl)-BM,

(155) N-[1-(5-ethynyl-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(4-methyl-oxazolidine-2-ketone-3-yl)-BM,

(156) N-[1-(5-ethynyl-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-([1,4] oxaza heptane-5-ketone-4-yl)-BM,

(157) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(2-methyl-tetrahydro pyridazine-1-yl)-BM,

And tautomer, enantiomer, diastereomer, mixture and salt, and preferred especially following compounds:

(1) 4-(azepan-2-ketone-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-BM,

(2) 4-(azepan-2-ketone-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-hydroxyl-ethyl]-3-methyl-BM,

(3) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group]-3-methyl-4-(pyrrolidin-2-one-1-yl)-BM,

(4) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(morpholine-3-ketone-4-yl)-3-trifluoromethyl-BM,

(5) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(6) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(7) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-hydroxyl-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(8) 4-(azepan-2-ketone-1-yl)-3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-BM,

(9) 4-(azepan-2-ketone-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-trifluoromethyl-BM,

(10) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-([1,3] oxaza heptane-2-ketone-3-yl)-BM,

(11) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group]-4-(morpholine-3-ketone-4-yl)-3-nitro-BM,

(12) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-([1,3] oxaza heptane-2-ketone-3-yl)-BM,

(13) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-([1,4] oxaza heptane-5-ketone-4-yl)-BM,

(14) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(piperidines-2-ketone-1-yl)-BM,

(15) N-[(1R)-1-(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-hydroxyl-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(16) N-[(1R, 2S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(17) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(thiomorpholine-3-ketone-4-yl)-BM,

(18) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(piperidines-2-ketone-1-yl)-BM,

(19) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-([1,3]-morpholine-2-ketone-3-yl)-BM,

(20) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(piperidines-2-ketone-1-yl)-3-trifluoromethyl-BM,

(21) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle hexane-2-yl)-3-methyl-BM,

(22) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-butyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(23) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-([1,3] oxaza heptane-2-ketone-3-yl)-3-trifluoromethyl-BM,

(24) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(1,1-dioxo-[1,2,6] sulphur diaza-cyclohexane-2-yl)-3-methyl-BM,

(25) N-[(1R)-1-(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(26) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-(1H-tetrazolium-5-yl)-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(27) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methoxyl group-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(28) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methylthio group-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(29) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(thiomorpholine-3-ketone-4-yl)-BM,

(30) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(morpholine-3-ketone-4-yl)-BM,

(31) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle hexane-2-yl)-BM,

(32) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle heptane-2-yl)-3-methyl-BM,

(33) 3-bromo-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(piperidines-2-ketone-1-yl)-BM,

(34) 3-bromo-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(piperidines-2-ketone-1-yl)-BM,

(35) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(furans-2-yl)-methyl]-3-methyl-4-(piperidines-2-ketone-1-yl)-BM,

(36) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(5-oxo-[1,4] oxaza heptane-4-yl)-BM,

(37) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(4-methyl-2-oxo-oxazolidine-3-yl)-BM,

(38) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-phenyl-methyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(39) 3-bromo-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(morpholine-3-ketone-4-yl)-BM,

(40) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-thiophene-2-yl)-methyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(41) N-[(1R)-1-(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-hydroxyl-ethyl]-4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle hexane-2-yl)-3-methyl-BM,

(42) N-[(1R)-1-(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-hydroxyl-ethyl]-3-methyl-4-([1,3] oxaza heptane-2-ketone-3-yl)-BM,

(43) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(4-(4S)-methyl-2-oxo-oxazolidine-3-yl)-BM,

(44) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(4,4-dimethyl--2-oxo-oxazolidine-3-yl)-BM,

(45) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(4-(4R)-methyl-2-oxo-oxazolidine-3-yl)-BM,

(46) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(4-(4R)-ethyl-2-oxo-oxazolidine-3-yl)-BM,

(47) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-fluoro-4-(morpholine-3-ketone-4-yl)-BM,

(48) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(1H-pyrazole-3-yl)-methyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(49) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(1H-1-methyl-pyrazole-3-yl)-methyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(50) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(5-methyl-morpholine-3-ketone-4-yl)-BM,

(51) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(tetrahydrochysene-pyrimid-2-one-1-yl)-BM,

(52) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-thiene-3-yl--methyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

(53) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(1 [, 3] oxaza heptane-2-ketone-3-yl)-BM,

(54) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group]-4-(piperazine-1-yl)-3-trifluoromethyl-BM,

(55) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group]-4-(morpholine-3-ketone-4-yl)-3-nitro-BM,

(56) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(piperazine-1-yl)-BM,

(57) N-[(1S)-1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-3-methyl-butyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM,

And tautomer, enantiomer, diastereomer, its mixture and salt.

In the scope of the application's case, with wherein available " isomer ", " steric isomer ", " diastereomer ", " enantiomer ", " chirality ", " racemic modification " or " racemic mixture " define as follows.To have the identical experiment formula but in the character of molecule or its atom bonded is arranged or the binding or the spatial disposition different compounds of atom are called " isomer ".Arrange difference and inconsistent in subspace, molecule Central Plains, be called " steric isomer " yet its atom has same type banded isomer.The steric isomer that does not show as picture and mirror image each other is called " diastereomer ", and the steric isomer that shows as picture and mirror image each other is called " enantiomer ".In the situation of asymmetric center or atom (being also referred to as three-dimensional center or chiral centre) existence, for example in the situation by four substituted carbon atoms of different substituents, molecule has the characteristic of " chirality ", has a pair of enantiomer.Can the absolute configuration of enantiomer with its three-dimensional center be characterized.Reach (S) explanation absolute configuration through symbol (R); It is by the Cahn-Ingold-Prelog sequence rule of utilization according to Cahn, Ingold and Prelog; Or rotate through the plane of explanation when polarized light and interaction of molecules and to confirm, be referred to as dextral or left-handed (promptly corresponding to (+) or (-) as symbol).Chipal compounds can exist for enantiomer independently or corresponding enantiomer mixture both.The mixture that contains two enantiomers of equivalent of compound is called " racemic modification " or " racemic mixture ".

According to the present invention, obtain the compound of general formula I through known method itself, for example through following method:

(a) in order to prepare the compound of following general formula

Wherein with R ³To R ⁵Like definition and Z in the preamble ¹Represent Wasserstoffatoms or blocking group and B ' to represent the group of following formula

R wherein ⁷And R ⁸As defining in the preamble:

The cyclization of following general formula compound

Randomly in reaction mixture, carry out

R wherein ³To R ⁵, R ⁷And R ⁸Like definition and Z in the preamble ¹Represent Wasserstoffatoms or blocking group, any blocking group that will use is afterwards sloughed.

Said cyclization is carrying out under the following condition easily: in solvent or solvent mixture; Said solvent such as ethanol, Virahol, Glacial acetic acid min. 99.5, benzene, chlorobenzene, toluene, YLENE, terepthaloyl moietie, glycol monomethyl methyl ether, diethylene glycol dimethyl ether, tetramethylene sulfone, N or tetraline, DMSO 99.8MIN., methylene dichloride, chloroform, tetracol phenixin; The temperature between 0 and 250 ℃ for example; But be preferable between 20 and 100 ℃; Randomly at condensation reagent, like Phosphorus Oxychloride, THIONYL CHLORIDE 97, sulfuryl chloride, sulfuric acid, tosic acid, methylsulfonic acid, hydrochloric acid, phosphoric acid, Tripyrophosphoric acid, acetic acid, acetic anhydride, N, N '-NSC 57182 exists down; Or, exist down like potassium ethylate or potassium tert.-butoxide randomly also at alkali.Yet cyclization also can carry out under solvent-free and/or condensation reagent exist.

Be pursuant to method of explanation in (e), can obtain the compound of general formula (IV) through compound with the following general formula of compound acylation (XXIV) of general formula (XXV)

Wherein n, R ⁷And R ⁸As defining in the preamble,

R wherein ³, R ⁴And R ⁵As defining in the preamble, Q represents halogen atom or hydroxyl, C _1-4-alkoxyl group or C _1-4-acyloxy and Z ¹Represent blocking group.

(b) in order to prepare the compound of following general formula

Wherein with R ³To R ⁵As defining Z in the preamble ¹Represent Wasserstoffatoms or blocking group, for example C _1-5-alkoxy carbonyl or benzyloxycarbonyl, and B ' represents the group of following formula

R wherein ⁷And R ⁸As defining in the preamble:

I) the transition metal-catalyzed coupling and the cyclisation of the compound of following general formula (VI) and general formula (VII) compound

R wherein ³Represent phenyl or heteroaryl and R ⁴Represent Wasserstoffatoms and R ⁵As defining in the preamble,

R wherein ⁸Like definition and Z in the preamble ¹Represent blocking group, for example ethanoyl or methylsulfonyl are sloughed blocking group afterwards.

Said reaction is being carried out under the following condition easily: in solvent or solvent mixture; Said solvent such as ethanol, Virahol, Glacial acetic acid min. 99.5, benzene, chlorobenzene, toluene, YLENE, terepthaloyl moietie, glycol monomethyl methyl ether, diethylene glycol dimethyl ether, tetramethylene sulfone, N, N-Methyl pyrrolidone, tetraline, DMSO 99.8MIN., methylene dichloride, chloroform or tetracol phenixin; The temperature between 0 and 250 ℃ for example; But be preferable between 20 and 120 ℃, easily at transition-metal catalyst, as chlorination two-(triphenylphosphine) closes palladium (II), chlorination two-(tricyclohexyl phosphine) close palladium (II), chlorination be two-(triethyl phosphine) close palladium (II) or chlorination two-(tri-o-tolyl phosphine) close palladium (II); And randomly at transition-metal catalyst; Exist down like cupric iodide (I), cupric bromide (I) or neutralized verdigris (I), and easily at alkali, like tetramethyl guanidine, Tetramethyl Ethylene Diamine or N; N '-dimethyl-ethylenediamine exists down, and randomly utilizes inert atmosphere (for example nitrogen or argon gas).

Ii) use the alkylation of general formula (IX) to reach the compound of the following general formula of reductive amination (VIII) subsequently

R wherein ⁷And R ⁸Represent halogen atom, C like definition and Y in the preamble _1-4-alkoxyl group, C _1-4-alkoxy amino or N-C _1-4-alkoxyl group-N-C _1-4-alkylamino,

R ⁴-M， (IX)

R wherein ⁴Represent metal like for example lithium, sodium or potassium like definition and M in the preamble, or metal is like for example magnesium, cadmium, copper or zinc, with suitable counter ion; As for example chlorine, bromine or iodine, or the combination of two metals, like for example magnesium and copper; Lithium and copper or zinc and copper are with suitable counter ion, like for example cyanogen, chlorine, bromine or iodine; And the group that contains its combination, obtain the reductive amination reaction of compound subsequently.

Said alkylated reaction is carrying out under the following condition easily: in solvent or solvent mixture; Said solvent such as benzene, chlorobenzene, toluene, YLENE, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetramethylene sulfone, N, N-Methyl pyrrolidone, tetraline, DMSO 99.8MIN., methylene dichloride, chloroform, tetracol phenixin, diethyl ether, t-butyl methyl ether or THF; For example; In-100 and+100 ℃ between temperature; But be preferable between-100 and 30 ℃; With alkylating reagent such as Grignard reagent, organolithium reagent, Gilman or Knochel cuprate (it can be prepared by the currently known methods in the document), randomly utilize inert atmosphere (for example nitrogen or argon gas).The reductive amination reaction of the ketone that forms after the alkylation subsequently is through carrying out with ammonia, oxyamine, alkoxyl group saddle, primary amine, hydroxyl-alkylamine or alkoxyl group-alkylamine; For example give body such as Peng Qinghuana, lithium aluminum hydride, sodium cyanoborohydride, sodium triacetoxy borohydride or diisobutyl aluminium hydride at solvent or solvent mixture afterwards or together with hydrogenate; As reducing in ethanol, Virahol, benzene, toluene, pyridine, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, N-alkyl morpholine, diethyl ether, t-butyl methyl ether, THF, hexane or the hexanaphthene; Or through randomly reaching down easily at catalyzer in pressure; Like Raney nickel (Raney nickel), palladium, palladium charcoal, platinum or platinum oxide; At solvent or solvent mixture, like ETHYLE ACETATE, ethanol, Virahol, benzene, toluene, pyridine, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, N-C _1-5Carry out hydrogenation in-alkyl morpholine, diethyl ether, the tertiary butyl-methyl ether, THF, hexane or the hexanaphthene.

(c) in order to prepare the compound of following general formula

R wherein ³To R ⁵As defining Z in the preamble ¹Represent Wasserstoffatoms or blocking group, for example C _1-5-alkoxy carbonyl or benzyloxycarbonyl, and B ' represents the group of following formula

R wherein ⁸As defining in the preamble:

The compound coupling and the cyclisation subsequently of the compound of following general formula and general formula (XII)

Wherein n and R ⁸As defining in the preamble

Wherein with R ³To R ⁵As defining Z in the preamble ¹Represent blocking group, for example C _1-5-alkoxy carbonyl or benzyloxycarbonyl, and Z ⁴Represent nucleofugic (nucleofugic) leavings group, for example chlorine, bromine or iodine atom, tosylate, trifluoromethanesulfonic acid root or methanesulfonate group, afterwards through the currently known methods in the document with blocking group Z ¹Slough.

Said reaction is being carried out under the following condition easily: in solvent or solvent mixture, and said solvent such as water, ethanol, Virahol, benzene, chlorobenzene, toluene, YLENE, terepthaloyl moietie, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, N, N-Methyl pyrrolidone, tetraline, DMSO 99.8MIN., tetramethylene sulfone, methylene dichloride, chloroform, tetracol phenixin or N-ethyl-diisopropylamine, N-C _1-5-alkyl morpholine, N-C _1-5-Alkylpiperidine, N-C _1-5-alkyl pyrrolidine, triethylamine, pyridine; The temperature between-30 and 250 ℃ for example; But be preferable between 0 and 150 ℃; Randomly, exist down like salt of wormwood, yellow soda ash, sodium hydrogencarbonate, potassium tert.-butoxide, sodium ethylate, hexamethyldisilazane potassium (Potassium hexamethyldisilazane), sodium hydride or diisopropylamine lithium easily at alkali.

(d) in order to prepare the compound of following general formula

Wherein A, R ¹And R ²As defining in the preamble, Q represents halogen atom, hydroxyl, C _1-4-alkoxyl group or C _1-4-acyloxy:

I) nucleophilic substitution of following general formula compound on the aromatic substance group of following general formula (XV)

A′-H， (XIV)

Wherein A ' represents 5-7 person's cycloalkylidene imino-, as mentioning in following of the definition of preamble A,

R wherein ¹And R ²Like definition and Z in the preamble ²Represent nitrile group or C _1-5-alkoxy carbonyl, and with after saponification Z ²Itrile group or C _1-5-alkoxy carbonyl and the carboxyl that obtains randomly further react and form the active carboxylic acid derivative of general formula X III.

Said nucleophilic substitution reaction is carrying out under the following condition easily: in solvent or solvent mixture, and said solvent such as ethanol, Virahol, benzene, chlorobenzene, toluene, YLENE, terepthaloyl moietie, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, N, N-Methyl pyrrolidone, tetraline, DMSO 99.8MIN., tetramethylene sulfone, methylene dichloride, chloroform, tetracol phenixin or N-ethyl-diisopropylamine, N-C _1-5-alkyl morpholine, N-C _1-5-Alkylpiperidine, N-C _1-5-alkyl pyrrolidine, triethylamine, pyridine; The temperature between-30 and 250 ℃ for example; But be preferable between 0 and 150 ℃; Optional easily in the presence of alkali, said alkali such as salt of wormwood, yellow soda ash, potassium tert.-butoxide, sodium ethylate, hexamethyldisilazane base potassium, sodium hydride or lithium diisopropylamine.

The ii) transition metal-catalyzed coupling reaction of following general formula compound on the group of following general formula aromatic substance

A′-H， (XIV)

R wherein ¹And R ²Like definition and Z in the preamble ²Represent itrile group or C _1-5-alkoxy carbonyl and Z ³Represent chlorine, bromine or iodine atom or trifluoromethanesulfonic acid foundation group, and with after saponification Z ²Nitrile group or C _1-5-alkoxy carbonyl and the carbonyl that obtains randomly further react and form the active carboxylic acid derivative of general formula X III.

Said reaction is implemented under the following condition easily to be carried out: in solvent or solvent mixture; Said solvent such as benzene,toluene,xylene, THF, dioxane, diethyl ether, t-butyl methyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetramethylene sulfone, N, N-Methyl pyrrolidone, tetraline, DMSO 99.8MIN., methylene dichloride, chloroform or tetracol phenixin; The temperature between-30 and 250 ℃ for example; But be preferable between 0 and 150 ℃; Easily in the presence of transition-metal catalyst; Said catalyzer such as Ni-gac, palladium-charcoal, four (triphenylphosphine) close palladium (O), three-(dibenzalacetone)-close two palladiums (0), palladium (II), Palladous chloride (II), chlorination two-(triphenylphosphine)-close palladium (II), chlorination be two-(tricyclohexyl phosphine)-close palladium (II), chlorination be two-(triethyl phosphine)-close palladium (II), chlorination two-(tri-o-tolyl phosphine)-close palladium (II); Randomly in the presence of part, said part such as triphenylphosphine, tri-o-tolyl phosphine, three-tertiary butyl phosphine, 1, two (the diphenylphosphine)-propane, 2 of 3-; 2 '-two (diphenylphosphine)-1; 1 '-dinaphthalene, 1,1 '-two (diphenylphosphine)-ferrocene, xantphos, and easily in the presence of alkali; Said alkali such as sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, tertiary butyl dimethyl methyl sodium silanolate, hexamethyldisilazane base potassium, lithium diisopropylamine, salt of wormwood, rubidium carbonate, cesium carbonate, potassiumphosphate, sodium hydride; Randomly, exist down, and utilize inert atmosphere (for example nitrogen or argon gas) to reach randomly under pressure easily like 18-hat-6-ether in complexing agent.

The iii) cycloalkylidene imino-of selective oxidation in following general formula compound,

Wherein A ' representative is randomly also through substituted 5-7 person 2-oxo-cycloalkylidene imino-, as mentioning R in following of the definition of preamble A ¹And R ²Like definition and Z in the preamble ²Representation carboxy, and randomly further react to form the active carboxylic acid derivative of general formula X III.

The general formula X III compound that obtains through the described method of for example preamble; Wherein A ' represents cycloalkylidene imino-and Q representation hydroxy; Form under the following condition of being reflected at of corresponding lactam adjacent to the methylene radical of nitrogen through oxidation and to carry out: with oxygenant such as potassium permanganate, potassiumchromate, SRM 935a, chromic oxide (VI), mercury chloride (II), selenium oxide (IV), plumbous oxide (IV), plumbous oxide (II; IV), permonosulphuric acid potassium, hydrogen peroxide, Youxiaolin; Randomly at suitable catalyzer; Exist down like nickelous chloride (II), NSC 51149 (II), ruthenium chloride (III), osmium chloride (VIII), vanadium oxide (IV), and/or in the presence of the crown ether like 18-hat-6, in solvent; In water, formic acid, acetate, ETHYLE ACETATE, benzene, pyridine, methylene dichloride, chloroform, tetracol phenixin or solvent mixture; Randomly under the 2-phase condition in the presence of suitable phase-transfer catalyst, said catalyzer is tetrabutylammonium chloride, Tetrabutylammonium bromide, zephiran chloride-triethyl ammonium or methyl chloride-trioctylammonium for example, randomly under sour existence like acetic acid, hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, sodium pyrosulfate, SODIUM PHOSPHATE, MONOBASIC and/or alkali such as sodium hydroxide, Pottasium Hydroxide, ammonia, pyridine, potassiumphosphate, potassium hydrogenphosphate or sodium-acetate; Temperature between-30 and 250 ℃, but be preferable between 0 and 150 ℃.For example, can be with this reaction as by J.H.Markgraf, C.A.Stickney, J.Heterocycl.Chem.2000,37 (1), 109 said carrying out.

The iv) transition metal-catalyzed coupling reaction of the compound of following general formula on the group of the aromatic substance of following general formula

A′-H， (XIV)

Wherein A ' represents 5-7 member, randomly substituted 2-oxo-cycloalkylidene imino-, and as mentioning in following of the definition of preamble A,

R wherein ¹And R ²Like definition and Z in the preamble ²Represent nitrile group or C _1-5-alkoxy carbonyl and Z ³Represent chlorine, bromine or iodine atom or trifluoromethanesulfonic acid foundation group, and with after saponification Z ²Nitrile group or C _1-5-alkoxy carbonyl and the carbonyl that randomly obtains further react and the active carboxylic acid derivative of formation general formula X II.

Said reaction is being carried out under the following condition easily: in solvent or solvent mixture; Said solvent such as benzene,toluene,xylene, THF, dioxane, diethyl ether, t-butyl methyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetramethylene sulfone, N, N-Methyl pyrrolidone, tetraline, DMSO 99.8MIN., methylene dichloride, chloroform or tetracol phenixin; The temperature between-30 and 250 ℃ for example; But be preferable between 0 and 200 ℃, easily in the presence of transition-metal catalyst, said catalyzer as four (triphenylphosphines) close palladium (0), three-(dibenzalacetone)-close two palladiums (0), palladium (II), Palladous chloride (II), chlorination two-(triphenylphosphine)-close palladium (II), chlorination be two-(tricyclohexyl phosphine)-close palladium (II), chlorination two-(triethyl phosphine)-close palladium (II), chlorination be two-(tri-o-tolyl phosphine)-close palladium (II); Randomly in the presence of part; Said part such as triphenylphosphine, tri-o-tolyl phosphine, three-tertiary butyl phosphine, 1, two (the diphenylphosphino)-propane, 2,2 of 3-'-two (diphenylphosphino)-1; 1 '-dinaphthalene, 1; 1 '-two (diphenylphosphino)-ferrocene, xantphos, or for example at transition-metal catalyst, exist down like cupric iodide (I), cupric bromide (I) or neutralized verdigris (I); And easily at alkali; Like tetramethyl guanidine, Tetramethyl Ethylene Diamine or N, N '-dimethyl-ethylenediamine exists down, and easily at alkali; Exist down like sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, tertiary butyl dimethyl-silicon sodium alkoxide, hexamethyldisilazane base potassium, diisopropylamine lithium, salt of wormwood, rubidium carbonate, cesium carbonate, potassiumphosphate, sodium hydride; Randomly, exist down, and utilize inert atmosphere (for example nitrogen or argon gas) to reach randomly under pressure easily like 18-hat-6-ether in complexing agent.

V) use the compound acylation/sulfonylation of general formula (XIX) and the compound of the following general formula of alkylation

R wherein ¹And R ²Like definition and Z in the preamble ²Represent nitrile group or C _1-5-alkoxy carbonyl

Wherein E represents carbonyl, carbonyl oxygen base, alkylsulfonyl or sulfamyl, randomly is set forth in like preamble to replace on the nitrogen-atoms, and of preamble, G represents chlorine, bromine or iodine atom or acid anhydride, C _1-5Alkoxyl group or benzotriazole oxygen base or E and G represent isocyano-and Z together ⁴Represent the freestone leavings group; For example chlorine, bromine or iodine atom, tosylate, trifluoromethanesulfonic acid root or methanesulfonate group; And n is the numeral between 3 and 5; And, can each methylene radical be replaced or replacement by heteroatoms in addition, and carry out intramolecular cyclization reaction through the alkylation of aniline nitrogen subsequently and slough freestone leavings group Z simultaneously according to the described explanation of preamble ⁴, saponification Z afterwards ²Nitrile group or C _1-5-alkoxy carbonyl and the carboxyl that randomly obtains further react and the active carboxylic acid derivative of formation general formula X III.

Said acidylate/sulfo group reaction is being carried out under the following condition easily: in solvent or solvent mixture, and said solvent such as benzene, chlorobenzene, toluene, YLENE, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, N, N-Methyl pyrrolidone, tetraline, DMSO 99.8MIN., tetramethylene sulfone, methylene dichloride, chloroform, tetracol phenixin, N-ethyl-diisopropylamine, N-C _1-5Alkyl morpholine, N-C _1-5Alkylpiperidine, N-C _1-5Alkyl pyrrolidine, triethylamine, pyridine; The temperature between-30 and 250 ℃ for example; But be preferable between 0 and 150 ℃; Easily in the presence of alkali, said alkali such as pyridine, triethylamine, right-dimethyl aminopyridine, salt of wormwood, yellow soda ash, potassium tert.-butoxide, sodium methylate, sodium ethylate or deacidite.

Intramolecularly alkylated reaction is subsequently carrying out under the following condition easily: in solvent or solvent mixture, and said solvent such as benzene, chlorobenzene, toluene, YLENE, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, N, DMSO 99.8MIN., tetramethylene sulfone, methylene dichloride, tetracol phenixin, N-ethyl-diisopropylamine, N-C _1-5Alkyl morpholine, N-C _1-5Alkylpiperidine, N-C _1-5Alkyl pyrrolidine, triethylamine, pyridine; The temperature between-30 and 250 ℃ for example; But be preferable between 0 and 150 ℃; Easily in the presence of alkali, said alkali such as pyridine, triethylamine, salt of wormwood, yellow soda ash, potassium tert.-butoxide, sodium methylate, sodium ethylate, sodium hydride, hexamethyldisilazane base potassium or lithium diisopropylamine.

Vi) carbamylization/the urine with the compound of following general formula forms

R wherein ¹And R ²Like definition and Z in the preamble ²Represent nitrile group or C _1-5-alkoxy carbonyl, and can obtaining by the compound of the currently known methods in the document by general formula X VIII, for example through in toluene with phosgene, with the compound reaction of following general formula

Z wherein ⁴Represent the freestone leavings group, for example chlorine, bromine or iodine atom, tosylate, trifluoromethanesulfonic acid root or methanesulfonate group, and E representation hydroxy, amino or C _1-3-alkylamino functional group and n are the numeral between 2 and 4, and according to the described explanation of preamble, can be with the extra replacement of each methylene radical, and carry out intramolecular cyclization reaction through the alkylation of aniline nitrogen subsequently and slough freestone leavings group Z simultaneously ⁴, saponification Z afterwards ²Itrile group or C _1-5-alkoxy carbonyl and the carboxyl that randomly obtains further react and the active carboxylic acid derivative of formation general formula X III.

Said carbamyl reaction is being carried out under the following condition easily: in solvent or solvent mixture, and said solvent such as benzene, chlorobenzene, toluene, YLENE, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, N, N-Methyl pyrrolidone, tetraline, DMSO 99.8MIN., tetramethylene sulfone, methylene dichloride, chloroform, tetracol phenixin, N-ethyl-diisopropylamine, N-C _1-5Alkyl morpholine, N-C _1-5Alkylpiperidine, N-C _1-5Alkyl pyrrolidine, triethylamine, pyridine, the temperature between-30 and 250 ℃ for example, but be preferable between 0 and 150 ℃.Intramolecularly alkylated reaction is subsequently for example carried out with the similar method of v) explaining down.

The vii) cyclisation metathesis reaction of the compound of following general formula (cyclisation metathesis)

R wherein ¹And R ²As defining Z in the preamble ²Represent itrile group, C _1-5-alkoxy carbonyl or carboxyl; E represents aminocarboxyl, amino-sulfonyl or randomly according to the substituted amino of the described explanation of preamble or carbonyl or alkylsulfonyl or oxygen or sulphur atom or chemical bond; And m and o represent numeral identical or different between 1 and 3 independently of one another; It can be by obtaining with the order alkylation and the acidylate/sulfonylation/carbamylization/sulphonamideization of corresponding reagent through known method in the method explained among this paper or the document, afterwards saponification Z ²Itrile group or C _1-5-alkoxy carbonyl and the carboxyl that randomly obtains further react and the active carboxylic acid derivative of formation general formula X III.

Cyclization through metathesis reaction is carrying out under the following condition easily: in solvent or solvent mixture; Said solvent such as benzene, chlorobenzene, toluene, YLENE, methyl alcohol, ethanol, propyl alcohol, diethyl ether, t-butyl methyl ether, THF, dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, N, N-Methyl pyrrolidone, tetraline, DMSO 99.8MIN., tetramethylene sulfone, methylene dichloride, chloroform, tetracol phenixin, pyridine; At catalyzer; Close ruthenium (first-generation Grubbs catalyzer) or tolylene-[1 like tolylene-two-(tricyclohexyl phosphine)-two chloro-; The inferior imidazolidyl of two (2,4, the 6-the trimethylphenyl)-2-of 3-]-two chloro-(tricyclohexyl phosphine)-close ruthenium (s-generation Grubbs catalyzer) to exist down; The temperature between-30 and 250 ℃ for example; But be preferable between 0 and 150 ℃, easily in inert atmosphere, for example under the argon gas.

(e) in order to prepare the compound of following general formula

Wherein A, B and R ¹To R ⁵As defining in the preamble:

With the carboxylic acid of general formula (XIII) or the compound of the following general formula of active carboxylic acid derivative's acidylate

Wherein B and R ³To R ⁵Like definition and Z in the preamble ¹Represent ar atmo,

Wherein A, R ¹And R ²Like definition and Q representation hydroxy or C in the preamble _1-4-alkoxyl group, halogen atom or acyloxy.

Said acylation reaction is carried out under following condition with corresponding halogenide or acid anhydride easily: in solvent; In methylene dichloride, chloroform, tetracol phenixin, ether, THF, dioxane, benzene, toluene, acetonitrile, N, sodium hydroxide solution or tetramethylene sulfone; Randomly exist down in inorganic or organic bases; Temperature between-20 and 200 ℃, but be preferable between-10 and 160 ℃.

Yet the also available free acid of said acylation reaction is carrying out under the following condition: randomly in the presence of acid activators or dewatering agent, as at isobutyl chlorocarbonate, THIONYL CHLORIDE 97, trimethylchlorosilane, hydrogenchloride, sulfuric acid, methylsulfonic acid, tosic acid, phosphorus trichloride, Vanadium Pentoxide in FLAKES, N; N '-dicyclohexyl carbonyl diimine/N-hydroxy-succinamide or 1-hydroxyl-benzotriazole, N, N '-carbonyl dimidazoles, O-(benzotriazole-1-yl)-N, N; N '; N '-tetramethyl--urea a tetrafluoro borate/N-methylmorpholine, O-(benzotriazole-1-yl)-N, N, N '; N '-tetramethyl--urea a tetrafluoro borate/N-ethyl diisopropyl amine, O-pentafluorophenyl group-N; N ' N ', N '-tetramethyl--urea hexafluorophosphate/triethylamine, N are under the existence of N '-thionyl imidazoles or triphenylphosphine/tetracol phenixin; Temperature between-20 and 200 ℃, but be preferable between-10 and 160 ℃.

Acid amides coupled additive method is illustrated in for example P.D.Bailey, and I.D.Collier, K.M.Morgan be in " Comprehensive Functional Group Interconversions " the 5th, after 257 pages, and 1995.

(f) for by corresponding compound general formula (II), (XXIV), (VII), (VIII), (XI) or compound (XXIII), wherein A, B and R ¹To R ⁷Like definition and R in the preamble ⁸Representative is connected to the C of aromatic group via carbon atom _2-3-alkynyl, and it carries ginseng key, wherein R simultaneously ⁸Represent bromine or iodine atom or trifluoromethanesulfonic acid root, boric acid or boric acid ester group:

Following general formula compound

Z wherein ⁵Represent Wasserstoffatoms, methyl or blocking group like for example trimethyl silyl, the tertiary butyl-dimetylsilyl, the tertiary butyl-diphenylmethyl siloyl group or triisopropyl; Then can it be sloughed; Carry out transition metal-catalyzed coupling reaction with general formula (II), (XXIV), (VII), (VIII), (XI) or compound (XXIII), wherein A, B and R ¹To R ⁷Like definition and R in the preamble ⁸Represent bromine or iodine atom or trifluoromethanesulfonic acid root, boric acid or boric acid ester group.

Said reaction is preferably carried out under following condition: in solvent, in acetonitrile, diethyl ether, THF, dioxane, water or N or solvent mixture, palladium catalyst as chlorination for example two-(triphenylphosphine)-close palladium (II), chlorination [1; 1 '-two (diphenylphosphine)-ferrocene]-close palladium (II) or four-(triphenylphosphine) to close palladium (0) existence down, at alkali, like triethylamine, N-isopropyl diethyl amine, N; N-di-isopropyl-ethylamine, potassium tert.-butoxide, yellow soda ash or cesium carbonate exist down, randomly in part, like triphenylphosphine, tri-o-tolyl phosphine, three-tertiary butyl phosphine, 1; Two (the diphenylphosphine)-propane, 2,2 of 3-'-two (diphenylphosphine)-1,1 '-dinaphthalene, 1; 1 '-two (diphenylphosphino)-ferrocene, xantphos exist down and randomly at transistion metal compound, as copper halide for example cupric iodide (I) exist down and the temperature between 20 and 120 ℃, be preferable over the temperature between 20 and 90 ℃; Under argon or nitrogen atmosphere (also referring to K.Sonogashira; Comprehensive Organic Synthesis, the 3rd, after 52 pages; Pergamon Press, Oxford1991).

Preferably with the silyl protecting group of any existence like trimethyl silyl for example in solvent or solvent mixture; Said solvent such as water, methyl alcohol, ethanol, Virahol, acetone, dioxane, THF or N are sloughed in the presence of alkali such as Lithium Hydroxide MonoHydrate, sodium hydroxide, salt of wormwood or sodium methylate.For at organic solvent like sloughing in for example diethyl ether, THF, N or the methylene dichloride, also can use fluoride reagents, like for example tetrabutylammonium, lithium fluoride or Potassium monofluoride, randomly add complexometric reagent, like 18-hat-6-ether.

In above-mentioned reaction, can with the reactive group of any existence such as hydroxyl, carboxyl, amino, alkylamino or imido based between the reaction period through general blocking group protection, after reaction, again it is sloughed.For example, the due care group for hydroxyl can be methoxyl group, benzyloxy, trimethyl silyl, ethanoyl, benzoyl-, the tertiary butyl, trityl, benzyl or tetrahydrofuran base;

Due care group for carboxyl can be trimethyl silyl, methyl, ethyl, the tertiary butyl, benzyl or THP trtrahydropyranyl;

Due care group for amino, alkylamino or imino-can be ethanoyl, trifluoroacetyl group, benzoyl-, ethoxy carbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxy-benzyl or 2; The 4-dimethoxy-benzyl; And in addition for amino, the phthalyl group also is the due care group.

Other blocking groups and slough and be illustrated in T.W.Greene, P.G.M.Wuts, " ProtectingGroups in Synthesis ", Wiley, 1991 and 1999.

Randomly can the blocking group of any use be sloughed subsequently; For example through hydrolysis in water-containing solvent, as in water, isopropanol, THF/water or dioxane/water, acid like trifluoroacetic acid, hydrochloric acid or vitriolic in the presence of or in the presence of alkali metal base such as Lithium Hydroxide MonoHydrate, sodium hydroxide or Pottasium Hydroxide; Or through the ether division; As in the presence of Iodotrimethylsilane, the temperature between 0 and 100 ℃ is preferable over the temperature between 10 and 50 ℃.

Yet, benzyl, methoxy-benzyl or benzyloxycarbonyl are sloughed through hydrogenolysis, for example; With hydrogen in the presence of catalyzer, in solvent, in methyl alcohol, ethanol, ETHYLE ACETATE, N, N/acetone or Glacial acetic acid min. 99.5 like Pd/C; Randomly add sour example hydrochloric acid, and the temperature between 0 and 50 ℃, but be preferable over room temperature; And at hydrogen pressure 1 to 7 crust, yet be preferably 1 to 5 crust.

Also can methoxybenzyl is following in solvent such as methylene dichloride, acetonitrile or acetonitrile/water based on oxygenant such as cerium ammonium nitrate (IV) existence, the temperature between 0 and 50 ℃ is sloughed but be preferable under the room temperature.

Easily with under the existence of methoxy based on boron tribromide, in solvent such as methylene dichloride ,-35 and-25 ℃ between temperature slough.

Preferably with 2, the 4-dimethoxy-benzyl is sloughed under methyl-phenoxide exists in trifluoracetic acid.

Preferably that the tertiary butyl or tert-butoxycarbonyl is sour through using, like trifluoracetic acid or hydrochloric acid, randomly utilize solvent such as methylene dichloride, dioxane or ether to handle and slough.

Preferably with the phthalyl group in the presence of diamine or primary amine such as methylamine, ethylamine or n-butylamine in solvent such as methyl alcohol, ethanol, Virahol, toluene or dioxane, the temperature between 20 and 50 ℃ is sloughed.

Sloughing through handling with four of catalytic amount-(triphenylphosphine)-close palladium (0) of allyloxy carbonyl is preferable in solvent such as the THF and is preferable over excess base, like morpholine or 1; 3-methone (dimedone) exists down; Temperature between 0 and 100 ℃ is preferable over room temperature and under rare gas element, or through with chlorination three-(triphenylphosphine) of catalytic amount-close rhodium (I) processing; In solvent such as aqueous ethanolic solution and randomly in alkali; As 1,4-diazabicylo [2.2.2] octane exists down, under the temperature between 20 and 70 ℃.

Can general formula (II) (wherein group B ' be is by the group representative of general formula (III)) and compounds (IV) be similar to for example K.Maekawa, J.Ohtani, Agr.Biol.Chem.1976,40,791-799 and preparing.

Moreover, can the compound of the general formula I that obtains be resolved to its enantiomer and/or diastereomer.

Therefore; For example; Can be through known method itself with the compound of the general formula I that obtains that exists with racemoid separately (referring to Allinger N.L. and Eliel E.L. in " Topics in Stereochemistry " the 6th; Wiley Interscience, 1971) become its optically active enantiomorph and can the compound of Formula I with at least 2 unsymmetrical carbons be resolved to its diastereomer based on the known method of its physical-chemical property difference utilization itself, as passing through red, orange, green, blue, yellow (ROGBY) and/or fractional crystallization; And, can it be resolved to enantiomer as above-mentioned subsequently if obtain these compounds with racemic form.

The separation of enantiomer preferably through in the post of chirality phase is separated or through from the optical activity solvent recrystallization or through with form the optically active substance of salt or verivate such as ester or acid amides with racemic compound; Particularly acid and activatory verivate and alcohols thereof reaction; And as the salt that so obtains based on the differential liberation of its solubleness or the non-enantiomer mixture of verivate, and can be with the free enantiomorph from pure diastereomeric salt or verivate separation through the effect of suitable reagent.The general optical activity acid of using is tartrate or dibenzoyl tartaric acid, two-o-tolyl tartrate, oxysuccinic acid, racemic melic acid, camphorsulfonic acid, L-glutamic acid, aspartic acid or the quinic acid of for example D-and L-form.Optical activity alcohol for example can be (+)-or (-)-TK-10 and for example in acid amides optically active acyl group for example can be (+)-or (-)-peppermint oxygen base carbonyl.

Moreover, can formula I compound be transformed into its salt, particularly for medicinal use, become physiologically acceptable salt with inorganic or organic acid.The acid that can be used for this purpose comprises for example hydrochloric acid, Hydrogen bromide, sulfuric acid, methylsulfonic acid, phosphoric acid, FUMARIC ACID TECH GRADE, succsinic acid, lactic acid, Hydrocerol A, tartrate or maleic acid.

Moreover, if the new compound of formula I contains carboxyl, optionally can convert itself and inorganic or organic bases to its salt subsequently, particularly become its physiologically acceptable salt for medicinal use.The alkali that is applicable to this purpose comprises for example sodium hydroxide, Pottasium Hydroxide, hexahydroaniline, thanomin, diethylolamine and trolamine.

As explained; The compound of general formula I and tautomer thereof, enantiomer, diastereomer and physiologically acceptable salt thereof have valuable pharmacological character; Antithrombotic acitivity particularly; It is preferably based on the effect to zymoplasm (thrombin) or Xa factor; For example suppress or Xa factor suppresses active, to the prolongation effect of aPTT time and/or to the restraining effect of relevant Tryase such as urokinase, the VIIa factor, the IXa factor, the XIa factor and the XIIa factor for zymoplasm.

It is following to the restraining effect of Xa factor to study the compound of listing in experimental section:

Method:

Doing enzyme kinetics with chromogenic substrate measures.The amount of the p-Nitroaniline (pNA) that will be discharged from colourless chromogenic substrate by human Xa factor is in the 405nm photometry.It is directly proportional with the enzymic activity of using.With different test substances concentration determinations by test substances to the inhibition (with respect to solvent control group) of enzymic activity and calculate IC thus ₅₀, the concentration of the Xa factor 50% that inhibition is used.

Material:

Three (hydroxymethyl)-aminomethane buffer solutions (100mMol) and sodium-chlor (150mMol), pH 8.0 adds 1mg/ml people's albuminoid part of V, no proteolytic enzyme

Xa factor (Calbiochem), specific activity: 217IU/mg is for the ultimate density of each reaction mixture: 7IU/ml

Substrate S 2765 (Chromogenix) is for the ultimate density of each reaction mixture: 0.3mM/l (1KM)

Test substances: ultimate density 100,30,10,3,1,0.3,0.1,0.03,0.01.0.003,0.001 μ Mol/l

Step:

23.5 times of spissated starting solns of 10 microlitre test substances or solvent (control group), 175 microlitre TRIS/HSA damping fluids and 25 microlitre 65.8U/L Xa factor working solutions were cultivated 10 minutes in 37 ℃.After adding 25 microlitre S, 2765 working solutions (2.82mMol/l) with sample with photometer (SpectraMax250) 405nm and 37 ℃ of measurements 600 seconds.

Estimate:

1. 21 MPs are confirmed maximum increase (Δ OD/ minute).

2. confirm to suppress % based on solvent control group.

3. make dosage/activity curve figure (suppressing %) to material concentration.

4. insert X-value (material concentration) in suppressing through Y=50% and confirm IC at dosage/activity curve ₅₀

The compound of all tests has the IC less than 100 μ mol/l ₅₀Value.

Compound prepared in accordance with the present invention is generally and well can tolerates.

In view of its pharmacological property; New compound of the present invention and physiologically acceptable salt thereof are suitable for prevention and treatment vein and artery thrombosis property disease, as for example preventing and treat the leg venous thrombosis, are used to prevent inaccessible again behind by-pass operation or the blood vessel prosthesis (PT (C) A); And the obturation in peripheral arterial disease; And be used for prevention and treatment pulmonary infarction, disseminated inravascular coagulation and serious septicemia, and be used to prevent and treat DVT with the patient of worsening COPD, be used to treat ulcerative colitis; Form with treatment and prevention coronary embolism, it is inaccessible to be used for preventing apoplectic and arm.In addition; Compound according to the present invention is suitable for supporting as the antithrombotic in thrombolytic treatment; For example with alteplase, reteplase, for the general enzyme of naphthalene, staphylokinase or streptokinase, be used to prevent the long-term restenosis behind PT (C) A, the ischemia incident that is used to prevent and treat patient with various forms coronary heart disease; The transfer and growth and the inflammation process that are used for prophylaxis of tumours; As in the treatment pulmonary fibrosis, be used for prevention and treatment rheumatic arthritis, be used to prevent and treat the sticking glutinous and/or scar tissue of the relevant tissue of scleroproein form and be used to promote the wound healing process.Can with the treatment of new compound and physiologically acceptable salt thereof go up with Xaxa, with anticoagulant such as fibrinogen deceptor antagonists (like ReoPro, eptifibatide, Tirofiban, roxifiban), with the physiological activator of blood coagulation system and suppressor factor and reorganization analogue (like protein C, TFPI, antithrombin) thereof, with accumulative suppressor factor of ADP-initiation (like chlorine than Gray, ticlopidine) and P ₂T receptor antagonist (like cangrelor) or use with bonded thromboxane receptor antagonist/synthetase inhibitors (like Terbogrel).

The required dosage that is effective suitably is 0.01 to 3mg/kg by intravenous route, is preferably 0.03 to 1.0mg/kg, and is 0.03 to 30mg/kg by oral route, is preferably 0.1 to 10mg/kg, all administrations every day 1 to 4 time in each situation.

For this purpose; Can formula I compound prepared in accordance with the present invention be chosen wantonly and other active substances; Prepare together with one or more general inert supports and/or thinner; Said carrier and/or thinner such as W-Gum, lactose, glucose, Microcrystalline Cellulose, Magnesium Stearate, PVP K120, Hydrocerol A, tartrate, water, water/ethanol, water/glycerine, water/sorbyl alcohol, water/polyoxyethylene glycol, Ucar 35,16 stearyl alcohol, CMC 99.5 or fatty substance such as solid fat or its suitable mixture are to produce general pharmaceutical prepn such as uncoated tablets or coating tablet, capsule, powder, suspension-s or suppository.

The following example is to be used for the present invention is described and not limit its scope:

Experimental section

Usually, for the compound of preparation obtained fusing point, IR, UV, ¹H-NMR and/or mass spectrum.Except as otherwise noted, utilize ready-made silica gel 60 F ₂₅₄The saturated R that obtains of TLC plate (E.Merck, Darmstadt, Item no.1.05714) slotless _fValue.Utilize ready-made aluminum oxide 60 F ₂₅₄The R that TLC plate (E.Merck, Darmstadt, Item no.1.05713) the saturated Alox of being determined at of slotless obtains under one's name _fValue.Utilize ready-made RP-8 F _254STLC plate (E.Merck, Darmstadt, Item no.1.15684) slotless is saturated to be determined at the R that anti-phase-8 obtains under one's name _fValue.The ratio that gives elutriant is meant the unit of the solvent volume of research.Utilization is by the silica gel (MATREX of Messrs Millipore supply ^TM, the 35-70 micron) and carry out chromatogram purification.If not detailed specified structure, it is the pure steric isomer or the mixture of enantiomer and diastereomer for the unclear compound of whether studying.

In the explanation of test, use following abbreviation:

The Boc tert-butoxycarbonyl

DIPEA N-ethyl-diisopropylamine

The DMSO DMSO 99.8MIN.

DMF N, dinethylformamide

Sat. saturated

H hour

I.vac. in the vacuum

Conc. spissated

NMM N-methyl-morpholine

NMP N-methyl-pyrrolidin-2-one

O is adjacent

PfTU O-pentafluorophenyl group-N, N, N ', N '-tetramethyl-urea hexafluorophosphate

PPA propane phosphonic acid cyclic anhydride

Quant. quantitative

R _fRetention factors

R _tRT

Rac. racemoid

TBTU O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate

The TEA triethylamine

The TFA trifluoracetic acid

The THF THF

Tert. uncle

∑ for be similar to that said method carries out yield in steps

The HPLC/MS data of embodiment 35 to 38 obtain under following condition:

(a) Waters ZMD, Alliance 2690 HPLC, Waters 2700 automatic samplers, Waters996 diode-array detector

Use following material as mobile phase:

A: contain 0.1% trifluoroacetic water

B: contain 0.1% trifluoroacetic acetonitrile

Time (minute) %A %B flow velocity (ml/min)

0.0 95 5 ?1.00

0.1 95 5 ?1.00

5.1 2 98 1.00

6.5 2 98 1.00

7.0 95 5 ?1.00

The stationary phase that uses is Waters post X-Terra ^TMMS C ₁₈3.5 micron, 4.6mm * 50mm (column temperature: be fixed in 25 ℃)

It is 210-500nm that diode-array detector produces wavelength region

Mass spectrograph sensing range: m/z 120 to m/z 950

(b) the HPLC/MS data of other embodiment (if providing) obtain under following condition:

HP 1100 with four-stage pump, Gilson G215 automatic sampler, HP diode-array detector.

The mobile phase of using is:

A: the water that contains 0.1%TFA

B: the acetonitrile that contains 0.08%TFA

Time (minute) %A %B flow velocity (ml/min)

0.0 95 5 ?0.4

0.15 95 5 ?0.4

4.65 2 98 0.4

6.0 2 98 0.4

6.5 95 5 ?0.4

The stationary phase that uses is Waters post X-Terra ^TMMS C ₁₈2.5 micron, 2.1mm * 50mm (column temperature: be fixed in 25 ℃)

It is 210-550nm that diode-array detector produces wavelength region

Mass spectrograph sensing range: m/z 120 to m/z 1000

Embodiment 1

3-chloro-N-[(1S)-(and 5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-([1,4] Diazesuberane-1-yl)-BM

(a) 4-(4-N-ethanoyl-[1,4] Diazesuberane-1-yl)-3-chloro-cyanobenzene

4.67 gram (30 mmole) 3-chloro-4-fluoro-cyanobenzenes and 4.27 gram (30 mmole) N-1-ethanoyl-[1,4] Diazesuberanes were stirred 6 hours in 90 ℃ in 5.0 milliliters of DIPEA.Then mixture is dissolved in the methylene dichloride in vacuum-evaporation and with resistates.Water cleans twice with organic phase, reaches through dried over sodium sulfate and in vacuum, evaporates.With the further reaction of resistates and without any other purifying.

Yield (yield): 7.50 grams (90%)

R _fValue: 0.20 (silica gel; Methylene dichloride/ethanol=50: 1)

(b) 3-chloro-4-([1,4] Diazesuberane-1-yl)-phenylformic acid

The resistates that will in embodiment 1a, obtain (7.50 grams, 27.0 mmoles) refluxed 8 hours in 50 milliliter of 25% potassium hydroxide solution.Then mixture is adjusted to pH 5 with concentrated hydrochloric acid.Solid sediment is filtered out dry and further reaction and without any other purifying.

Yield: 5.60 grams (81%)

R _fValue: 0.0 (silica gel; Methylene dichloride/ethanol=9: 1)

(c) 3-chloro-4-([1,4] Diazesuberane-1-yl)-oil of Niobe

The resistates that will in embodiment 1b, obtain (3.00 grams, 11.8 mmoles) is suspended in 100 ml methanol and with hydrogenchloride and in 1 hour, under agitation sends into and be heated to reflux temperature with pipe.Then with mixture in vacuum-evaporation, resistates is mixed with 5% sodium hydrogen carbonate solution and with dichloromethane extraction 3 times.With the organic phase that merges through dried over sodium sulfate.To in vacuum, evaporate the further reaction and of the remaining residue in back without any other purifying.

Yield: 2.25 grams (71%)

R _fValue: 0.10 (silica gel; Methylene dichloride/ethanol=4: 1+2% ammonia)

C ₁₃H ₁₇ClN ₂O ₂(268.75)

Mass spectrum: (M+H) ⁺=269/271 (chlorine isotope)

(d) 4-(4-N-Boc-[1,4] Diazesuberane-1-yl)-3-chloro-oil of Niobe

The resistates that will in embodiment 1c, obtain (1.00 grams, 3.72 mmoles) is mixed in 10 milliliters of methylene dichloride with 0.53 gram (3.80 mmole) salt of wormwood and then 0.83 gram (3.80 mmole) two-tertiary butyl pyrocarbonate is dropwise added.Then with mixture in stirring at room 16 hours.Then it is released with methylene dichloride alkene, clean twice, reach through dried over sodium sulfate and in vacuum, evaporate with water.Then be carried out at the chromatographic analysis purifying (elutriant: methylene dichloride/ethanol 99: 1) on the silica gel.

Yield: 1.34 grams (98%)

R _fValue: 0.50 (silica gel; Methylene dichloride/ethanol=50: 1)

C ₁₈H ₂₅ClN ₂O ₄(368.86)

Mass spectrum: (M+H) ⁺=369/371 (chlorine isotope)

(e) 4-(4-N-Boc-[1,4] Diazesuberane-1-yl)-3-chloro-phenylformic acid

0.60 gram (1.63 mmole) 4-(4-N-Boc-[1,4] Diazesuberane-1-yl)-3-chloro-oil of Niobe is dissolved in 10 ml methanol, mixes with 4 milliliters of 2M potassium hydroxide solutions to reach and stirred 3 hours in 40 ℃.Then mixture is evaporated in vacuum, resistates is used distilled water diluting, with the potassium hydrogen sulfate saturated solution acidifying and with ethyl acetate extraction 3 times.With the organic phase that merges through dried over sodium sulfate and use evaporation concentration.With the further reaction of resistates and without any other purifying.

Yield: 0.50 gram (87%)

R _fValue: 0.05 (silica gel; Methylene dichloride/ethanol=50: 1)

C ₁₇H ₂₃ClN ₂O ₄(354.84)

(f) 4-(4-N-Boc-[1,4] Diazesuberane-1-yl)-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-BM

With 532 milligrams of (1.50 mmole) 4-(4-N-Boc-[1,4] Diazesuberane-1-yl)-3-chloro-phenylformic acid be suspended among 15 milliliters of THF and after adding 546 milligrams of (1.70 mmole) TBTU and 646 milligrams of (5.0 mmole) DIPEA in stirring at room 30 minutes.Then with 403 milligrams (1.50 mmoles) (1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine dihydrochloride add and with mixture in room temperature restir 16 hours.Then it is evaporated in vacuum, resistates is dissolved in the ETHYLE ACETATE, organic phase is cleaned with 5% sodium hydrogen carbonate solution and water and through dried over sodium sulfate.After the evaporation, remaining resistates is passed through silica gel chromatography purifying (elutriant gradient: petrol ether/ethyl acetate: 90: 10-＞60: 40) in the vacuum

Yield: 630 milligrams (79%)

R _fValue: 0.50 (silica gel; Methylene dichloride/ethanol=19: 1)

C ₂₆H ₃₁Cl ₂N ₅O ₃(532.48)

Mass spectrum: (M+H) ⁺=532/534/536 (chlorine isotope)

(g) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-([1,4] Diazesuberane-1-yl)-BM

610 milligrams of (1.15 mmole) 4-(4-N-Boc-[1,4] Diazesuberane-1-yl)-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-the ethyl]-solution of BM in 30 milliliters of methylene dichloride is mixed with 3 milliliters of TFA and in stirring at room 3 hours.Then it is evaporated in vacuum, resistates is dissolved in the ETHYLE ACETATE, clean and through dried over sodium sulfate with 5% sodium hydrogen carbonate solution and water.After the evaporation, resistates is passed through silica gel chromatography purifying (elutriant gradient: petrol ether/ethyl acetate: 80: 20-＞50: 50) in the vacuum.

Yield: 380 milligrams (77%)

R _fValue: 0.10 (silica gel; Methylene dichloride/ethanol=9: 1)

C ₂₁H ₂₃Cl ₂N ₅O(432.36)

Mass spectrum: (M+H) ⁺=432/434/436 (chlorine isotope)

Prepare following compounds with similarity method:

Enforcement executes 2

4-(4-N-Boc-piperazine-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-trifluoromethyl-BM

(a) 4-(piperazine-1-yl)-3-trifluoromethyl-phenylformic acid

With 37.9 gram (195 mmole) piperazine hexahydrates be suspended in 12.4 in 40 milliliters of ethanol grams (66 mmole) 4-fluoro-3-trifluoromethyl-cyanobenzene and refluxed 2 hours.Then 13.7 milliliters of (261 mmole) 50% sodium hydroxide solutions and 13.7 ml waters are added and mixture was refluxed 3.5 hours again and kept 15 hours in room temperature again.Then 43.5 milliliters of concentrated hydrochloric acids are added and mixture is cooled to 10 ℃ and stirred 30 minutes.With the deposition suction filtration that obtains, clean and 40 ℃ of dryings 24 hours in the drying by circulating air device with some water.

Yield: 20.8 grams (quantitatively)

(b) 4-(piperazine-1-yl)-3-trifluoromethyl-oil of Niobe

5.00 gram (18.2 mmole) 4-(piperazine-1-yl)-3-trifluoromethyl-phenylformic acid were stirred 16 hours in 50 ml methanol hydrochloric acid.After reaction mixture evaporated in vacuum, resistates and Virahol are stirred.Solid filtering is fallen, clean and 60 ℃ of dryings in the drying by circulating air device with diethyl ether.

Yield: 5.00 grams (76%)

C ₁₃H ₁₅F ₃N ₂O ₂*2HCl(288.27/361.19)

Mass spectrum: (M+H) ⁺=289

R _fValue: 0.58 (silica gel; Hexanaphthene/methylene dichloride/ethanol=70: 15: the 15+2% concentrated ammonia solution)

(c) 4-(4-N-Boc-piperazine-1-yl)-3-trifluoromethyl-oil of Niobe

5.77 gram (11.78 mmole) 4-(piperazine-1-yl)-3-trifluoromethyl-oil of Niobe are placed 100 milliliters of THF and mix with the sour two-tertiary butyl ester of 4.47 gram (20.5 mmole) cokes.After stirring 40 hours under the room temperature nitrogen atmosphere with reaction mixture in vacuum-evaporation, resistates is mixed with water and saturated nacl aqueous solution and uses ethyl acetate extraction.The organic phase water that merges, semi-saturation and saturated nacl aqueous solution are cleaned, reach through dried over mgso and in vacuum, evaporate.Resistates is passed through silica gel chromatography purifying (elutriant gradient: petrol ether/ethyl acetate: 9: 1-＞8: 1).

Yield: 2.60 grams (34%)

R _fValue: 0.52 (silica gel; Petrol ether/ethyl acetate 7: the 3+1% concentrated ammonia solution)

C ₁₈H ₂₃F ₃N ₂O ₄(388.39)

Mass spectrum: (M+H) ⁺=389

(d) 4-(4-N-Boc-piperazine-1-yl)-3-trifluoromethyl-phenylformic acid

2.60 gram (6.69 mmole) 4-(4-N-tert-butoxycarbonyl-piperazine-1-yl)-3-trifluoromethyl-oil of Niobe are dissolved in 10 ml methanol to reach mix with 12.3 milliliters of (12.3 mmole) 1M potassium hydroxide solutions.After 15 minutes, add again after 10 ml methanol reaction mixture in stirring at room 42 hours.Then mixture is evaporated in vacuum, resistates is mixed with ice and uses acidifying with acetic acid.With the throw out suction filtration that obtains, clean and in 50 ℃ of drying by circulating air devices, reach in KOH and SiO with water ₂40 ℃ of drying pistols in dry.

Yield: 2.40 grams (96%)

R _fValue: 0.41 (silica gel; Petrol ether/ethyl acetate=1: 1+1% acetic acid)

C ₁₇H ₂₁F ₃N ₂O ₄(374.36)

Mass spectrum: (M-H) ^-=373

(e) 4-(4-N-Boc-piperazine-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-trifluoromethyl-BM

Be similar to embodiment 1f by 4-(4-N-Boc-piperazine-1-yl)-3-trifluoromethyl-phenylformic acid, TBTU, NMM and (1S)-(ethylamine of 5-chloro-1H-benzimidazolyl-2 radicals-yl) prepare in NMP and passes through silica gel chromatography purifying (elutriant gradient: petrol ether/ethyl acetate=50: 50) subsequently 1-.

Yield: 57%

R _fValue: 0.20 (silica gel; Petrol ether/ethyl acetate=1: 1)

C ₂₆H ₂₉ClF ₃N ₅O ₃(552.00)

Mass spectrum: (M+H) ⁺=552/554 (chlorine isotope)

Embodiment 3

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(piperazine-1-yl)-3-trifluoromethyl-BM

Being similar to embodiment 1g is prepared in methylene dichloride by 4-(4-N-Boc-piperazine-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-trifluoromethyl-BM and TFA.

Yield: 73%

R _fValue: 0.28 (silica gel; Methylene chloride=90: the 10+ ammonia soln)

C ₂₁H ₂₁ClF ₃N ₅O*2CF ₃COOH(679.93/451.88)

Mass spectrum: (M+H) ⁺=452/454 (chlorine isotope)

The sequential system that is similar to explanation in embodiment 2 and 3 is got the row compound ready:

Embodiment 5

4-(4-N-ethanoyl-piperazine-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-trifluoromethyl-BM

220 milligrams of (0.32 mmole) N-that will be in 5 milliliters of THF [(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(piperazine-1-yl)-3-trifluoromethyl-BM-two trifluoroacetate mixes with 0.23 milliliter of (1.65 mmole) TEA; 50 microlitres (0.70 mmole) Acetyl Chloride 98Min. is dropwise added, and stir simultaneously to reach in ice bath, to cool off to reach under room temperature and stirred 2 hours.Reaction mixture is poured in the frozen water then with ethyl acetate extraction.Organic phase water and saturated nacl aqueous solution are cleaned, reach through dried over sodium sulfate and in vacuum, evaporate.With the solvent mixture development (trituration) of resistates with ETHYLE ACETATE and diethyl ether, filter out, clean and drying in 50 ℃ of drying pistols with diethyl ether.

Yield: 0.13 gram (81%)

R _fValue: 0.55 (silica gel; Methylene dichloride/ethanol=9: the 1+ ammonia soln)

C ₂₃H ₂₃ClF ₃N ₅O ₂(493.92)

Mass spectrum: (M+H) ⁺=494/496 (chlorine isotope)

Embodiment 6

4-(azepan-2-ketone-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-BM

(a) 4-(6-bromo-caproyl-amino)-3-methyl-oil of Niobe

The solution of 2.14 gram (10 mmole) 6-bromo-caproyl chlorides in 5.0 milliliters of THF is restrained (10 mmole) 4-amino-3-methyl-oil of Niobe in 50 milliliters of THF that contain 2 milliliters of DIPEA in slowly dropwise being added to 1.65 under the stirring at room., after 16 hours mixture in vacuum-evaporation, is dissolved in resistates in the methylene dichloride in stirring at room, water cleans twice and through dried over sodium sulfate.To in vacuum, evaporate the further reaction and of the remaining resistates in back without any other purifying.

Yield: 3.30 grams (96%)

R _fValue: 0.40 (silica gel; Petrol ether/ethyl acetate=4: 1)

C ₁₅H ₂₀BrNO ₃(342.24)

(b) 4-(azepan-2-ketone-1-yl)-3-methyl-oil of Niobe

The product that 3.20 grams (9.35 mmole) are obtained in embodiment 5a refluxed 4 hours in freshly prepd 1.00 gram (43.5 Bo mole) sodium solution in 80 ml methanol.Then with mixture in vacuum-evaporation, with resistates with the 2M acidifying with acetic acid and use ethyl acetate extraction.With the organic phase water cleaning that merges and through dried over sodium sulfate.Further reaction and of the resistates that will obtain after will in vacuum, evaporating without any other purifying.

Yield: 1.90 grams (product of pollution)

R _fValue: 0.30 (silica gel; Methylene dichloride/ethanol=50: 1)

C ₁₅H ₁₉NO ₃(261.32)

Mass spectrum: (M+H) ⁺=262

(c) 4-(azepan-2-ketone-1-yl)-3-methyl-phenylformic acid

Will be in 30 ml methanol 1.90 restrain that the product that in embodiment 5b, obtains mixes with 10 milliliters of 2M sodium hydroxide solutions and in stirring at room 16 hours.In vacuum after the evaporation, resistates is mixed with water and uses the concentrated hydrochloric acid acidifying.The sedimentation and filtration that forms is fallen and drying.After being dissolved in methyl alcohol and adding to silica gel, through silica gel chromatography with product purification (elutriant gradient: petrol ether/ethyl acetate 70: 30-＞50: 50).

Yield: 0.23 gram (through 2 steps 10%)

R _fValue: 0.10 (silica gel; Petrol ether/ethyl acetate=1: 2)

C ₁₄H ₁₇NO ₃(247.30)

Mass spectrum: (M+H) ⁺=248

(d) 4-(azepan-2-ketone-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-BM

Be similar to embodiment 1f by 4-(azepan-2-ketone-1-yl)-3-methyl-phenylformic acid, TBTU, DIPEA and (1S)-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine prepare in THF and passes through silica gel chromatography purifying (elutriant gradient: ETHYLE ACETATE/alcohol 95: 5-＞90: 10) subsequently 1-.

Yield: 61%

R _fValue: 0.30 (silica gel; ETHYLE ACETATE)

C ₂₃H ₂₅ClN ₄O ₂(424.93)

Mass spectrum: (M+H) ⁺=425/427 (chlorine isotope)

Prepare following compounds with similarity method:

Embodiment 9

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(pyrrolidin-2-one-1-yl)-BM

(a) 4-(pyrrolidin-2-one-1-yl)-phenylformic acid

19.2 gram (140 Bo mole) 4-amino-phenylformic acid were refluxed 20 hours in 100 milliliters of DMF with 25.8 milliliters of (180 Bo mole) 4-bromo-butyric acid ethyl esters.After vacuum-evaporation, with resistates and 100 ml waters and 50 milliliters of sherwood oils mix and vigorous stirring 50 minutes.Throw out is filtered out, and recrystallize reaches in 80 ℃ of dryings in ethanol.

Yield: 9.36 grams (33%)

C ₁₁H ₁₁NO ₃(205.22)

Mass spectrum: (M+H) ⁺=206

(b) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(pyrrolidin-2-one-1-yl)-BM

Be similar to embodiment 1f by 4-(pyrrolidin-2-one-1-yl)-phenylformic acid, TBTU, DIPEA and (1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine prepare in THF and subsequently through water, dilute sodium bicarbonate solution, water and the solution of saturated nacl aqueous solution erase residual thing in ETHYLE ACETATE, through dried over sodium sulfate and in vacuum removal solvent and purifying.

Yield: 61%

R _fValue: 0.50 (silica gel; Methylene dichloride/ethanol=9: 1)

C ₂₀H ₁₉ClN ₄O ₂(382.85)

Mass spectrum: (M+H) ⁺=383/385 (chlorine isotope)

Embodiment 12

3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(4-N-methyl-[1,4] Diazesuberane-1-yl)-BM

(a) 3-chloro-4-(4-N-methyl-[1,4] Diazesuberane-1-yl)-cyanobenzene

Be similar to embodiment 1a and in DIPEA, prepare, subsequently through silica gel chromatography purifying (elutriant gradient: methylene dichloride/ethanol 98: 2-＞94: 6) by 3-chloro-4-fluoro-cyanobenzene and 1-methyl-[1,4] Diazesuberane.

Yield: 71%

R _fValue: 0.20 (silica gel; Methylene dichloride/ethanol=19: 1)

C ₁₃H ₁₆ClN ₃(249.75)

Mass spectrum: (M+H) ⁺=250/252 (chlorine isotope)

(b) 3-chloro-4-(4-N-methyl-[1,4] Diazesuberane-1-yl)-phenylformic acid

Being similar to embodiment 1b is prepared in 25% potassium hydroxide aqueous solution by 3-chloro-4-(4-methyl-[1,4] Diazesuberane-1-yl)-cyanobenzene.

Yield: 99%

C ₁₃H ₁₇ClN ₂O ₂*HCl(268.74/305.21)

Mass spectrum: (M+H) ⁺=269/271 (chlorine isotope)

(c) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(4-N-methyl-[1,4] Diazesuberane-1-yl)-BM

Be similar to embodiment 1f by 3-chloro-4-(4-methyl-[1; 4] Diazesuberane-1-yl)-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine, TBTU and DIPEA prepare in THF, subsequently through chromatographic analysis purifying (the elutriant gradient: petrol ether/ethyl acetate 50: 50-＞20: 80) on silica gel for phenylformic acid, (S)-1-.

Yield: 34%

R _fValue: 0.30 (silica gel; Methylene dichloride/ethanol=9: the 1+1 ammonia soln)

C ₂₂H ₂₅Cl ₂N ₅O(446.38)

Mass spectrum: (M+H) ⁺=446/448/450 (chlorine isotope)

Embodiment 13

3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(2-methyl-tetramethyleneimine-1-yl)-BM

(a) 3-chloro-4-(2-methyl-tetramethyleneimine-1-yl)-cyanobenzene

Restraining (37.9 mmole) 3-chloro-4-fluoro-cyanobenzenes with 5.90 is dissolved among 65 milliliters of DMF under nitrogen atmosphere and and 5.45 gram (39.5 mmole) salt of wormwood and 4.2 milliliters of (3.5 grams, 39.5 mmoles) 2-methyl-tetramethyleneimine mixing.In 90 ℃ stir 2.5 days after, reaction mixture is poured in 400 ml waters and is used ethyl acetate extraction.The organic phase that merges with rare and saturated nacl aqueous solution cleaning many times, is reached through dried over mgso and in vacuum, to evaporate.With the further reaction of remaining resistates and without any other purifying.

Yield: 7.90 grams (94%)

R _fValue: 0.40 (silica gel; Petrol ether/ethyl acetate=9: the 1+0.5% ammonia soln)

C ₁₂H ₁₃ClN ₂(220.70)

Mass spectrum: (M+H) ⁺=221/223 (chlorine isotope)

(b) 3-chloro-4-(2-methyl-tetramethyleneimine-1-yl)-phenylformic acid

The product that 8.0 grams (40 mmole) are obtained in embodiment 13a stirred 2.75 hours in 90 ℃ in 65 milliliters of 10M sodium hydroxide solutions and 65 milliliters of alcoholic acid mixtures.Then reaction mixture is poured in the frozen water, mixed with concentrated hydrochloric acid and the volatility organic composition divided in vacuum and evaporate.Remaining water is used dichloromethane extraction, mix and be adjusted to pH 4.5 with half concentrating hydrochloric acid and 2N potassium hydrogen sulfate solution with ice.With the throw out restir that forms 10 minutes, then filter out, water cleans and in 55 ℃ of dryings.

Yield: 8.30 grams (87%)

R _fValue: 0.55 (silica gel; Petrol ether/ethyl acetate=6: 4+1% acetic acid)

C ₁₂H ₁₄ClNO ₂(238.72)

Mass spectrum: (M+H) ⁺=240/242 (chlorine isotope)

(c) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(2-methyl-tetramethyleneimine-1-yl)-BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine, TBTU and TEA prepare in DMF by 3-chloro-4-(2-methyl-tetramethyleneimine-1-yl)-phenylformic acid, (1S)-1-to be similar to embodiment 1f; Then precipitate, filter and the water cleaning through pouring in the dilute sodium bicarbonate solution.Then with product in 55 ℃ of dryings.

Yield: 92%

R _fValue: 0.66 (silica gel; Methylene dichloride/ethanol=9: 1)

C ₂₁H ₂₂Cl ₂N ₄O(417.34)

Mass spectrum: (M+H) ⁺=415/417/419 (chlorine isotope)

Prepare following compounds with similarity method:

Embodiment 21

N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(morpholine-3-ketone-4-yl)-3-trifluoromethyl-BM

(a) 4-(morpholine-3-ketone-4-yl)-3-trifluoromethyl-phenylformic acid

Be suspended in 40 ml waters 1.00 gram (3.63 mmole) 4-(morpholine-4-yl)-3-trifluoromethyl-phenylformic acid (through being similar to the synthetic order preparation of embodiment 13a and 13b) and with 150 milligrams of (3.75 mmole) sodium hydroxide addings.Then stirred 1.5 hours in 45 ℃ with 1.73 gram (10.92 mmole) potassium permanganate addings and with mixture.Then reaction mixture is cooled off in ice bath and Sulfothiorine is added colourless up to all.Behind ethyl acetate extraction 3 times, with the organic phase that merges through dried over sodium sulfate and in vacuum, evaporate.After adding to resistates on the silica gel, it is passed through silica gel chromatography purifying (elutriant: methylene chloride 95: 5).

Yield: 340 milligrams (32%)

C ₁₂H ₁₀F ₃NO ₄(289.21)

Mass spectrum: (M+H) ⁺=290

(b) N '-(2-amino-4-chloro-phenyl)-N-Boc-(S)-O-methyl-Si amine amide and N '-(2-amino-5-chloro-phenyl)-N-Boc-(S)-O-methyl-Si amine amide

With 30.0 gram (137 mmole) N-Boc-(S)-O-methyl-Si amino acids and 21.9 gram (154 mmole) 4-chloro-1; The 2-phenylenediamine is dissolved among 658 milliliters of THF together, and in ice bath, stirs down with 43.9 milliliters of (316 mmole) triethylamines and 103 milliliters of (173 mmole) 50%PPA solution addings in ETHYLE ACETATE.In ice bath, stir after 15 minutes, mixture heating up to room temperature, is poured into to reach in the water water is used ethyl acetate extraction.The organic phase that merges is cleaned with saturated sodium carbonate solution and water, reach through dried over sodium sulfate and in vacuum, evaporate.Resistates is passed through silica gel chromatography purifying (elutriant gradient: methylene chloride=30: 1-＞9: 1).

Yield: 33.47 gram (72%) two regional isomer (regioisomers) mixtures

C ₁₅H ₂₂ClN ₃O ₄(343.81)

Mass spectrum: (M-H) ^-=342/344 (chlorine isotope)

R _fValue: 0.80 (silica gel; Methylene dichloride/ethanol=9: 1)

(c) (1R)-and N-Boc-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethylamine

26.01 mixtures that in embodiment 21b, obtain of gram (75.65 mmole) are dissolved in 1500 milliliters of toluene and with 20.8 milliliters of (364 mmole) acetic acid and 10.0 mol sieves (4A) add.Reaction mixture was stirred 5 hours in 60 ℃.Reaction mixture is filtered, clean with ETHYLE ACETATE once again and organic phase is cleaned with the semi-saturation sodium hydrogen carbonate solution, reach through dried over sodium sulfate and in vacuum, evaporate.Resistates is stirred with diethyl ether and with the crystallization suction filtration that forms.To filtrate in vacuum evaporation and with resistates through three batches of silica gel chromatography purifying (elutriant gradients: methylene chloride=80: 1-＞50: 1).

Yield: 13.85 grams (56%)

C ₁₅H ₂₀ClN ₃O ₃(325.79)

Mass spectrum: (M+H) ⁺=326/328 (chlorine isotope)

R _fValue: 0.29 (silica gel; Methylene dichloride/ethanol=30: 1)

(d) (1R)-and 1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethylamine

0.50 gram (1.54 mmole) that will be in 1.5 milliliters of methylene dichloride (1R)-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethylamine mixes with 1.54 milliliters of (20.0 mmole) TFA and reaches in stirring at room 2 hours N-Boc-1-.Then pour mixture into saturated sodium bicarbonate solution and after mixing fully, with water with methylene dichloride and ethyl acetate extraction.The organic phase that merges is reached through silica gel chromatography purifying (elutriant: methylene chloride=9: the 1+1% concentrated ammonia solution) through dried over sodium sulfate.

Yield: 0.35 gram (quantitatively)

C ₁₀H ₁₂ClN ₃O(225.68)

Mass spectrum: (M-H) ^-=224/226 (chlorine isotope)

R _fValue: 0.40 (silica gel; Methylene dichloride/ethanol=9: the 1+1% concentrated ammonia solution)

(e) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(morpholine-3-ketone-4-yl)-3-trifluoromethyl-BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethylamine, TBTU and NMM prepare to be similar to embodiment 1f because 4-(morpholine-3-ketone-4-yl)-3-trifluoromethyl-phenylformic acid, (1R)-1-among the DMF; Then precipitate, filter and drying in vacuum through pouring in the water.

Yield: 63%

R _fValue: 0.57 (silica gel; Methylene dichloride/ethanol=9: 1)

C ₂₂H ₂₀ClF ₃N ₄O ₄(496.88)

Mass spectrum: (M+H) ⁺=497/499 (chlorine isotope)

Prepare following compounds with similarity method:

Embodiment 22

N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethylamine, TBTU and NMM prepare in DMF by 3-methyl-4-(morpholine-3-ketone-4-yl)-phenylformic acid (through being similar to the synthetic order preparation of embodiment 30a, 2d and 21a), (1R)-1-to be similar to embodiment 1f; Then pour in the water; Use ethyl acetate extraction; Through dried over sodium sulfate, in vacuum, evaporate, and through silica gel chromatography purifying (elutriant gradient: ETHYLE ACETATE/Virahol/ethanol 9: 1: 0-＞9: 0: 1).

Yield: 99%

R _fValue: 0.13 (silica gel; Methylene dichloride/Virahol=19: 1)

C ₂₂H ₂₃ClN ₄O ₄(442.91)

Mass spectrum: (M+H) ⁺=443/445 (chlorine isotope)

Prepare following compounds with similarity method:

Embodiment 27

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(morpholine-3-ketone-4-yl)-BM

254 milligrams of (1.15 mmole) 4-(morpholine-3-ketone-4-yl)-phenylformic acid (through being similar to the synthetic order preparation of embodiment 30a, 2d and 21a) is placed 5 milliliters of DMF and 428 milligrams of (1.0 mmole) PfTU and 514 microlitres (3.0 mmole) DIPEA are added.In stirring at room after 10 minutes, with 232 milligrams (1.0 mmoles) (1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine-hydrochloride add and with mixture in stirring at room 16 hours.Then reaction mixture is filtered to reach through alkali alumina and in vacuum, evaporate.Resistates is passed through silica gel chromatography purifying (elutriant gradient: methylene chloride 100: 0-＞90: 10), corresponding part is evaporated, resistates is dissolved in acetonitrile/water and lyophilize in vacuum.

Yield: 77%

C ₂₀H ₁₉ClN ₄O ₃(398.85)

Mass spectrum: (M+H) ⁺=399/401 (chlorine isotope)

Prepare following compounds with similarity method:

Embodiment 29

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(4-N-methyl-[1,4] Diazesuberane-1-yl)-BM

(a) 4-fluoro-3-methyl-Benzoyl chloride 99min.

14.00 gram (90.8 mmole) 4-fluoro-3-methyl-phenylformic acid were refluxed 1 hour with 50 milliliters of sulfurous acid chlorine and then in vacuum, evaporate.With the further reaction of resistates and without any other purifying.

Yield: 15.70 grams (quantitatively)

C ₈H ₆ClFO(172.59)

(b) 4-fluoro-3-methyl-BM

15.70 gram (91.0 mmole) the 4-fluoro-3-methyl-Benzoyl chloride 99min.s that are dissolved in 30 milliliters of THF are dropwise added to 300 milliliters of concentrated ammonia solutions and then in stirring at room 2 hours.The sedimentation and filtration that forms is fallen, clean and drying with water.

Yield: 10.00 grams (72%)

C ₈H ₈FNO(153.16)

R _fValue: 0.31 (aluminum oxide; Methylene chloride=50: 1)

(c) 4-fluoro-3-methyl-cyanobenzene

10.00 gram (65.29 mmole) 4-fluoro-3-methyl-BMs and 50 milliliters of Phosphorus Oxychlorides one are arised from 60 ℃ to be stirred to reach in 4 hours and then in vacuum, evaporates.Resistates is poured in the frozen water, the sedimentation and filtration that forms is fallen and cleans with water.After with acetic acid ethyl dissolution, organic phase is cleaned with the unsaturated carbonate potassium solution, evaporate fully through dried over sodium sulfate and in vacuum.

Yield: 8.00 grams (91%)

C ₈H ₆FN(135.14)

R _fValue: 0.84 (silica gel; Methylene dichloride)

(d) 3-methyl-4-(4-N-methyl-[1,4] Diazesuberane-1-yl)-cyanobenzene

7.00 gram (51.8 mmole) 4-fluoro-3-methyl-cyanobenzenes and 1-N-methyl-[1,4] Diazesuberane one are arised from stirring and 110 ℃ of 1 weeks of following heating.In vacuum after the evaporation, with resistates in separating (elutriant: methylene dichloride) and with corresponding part purifying (elutriant gradient: methylene chloride 100: 1-＞9: 1) on silica gel once again on the aluminum oxide.

Yield: 1.70 grams (14%)

C ₁₄H ₁₉N ₃(229.33)

Mass spectrum: (M+H) ⁺=230

R _fValue: 0.25 (silica gel; Methylene chloride=9: 1)

(e) 3-methyl-4-(4-N-methyl-[1,4] Diazesuberane-1-yl)-phenylformic acid

Be similar to embodiment 1b was prepared through refluxing by 3-methyl-4-(4-N-methyl-[1,4] Diazesuberane-1-yl)-cyanobenzene and 25% potassium hydroxide solution in 36 hours.In vacuum after the evaporation, with resistates in separating (elutriant: methylene dichloride) and with corresponding part purifying (elutriant gradient: methylene chloride 100: 1-＞9: 1) on silica gel once again on the aluminum oxide.

Yield: 14%

C ₁₄H ₁₉N ₂O ₂(248.33)

Mass spectrum: (M+H) ⁺=249

R _fValue: 0.30 (RP-8; Methyl alcohol/5% sodium chloride aqueous solution=6: 4)

(f) 3-methyl-4-(4-N-methyl-[1,4] Diazesuberane-1-yl)-Benzoyl chloride 99min.

Be similar to embodiment 29a by 3-methyl-4-(4-N-methyl-[1,4] Diazesuberane-1-yl)-phenylformic acid and THIONYL CHLORIDE 97 preparation.

Yield: quantitatively

C ₁₄H ₁₉ClN ₂O*HCl(266.77/303.23)

(g) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(4-N-methyl-[1,4] Diazesuberane-1-yl)-BM

With 489 milligrams of (1.61 mmole) 3-methyl-4-(4-N-methyl-[1,4] Diazesuberane-1-yl)-Benzoyl chloride 99min. and 400 milligrams of (3.96 mmole) TEA one arise from that room temperature is positioned among 10 milliliters of THF and in stir down with 433 milligrams (1.61 mmoles) (1S)-(solution of 5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine dropwise adds 1-., after 16 hours mixture is evaporated in vacuum in stirring at room, resistates is mixed with water and uses ethyl acetate extraction.The organic phase that merges is cleaned with saturated nacl aqueous solution, reach through dried over sodium sulfate and in vacuum, evaporate.Resistates is passed through chromatogram purification (the elutriant gradient: methylene chloride 100: 1) on aluminum oxide.With the part after the evaporation with hydrochloric acid ethereal solution processing, after with twice of ETHYLE ACETATE and the complete concentration and evaporation of diethyl ether, in 70 ℃ of vacuum-evaporation.

Yield: 120 milligrams (16%)

C ₂₃H ₂₈ClN ₅O*HCl(462.43/425.96)

Mass spectrum: (M+H) ⁺=426/428 (chlorine isotope)

R _fValue: 0.47 (aluminum oxide; Methylene chloride 19: 1)

Embodiment 30

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(piperazine-1-yl)-BM

(a) 4-(N-Boc-piperazine-1-yl)-3-methyl-oil of Niobe

With 4.00 gram (17.5 mmole) 4-bromo-3-methyl-toluates and 3.92 gram (21.0 mmole) N-Boc-piperazines, 39.2 milligrams of (175 micromole) palladium (II), 50.7 milligrams of (175 micromole) three-tertiary butyl phosphorus-a tetrafluoro borates and 11.12 restrain (52.4 mmole) salt of wormwood in 35 milliliters of toluene one arise from microwave oven, be heated under the argon atmospher 150 ℃ 10 minutes.Then reaction mixture is poured in the water into vigorous stirring and with ethyl acetate extraction 3 times.The organic phase that merges through dried over sodium sulfate, is added to silica gel and passes through silica gel chromatography purifying (elutriant: methylene chloride 80: 1).

Yield: 1.42 grams (24%)

C ₁₈H ₂₆N ₂O ₄(334.42)

Mass spectrum: (M+H) ⁺=335

R _fValue: 0.52 (silica gel; Methylene chloride=50: 1)

(b) 4-(N-Boc-piperazine-1-yl)-3-methyl-phenylformic acid

1.42 gram (4.24 mmole) 4-(N-Boc-piperazine-1-yl)-3-methyl-oil of Niobe are dissolved among 7 milliliters of THF and with 9.25 ml waters and 893 milligrams of (21.3 mmole) lithium hydroxide monohydrate addings.In stirring at room after 16 hours, with mixture heating up to 45 ℃ 2 hours.Then other 893 milligrams of (21.3 mmole) lithium hydroxide monohydrate are added, with mixture in stirring at room 4 days.Then it is used ethyl acetate extraction with the neutralization of 1M hydrochloric acid and with reaction mixture.The organic phase that merges is evaporated fully through dried over sodium sulfate and in vacuum.

Yield: 1.29 grams (95%)

C ₁₇H ₂₄N ₂O ₄(320.39)

Mass spectrum: (M+H) ⁺=321

R _fValue: 0.29 (silica gel; Methylene chloride=15: 1)

(c) 4-(N-Boc-piperazine-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine, TBTU and NMM prepare in DMF by 4-(N-Boc-piperazine-1-yl)-3-methyl-phenylformic acid, (1S)-1-to be similar to embodiment 1f; Then stir and get in the dense sodium hydrogen carbonate solution; Use ethyl acetate extraction; Through dried over sodium sulfate, in vacuum, evaporate, and through silica gel chromatography purifying (elutriant gradient: methylene chloride 50: 1-＞15: 1).

Yield: 85%

R _fValue: 0.15 (silica gel; Methylene chloride=30: 1)

C ₂₆H ₃₂N ₅O ₃(498.03)

Mass spectrum: (M+H) ⁺=498/500 (chlorine isotope)

(d) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(piperazine-1-yl)-BM

Being similar to embodiment 1g is prepared in methylene dichloride by 4-(N-Boc-piperazine-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-BM and TFA.

Yield: quantitatively

C ₂₁H ₂₄ClN ₅O(397.91)

Mass spectrum: (M+H) ⁺=398/400 (chlorine isotope)

R _fValue: 0.14 (silica gel; Methylene chloride=9: 1)

Prepare following compounds with similarity method:

Embodiment 31

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(piperazine-2-ketone-1-yl)-BM

(a) 4-(N-Boc-piperazine-2-ketone-1-yl)-3-methyl-oil of Niobe

With 758 milligrams of (3.31 mmole) 4-bromo-3-methyl-toluates and 796 milligrams of (21.0 mmole) 4-N-Boc-piperazine-2-ketone, 31.8 milligrams of (167 micromole) cupric iodides (I), 35.1 microlitres (330 micromole) N, N '-dimethyl-ethylenediamine and 0.92 gram (6.62 mmole) salt of wormwood suspend together in 6.6 milliliters of toluene and stirred 1.5 hours in microwave oven, being heated to 140 ℃ under the argon atmospher.Then reaction mixture is poured in the water into vigorous stirring and with ethyl acetate extraction 3 times.The organic phase that merges through dried over sodium sulfate, is added to reach on the silica gel and passes through silica gel chromatography purifying (elutriant: methylene chloride 50: 1).

Yield: 679 milligrams (59%)

C ₁₈H ₂₄N ₂O ₅(348.40)

Mass spectrum: (M+H) ⁺=349

R _fValue: 0.25 (silica gel; Methylene chloride=50: 1)

(b) 4-(N-Boc-piperazine-2-ketone-1-yl)-3-methyl-phenylformic acid

775 milligrams of (2.22 mmole) 4-(N-Boc-piperazine-2-ketone-1-yl)-3-methyl-oil of Niobe is dissolved among 3.7 milliliters of THF and 4.9 ml waters and 468 milligrams of (11.2 mmole) lithium hydroxide monohydrate are added.After 16 hours, mixture is used ethyl acetate extraction with the neutralization of 1M hydrochloric acid and with reaction mixture in stirring at room.The organic phase that merges is evaporated fully through dried over sodium sulfate and in vacuum.

Yield: 664 milligrams (89%)

C ₁₇H ₂₂N ₂O ₅(334.38)

Mass spectrum: (M+H) ⁺=335

R _fValue: 0.31 (silica gel; Methylene chloride=15: 1)

(c) 4-(N-Boc-piperazine-2-ketone-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine, TBTU and NMM prepare in DMF by 4-(N-Boc-piperazine-1-yl)-3-methyl-phenylformic acid, (1S)-1-to be similar to embodiment 1f; Then stir and get in the dense sodium hydrogen carbonate solution; Use ethyl acetate extraction; Through dried over sodium sulfate, in vacuum, evaporate, and through silica gel chromatography purifying (elutriant: methylene chloride 30: 1).

Yield: 71%

R _fValue: 0.30 (silica gel; Methylene chloride=15: 1)

C ₂₆H ₃₀ClN ₅O ₄(512.01)

Mass spectrum: (M+H) ⁺=512/514 (chlorine isotope)

(d) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(piperazine-2-ketone-1-yl)-BM

Yield: 36%

C ₂₁H ₂₂ClN ₅O ₂(411.90)

Mass spectrum: (M+H) ⁺=412/414 (chlorine isotope)

R _fValue: 0.42 (silica gel; Methylene chloride=9: 1)

Prepare following compounds with similarity method:

Embodiment 32

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(piperidines-2-ketone-1-yl)-BM

(a) 3-methyl-4-(piperidines-2-ketone-1-yl)-oil of Niobe

Be similar to embodiment 31a by 4-bromo-3-methyl-toluate and piperidines-2-ketone at cupric iodide (I), N, N '-dimethyl-ethylenediamine and salt of wormwood exist down and in toluene and dioxane, in argon atmospher, prepare.

Yield: 34%

C ₁₄H ₁₇NO ₃(247.30)

Mass spectrum: (M+H) ⁺=248

R _fValue: 0.21 (silica gel; Petrol ether/ethyl acetate=1: 1)

(b) 3-methyl-4-(piperidines-2-ketone-1-yl)-phenylformic acid

Be similar to embodiment 2d by preparing in 3-methyl-4-(piperidines-2-ketone-1-yl)-oil of Niobe and the 1M sodium hydrate methanol solution.

Yield: 83%

C ₁₃H ₁₅NO ₃(233.27)

Mass spectrum: (M+H) ⁺=234

R _fValue: 0.51 (silica gel; ETHYLE ACETATE/ethanol=9: the 1+ strong aqua)

(c) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(piperidines-2-ketone-1-yl)-BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine, TBTU and NMM prepare in DMF by 3-methyl-4-(piperidines-2-ketone-1-yl)-phenylformic acid, (1S)-1-to be similar to embodiment 1f; Then stir and get into frozen water; Mix with ammonia soln, filter, be dissolved in the methylene dichloride; In vacuum, evaporate, and through silica gel chromatography purifying (elutriant gradient: ETHYLE ACETATE/(methyl alcohol/strong aqua 19: 1) 1: 0-＞9: 1).

Yield: 32%

R _fValue: 0.30 (silica gel; ETHYLE ACETATE/ethanol=9: 1+1% acetic acid)

C ₂₂H ₂₃ClN ₄O ₂(410.91)

Mass spectrum: (M+H) ⁺=411/413 (chlorine isotope)

Prepare following compounds with similarity method:

Embodiment 33

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(N-methyl-piperazine-1-yl)-3-trifluoromethyl-BM

170 milligrams of (0.24 mmole) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(piperazine-1-yl)-3-trifluoromethyl-BM is suspended in 2 milliliter 1, in the 2-ethylene dichloride and under nitrogen atmosphere, mix with 20 milligrams of (0.67 mmole) Paraformaldehyde 96s and 76 milligrams of (0.36 mmole) sodium triacetoxy borohydrides.After adding 5 milliliters of THF, with reaction mixture in stirring at room 6 hours, then add 100 milligrams of (3.33 mmole) Paraformaldehyde 96s and 100 milligrams of (0.47 mmole) sodium triacetoxy borohydrides with mixture in room temperature restir 22 hours.Then it is mixed with saturated sodium bicarbonate solution and use ethyl acetate extraction.The organic phase that merges through dried over mgso, is evaporated in vacuum, and through silica gel chromatography purifying (elutriant gradient: methylene dichloride/(methyl alcohol/strong aqua 19: 1) 100: 0-＞92: 8).

Yield: 70 milligrams (59%)

C ₂₃H ₂₅ClF ₃N ₅O ₂(495.94)

Mass spectrum: (M+H) ⁺=496/498 (chlorine isotope)

R _fValue: 0.25 (silica gel; Methylene chloride=9: the 1+1% ammonia soln)

Embodiment 34

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylsulfonyl-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM

Under-15 ℃, be dissolved in 150 milligrams of (0.32 mmole) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM in the mixture of 10 milliliters of methylene dichloride and 1 milliliter of acetic acid and mix with 204 milligrams of (0.89 mmole) 3-chlorine peroxybenzoic acid.Then mixture was stirred 30 minutes in-15 to-10 ℃, be heated to room temperature and restir 16 hours.Then reaction mixture cleans twice with 5% sodium hydrogen carbonate solution, through dried over sodium sulfate, in vacuum, evaporate, and through silica gel chromatography purifying (elutriant: methylene dichloride/alcohol 95: 5).

Yield: 80 milligrams (50%)

C ₂₃H ₂₅ClN ₄O ₅S(505.00)

Mass spectrum: (M+H) ⁺=505/507 (chlorine isotope)

R _fValue: 0.45 (silica gel; Methylene dichloride/ethanol=9: 1)

Embodiment 35

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group]-4-(pyrrolidin-2-one-1-yl)-BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group amine, PfTU and TEA in room temperature preparation, and are similar to embodiment 1g subsequently and slough Boc with TFA in DMSO by 4-(pyrrolidin-2-one-1-yl)-phenylformic acid, (1S)-1-to be similar to embodiment 27.

HPLC-MS result:

RT: 3.69 minutes

C ₂₂H ₂₃ClN ₄O ₂S(442.97)

Mass spectrum: (M+H) ⁺=443/445 (chlorine isotope)

Prepare following compounds with similarity method:

Embodiment 39

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-([1,3] oxaza heptane-2-ketone-3-yl)-BM

(a) 4-isocyanato (isocyanoto)-3-methyl-oil of Niobe

1.50 gram (9.08 mmole) 4-amino-3-methyl-oil of Niobe are dissolved in 250 milliliters of dioxane and with 1.3 milliliters of (10.7 mmole) superpalites and mix, stirred refluxed 5.5 hours.Then mixture is evaporated in vacuum and with further reaction and of resistates without any other purifying.

Yield: 1.74 grams (quantitatively)

C ₁₀H ₉NO ₃(191.19)

(b) 4-(N-[4-chlorine butoxy carbonyl]-amino)-3-methyl-oil of Niobe

Mix with 1.07 milliliters of (9.11 mmole) 85%4-chloro-fourths-1-alcohol being dissolved in the gram of 1.74 in 100 milliliters of toluene (9.08 mmole) 4-isocyanato-3-methyl-oil of Niobe.Mixture was stirred refluxed 17 hours.In vacuum, after the evaporation resistates is passed through silica gel chromatography purifying (elutriant gradient: petrol ether/ethyl acetate 17: 3-＞17: 4).

Yield: 1.19 grams (44%)

C ₁₄H ₁₈ClNO ₄(299.76)

Mass spectrum: (M-H) ^-=298/300 (chlorine isotope)

R _fValue: 0.45 (silica gel; Petrol ether/ethyl acetate=80: 20)

(c) 3-methyl-4-([1,3] oxaza heptane-2-ketone-3-yl)-oil of Niobe

300 milligrams of (1.00 mmole) 4-(N-[4-chlorine butoxy carbonyl]-amino)-3-methyl-oil of Niobe is dissolved among 10 milliliters of DMF and with 168 milligrams of (1.50 mmole) potassium tert.-butoxides mixes, stirred 3 hours in 60 ℃.Reaction mixture is mixed with water and with ethyl acetate extraction 3 times.With the organic phase that merges through dried over sodium sulfate and in vacuum, evaporate.Then resistates is passed through silica gel chromatography purifying (elutriant: petrol ether/ethyl acetate 3: 2).

Yield: 160 milligrams (61%)

R _fValue: 0.26 (silica gel; Petrol ether/ethyl acetate 3: 2)

C ₁₄H ₁₇NO ₄(263.30)

Mass spectrum: (M+H) ⁺=264

(d) 3-methyl-4-([1,3] oxaza heptane-2-ketone-3-yl)-phenylformic acid

150 milligrams of (0.57 mmole) 3-methyl-4-([1,3] oxaza heptane-2-ketone-3-yl)-oil of Niobe is suspended in 1 milliliter of ethanol and with 0.26 milliliter of (0.87 mmole) 8% lithium hydroxide aqueous solution mixes.With mixture in stirring at room 3 hours and then in vacuum, evaporate.With ethyl acetate extraction twice, acidifying then reaches again with the ethyl ester extracted twice with aqueous residue.With the organic phase that merges through dried over sodium sulfate and in vacuum, evaporate.

Yield: 122 milligrams (86%)

C ₁₃H ₁₅NO ₄(249.27)

Mass spectrum: (M+H) ⁺=250

R _fValue: 0.14 (silica gel; Methylene dichloride/ethanol=95: 5)

(e) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-([1,3] oxaza heptane-2-ketone-3-yl)-BM

Be similar to embodiment 1f by 3-methyl-4-([1; 3] oxaza heptane-2-ketone-3-yl)-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine, TBTU and NMM prepare in DMF, then with the TFA acidifying and through residue purified by chromatography (preparation HPLC) for phenylformic acid, (1S)-1-.

Yield: 54%

C ₂₂H ₂₃ClN ₄O ₃*2CF ₃COOH(654.96/426.90)

Mass spectrum: (M+H) ⁺=427/429 (chlorine isotope)

R _t: 2.42 minutes

Prepare following compounds with similarity method:

Embodiment 41

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group]-4-(morpholine-3-ketone-4-yl)-3-nitro-BM

(a) 4-(morpholine-3-ketone-4-yl)-3-nitro-oil of Niobe

1.00 gram (3.85 mmole) 4-chloro-3-nitro-oil of Niobe are dissolved under nitrogen atmosphere in 6 milliliters of dioxane that contain 389 milligrams of (3.85 mmole) morpholine-3-ketone and 36.6 milligrams of (40 mmole) three-(dibenzalacetones)-close, two palladiums (0), 67.1 milligrams of (116 micromole) xantphos and 1.75 gram (5.38 mmole) cesium carbonates are added.In nitrogen atmosphere and stir down, with reaction mixture be heated to 95 ℃ 16 hours.Then, solution is evaporated in vacuum and evaporates with ether its filtration.With the further reaction of resistates and without any other purifying.Yield: 1.31 grams (quantitatively)

C ₁₂H ₁₂N ₂O ₆(280.24)

Mass spectrum: (M+H) ⁺=281

R _fValue: 0.45 (anti-phase 8; Methyl alcohol/5% sodium chloride solution=6: 4).

(b) 4-(2-carboxyl methoxyl group-ethylamino)-3-nitro-phenylformic acid

400 milligrams of (1.43 mmole) 4-(morpholine-3-ketone-4-yl)-3-nitro-oil of Niobe is dissolved in 15 ml methanol and mixes with 4.5 milliliters of (4.5 mmole) 1M lithium hydroxide solutions.With mixture in stirring at room 2 hours.Then it is evaporated in vacuum, resistates is diluted with water, cooling and use the 2M hcl acidifying in ice bath.Cooling after 10 minutes filters out the throw out that forms in ice bath, and water cleans up to neutrality and dry in 50 ℃ of desiccator cabinets.

Yield: 290 milligrams (72%)

C ₁₁H ₁₂N ₂O ₇(284.23)

Mass spectrum: M+=284

R _fValue: 0.59 (anti-phase 8; Methyl alcohol/5% sodium chloride solution=6: 4).

(c) 4-(morpholine-3-ketone-4-yl)-3-nitro-Benzoyl chloride 99min.

290 milligrams of (1.02 mmole) 4-(2-carboxyl methoxyl group-ethylamino)-3-nitro-phenylformic acid that will be in 100 milliliters of methylene dichloride and 0.186 milliliter of (2.55 mmole) THIONYL CHLORIDE 97 and 2 DMF mix and refluxed 1 day.In vacuum behind this solution of evaporation, with it with toluene evaporates and with further reaction and of resistates without any other purifying.

Yield: 290 milligrams (quantitatively)

C ₁₁H ₉ClN ₂O ₅(284.66)

(d) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group]-4-(morpholine-3-ketone-4-yl)-3-nitro-BM

With 237 milligrams (0.93 mmoles) (1S)-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group amine and 0.257 milliliter of TEA are dissolved among 10 milliliters of THF and with 290 milligrams of (1.02 mmole) 4-(morpholine-3-ketone-4-yl)-solution of 3-nitro-Benzoyl chloride 99min. in 10 milliliters of THF and dropwise add 1-.With reaction mixture in stirring at room 16 hours and then in vacuum, evaporate.Resistates is passed through silica gel chromatography purifying (elutriant gradient: methylene dichloride/ethanol 100: 0-＞95: 5)

Yield: 34%

C ₂₂H ₂₂ClN ₅O ₅S(503.97)

Mass spectrum: (M-H) ^-=502/504 (chlorine isotope)

R _fValue: 0.46 (silica gel; Methylene dichloride/ethanol=9: 1).

Embodiment 42

3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(tetrahydropyrimidine-2-ketone-1-yl)-BM

(a) 4-(3-Boc-amino-propyl group-amino)-3-chloro-cyanobenzene

3.49 gram (20 mmole) 3-Boc-amino-propyl group amine in 5 milliliters of DMF are mixed with 2.75 milliliters of (25 mmole) NMM.After adding 3.11 gram (20 mmole) 3-chloro-4-fluoro-cyanobenzenes, mixture was stirred 3.5 hours under nitrogen atmosphere and room temperature, be heated to 105 ℃ 20 minutes and use ethyl acetate extraction.Organic phase water that merges and saturated saturated nacl aqueous solution are cleaned, reach through dried over mgso and in vacuum, evaporate.With the further reaction of resistates and without any other purifying.

Yield: 5.50 grams (89%)

C ₁₅H ₂₀N ₃O ₂(309.80)

Mass spectrum: (M+H) ⁺=310/312 (chlorine isotope)

R _fValue: 0.40 (silica gel; Petrol ether/ethyl acetate=2: 1).

(b) 4-(3-amino-propyl group is amino)-3-chloro-cyanobenzene

With 4.50 gram (14.5 mmole) 4-(3-Boc-amino-propyl group-amino)-3-chloro-cyanobenzenes be dissolved in 50 milliliters of dioxane and with 200 milliliters of 6M mixed in hydrochloric acid.Mixture in stirring at room 2 hours, is then cleaned with ether and water is poured in 125 milliliters of ice-cold concentrated ammonia solutions.Then mixture is used ethyl acetate extraction, organic phase water that merges and saturated nacl aqueous solution are cleaned, reach through dried over mgso and in vacuum, evaporate.With the further reaction of resistates and without any other purifying.

Yield: 1.40 grams (46%)

C ₁₀H ₁₂ClN ₃(209.68)

Mass spectrum: (M+H) ⁺=210/212 (chlorine isotope)

R _fValue: 0.30 (silica gel; Methylene chloride=9: the 1+1% concentrated ammonia solution).

(c) 3-chloro-4-(tetrahydropyrimidine-2-ketone-1-yl)-cyanobenzene

349 milligrams of (2.15 mmole) N that will be in 3 milliliters of NMP; The solution of N '-carbonyl-diimidazole and 450 milligrams of (2.15 mmole) 4-(3-amino-propyl group is amino)-3-chloro-cyanobenzene is in mixing under the stirring at room and in case after dissolving fully, is heated to 145 ℃ of 1 hour and 155 ℃ 1.5 hours.The reaction mixture water is cleaned and uses ethyl acetate extraction.Organic phase water that merges and saturated nacl aqueous solution are cleaned, reach through dried over mgso and in vacuum, evaporate.Then resistates is passed through silica gel chromatography purifying (elutriant gradient: ETHYLE ACETATE/(methyl alcohol/concentrated ammonia solution 19: 1) 100: 0-＞95: 5).

Yield: 260 milligrams (51%)

R _fValue: 0.40 (silica gel; ETHYLE ACETATE/ethanol=9: the 1+1% concentrated ammonia solution).

C ₁₁H ₁₀ClN ₃O(235.68)

Mass spectrum: (M+H) ⁺=236/238 (chlorine isotope)

(d) 3-chloro-4-(tetrahydropyrimidine-2-ketone-1-yl)-phenylformic acid

350 milligrams of (1.49 mmole) 3-chloro-4-(tetrahydropyrimidine-2-ketone-1-yl)-cyanobenzene is suspended in 5 milliliters of ethanol and with 2.0 milliliters of 10M aqueous sodium hydroxide solutions and mixes.Mixture was stirred 1 hour and then in vacuum, evaporated in 100 ℃.Aqueous residue is mixed with ice, with acidifying with acetic acid and use ethyl acetate extraction.Organic phase water that merges and saturated nacl aqueous solution are cleaned, reach through dried over mgso and in vacuum, evaporate.Then water is used the 6M hcl acidifying,, the organic phase that merges is cleaned with saturated nacl aqueous solution, through dried over mgso and in vacuum, evaporate with ethyl acetate extraction 5 times.

Yield: 340 milligrams (90%)

C ₁₁H ₁₁ClN ₂O ₃(254.68)

Mass spectrum: (M+H) ⁺=255/257 (chlorine isotope)

R _fValue: 0.35 (silica gel; Methylene chloride=9: 1+1% acetic acid).

(e) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(tetrahydropyrimidine-2-ketone-1-yl)-BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine, TBTU and NMM prepare in DMF by 3-chloro-4-(tetrahydropyrimidine-2-ketone-1-yl)-phenylformic acid, (1S)-1-to be similar to embodiment 1f; Then pour in the frozen water, add concentrated ammonia solution, filter; Water cleans and mat chromatographic analysis purifying (elutriant gradient ETHYLE ACETATE/(methyl alcohol/concentrated ammonia solution 19: 1)=98: 2-＞90: 10) on silica gel; Through active carbon filtration,, reach in 70 ℃ of drying pistols dry afterwards with the ether development.

Yield: 32%

C ₂₀H ₁₉Cl ₂N ₅O ₂(432.31)

Mass spectrum: (M+H) ⁺=432/434/436 (chlorine isotope)

R _fValue: 0.40 (silica gel; Methylene chloride=9: 1+1% acetic acid).

Prepare following compounds with similarity method:

Embodiment 46

3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(piperidines-2-ketone-1-yl)-BM

(a) 3-chloro-4-(5-chloro-pentanoyl-amino)-oil of Niobe

Will be in 696 microlitres among 10 milliliters of THF (0.84 gram, 5.39 mmoles) 5-chloro-valeryl chloride slowly dropwise adds as for the gram of 1.00 among the 20 milliliters of THF that contain 1 milliliter of TEA that stir in the ice bath (5.39 mmole) 4-amino-3-chloro-oil of Niobe.Stirring at room 16 hours, in 50 ℃ 3 hours and in reflux temperature after 3 hours, mixture is poured in the water and is used ethyl acetate extraction.With organic phase after dried over sodium sulfate, with mixture in vacuum, evaporate and with remaining resistates through silica gel chromatography purifying (elutriant: petrol ether/ethyl acetate 85: 15).

Yield: 300 milligram (14.6%) 80% product

C ₁₃H ₁₅Cl ₂NO ₃(304.18)

Mass spectrum: (M+H) ⁺=304/306/308 (chlorine isotope)

R _tValue: 3.29 minutes

(b) 3-chloro-4-(piperidines-2-ketone-1-yl)-oil of Niobe

The product that 300 milligrams (0.79 mmoles) are obtained in embodiment 46a be dissolved among 10 milliliters of DMF and mix with 180 milligrams of (1.60 mmole) the 3rd butanols potassium and be heated to 60 ℃ 3 hours.Then pour into reaction mixture in the water and use ethyl acetate extraction.The organic phase that merges through dried over sodium sulfate, is evaporated in vacuum, the resistates that obtains is passed through silica gel chromatography purifying (elutriant: methylene dichloride/Virahol 98: 2).

Yield: 159 milligrams (75%)

C ₁₃H ₁₄ClNO ₃(267.71)

Mass spectrum: (M+H) ⁺=268/270 (chlorine isotope)

R _fValue: 0.18 (silica gel; Methylene dichloride/Virahol=49: 1)

(c) 3-chloro-4-(piperidines-2-ketone-1-yl)-phenylformic acid

Be similar to embodiment 39d by 3-chloro-4-(piperidines-2-ketone-1-yl)-oil of Niobe and 8% Lithium Hydroxide MonoHydrate in the alcoholic acid formulations prepared from solutions.

Yield: 36%

C ₁₂H ₁₂ClNO ₃(247.30)

Mass spectrum: (M+H) ⁺=252/254 (chlorine isotope)

R _fValue: 0.27 (silica gel; Methylene dichloride/ethanol=9: 1)

(d) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(piperidines-2-ketone-1-yl)-BM

Be similar to embodiment 1f by 3-chloro-4-(piperidines-2-ketone-1-yl)-phenylformic acid, TBTU, NMM and (1R)-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethylamine prepare in DMF and subsequently in passing through silica gel chromatography purifying (elutriant gradient: ETHYLE ACETATE/alcohol 95: 5-＞90: 10) 1-.

Yield: 70%

C ₂₂H ₂₂Cl ₂N ₄O ₃(461.35)

Mass spectrum: (M-H) ^-=459/461/463 (chlorine isotope)

R _fValue: 0.19 (silica gel; Methylene dichloride/ethanol=19: 1)

Prepare following compounds with similarity method:

Embodiment 47

N-[(1R)-1-(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-hydroxyl-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM

(a) N '-(2-amino-4-bromo-phenyl)-N-Boc-(S)-Si amine amide and N '-(2-amino-5-bromo-phenyl)-N-Boc-(S)-Si amine amide

With 5.49 grams (26.7 mmole) (S)-N-Boc-silk amino acid and 5.00 restrains (26.7 mmole) 4-bromo-1; The 2-phenylenediamine is dissolved among 125 milliliters of THF together; And under the ice bath cooling, restraining (26.7 mmole) N with 5.52, the solution of N '-NSC 57182 in 20 milliliters of THF dropwise adds.With reaction mixture in stirring at room 16 hours.After in vacuum, evaporating, with resistates mat chromatographic analysis purifying (elutriant: methylene chloride 98: 2) on silica gel.

Yield: the mixture of (48%) two regional isomer of 4.76 grams

C ₁₄H ₂₀BrN ₃O ₄(374.24)

Mass spectrum: (M+H) ⁺=374/376 (bromine isotope)

(b) (1R)-and N-Boc-1-(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-hydroxyl-ethylamine

3.00 mixtures that in 47a, obtain of gram (8.02 mmole) are dissolved in 30 milliliters of acetic acid and in 50 ℃ stirred 2 hours.To react to mix and dropwise add to 10% sodium hydroxide solution and with ethyl acetate extraction 3 times.With the organic phase that merges through dried over mgso and in vacuum, evaporate, and with resistates from the methyl alcohol recrystallize.

Yield: 1.96 grams (69%)

C ₁₄H ₁₈BrN ₃O ₃(356.22)

R _fValue: 0.59 (silica gel; Petrol ether/ethyl acetate=1: 1)

(c) (1R)-and 1-(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-hydroxyl-ethylamine

2.00 grams (5.62 mmole) that will be in 40 milliliters of ETHYLE ACETATE (1R)-(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethylamine and 8.0 milliliters of 4M hydrochloric acid mix in ice bath, to cool off simultaneously in dioxane and reach in stirring at room 16 hours N-Boc-1-.Reaction mixture is evaporated in vacuum and the throw out that forms is filtered out.

Yield: 1.11 grams (67%)

C ₉H ₁₀BrN ₃O*HCl(292.57/256.10)

Mass spectrum: (M+H) ⁺=256/258 (bromine isotope)

(d) N-[(1R)-1-(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-hydroxyl-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM

(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-hydroxyl-ethylamine, TBTU and NMM prepare in DMF, use the preparation HPLC purifying subsequently by 3-methyl-4-(morpholine-3-ketone-4-yl)-phenylformic acid, (1R)-1-to be similar to embodiment 1f.

Yield: 52%

C ₂₁H ₂₁BrN ₄O ₄*CF ₃COOH(587.35/473.32)

Mass spectrum: (M+H) ⁺=473/475 (bromine isotope)

R _fValue: 0.32 (silica gel; Methylene dichloride/Virahol=19: 1)

Prepare following compounds with similarity method:

Embodiment 48

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(1,1-dioxo-different thiophene alkane azoles-2-yl)-3-methyl-BM

(a) 4-(3-chloro-propyl group-alkylsulfonyl-amino)-3-methyl-oil of Niobe

With being dissolved in that 100 milligrams of (0.61 mmole) 4-amino-3-methyl-oil of Niobe in 3 milliliters of pyridines mix with 82 microlitres (0.67 mmole) 3-chlorine, third SULPHURYL CHLORIDE and stirring at room 16 hours.With reaction soln mix with water and ETHYLE ACETATE and then with water once again with ethyl acetate extraction.With the organic phase that merges through dried over sodium sulfate and in vacuum, evaporate.With the further reaction of resistates and without any other purifying.

Yield: 170 milligrams (92%)

C ₁₂H ₁₆ClNO ₄S(305.78)

Mass spectrum: (M+H) ⁺=306/308 (chlorine isotope)

R _fValue: 0.10 (silica gel; Petrol ether/ethyl acetate=8: 2)

(b) 4-(1,1-dioxo-isothiazolidine-2-yl)-3-methyl-oil of Niobe

With being dissolved in that 370 milligrams of (0.85 mmole) 70%4-(3-chloro-propyl group-alkylsulfonyl-amino)-3-methyl-toluate among 26 milliliters of DMF mixes with 275 milligrams of (2.45 mmole) potassium tert.-butoxides and stirring at room 16 hours.Reaction mixture is mixed with water and uses ethyl acetate extraction.The organic phase that merges through dried over sodium sulfate, is evaporated in vacuum, and resistates is passed through silica gel chromatography purifying (elutriant: methylene dichloride/Virahol=98: 2).

Yield: 177 milligrams (47%)

C ₁₂H ₁₅NO ₄S(269.32)

Mass spectrum: (M+H) ⁺=270

R _fValue: 0.10 (silica gel; Petrol ether/ethyl acetate=7: 3)

(c) 4-(1,1-dioxo-isothiazolidine-2-yl)-3-methyl-phenylformic acid

With 170 milligrams of (0.63 mmole) 4-(1,1-dioxo-isothiazolidine-2-yl)-3-methyl-toluate in 2 milliliters of ethanol with 0.6 milliliter of 2M sodium hydroxide solution stirring at room 3 hours.Then reaction soln is evaporated in vacuum, with water and 0.6 milliliter of 2M mixed in hydrochloric acid and use ethyl acetate extraction.The organic phase that merges through dried over sodium sulfate, is evaporated in vacuum, and with the further reaction of resistates and without any other purifying.

Yield: 148 milligrams (92%)

C ₁₁H ₁₃NO ₄S(255.30)

Mass spectrum: (M-H) ^-=254

RT: 2.23 minutes

(d) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(1,1-dioxo-isothiazolidine-2-yl)-3-methyl-BM

Be similar to embodiment 1f by 4-(1,1-dioxo-isothiazolidine-2-yl)-3-methyl-phenylformic acid,

(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine, TBTU and NMM prepare in DMF, use ethyl acetate extraction subsequently, through sal epsom, after activated carbon and the silica dehydrator on silica gel purifying (elutriant: methylene dichloride/Virahol=95: 5).

Yield: 37%

C ₂₀H ₂₁ClN ₄O ₃S(432.93)

Mass spectrum: (M+H) ⁺=433/435 (chlorine isotope)

R _fValue: 0.32 (silica gel; Methylene dichloride/Virahol=19: 1)

Prepare following compounds with similarity method:

Embodiment 54

3-amino-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group]-4-(morpholine-3-ketone-4-yl)-BM

Mix and refluxed 2 hours being dissolved in 65 milligrams of (0.13 mmole) N-in 2 milliliters of ETHYLE ACETATE [(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methylthio group-propyl group]-4-(morpholine-3-ketone-4-yl)-3-nitro-BM and 143 milligrams of (0.63 mmole) tin chloride (II) duohydrates and 130 milligrams of (1.55 mmole) sodium hydrogencarbonates.Reaction soln is mixed with frozen water, stirred 10 minutes and then the throw out that forms was filtered out.After dry 3 days resistates is passed through silica gel chromatography purifying (elutriant gradient: methylene dichloride/ethanol 100: 0-＞91: 9).

Yield: 5 milligrams (8.2%)

C ₂₂H ₂₄ClN ₅O ₃S(473.99)

Mass spectrum: (M+H) ⁺=474/476 (chlorine isotope)

R _fValue: 0.48 (silica gel; Methylene dichloride/ethanol=9: 1)

Embodiment 61

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(5,6-two dehydrogenations-azepan-2-ketone-1-yl)-BM

(a) 3-methyl-4-(penta-4-alkene-1-acyl group-amino)-oil of Niobe

Being similar to embodiment 46a is prepared in the THF that contains TEA by 4-amino-3-methyl-toluate and 4-amylene-1-acyl chlorides.

Yield: 46%

C ₁₄H ₁₇NO ₃(247.30)

Mass spectrum: (M+H) ⁺=248

R _tValue: 2.88 minutes

(b) 4-(allyl group-penta-4-alkene-1-acyl group-amino)-3-methyl-oil of Niobe

Mix with 500 milligrams of (4.37 mmole) potassium tert.-butoxides and under 40 ℃ of stirrings, 350 microlitres (489 milligrams, 4.04 mmoles) allyl bromide 98 is slowly added being dissolved in the gram of 1.00 among 5 milliliters of DMF (4.04 mmole) 3-methyl-4-(penta-4-alkene-1-acyl group-amino)-oil of Niobe.Then with mixture heating up to 70 ℃ 3 hours.Then pour into reaction mixture in the water and use ethyl acetate extraction.The organic phase that merges through dried over sodium sulfate, is evaporated in vacuum, resistates is added to reach on the silica gel pass through silica gel chromatography purifying (elutriant: petrol ether/ethyl acetate 9: 1).

Yield: 58%

C ₁₇H ₂₁NO ₃(287.36)

Mass spectrum: (M+H) ⁺=288

R _fValue: 0.46 (petrol ether/ethyl acetate=9: 1)

(c) 4-(4,5-two dehydrogenations-azepan-2-ketone-1-yl)-3-methyl-oil of Niobe

150 milligrams of (0.52 mmole) 4-(allyl group-penta-4-alkene-1-acyl group-amino)-3-methyl-oil of Niobe is dissolved in 110 milliliters of degassing methylene dichloride and with argon gas washing 30 minutes.Then 88 milligrams of (104 micromole) tolylenes-[1, the inferior imidazolidyl of two (2,4, the 6-the trimethylphenyl)-2-of 3-]-two chloro-(tricyclohexyl phosphine)-close ruthenium (s-generation Grubbs catalyzer) is added and mixture was refluxed 4.5 hours.Then it is evaporated in vacuum, resistates is added to reach on the silica gel pass through silica gel chromatography purifying (elutriant: petrol ether/ethyl acetate 3: 2).

Yield: 83 milligrams (61%)

R _fValue: 0.22 (silica gel, petrol ether/ethyl acetate=3: 2)

C ₁₅H ₁₇NO ₃(259.31)

Mass spectrum: (M+H) ⁺=260

(d) 4-(4,5-two dehydrogenations-azepan-2-ketone-1-yl)-3-methyl-phenylformic acid

Be similar to embodiment 39d by 4-(4,5-two dehydrogenations-azepan-2-ketone-1-yl)-3-methyl-oil of Niobe and the formulations prepared from solutions of 8% Lithium Hydroxide MonoHydrate in ethanol.

Yield: 51%

R _fValue: 0.05 (silica gel; Methylene chloride=19: 1)

C ₁₄H ₁₅NO ₃(245.28)

Mass spectrum: (M+H) ⁺=246

(e) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(4,5-two dehydrogenations-azepan-2-ketone-1-yl)-3-methyl-BM

Be similar to embodiment 1f by 4-(4,5-two dehydrogenations-azepan-2-ketone-1-yl)-3-methyl-phenylformic acid, TBTU, NMM and (1S)-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine prepare in DMF and reaches mat preparation HPLC purifying subsequently 1-.

Yield: 32%

R _fValue: 0.44 (silica gel; Methylene chloride=19: 1)

C ₂₃H ₂₃ClN ₄O ₂*CF ₃COOH(536.94/422.91)

Mass spectrum: (M+H) ⁺=423/425 (chlorine isotope)

Embodiment 63

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(1,3-dioxo-thiomorpholine-4-yl)-3-methyl-BM

With 204 milligrams of (0.48 mmole) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-(thiomorpholine-3-ketone-4-yl)-BM is in the mixture of-15 ℃ of 12 milliliters of methylene dichloride of dissolving and 1.2 milliliters of acetic acid and mix with 110 milligrams of (0.48 mmole) 3-chlorine peroxybenzoic acid.Then mixture was stirred 1 hour in-15 to-10 ℃, be heated to room temperature and restir 3 hours.Then reaction mixture and half being concentrated sodium hydrogen carbonate solution mixes and extracts with 19: 1 solvent mixture of methylene chloride.The organic phase water that merges is cleaned,, in vacuum, evaporate through dried over mgso, and through silica gel chromatography purifying (elutriant gradient: ETHYLE ACETATE/(ethanol/concentrated ammonia solution 19: 1)=1: 0-＞4: 1).

Yield: 100 milligrams (47%)

C ₂₁H ₂₁ClN ₄O ₃S(444.94)

Mass spectrum: (M+H) ⁺=445/447 (chlorine isotope)

R _fValue: 0.15 (silica gel; ETHYLE ACETATE/ethanol=4: the 1+1% concentrated ammonia solution)

Prepare following compounds with similarity method:

Embodiment 69

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methoxyl group-4-(piperidines-2-ketone-1-yl)-BM

(a) 4-(5-chloro-pentanoyl-amino)-3-methoxyl group-oil of Niobe

Being similar to embodiment 6a is prepared in THF and TEA by 4-amino-3-methoxyl group-oil of Niobe and 5-chloro-valeryl chloride.

Yield: 99%

C ₁₄H ₁₈ClNO ₄(299.76)

Mass spectrum: (M+H) ⁺=300/302 (chlorine isotope)

R _tValue: 3.14 minutes

(b) 3-methoxyl group-4-(piperidines-2-ketone-1-yl)-oil of Niobe

Mixes with 1.26 gram (11.2 mmole) potassium tert.-butoxides and reach being dissolved in 2.25 among 60 milliliters of DMF gram (7.51 mmole) 4-(5-chloro-pentanoyl-amino)-3-methoxyl group-oil of Niobe 60 ℃ of stirrings 2.5 hours.Then mixture is evaporated in vacuum, resistates is mixed with water and uses ethyl acetate extraction.The organic phase that merges through dried over sodium sulfate, is evaporated in vacuum, and the resistates that obtains is passed through silica gel chromatography purifying (elutriant gradient: petrol ether/ethyl acetate 3: 2-＞0: 1).

Yield: 0.99 gram (50%)

R _tValue: 2.56 minutes

C ₁₄H ₁₇NO ₄(263.30)

Mass spectrum: (M+H) ⁺=264

(c) 3-methoxyl group-4-(piperidines-2-ketone-1-yl)-phenylformic acid

Being similar to embodiment 39d is prepared in ethanol by 3-methoxyl group-4-(piperidines-2-ketone-1-yl)-oil of Niobe and Lithium Hydroxide MonoHydrate.

Yield: 95%

R _fValue: 0.10 (silica gel; Petrol ether/ethyl acetate=1: 2)

C ₁₃H ₁₅NO ₄(249.27)

Mass spectrum: (M+H) ⁺=250

(d) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methoxyl group-4-(piperidines-2-ketone-1-yl)-BM

Be similar to embodiment 1f by 3-methoxyl group-4-(piperidines-2-ketone-1-yl)-phenylformic acid, TBTU, NMM and (1S)-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine prepare to reach in DHF and uses the preparation HPLC purifying subsequently 1-.

Yield: 75%

R _tValue: 2.35 minutes

C ₂₂H ₂₃ClN ₄O ₃*CF ₃COOH(540.93/426.90)

Mass spectrum: (M+H) ⁺=427/429 (chlorine isotope)

Prepare following compounds with similarity method:

Embodiment 73

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(1,1-dioxo-6-methyl)-[1,2,6] sulphur diaza-cyclohexane-2-yl)-3-methyl-BM

(a) 4-(1,1-dioxo-6-methyl-[1,2,6] sulphur diaza-cyclohexane-2-yl)-3-methyl-oil of Niobe

With 400 milligrams of (1.41 mmole) 4-(1 that are dissolved among 4 milliliters of DMF; 1-dioxo-[1; 2,6] sulphur diaza-cyclohexane-2-yl)-3-methyl-oil of Niobe mixes with 240 milligrams of (2.41 mmole) potassium tert.-butoxides and 96 microlitres (1.54 mmole) methyl-iodide and stirred 5 hours at 40 ℃ in 40 ℃.Reaction soln is evaporated in vacuum, mix with water and water is used ethyl acetate extraction.With the organic phase that merges through dried over sodium sulfate and in vacuum, evaporate.

Yield: 220 milligrams (52%)

C ₁₃H ₁₈N ₂O ₄S(298.36)

Mass spectrum: (M+H) ⁺=299

R _fValue: 0.44 (silica gel; Petrol ether/ethyl acetate=3: 2)

(b) 4-(1,1-dioxo-6-methyl-[1,2,6] sulphur diaza-cyclohexane-2-yl)-3-methyl-phenylformic acid

Being similar to embodiment 39d is prepared in ethanol by 4-(1,1-dioxo-3-methyl-[1,2,6] sulphur diaza-cyclohexane-2-yl)-3-methyl-oil of Niobe and Lithium Hydroxide MonoHydrate.

Yield: (81%)

C ₁₂H ₁₆N ₂O ₄S(284.34)

Mass spectrum: (M+H) ⁺=285

R _fValue: 0.07 (silica gel; Methylene chloride=19: 1)

(c) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(1,1-dioxo-6-methyl-[1,2,6] sulphur diaza-cyclohexane-2-yl)-3-methyl-BM

Be similar to embodiment 1f by 4-(1; 1-dioxo-6-methyl-[1; 2,6] sulphur diaza-cyclohexane-2-yl)-3-methyl-phenylformic acid, (1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamino, TBTU and NMM prepares in DMF and subsequently by the preparation HPLC purifying.

Yield: 55%

C ₂₁H ₂₄ClN ₅O ₃S*CF ₃COOH(576.00/461.97)

Mass spectrum: (M+H) ⁺=462/464 (chlorine isotope)

R _tValue: 2.50 minutes

Prepare following compounds with similarity method:

Embodiment 75

N-[(1R)-1-(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM

(a) N '-(2-amino-4-bromo-phenyl)-N-Boc-(S)-O-methyl-Si amine amide and N '-(2-amino-5-bromo-phenyl)-N-Boc-(S)-O-methyl-Si amine amide

The dicyclohexyl amine salt of 2.50 gram (6.24 mmole) N-Boc-(S)-O-methyl-Si amino acids is dissolved in 20 milliliter of 5% Hydrocerol A, with water with 20 milliliters of ethyl acetate extractions 2 times, with the organic phase that merges through dried over sodium sulfate and in vacuum except that desolvating.With resistates and 1.23 gram (6.55 mmole) 4-bromo-1; The 2-phenylenediamine is dissolved among 30 milliliters of THF together, and stirs down with 1.42 milliliters of (14.0 mmole) triethylamines and 4.97 milliliters of (7.80 mmole) 50%PPA solution addings in ETHYLE ACETATE in ice bath.In ice bath, stir after 5 minutes, with mixture in being heated to room temperature and in stirring at room 23 hours.Reaction mixture is poured in 100 ml waters and water is used ethyl acetate extraction.The organic phase that merges is extracted with saturated sodium carbonate solution and water, reach through dried over sodium sulfate and in vacuum, evaporate.

Yield: the mixture of (98%) two regional isomer of 2.38 grams

C ₁₅H ₂₂BrN ₃O ₄(388.26)

Mass spectrum: (M+H) ⁺=388/390 (bromine isotope)

R _fValue: 0.63/0.68 (silica gel; Methylene dichloride/ethanol=9: 1)

(b) (1R)-and N-Boc-1-(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethylamine

2.38 mixtures that in embodiment 75a, obtain of gram (6.13 mmole) are dissolved in 150 milliliters of toluene and 1.84 milliliters of (30.7 mmole) acetic acid and with 4.00 mol sieves (3A) add.Reaction mixture was stirred 3 hours and then in ice bath, cooled off 15 minutes in 55 ℃.Reaction mixture is filtered and pours in water and each mixture of 500 milliliters of ETHYLE ACETATE.After violent the mixing organic phase is separated, clean, reach through dried over sodium sulfate and in vacuum, evaporate with saturated nacl aqueous solution.Resistates is passed through silica gel chromatography purifying (elutriant gradient: methylene dichloride/ethanol 100: 0-＞97: 3).

Yield: 1.40 grams (62%)

C ₁₅H ₂₀BrN ₃O ₃(370.24)

Mass spectrum: (M+H) ⁺=370/372 (bromine isotope)

R _fValue: 0.81 (silica gel; Methylene dichloride/ethanol=9: 1)

(c) (1R)-1-(5-bromo-1H-benzoglyoxaline-1-yl)-2-methoxyl group-ethylamine

(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethylamine and TFA prepare in methylene dichloride by (1R)-N-Boc-1-to be similar to embodiment 1g.

Yield: 51%

C ₁₀H ₁₂BrN ₃O(270.13)

Mass spectrum: (M+H) ⁺=270/272 (bromine isotope)

R _fValue: 0.20 (silica gel; Methylene dichloride/ethanol=9: 1)

(d) N-[(1R)-1-(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM

(5-bromo-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethylamine, TBTU and DIPEA prepare in THF, subsequently because the silica gel chromatography purifying by 3-methyl-4-(morpholine-3-ketone-4-yl)-phenylformic acid, (1R)-1-to be similar to embodiment 1f.

Yield: quantitatively

C ₂₂H ₂₃BrN ₄O ₄(487.35)

Mass spectrum: (M+H) ⁺=487/489 (bromine isotope)

R _fValue: 0.56 (silica gel; Methylene dichloride/ethanol=9: 1)

Embodiment 76

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-(1H-tetrazolium-5-yl)-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl) BM

(a) (2S)-2-(benzyloxycarbonyl-amino)-4-cyanic acid-ethyl n-butyrate

With 5.00 grams (11.3 mmole) (2S)-2-(benzyloxycarbonyl-amino)-4-cyanic acid-butyric acid dicyclohexyl ammonium salt is stirred in 100 milliliter of 5% citric acid solution and then uses ethyl acetate extraction.The organic phase that merges is evaporated in vacuum through dried over sodium sulfate and with solvent.Resistates is dissolved among 70 milliliters of THF, with 4.35 gram (13.5 mmole) TBTU and 6.35 milliliters of (33.8 mmole) DIPEA add and with mixture in stirring at room 10 minutes.Then refluxed 16 hours with 50 milliliters of ethanol addings and with mixture.Then reaction mixture is evaporated in vacuum, be dissolved in the ETHYLE ACETATE, clean, reach through dried over sodium sulfate and in vacuum, evaporate with semi-saturation sodium hydrogen carbonate solution and water.

Yield: 3.20 grams (98%)

C ₁₅H ₁₈N ₂O ₄(290.32)

Mass spectrum: (M+NH ₄) ⁺=308

R _fValue: 0.80 (silica gel; Methylene dichloride/ethanol=9: 1)

(b) (2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazolium-5-yl)-ethyl n-butyrate

With 3.20 grams (11.0 mmole) (2S)-2-(benzyloxycarbonyl-amino)-4-cyanic acid-ethyl n-butyrate is dissolved in 40 milliliters of toluene and 1.08 gram (16.5 mmole) sodiumazide and 2.28 gram (16.5 mmole) triethylamine hydrochlorides added.With reaction mixture be heated to 85 ℃ 24 hours, be cooled to room temperature and water the extraction.The water that merges is acidified to pH2 with half concentrated hydrochloric acid, and with the throw out suction filtration that forms, water cleans and reaches in 50 ℃ of dryings.

Yield: 2.90 grams (79%)

C ₁₅H ₁₉N ₅O ₄(333.34)

Mass spectrum: (M+H) ⁺=334

R _fValue: 0.50 (silica gel; Methylene dichloride/ethanol=9: 1)

(c) (2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazolium-5-yl)-butyric acid

Being similar to embodiment 30b is prepared in the solvent mixture of water and THF by (2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazolium-5-yl)-ethyl n-butyrate and Lithium Hydroxide MonoHydrate.

Yield: quantitatively

C ₁₃H ₁₅N ₅O ₄(305.29)

Mass spectrum: (M+H) ⁺=306

R _fValue: 0.30 (silica gel; Methylene dichloride/ethanol=4: 1)

(d) N '-(2-amino-4-chloro-phenyl)-(2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazolium-5-yl)-yulocrotine and N '-(2-amino-5-chloro-phenyl)-(2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazolium-5-yl)-butyric acid amine

Be similar to embodiment 47a by (2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazolium-5-yl)-butyric acid and 4-chloro-1,2-phenylenediamine and DCC prepare in THF.

Yield: quantitatively, the mixture of two regional isomers has pollution a little

C ₁₉H ₂₀ClN ₇O ₃(429.86)

R _fValue: 0.20 (silica gel; Methylene dichloride/ethanol=9: 1)

(e) (1S)-and N-(benzyloxycarbonyl)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-(1H-tetrazolium-5-yl)-propyl group amine

Be similar to embodiment 47b because product that obtains among the embodiment 76d and acetic acid preparation.

Yield: quantitatively

C ₁₉H ₁₈ClN ₇O ₂*CH ₃COOH(471.90/411.85)

R _fValue: 0.25 (silica gel; Methylene dichloride/ethanol/strong aqua=4: 1: 0.1)

(f) (1S)-and 1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-(1H-tetrazolium-5-yl)-propyl group amine

2.10 grams (4.45 mmole) that will be in 30 milliliters of methylene dichloride (1S)-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-(1H-tetrazolium-5-yl)-propyl group amine mixes with 1.9 milliliters of (13.4 mmole) iodo trimethyl silanes and reaches in stirring at room 16 hours N-(benzyloxycarbonyl)-1-.Then 20 ml methanol are added, mixture is evaporated in vacuum in room temperature restir 30 minutes and with reaction mixture fully.Resistates is passed through silica gel chromatography purifying (elutriant gradient: methylene dichloride/(ethanol/strong aqua 95: 5)=70/30-＞60: 40).

Yield: 690 milligrams (56%)

C ₁₁H ₁₂ClN ₇(277.71)

Mass spectrum: (M+H) ⁺=278/280 (chlorine isotope)

R _fValue: 0.15 (silica gel; Methylene dichloride/ethanol=3: the 2+1% strong aqua)

(g) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-(1H-tetrazolium-5-yl)-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-(1H-tetrazolium-5-yl)-propyl group amine, TBTU and DIPEA prepare in THF, subsequently through the silica gel chromatography purifying by 3-methyl-4-(morpholine-3-ketone-4-yl)-phenylformic acid, (1S)-1-to be similar to embodiment 1f.

Yield: 33%

C ₂₃H ₂₃ClN ₈O ₃(494.93)

Mass spectrum: (M+H) ⁺=495/497 (chlorine isotope)

R _fValue: 0.20 (silica gel; Methylene dichloride/ethanol=4: 1)

Embodiment 77

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methoxyl group-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM

(a) N '-(2-amino-4-chloro-phenyl)-(2S)-2-(Boc-is amino)-3-methoxyl group-propionic acid amide and N '-(2-amino-5-chloro-phenyl)-(2S)-2-(Boc-is amino)-3-methoxyl group-propionic acid amide

With 4.90 grams (21.0 mmole) (2S)-2-(Boc-amino)-3-methoxyl group-propionic acid is dissolved among 20 milliliters of THF and mixes with 13.57 gram (42.0 mmole) TBTU and 5.76 milliliters of (52.5 mmole) triethylamines and reach in stirring at room 30 minutes.3.00 gram (21.0 mmole) 4-chloro-1 that then will be in 20 milliliters of THF, 2-phenylenediamine add and with mixture in stirring at room 16 hours.Then reaction mixture is evaporated in vacuum, pour in the water and use ethyl acetate extraction.The organic phase that merges is cleaned with saturated sodium bicarbonate solution, reach through dried over sodium sulfate and in vacuum, evaporate.Resistates is passed through silica gel chromatography purifying (elutriant: methylene chloride 99: 1).

Yield: the mixture of (75%) two regional isomer of 5.60 grams

C ₁₆H ₂₄ClN ₃O ₃(357.83)

Mass spectrum: (M+H) ⁺=358/360 (chlorine isotope)

R _fValue: 0.26 (silica gel; Methylene chloride=99: 1)

(b) (1S)-and N-Boc-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methoxyl group-propyl group amine

Be similar to embodiment 47b because product that obtains among the embodiment 77a and acetic acid preparation.

Yield: 96%

C ₁₆H ₂₂ClN ₃O ₃(339.82)

Mass spectrum: (M+H) ⁺=340/342 (chlorine isotope)

R _fValue: 0.80 (silica gel; Methylene chloride=19: 1)

(c) (1S)-and 1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methoxyl group-propyl group amine

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methoxyl group-propyl group amine and TFA prepare in methylene dichloride by (1S)-N-Boc-1-to be similar to embodiment 1g.

Yield: 31%

C ₁₁H ₁₄ClN ₃O(239.70)

Mass spectrum: (M+H) ⁺=240/242 (chlorine isotope)

R _fValue: 0.10 (silica gel; Methylene dichloride/ethanol=9: 1)

(d) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-3-methoxyl group-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-propyl group amine, TBTU and DIPEA prepare in THF, subsequently through the silica gel chromatography purifying by 3-methyl-4-(morpholine-3-ketone-4-yl)-phenylformic acid, (1S)-1-to be similar to embodiment 1f.

Yield: 59%

C ₂₃H ₂₅ClN ₄O ₄(456.92)

Mass spectrum: (M+H) ⁺=457/459 (chlorine isotope)

R _fValue: 0.51 (silica gel; Methylene dichloride/ethanol=9: 1)

Prepare following compounds with similarity method

Embodiment 82

3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(3,6-dihydro-[1,2] oxazine-2-yl)-BM

(a) 3-chloro-4-nitroso-group (nitroso)-oil of Niobe

With adding in 6.0 milliliters of vitriol oils under 8.00 gram (29.6 mmole) potassium hydrogen persulfates stirrings, under room temperature under the nitrogen atmosphere, stirred 30 minutes, mixture is stirred in the 50 gram ice and with 14 restrains the yellow soda ash neutralization.The solution that obtains and 2.78 gram (15.0 mmole) 4-amino-suspension-s of 3-chloro-oil of Niobe in 300 ml waters are mixed reach in stirring at room 16 hours.With the reaction mixture suction filtration, filter cake is cleaned with water, in air drying and through silica gel chromatography purifying (elutriant: petrol ether/ethyl acetate=9: 1).

Yield: 1.00 grams (33%)

C ₈H ₆ClNO ₃(199.59)

Mass spectrum: (M+H) ⁺=199/201 (chlorine isotope)

R _fValue: 0.55 (silica gel; Petrol ether/ethyl acetate=4: 1)

(b) 3-chloro-4-(3, the 6-dihydro-[1,2] oxazine-2-yl)-oil of Niobe

1.00 gram (5.01 mmole) 3-chloro-4-nitroso-group-oil of Niobe are placed 10 milliliters of chloroforms and under 0 ℃ of stirring, 1.10 gram (20.3 mmole) divinyl dropwise added in the freshly prepd solution of 6 milliliters of chloroforms.Reaction mixture 0-10 ℃ was stirred 30 minutes and in room temperature 16 hours, in vacuum, evaporated, and through silica gel chromatography purifying (elutriant: petrol ether/ethyl acetate=19: 1).

Yield: 1.00 grams (79%)

C ₁₂H ₁₂ClNO ₃(253.68)

Mass spectrum: (M+H) ⁺=254/256 (chlorine isotope)

R _fValue: 0.50 (silica gel; Petrol ether/ethyl acetate=4: 1)

(c) 3-chloro-4-(3, the 6-dihydro-[1,2] oxazine-2-yl)-phenylformic acid

Be similar to embodiment 2d by 3-chloro-4-(3, the 6-dihydro-[1,2] oxazine-2-yl)-oil of Niobe and sodium hydroxide prepares in water and alcoholic acid solvent mixture.

Yield: 90%

C ₁₁H ₁₀ClNO ₃(239.66)

Mass spectrum: (M-H) ^-=238/240

R _fValue: 0.20 (silica gel; Petrol ether/ethyl acetate=4: 1)

(d) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(3,6-dihydro-[1,2] oxazine-2-yl)-BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine, TBTU and NMM prepare in DMF by 3-chloro-4-(3,6-dihydro-[1,2] oxazine-2-yl)-BM, (1S)-1-to be similar to embodiment 1f.

Yield: 88%

C ₂₀H ₁₈Cl ₂N ₄O ₂(417.29)

Mass spectrum: (M+H) ⁺=417/419/421 (chlorine isotope)

R _fValue: 0.35 (silica gel; Petrol ether/ethyl acetate=1: 1)

Embodiment 83

3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle hexane-2-yl)-BM

(a) 2-chloro-N-(4-chlorobutyl-alkylsulfonyl)-4-methyl-aniline

1.30 milliliters of (10.7 mmole) 2-chloro-4-methyl-aniline are placed 30 milliliters of pyridines, mixes reaching with 2.67 gram (10.5 mmole) 75%m4-chlorobutyl-SULPHURYL CHLORIDEs stirring at room 16 hours.Reaction mixture is poured in the water and with ethyl acetate extraction.The organic phase that merges is cleaned with 6M hydrochloric acid, reach through dried over sodium sulfate and in vacuum, evaporate.Resistates is passed through silica gel chromatography purifying (elutriant gradient: petrol ether/ethyl acetate=9: 1-＞7: 3).

Yield: 1.27 grams (40%)

C ₁₁H ₁₅Cl ₂NO ₂S(296.21)

Mass spectrum: (M+H) ⁺=296/298/300 (chlorine isotope)

R _fValue: 0.42 (silica gel; Petrol ether/ethyl acetate=4: 1)

(b) 3-chloro-4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle hexane-2-yl)-toluene

1.27 gram (4.29 mmole) 2-chlorine N-(4-chlorobutyl-alkylsulfonyl)-4-methyl-aniline and 722 milligrams of (6.43 mmole) potassium tert.-butoxides one are arised from 60 ℃ of stirrings 16 hours in 50 milliliters of DMF.Then reaction mixture is poured in the water and reached with ethyl acetate extraction.With the organic machine layer that merges through dried over sodium sulfate and in vacuum, evaporate.Resistates is passed through silica gel chromatography purifying (elutriant: petrol ether/ethyl acetate=3: 2).

Yield: 850 milligrams (76%)

C ₁₁H ₁₄ClNO ₂S(259.75)

Mass spectrum: (M+H) ⁺=260/262 (chlorine isotope)

R _fValue: 0.27 (silica gel; Petrol ether/ethyl acetate=4: 1)

(c) 3-chloro-4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle hexane-2-yl)-phenylformic acid

250 milligrams of (0.96 mmole) 3-chloro-4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle hexane-2-yl)-toluene is suspended in 10 ml waters and mixes with 456 milligrams of (2.89 mmole) potassium permanganate and 39 milligrams of (0.98 mmole) sodium hydroxide.With reaction mixture refluxed 4 hours.After being cooled to room temperature, Sulfothiorine is added so that mixture fades, then it is used ethyl acetate extraction.With the organic phase that merges through dried over sodium sulfate and in vacuum, evaporate.Resistates is passed through silica gel chromatography purifying (elutriant: methylene chloride=19: 1).

Yield: 50 milligrams (18%)

C ₁₁H ₁₂ClNO ₄S(289.74)

Mass spectrum: (M+H) ⁺=290/292

R _tValue: 2.50 minutes

(d) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle hexane-2-yl)-BM

Be similar to embodiment 1f by 3-chloro-4-(1; 2-dioxo-[1; 2] sulfur nitrogen heterocycle hexane-2-yl)-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethylamine, TBTU and NMM prepare in DMF, and mat preparation HPLC purifying subsequently for phenylformic acid, (1R)-1-.

Yield: 34%

C ₂₁H ₂₂Cl ₂N ₄O ₄S(497.40)

Mass spectrum: (M+H) ⁺=497/499/501 (chlorine isotope)

R _tValue: 2.53 minutes

Embodiment 84

N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle heptane-2-yl)-3-methyl-BM

(a) 4-(5-chlorine amyl group-alkylsulfonyl-amino)-3-methyl-oil of Niobe

Being similar to embodiment 83a is prepared in pyridine by 4-amino-3-methyl-phenylformic acid and 5-chlorine amyl group-SULPHURYL CHLORIDE.

Yield: 43%

C ₁₄H ₂₀ClNO ₄S(333.83)

Mass spectrum: (M+H) ⁺=334/336 (chlorine isotope)

R _fValue: 0.72 (silica gel; Petrol ether/ethyl acetate=7: 3)

(b) 4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle heptane-2-yl)-3-methyl-oil of Niobe

Being similar to embodiment 83b is prepared in DMF by 4-(5-chlorine amyl group-alkylsulfonyl-amino)-3-methyl-oil of Niobe and potassium tert.-butoxide.

Yield: 19%

C ₁₄H ₁₉NO ₄S(297.37)

Mass spectrum: (M+H) ⁺=298

R _fValue: 0.30 (silica gel; Petrol ether/ethyl acetate=4: 1)

(c) 4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle heptane-2-yl)-3-methyl-phenylformic acid

Being similar to embodiment 39d is prepared in water and alcoholic acid solvent mixture by 4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle heptane-2-yl)-3-methyl-oil of Niobe and Lithium Hydroxide MonoHydrate.

Yield: 60%

C ₁₃H ₁₇NO ₄S(283.34)

Mass spectrum: (M+H) ⁺=284

R ^tValue: 2.60 minutes

(d) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(1,1-dioxo-[1,2] sulfur nitrogen heterocycle heptane-2-yl)-3-methyl-BM

Be similar to embodiment 1f by 4-(1; 1-dioxo-[1; 2] sulfur nitrogen heterocycle heptane-2-yl)-3-methyl-phenylformic acid, (1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethylamine, TBTU and NMM prepare in DMF, and subsequently through the silica gel chromatography purifying.

Yield: 75%

C ₂₃H ₂₇ClN ₄O ₄S(491.00)

Mass spectrum: (M+H) ⁺=491/493 (chlorine isotope)

R _tValue: 2.60 minutes

Embodiment 89

3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-([1,2] morpholine-2-yl)-BM

With 209 milligrams of (0.50 mmole) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(3; 6-dihydro-[1,2] oxazine-2-yl)-BM and 100 milligrams of 10%Pd/C one arise from 5 milliliters of ETHYLE ACETATE in room temperature hydrogenation 7 minutes under 5 crust nitrogen atmosphere.Then, will filtrate and in vacuum, evaporate and evaporate with ether again the mixture suction filtration.

Yield: 200 milligrams (95%)

C ₂₀H ₂₀Cl ₂N ₄O ₂(419.30)

Mass spectrum: (M+H) ⁺=419/421/423 (chlorine isotope)

R _fValue: 0.40 (silica gel; Petrol ether/ethyl acetate=1: 1)

Embodiment 90

N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(5-oxo-[1,4] oxaza heptane-4-yl)-BM

(a) 3-(2-benzyloxy-oxyethyl group)-ethyl propionate

8.53 milliliters of (60.0 mmole) benzyloxy-ethanol are mixed with 13 milligrams of (0.57 mmole) sodium in 40 milliliters of THF, then dissolve, under argon atmospher, add 5.95 milliliters of (54.7 mmole) ethyl propenoates and in stirring at room 20 hours when it.With in 0.6 milliliter of 1M hydrochloric acid and after, reaction mixture in vacuum-evaporation, is dissolved in resistates saturated nacl aqueous solution and uses ethyl acetate extraction.The organic phase that merges is cleaned with saturated nacl aqueous solution, reach through dried over sodium sulfate and in vacuum, evaporate.Resistates is passed through silica gel chromatography purifying (elutriant: petrol ether/ethyl acetate=4: 1).

Yield: 3.73 grams (25%)

C ₁₄H ₂₀O ₄(252.31)

Mass spectrum: (M+H) ⁺=253

R _fValue: 0.48 (silica gel; Petrol ether/ethyl acetate=4: 1)

(b) 3-(2-hydroxyl-oxyethyl group)-ethyl propionate

3.73 gram (14.8 mmole) 3-(2-benzyloxy-oxyethyl group)-ethyl propionates and 665 milligrams of 10%Pd/C one arised from 70 milliliters of ethanol in room temperature clung under the nitrogen atmosphere hydrogenation 44 minutes in 3.Then, will filtrate and in vacuum, evaporate the mixture suction filtration.

Yield: 2.26 grams (94%)

C ₇H ₁₄O ₄(162.18)

Mass spectrum: (M+H) ⁺=163

(c) 3-(2-chloro-oxyethyl group)-ethyl propionate

2.26 gram (13.9 mmole) 3-(2-hydroxyl-oxyethyl group)-ethyl propionates are suspended in 5 milliliters of (68.5 mmole) THIONYL CHLORIDE 97s and with 20 microlitres (0.27 mmole) DMF and add.With reaction mixture refluxed 4 hours and then in vacuum, evaporate.With the further reaction of product and without any other purifying.

Yield: quantitatively

C ₇H ₁₃O ₃(180.63)

Mass spectrum: (M+H) ⁺=181/183 (chlorine isotope)

(d) 3-(2-chloro-oxyethyl group)-propionic acid

2.00 gram (11.1 mmole) 3-(2-chloro-oxyethyl group)-ethyl propionates are suspended in 8 milliliters of ethanol and 4.96 milliliters of (16.6 mmole) 8% lithium hydroxide solutions are added.Mixture in stirring at room 4 hours, is then evaporated in vacuum, use the 2M hcl acidifying, mix with diethyl ether and through dried over sodium sulfate.Then it is filtered out and in vacuum, evaporate.

Yield: 1.51 grams (89%)

C ₅H ₉ClO ₃(152.58)

Mass spectrum: (M-H) ^-=151/153 (chlorine isotope)

(e) 3-(2-chloro-oxyethyl group)-propionyl chloride

Being similar to embodiment 90c is prepared in DMF by 3-(2-chloro-oxyethyl group)-propionic acid and THIONYL CHLORIDE 97.

Yield: 91%

C ₅H ₈Cl ₂O ₂(171.02)

(f) 4-[3-(2-chloro-oxyethyl group)-propionyl group-amino]-3-methyl-oil of Niobe

1.70 gram (10.3 mmole) 4-amino-3-methyl-oil of Niobe that will be in 10 milliliters of THF mix with 2.84 milliliters of (20.6 mmole) triethylamines and reach in stirring at room 20 minutes.Then with 1.78 gram (10.4 mmole) 3-(2-chloro-oxyethyl group)-propionyl chlorides in the solution of 25 milliliters of THF dropwise add and with mixture in room temperature restir 2.5 hours.Then use ethyl acetate extraction with the water adding and with mixture.The organic phase that merges is evaporated fully through dried over sodium sulfate and in vacuum.Resistates is passed through silica gel chromatography purifying (elutriant gradient: petrol ether/ethyl acetate=7: 3-＞6: 4).

Yield: 1.25 grams (41%)

C ₁₄H ₁₈ClNO ₄(299.75)

Mass spectrum: (M+H) ⁺=300/302 (chlorine isotope)

R _fValue: 0.15 (silica gel; Petrol ether/ethyl acetate=7: 3)

(g) 3-methyl-4-(5-oxo-[1,4] oxaza heptane-4-yl)-oil of Niobe

900 milligrams of (3.00 mmole) 4-[3-(2-chloro-oxyethyl group)-propionyl group-amino]-3-methyl-oil of Niobe is arised from 60 ℃ with 520 milligrams of (4.63 mmole) potassium tert.-butoxides and 12 milligrams of (80 micromole) Soiodins one in 40 milliliters of DMF stirred 3 hours.In vacuum, after the evaporation, resistates is mixed with water, reach through dried over sodium sulfate with ethyl acetate extraction and with the organic phase that merges and in vacuum, evaporate.Resistates is passed through silica gel chromatography purifying (elutriant: petrol ether/ethyl acetate=11: 9).

Yield: 310 milligrams (39%)

C ₁₄H ₁₇NO ₄(263.29)

Mass spectrum: (M+H) ⁺=264

(h) 3-methyl-4-(5-oxo-[1,4] oxaza heptane-4-yl)-phenylformic acid

Being similar to embodiment 39d is prepared in water and alcoholic acid solvent mixture by 3-methyl-4-(5-oxo-[1,4] oxaza heptane-4-yl)-oil of Niobe and Lithium Hydroxide MonoHydrate.

Yield: 69%

C ₁₃H ₁₅NO ₄(249.26)

Mass spectrum: (M+H) ⁺=250

R _tValue: 2.06 minutes

(i) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-methyl-4-(5-oxo-[1,4] oxaza heptane-4-yl)-BM

Be similar to embodiment 1f by 3-methyl-4-(5-oxo-[1,4] oxaza heptane-4-yl)-phenylformic acid, (1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethylamine, TBTU and NMM prepares and subsequently by the preparation HPLC purifying in DMF.

Yield: 83%

C ₂₃H ₂₅ClN ₄O ₄(456.92)

Mass spectrum: (M+H) ⁺=457/459 (chlorine isotope)

R _tValue: 2.23 minutes

Embodiment 91

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(4,4-dimethyl--2-oxo-imidazolidine-1-yl)-3-methyl-BM

(a) 4-(3-[1,1-dimethyl--2-hydroxyl-ethyl]-urine base (ureido))-3-methyl-oil of Niobe

5.70 gram (29.8 mmole) 4-isocyanato-3-methyl-oil of Niobe are dissolved among 100 milliliters of THF and with 2.86 milliliters of (30.0 mmole) 2-amino-2-methyls-solution of third-1-alcohol in 25 milliliters of THF and dropwise add.With mixture in stirring at room 2 hours and then in vacuum, evaporate.With the further reaction of resistates and without any other purifying.

Yield: 8.40 grams (quantitatively)

C ₁₄H ₂₀N ₂O ₄(280.32)

Mass spectrum: (M-H) ^-=279

R _fValue: 0.20 (silica gel; Methylene dichloride/ethanol=19: 1)

(b) 4-(4,4-dimethyl--2-oxo-imidazolidine-1-yl)-3-methyl-oil of Niobe

7.00 gram (25.0 mmole) 4-(3-[1,1-dimethyl--2-hydroxyl-ethyl]-urine base)-3-methyl-oil of Niobe are dissolved among 400 milliliters of THF and restrain (60.0 mmole) potassium tert.-butoxides and mix with 6.73 in 0 ℃., after 15 minutes the solution of 5.72 gram (30.0 mmole) tosic acid in 50 milliliters of THF is dropwise added in 0 ℃ of stirring., after 10 minutes 300 ml waters are added in 0 ℃ of stirring, mixture is evaporated in vacuum with the neutralization of 1M hydrochloric acid and with THF.Resistates is used dichloromethane extraction.With the organic phase that merges through dried over sodium sulfate and in vacuum, evaporate.Then resistates is passed through silica gel chromatography purifying (elutriant gradient: methylene dichloride/ethanol 100: 0-＞97: 3).

Yield: 2.50 grams (38%)

C ₁₄H ₁₈N ₂O ₃(262.30)

Mass spectrum: (M+H) ⁺=263

R _fValue: 0.30 (silica gel; Methylene dichloride/ethanol=19: 1)

(c) 4-(4,4-dimethyl--2-oxo-imidazolidine-1-yl)-3-methyl-phenylformic acid

2.70 gram (10.3 mmole) 4-(4,4-dimethyl--2-oxo-imidazolidine-1-yl)-3-methyl-oil of Niobe are suspended in 75 ml methanol and restrain the solution of (30.0 mmole) Pottasium Hydroxide in 10 ml waters and mix with 1.68.With it in stirring at room 3 hours and then in vacuum, evaporate.With the aqueous residue dilute with water, with the 1M hcl acidifying and with the throw out suction filtration that obtains, water cleans and is dry.

Yield: 2.30 grams (90%)

C ₁₃H ₁₆N ₂O ₃(248.28)

Mass spectrum: (M+H) ⁺=249

R _fValue: 0.50 (silica gel; Methylene dichloride/ethanol=9: 1)

(d) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-3-methyl-4-([1,3] oxaza heptane-2-ketone-3-yl)-BM

Be similar to embodiment 1f by 4-(4,4-dimethyl--2-oxo-imidazolidine-1-yl)-3-methyl-phenylformic acid, (1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamino, TBTU and DIPEA prepares and subsequently through the silica gel chromatography purifying in THF.

Yield: 59%

C ₂₂H ₂₄ClN ₅O ₂(425.91)

Mass spectrum: (M+H) ⁺=426/428 (chlorine isotope)

R _fValue: 0.40 (silica gel; Methylene chloride=9: 1)

Prepare following compounds with similarity method:

Embodiment 93

3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(4-methyl-2-oxo-oxazolidine-3-yl)-BM

(a) 3-chloro-4-(2-hydroxyl-1-methyl-ethylamino)-cyanobenzene

With 4.00 gram (25.7 mmole) 3-chloro-4-fluoro-cyanobenzenes and 8.00 restrain (106.5 mmole) 2-amino-1-propyl alcohol be heated under in 20 milliliters of DMSO, stirring 60 ℃ 2 hours.Then pour into reaction mixture in the water and use ethyl acetate extraction.Organic phase water that merges and saturated nacl aqueous solution are cleaned, reach through dried over sodium sulfate and in vacuum, evaporate.

Yield: 5.20 grams (96%)

C ₁₀H ₁₁ClN ₂O(210.66)

Mass spectrum: (M+H) ⁺=211/213 (chlorine isotope)

R _fValue: 0.27 (silica gel; Methylene chloride=19: 1)

(b) 3-chloro-4-(2-hydroxyl-1-methyl-ethylamino)-phenylformic acid

5.20 gram (24.7 mmole) 3-chloro-4-(2-hydroxyl-1-methyl-ethylamino)-cyanobenzenes were stirred refluxed 6 hours in 50 milliliters of concentrated hydrochloric acids.Then mixture is evaporated in vacuum, transfer to alkalescence and use ethyl acetate extraction with concentrated ammonia solution.Behind the acidifying with acetic acid water, mixture is used ethyl acetate extraction, organic phase water that merges and saturated nacl aqueous solution are cleaned, reach through dried over sodium sulfate and in vacuum, evaporate.

Yield: 5.00 grams (88%)

C ₁₀H ₁₂ClNO ₃(229.66)

Mass spectrum: (M+H) ⁺=230/232 (chlorine isotope)

R _fValue: 0.44 (silica gel; Methylene chloride=9: 1)

(c) 3-chloro-4-(2-hydroxyl-1-methyl-ethylamino)-ethyl benzoate

5.00 gram (21.8 mmole) 3-chloro-4-(2-hydroxyl-1-methyl-ethylamino)-phenylformic acid stirring at room in 100 milliliters of saturated alcohol hydrochloric acids was reached then in vacuum-evaporation in 16 hours.Resistates water and concentrated ammonia solution are mixed and use ethyl acetate extraction.Organic phase water that merges and saturated nacl aqueous solution are cleaned, reach through dried over sodium sulfate and in vacuum, evaporate.Resistates is passed through silica gel chromatography purifying (elutriant: methylene chloride 50: 1).

Yield: 3.40 grams (61%)

C ₁₂H ₁₆ClNO ₃(257.71)

Mass spectrum: (M+H) ⁺=258/260 (chlorine isotope)

R _fValue: 0.34 (silica gel; Methylene chloride=19: 1)

(d) 3-chloro-4-(4-methyl-2-oxo-oxazolidines-3-yl)-ethyl benzoate

With 0.50 gram (1.94 mmole) 3-chloro-4-(2-hydroxyl-1-methyl-ethylamino)-ethyl benzoate place 30 milliliters of THF with 0.22 gram (2.20 mmole) triethylamine and under stirring at room with 1.10 milliliters of (2.08 mmole) 20% phosgene in the adding of the solution of toluene.Mixture in stirring at room 1 hour, is then added 1 ml water and with mixture restir 10 minutes.Then with mixture in vacuum-evaporation, mix with water and use ethyl acetate extraction.Organic phase water that merges and saturated nacl aqueous solution are cleaned, reach through dried over sodium sulfate and in vacuum, evaporate.

Yield: 0.54 gram (98%)

C ₁₃H ₁₄ClNO ₄(283.71)

Mass spectrum: (M+H) ⁺=284/286 (chlorine isotope)

R _fValue: 0.71 (silica gel; Methylene chloride=19: 1)

(e) 3-chloro-4-(4-methyl-2-oxo-oxazolidines-3-yl)-phenylformic acid

With 0.90 gram (3.17 mmole) 3-chloro-4-(4-methyl-2-oxo-oxazolidines-3-yl)-ethyl benzoate in 50 ml methanol that contain 10 milliliters of 1M lithium hydroxide aqueous solutions stirring at room 1 hour.Then mixture is evaporated to 20 milliliters in vacuum, with the concentrated hydrochloric acid acidifying and use ethyl acetate extraction.The organic phase that merges is cleaned with saturated nacl aqueous solution, through dried over sodium sulfate and vacuum concentration.With resistates crystallization and suction filtration in a small amount of diethyl ether.

Yield: 0.45 gram (56%)

C ₁₁H ₁₀ClNO ₄(255.65)

Mass spectrum: (M+H) ⁺=256/258 (chlorine isotope)

R _fValue: 0.26 (silica gel; Methylene chloride=9: 1)

(f) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(4-methyl-2-oxo-oxazolidine-3-yl)-BM

Be similar to embodiment 1f by 3-chloro-4-(4-methyl-2-oxo-oxazolidine-3-yl)-phenylformic acid, (1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine, TBTU and DIPEA prepares and through the residue purified by chromatography on aluminum oxide in THF.

Yield: 45%

C ₂₀H ₁₈Cl ₂N ₄O ₃(433.29)

Mass spectrum: (M+H) ⁺=433/435/437 (chlorine isotope)

R _fValue: 0.65 (silica gel; Methylene chloride=9: 1)

Prepare following compounds with similarity method:

Embodiment 95

N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-phenyl-methyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM

(a) N '-(2-amino-4-chloro-phenyl)-N-Boc-phenyl-Gan amine amide and N '-(2-amino-5-chloro-phenyl)-N-Boc-phenyl-Gan amine amide

Be similar to embodiment 47a by N-Boc-phenyl-glycine, 4-chloro-1,2-phenylenediamine and DCC prepare in THF.

Yield: quantitatively, the mixture of two regional isomers

C ₁₉H ₂₂ClN ₃O ₃(375.85)

Mass spectrum: (M+H) ⁺=376/378 (chlorine isotope)

R _fValue: 0.41 (silica gel; Methylene dichloride/ethanol=19: 1)

(b) N-ethanoyl-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-phenyl-methylamine

Be dissolved in 8 milliliters of acetic acid 3.65 mixtures that in 95a, obtain of gram (9.71 mmole) and stirring and refluxing 6 hours.With reaction mixture in vacuum, evaporate and with resistates through silica gel chromatography purifying (elutriant gradient: methylene dichloride/ethanol=100: 0-＞94: 6).

Yield: 1.34 grams (46%)

C ₁₆H ₁₄ClN ₃O(229.76)

Mass spectrum: (M+H) ⁺=300/302 (chlorine isotope)

R _fValue: 0.19 (silica gel; Methylene dichloride/ethanol=19: 1)

(c) 1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-phenyl-methylamine

1.34 gram (4.47 mmole) N-ethanoyl-1-that will be in 9 milliliters of ethanol (5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-phenyl-methylamine mix with 18 milliliters of concentrated hydrochloric acids and be heated to 50 ℃ 2 days.Reaction mixture is evaporated in vacuum and dissolving twice and reevaporate in ethanol.

Yield: 1.26 grams (96%)

C ₁₄H ₁₂ClN ₃*HCl(294.18/257.72)

Mass spectrum: (M+H) ⁺=258/260 (chlorine isotope)

(d) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-phenyl-methyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-phenyl-methylamine, TBTU and DIPEA prepare in THF by 3-methyl-4-(morpholine-3-ketone-4-yl)-phenylformic acid, 1-to be similar to embodiment 1f.

Yield: 89%

C ₂₆H ₂₃ClN ₄O ₃(474.94)

Mass spectrum: (M+H) ⁺=475/477 (chlorine isotope)

R _fValue: 0.68 (silica gel; Methylene dichloride/ethanol=9: 1)

Prepare following compounds with similarity method:

Embodiment 96

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl) BM

(a) N '-(2-amino-4-chloro-phenyl)-(2S)-2-(Boc-is amino)-yulocrotine and N '-(2-amino-5-chloro-phenyl)-(2S)-2-(Boc-is amino)-yulocrotine

Be similar to embodiment 47a by (2S)-2-N-(Boc-is amino)-butyric acid, 4-chloro-1,2-phenylenediamine and DCC prepare in THF.

Yield: the mixture of 89% two regional isomer

C ₁₅H ₂₂ClN ₃O ₃(327.81)

Mass spectrum: (M+H) ⁺=328/330 (chlorine isotope)

R _fValue: 0.63 (silica gel; Methylene dichloride/ethanol=19: 1)

(b) (1S)-and N-Boc-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-propyl group amine

Be similar to embodiment 47b because mixture that obtains among the embodiment 95a and acetic acid preparation reach through silica gel chromatography purifying resistates.

Yield: 94%

C ₁₅H ₂₀ClN ₃O ₂(309.79)

Mass spectrum: (M+H) ⁺=310/312 (chlorine isotope)

R _fValue: 0.63 (silica gel; Methylene dichloride/ethanol=19: 1)

(c) (1S)-and 1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-phenyl-methylamine

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-propyl group amine and trifluoracetic acid prepare in methylene dichloride by (1S)-N-Boc-1-to be similar to embodiment 47c.

Yield: quantitatively

C ₁₀H ₁₂ClN ₃*2CF ₃COOH(437.72/209.68)

Mass spectrum: (M+H) ⁺=210/212 (chlorine isotope)

(d) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-propyl group]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-propyl group amine, TBTU and DIPEA prepare in THF by 3-methyl-4-(morpholine-3-ketone-4-yl)-phenylformic acid, (1S)-1-to be similar to embodiment 1f.

Yield: 17%

C ₂₂H ₂₃ClN ₄O ₃(426.90)

Mass spectrum: (M+H) ⁺=427/429 (chlorine isotope)

R _fValue: 0.45 (silica gel; Methylene dichloride/ethanol=9: 1)

Prepare following compounds with similarity method:

Embodiment 106

N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-fluoro-4-(morpholine-3-ketone-4-yl) BM

(a) 4-[(2-chloro-oxyethyl group)-ethanoyl-amino]-3-fluoro-ethyl benzoate

Being similar to embodiment 46a is prepared in THF by (2-chloro-oxyethyl group)-Acetyl Chloride 98Min. and 4-amino-3-fluoro-ethyl benzoate and TEA.

Yield: 44%

C ₁₃H ₁₅ClFNO ₄(303.71)

Mass spectrum: (M+H) ⁺=303/306 (chlorine isotope)

R _fValue: 0.29 (silica gel; Methylene dichloride)

(b) 4-(2-carboxyl methoxyl group-ethylamino)-3-fluoro-phenylformic acid

580 milligrams of (1.91 mmole) 4-[(2-chloro-oxyethyl group)-ethanoyl-amino]-3-fluoro-ethyl benzoate in 6 milliliters of dioxane is mixed with 3.82 milliliters of (7.64 mmole) 2M potassium hydroxide solutions and 2 ml waters.Then with mixture heating up to 70 ℃ 2 hours, dilute with water and use the 6M hcl acidifying then.After adding methylene dichloride, with the throw out suction filtration that forms and dry in 50 ℃ of desiccator cabinets.

Yield: 390 milligrams (79%)

C ₁₁H ₁₂FNO ₅(257.22)

Mass spectrum: (M+H) ⁺=258

R _fValue: 0.66 (anti-phase RP-8; Methyl alcohol/5%NaCl solution=6: 4)

(c) 3-fluoro-4-(morpholine-3-ketone-4-yl)-Benzoyl chloride 99min.

Being similar to embodiment 41c is prepared in methylene dichloride and DMF by 4-(2-carboxyl-methoxyl group-ethylamino)-3-fluoro-phenylformic acid and THIONYL CHLORIDE 97.

Yield: quantitatively

C ₁₁H ₉ClFNO ₃(257.65)

(d) N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-3-fluoro-4-(morpholine-3-ketone-4-yl)-BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethylamine and TEA prepare in THF by 3-fluoro-4-(morpholine-3-ketone-4-yl)-Benzoyl chloride 99min. and (1R)-1-to be similar to embodiment 41d.

Yield: 47%

C ₂₁H ₂₀ClFN ₄O ₄(446.86)

Mass spectrum: (M+H) ⁺=447/449 (chlorine isotope)

R _fValue: 0.40 (silica gel; Methylene dichloride/ethanol=9: 1)

Embodiment 109

N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(pyridin-3-yl)-methyl]-3-methyl-4-(morpholine-3-ketone-4-yl) BM

(a) N '-(2-amino-4-chloro-phenyl)-2-(Boc-is amino)-2-(pyridin-3-yl)-ethanamide and N '-(2-amino-5-chloro-phenyl--2-(Boc-is amino)-2-(pyridin-3-yl)-ethanamide

With 1.00 gram (3.96 mmole) N-Boc-amino-2-(pyridin-3-yl)-acetate and 0.59 gram (4.16 mmole) 4-chloro-1,2-phenylenediamine one arise from 0 ℃ place 20 milliliters of THF and with 2.92 milliliters of (4.96 mmole) 50%PPA in the solution of ETHYLE ACETATE and 1.24 milliliters of (8.92 mmole) TEA addings.In 0 ℃ stir 30 minutes after, with mixture in stirring at room 5 hours and then evaporation is fully in vacuum.Resistates is passed through silica gel chromatography purifying (elutriant gradient: methylene dichloride/ethanol 10: 0-＞9: 1).

Yield: the mixture of (88%) two regional isomer of 1.32 grams

C ₁₈H ₂₁ClN ₄O ₃(376.84)

Mass spectrum: (M+H) ⁺=377/379 (chlorine isotope)

R _fValue: 0.40 (silica gel; Methylene dichloride/ethanol=9: 1)

(b) N-Boc-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(pyridin-3-yl)-methylamine

Be similar to embodiment 47b because product that obtains among the embodiment 111a and acetic acid preparation.

Yield: 81%

C ₁₈H ₁₉ClN ₄O ₂(358.82)

Mass spectrum: (M+H) ⁺=359/361 (chlorine isotope)

R _fValue: 0.51 (silica gel; Methylene dichloride/ethanol=9: 1)

(c) 1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(pyridin-3-yl)-methylamine

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(pyridin-3-yl)-methylamine and trifluoracetic acid prepare in methylene dichloride by N-Boc-1-to be similar to embodiment 1g.

Yield: 66%

C ₁₃H ₁₁ClN ₄(258.71)

Mass spectrum: (M+H) ⁺=259/261 (chlorine isotope)

R _fValue: 0.62 (silica gel; Methylene dichloride/ethanol=9: 1)

(d) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(pyridin-3-yl)-methyl]-3-methyl-4-(morpholine-3-ketone-4-yl) BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(pyridin-3-yl)-methylamine prepares in THF with TBTU and DIPEA by 3-methyl-4-(morpholine-3-ketone-4-yl)-phenylformic acid and 1-to be similar to embodiment 1f.

Yield: 84%

C ₂₅H ₂₂ClN ₅O ₃(475.93)

Mass spectrum: (M+H) ⁺=476/478 (chlorine isotope)

R _fValue: 0.31 (silica gel; Methylene dichloride/ethanol=9: 1)

Embodiment 110

N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(1-methyl-pyrazole-3-yl)-methyl]-3-methyl-4-(morpholine-3-ketone-4-yl) BM

(a) ethoxy carbonyl-methoxyimino-(1-methyl-pyrazole-3-yl)-methyl acetate

5.00 gram (20.7 mmole) ethoxy carbonyl-methoxyimino-(pyrazole-3-yl)-acetate and 5.73 are restrained (41.5 mmole) salt of wormwood one to be arised from room temperature and places 20 milliliters of DMF; Stirring generates up to gas and finishes, and then stirs 2 hours in 50 ℃ with 2.58 milliliters of (41.5 mmole) methyl-iodides addings and with mixture.After reaction mixture evaporated in vacuum, resistates is mixed with water and ETHYLE ACETATE, the organic phase water is cleaned, evaporation is fully through dried over mgso and in vacuum.Resistates is passed through silica gel chromatography purifying (elutriant gradient: petrol ether/ethyl acetate=80: 20-＞65: 35).

Yield: the regional isomer intermixture of 2.61 grams (26%)

C ₁₁H ₁₅N ₃O ₅(269.25)

Mass spectrum: (M+H) ⁺=270

R _fValue: 0.25 (silica gel; Petrol ether/ethyl acetate=1: 1)

(b) 2-amino-2-(1-methyl-pyrazole-3-yl)-methyl acetate

With 2.61 the gram (9.69 mmole) ethoxy carbonyl-methoxyimino-(1-methyl-pyrazole-3-yl)-methyl acetates in contain 1.1 the gram 5%Pd/C 60 milliliters of ethanol in the following 50 ℃ of hydrogenations of 3.4 bar pressure nitrogen atmosphere 16 hours.Then with the mixture suction filtration and will filtrate in vacuum evaporation fully.

Yield: 1.90 grams (quantitatively) have pollution a little

C ₇H ₁₁N ₃O ₂(169.18)

Mass spectrum: (M+H) ⁺=170

R _fValue: 0.30 (silica gel; Methylene dichloride/ethanol=9: 1)

(c) N-Boc-2-amino-2-(1-methyl-pyrazole-3-yl)-methyl acetate

Being similar to embodiment 1d is prepared in methylene dichloride by 2-amino-2-(1-methyl-pyrazole-3-yl)-methyl acetate and coke acid two-tertiary butyl ester and TEA.

Yield: 81%

C ₁₂H ₁₉N ₃O ₄(269.30)

Mass spectrum: (M+H) ⁺=270

(d) N-Boc-2-amino-2-(1-methyl-pyrazole-3-yl)-acetate

1.16 gram (4.31 mmole) N-Boc-2-amino-2-(1-methyl-pyrazole-3-yl)-methyl acetates in 16 milliliters of THF are mixed with 10 ml waters and 10 milliliters of 1M lithium hydroxide solutions are added., after 2 hours mixture is evaporated in vacuum in stirring at room, resistates is mixed with water, filter, and will filtrate accent liquid to pH5 with potassium hydrogen sulfate solution.After being in the vacuum evaporation fully, resistates is handled suction filtration and will filtrate in vacuum evaporation fully with methylene dichloride and small amount of ethanol.

Yield: 0.92 gram (84%)

C ₁₁H ₁₇N ₃O ₄(255.27)

Mass spectrum: (M+H) ⁺=256

R _fValue: 0.1 (silica gel; Methylene dichloride/ethanol=8: 2)

(e) N '-(2-amino-4-chloro-phenyl)-2-(Boc-is amino)-2-(1-methyl-pyrazole-3-yl)-ethanamide and N '-(2-amino-5-chloro-phenyl)-2-(Boc-is amino)-2-(1-methyl-pyrazole-3-yl)-ethanamide

Be similar to embodiment 111a by N-Boc-2-amino-2-(1-methyl-pyrazole-3-yl)-acetate, 4-chloro-1,2-phenylenediamine and the PPA in ETHYLE ACETATE and the preparation of the NMM in methylene dichloride.

Yield: the mixture of 55% two regional isomer

C ₁₇H ₂₂ClN ₅O ₃(379.84)

R _fValue: 0.61 (silica gel; Methylene dichloride/ethanol=9: 1)

(f) N-Boc-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(1-methyl-pyrazole-3-yl)-methylamine

Be similar to embodiment 47b because product that obtains among the embodiment 112e and acetic acid preparation.

Yield: 81%

C ₁₇H ₂₀ClN ₅O ₂(361.83)

Mass spectrum: (M+H) ⁺=362/364 (chlorine isotope)

R _fValue: 0.60 (silica gel; Methylene dichloride/ethanol=9: 1)

(g) 1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(1-methyl-pyrazole-3-yl)-methylamine

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(1-methyl-pyrazole-3-yl)-methylamine and trifluoracetic acid prepare in methylene dichloride by N-Boc-1-to be similar to embodiment 1g.

Yield: 77%

C ₁₂H ₁₂ClN ₅(261.71)

Mass spectrum: (M-NH ₃+ H) ⁺=245/247 (chlorine isotope)

R _fValue: 0.30 (silica gel; Methylene dichloride/ethanol/concentrated ammonia solution=9: 1: 0.1)

(h) N-[1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(1-methyl-pyrazole-3-yl)-methyl]-3-methyl-4-(morpholine-3-ketone-4-yl) BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-1-(1-methyl-pyrazole-3-yl)-methylamine prepares in THF with TBTU and DIPEA by 3-methyl-4-(morpholine-3-ketone-4-yl)-phenylformic acid and 1-to be similar to embodiment 1f.

Yield: 38%

C ₂₄H ₂₃ClN ₆O ₃(478.93)

Mass spectrum: (M+H) ⁺=479/481 (chlorine isotope)

R _fValue: 0.50 (silica gel; Methylene dichloride/ethanol=9: 1)

Embodiment 111

3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(5-methyl-morpholine-3-ketone-4-yl) BM

(a) 4-[2-(tert-butoxycarbonyl-methoxyl group)-1-methyl-ethylamino]-3-chloro-ethyl benzoate

1.12 gram (4.35 mmole) 3-chloro-4-(2-hydroxyl-1-methyl-ethylamino)-ethyl benzoates were incorporated in stirring at room 5 minutes with 10 milliliters of DMF that contain 0.21 gram (4.78 mmole) 55% sodium hydride dispersion are mixed.Then 0.67 milliliter of bromine tert-butyl acetate is added and with mixture in room temperature restir 16 hours.Then pour into reaction mixture in the water and use ethyl acetate extraction.Organic phase water that merges and saturated nacl aqueous solution are cleaned, evaporate fully through dried over sodium sulfate and in vacuum.Resistates is passed through silica gel chromatography purifying (elutriant gradient: sherwood oil/ethanol ethyl ester=95: 5-＞80: 20).

Yield: 230 milligrams (14%)

C ₁₈H ₂₆ClNO ₅(371.86)

Mass spectrum: (M+H) ⁺=372/374 (chlorine isotope)

R _fValue: 0.65 (silica gel; Petrol ether/ethyl acetate=7: 3)

(b) 3-chloro-4-[2-(hydroxycarbonyl group-methoxyl group)-1-methyl-ethylamino]-ethyl benzoate

Being similar to embodiment 1g is prepared in methylene dichloride by 4-[2-(tert-butoxycarbonyl-methoxyl group)-1-methyl-ethylamino]-3-chloro-ethyl benzoate and trifluoracetic acid.

Yield: 87%

C ₁₄H ₁₈ClNO ₅(315.75)

Mass spectrum: (M+H) ⁺=316/318 (chlorine isotope)

R _fValue: 0.40 (silica gel; Methylene dichloride/ethanol=9: 1)

(c) 3-chloro-4-(5-methyl-morpholine-3-ketone-4-yl)-ethyl benzoate

Being similar to embodiment 41c is prepared in methylene dichloride by 3-chloro-4-[2-(hydroxycarbonyl group-methoxyl group)-1-methyl-ethylamino]-ethyl benzoate and THIONYL CHLORIDE 97 and DMF.

Yield: 69% (pollution is arranged)

C ₁₄H ₁₆ClNO ₄(297.73)

Mass spectrum: (M+H) ⁺=298/300 (chlorine isotope)

R _fValue: 0.40 (silica gel; Methylene dichloride/ethanol=19: 1)

(d) 3-chloro-4-(5-methyl-morpholine-3-ketone-4-yl)-phenylformic acid

Being similar to embodiment 31b is prepared in THF and water by 3-chloro-4-(5-methyl-morpholine-3-ketone-4-yl)-ethyl benzoate and Lithium Hydroxide MonoHydrate.

Yield: 91%

C ₁₂H ₁₂ClNO ₄(269.68)

R _fValue: 0.30 (silica gel; Methylene dichloride/ethanol=9: 1)

(e) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(5-methyl-morpholine-3-ketone-4-yl)-BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethylamine prepares in DMF with TBTU and TEA by 3-chloro-4-(5-methyl-morpholine-3-ketone-4-yl)-phenylformic acid and (1R)-1-to be similar to embodiment 1f.

Yield: 28%

C ₂₂H ₂₂Cl ₂N ₄O ₄(477.34)

Mass spectrum: (M-H) ^-=475/477/479 (chlorine isotope)

R _fValue: 0.50 (silica gel; Methylene dichloride/ethanol=9: 1)

Embodiment 112

3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(3-dimethyl amine-tetramethyleneimine-1-yl)-BM

(a) 3-chloro-4-(3-dimethylamino-tetramethyleneimine-1-yl)-cyanobenzene

0.75 gram (4.82 mmole) 3-chloro-4-fluoro-cyanobenzene and 0.65 milliliter of (0.58 gram, 5.06 mmoles) 3-dimethyl amine-tetramethyleneimine one are arised among 12 milliliters of DHF and mix under the room temperature argon atmospher with 231 milligrams of (5.30 mmole) 55% sodium hydride dispersions.In stirring at room after 3.5 hours, with reaction mixture pour in the water and thorough mixing after use ethyl acetate extraction.The organic phase that merges is cleaned with saturated nacl aqueous solution, evaporate fully through dried over mgso and in vacuum.

Yield: 1.11 grams (92%)

C ₁₃H ₁₆ClN ₃(249.74)

Mass spectrum: (M+H) ⁺=250/252 (chlorine isotope)

R _fValue: 0.42 (silica gel; Petrol ether/ethyl acetate=1: 1)

(b) 3-chloro-4-(3-dimethylamino-tetramethyleneimine-1-yl)-phenylformic acid

Be similar to embodiment 13b by 3-chloro-4-(3-dimethylamino-tetramethyleneimine-1-yl)-cyanobenzene and 10M sodium hydroxide solution and ethanol preparation.

Yield: 27%

C ₁₃H ₁₇ClN ₂O ₂(268.74)

Mass spectrum: (M+H) ⁺=269/271 (chlorine isotope)

(c) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(3-dimethylamino-tetramethyleneimine-1-yl)-BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine prepares in DMF with TBTU and TEA by 3-chloro-4-(3-dimethyl amine-tetramethyleneimine-1-yl)-phenylformic acid and (1S)-1-to be similar to embodiment 1f.

Yield: 74%, pollution is arranged a little

C ₂₂H ₂₅Cl ₂N ₅O(446.37)

Mass spectrum: (M+H) ⁺=446/448/450 (chlorine isotope)

R _fValue: 0.65 (silica gel; Methylene chloride=8: the 2+0.5% concentrated ammonia solution)

Embodiment 113

N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(pyrazolidine-3-ketone-1-yl)-trifluoromethyl-BM

(a) 4-(pyrazolidine-3-ketone-1-yl)-3-trifluoromethyl-cyanobenzene

1.00 gram (5.29 mmole) 4-fluoro-3-trifluoromethyl-cyanobenzenes and 1.35 milliliters of (12.0 mmole) potassium tert.-butoxides one are arised from and stirred 35 minutes under the room temperature argon atmospher and then with 1.00 gram (8.16 mmole) pyrazolidines-3-keto hydrochlorides adding in 3 milliliters of DMSO in 4 milliliters of DMF.In stirring at room after 68 hours, reaction mixture is poured in the semi-saturation sodium chloride solution and used ethyl acetate extraction.The organic phase that merges is evaporated fully through dried over mgso and in vacuum.

Yield: 0.58 gram (43%)

C ₁₁H ₈F ₃N ₃O(255.20)

Mass spectrum: (M+H) ⁺=256

R _fValue: 0.15 (silica gel; Methylene dichloride+0.5% concentrated ammonia solution)

(b) 4-(pyrazolidine-3-ketone-1-yl)-3-trifluoromethyl-phenylformic acid

Be similar to embodiment 13b by 3-chloro-4-(3-dimethylamino tetramethyleneimine-1-yl) cyanobenzene and 10M sodium hydroxide solution and ethanol preparation.

Yield: 56%

C ₁₁H ₉F ₃N ₂O ₃(274.20)

R _fValue: 0.60 (silica gel; Methylene dichloride/ethanol=8: 2+0.5% acetic acid)

(c) N-[(1S)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethyl]-4-(pyrazolidine-3-ketone-1-yl)-3-trifluoromethyl-BM

(5-chloro-1H-benzimidazolyl-2 radicals-yl)-ethylamine prepares in DMF with TBTU and TEA by 4-(pyrazolidine-3-ketone-1-yl)-3-trifluoromethyl-phenylformic acid and (1S)-1-to be similar to embodiment 1f.

Yield: 12%, pollution is arranged a little

C ₂₀H ₁₇ClF ₃N ₅O ₂*2CF ₃COOH(679.88/451.83)

Mass spectrum: (M+H) ⁺=452/454 (chlorine isotope)

R _fValue: 0.58 (silica gel; Methylene chloride=8: the 2+0.5% concentrated ammonia solution)

Embodiment 127

N-[(1S)-1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-3-methyl-butyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM

(a) (1S)-N-Boc-1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-3-methyl-butylamine

1.68 gram (6.37 mmole) [1-(2-chloro-ethanoyl)-3-methyl-butyl]-t-butyl carbamates that will be in 15 ml methanol mix under stirring at room with 819 milligrams of (6.37 mmole) 2-amino-4-chloro-pyridines and with mixture backflow 3 days.In vacuum after the evaporation, resistates mixed reaching with 5% sodium hydrogen carbonate solution in stirring at room 20 hours.Then it is used dichloromethane extraction, the organic phase that merges is evaporated fully through dried over sodium sulfate and in vacuum.Resistates is passed through silica gel chromatography purifying (elutriant gradient: methylene dichloride/ethanol=100: 0-＞94: 6).

Yield: 180 milligrams (8%)

C ₁₇H ₂₄ClN ₃O ₂(337.85)

Mass spectrum: (M+H) ⁺=338/340 (chlorine isotope)

R _fValue: 0.61 (silica gel; Methylene dichloride/ethanol=9: 1)

(b) (1S)-1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-3-methyl-butylamine

Being similar to embodiment 1g is prepared in methylene dichloride by (1S)-N-Boc-1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-3-methyl-butylamine and trifluoracetic acid.

Yield: quantitatively

C ₁₂H ₁₆ClN ₃*2CF ₃CO ₂H(465.78/237.73)

Mass spectrum: (M+H) ⁺=238/240 (chlorine isotope)

(c) N-[(1S)-1-(5-chloro-imidazo [1,2a] pyridine-2-yl)-3-methyl-butyl]-3-methyl-4-(morpholine-3-ketone-4-yl)-BM

Being similar to embodiment 1f is prepared in THF with TBTU and DIPEA by 3-methyl-4-(morpholine-3-ketone-4-yl)-phenylformic acid and (1S)-1-(7-chloro-imidazo [1,2a] pyridine-2-yl)-3-methyl-butylamine.

Yield: quantitatively

C ₂₄H ₂₇ClN ₄O ₃(454.95)

Mass spectrum: (M+H) ⁺=455/457 (chlorine isotope)

R _fValue: 0.54 (silica gel; Methylene dichloride/ethanol=9: 1)

The following example explanation contains the preparation of the compound of Formula I of any needs as some pharmaceutical prepns of active substance:

Example I

Per 10 milliliters of dried ampoules that contain 75 milligrams of active substances

Form:

75.0 milligrams of active substances

50.0 milligrams in N.F,USP MANNITOL

Water for injection adds to 10.0 milliliters

Preparation:

Active substance and N.F,USP MANNITOL are dissolved in the water.After the packing with the solution lyophilize.In order to produce the solution that to inject use at any time, product is dissolved in the water.

Example II

Per 2 milliliters of dried ampoules that contain 35 milligrams of active substances

EXAMPLE IV

The tablet that contains 350 milligrams of active substances

Form:

(1) active substance is 350.0 milligrams

(2) lactose is 136.0 milligrams

(3) W-Gum is 80.0 milligrams

(4) PVP K120 is 30.0 milligrams

(5) Magnesium Stearate 4.0 milligram

600.0 milligram

Preparation:

(1), (2) and (3) are mixed and with the aqueous solution granulation of (4).(5) are added to dried particulate material.Thus mixture medicine compressing tablet, biplaneization, on facet on the two sides and one side, have the indenture of cutting apart.The diameter of tablet: 12 millimeters.

EXAMPLE V

The capsule that contains 50 milligrams of active substances

Form:

(1) active substance is 50.0 milligrams

(2) the exsiccant W-Gum is 58.0 milligrams

(3) ground lactose is 50.0 milligrams

(4) Magnesium Stearate 2.0 milligram

160.0 milligram

Preparation:

(1) is ground with (3).This trituration is added to the mixture of (2) and (4) under violent the mixing.

This powdered mixture is packed in capsule filler in No. 3 snap fit capsules.

Example VI

The capsule that contains 350 milligrams of active substances

Form:

(1) active substance is 350.0 milligrams

(2) the exsiccant W-Gum is 46.0 milligrams

(3) ground lactose is 30.0 milligrams

(4) Magnesium Stearate 4.0 milligram

430.0 milligram

Preparation:

This powdered mixture is packed in capsule filler in No. 0 snap fit capsule.

Example VII A

The suppository that contains 100 milligrams of active substances

1 suppository contains:

100.0 milligrams of active substances

600.0 milligrams of polyoxyethylene glycol (molecular weight 1500)

460.0 milligrams of polyoxyethylene glycol (molecular weight 6000)

The polyoxyethylene Arlacel-60 840.0 milligram

(polyethylene sorbitan monostearate) 2000.0 milligrams

Preparation:

Polyoxyethylene glycol is melted in the polyoxyethylene Arlacel-60.Active substance after 40 ℃ will be pulverized is scattered in the melt equably.It is cooled to 38 ℃ and pour in the chilly suppository mold.

Claims

1. the substituted carboxylic acid amide of general formula I

Wherein

A represents the group of following general formula

Wherein

M represents numeral 1 or 2,

The group of following general formula

Wherein

M represents numeral 1 or 2,

X ²Represention oxygen atom or-NR ^6bGroup,

X ³Represent methylene radical, carbonyl or alkylsulfonyl,

X ⁴Represent oxygen or sulphur atom ,-NR ^6bOr carbonyl,

X ⁵Represent carbonyl or alkylsulfonyl,

X ⁶Represention oxygen atom ,-NR ^6bOr methylene radical,

X ⁷Represent oxygen or sulphur atom or-NR ^6bGroup,

X ⁸Represent methylene radical or carbonyl,

X ⁹Representative-NR ^6bOr carbonyl,

X ¹⁰Represent sulfinyl or alkylsulfonyl, and

In above-mentioned substituted 5-to 7-member group A, the heteroatoms of randomly introducing as substituting group and another heteroatoms proper what a carbon atom of not being separated by,

R ¹Represent hydrogen, fluorine, chlorine or bromine atom, wherein Wasserstoffatoms can be whole or in part by the substituted C of fluorine atom _1-3-alkyl, C _2-3-thiazolinyl, C _2-3-alkynyl, nitro, amino, C _1-3-alkoxyl group, list-, two-or trifluoromethoxy,

R ²Represent hydrogen, fluorine, chlorine or bromine atom or C _1-3-alkyl,

R ³Represent Wasserstoffatoms, C _2-3-thiazolinyl or C _2-3-alkynyl or straight or branched C _1-6-alkyl, wherein Wasserstoffatoms can be whole or in part replaced by fluorine atom, and randomly by nitrile, hydroxyl, wherein Wasserstoffatoms can be whole or in part by the substituted C of fluorine atom _1-5-alkoxyl group, allyloxy, alkynes propoxy-, benzyloxy, C _1-5-alkyl-carbonyl oxygen base, C _1-5Alkoxy-carbonyl oxy, carboxyl-C _1-3-alkoxyl group, C _1-5-alkoxy carbonyl-C _1-3-alkoxyl group, C _1-8-alkoxycarbonyl amino, sulfydryl, C _1-3-alkylthio, C _1-3-alkyl sulphinyl, C _1-3-alkyl sulphonyl, C _1-3-alkyl-carbonyl-amino-C _1-3-alkylthio, C _1-3-alkyl-carbonyl-amino-C _1-3-alkyl sulphinyl, C _1-3-alkyl-carbonyl-amino-C _1-3-alkyl sulphonyl, carboxyl, C _1-3-alkoxy carbonyl, allyloxy carbonyl, alkynes propoxycarbonyl, benzyloxycarbonyl, aminocarboxyl, C _1-3-alkyl amino-carbonyl, two-(C _1-3-alkyl)-aminocarboxyl, C _3-6-cycloalkylidene imino-carbonyl, amino-sulfonyl, C _1-3-alkyl amino sulfonyl, two-(C _1-3-alkyl)-amino-sulfonyl, C _3-6-cycloalkylidene imino-alkylsulfonyl, amino, C _1-3-alkylamino, two-(C _1-3-alkyl)-amino, C _1-5-alkyl-carbonyl-amino, C _1-3-alkyl sulfonyl-amino, N-(C _1-3-alkyl sulphonyl)-C _1-3-alkylamino, C _3-6-cycloalkyl amino carbonyl, amino carbonyl amino, C _1-3-alkyl amino-carbonyl is amino, two-(C _1-3-alkyl)-amino carbonyl amino, 4-to 7-member cycloalkylidene imino-carbonylamino, benzyloxycarbonyl are amino, phenylcarbonyl group is amino or guanidino group replaces,

3-to 7-member naphthenic base, cycloalkylidene imino-, naphthenic base-C _1-3-alkyl or cycloalkylidene imino--C _1-3-alkyl, wherein the methylene radical in circular part can be by randomly by C _1-3-alkyl or C _1-3-alkyl-carbonyl is substituted-replacement of NH-group or by the Sauerstoffatom replacement and wherein other adjacent to-NH-,-N (C _1-3-alkyl-carbonyl)-or-N (C _1-3-alkyl)-methylene of group is based on can be by carbonyl or alkylsulfonyl replacement under the various situation, its restricted condition be as in the cycloalkylidene imino-of aforementioned definitions two nitrogen-atoms of eliminating apart proper what a-CH ₂-group,

R ⁴Represent Wasserstoffatoms or C _1-3-alkyl or

R ³And R ⁴Represent C with its bonded carbon atom _3-7-naphthenic base, and

C _3-7A methylene radical of-naphthenic base can be by imino-, C _1-3-alkyl imino, acyl group imino-or the replacement of alkylsulfonyl imino-,

R ⁵Represent Wasserstoffatoms or C _1-3-alkyl,

B represents the group of following formula

Wherein

N represents numeral 1 or 2,

R ⁸Represent hydrogen, fluorine, chlorine, bromine or iodine atom independently of one another, wherein Wasserstoffatoms can be whole or in part by the substituted C of fluorine atom _1-3-alkyl, C _2-3-thiazolinyl or C _2-3-alkynyl, hydroxyl, C _1-3-alkoxyl group, trifluoromethoxy, amino, nitro or itrile group,

And except as otherwise noted, the term of being mentioned in the preamble definition " heteroaryl " means and is selected from following monocycle 5-or 6-person's heteroaryl: pyridyl, N-oxo-pyridyl, pyrazolyl, pyridazinyl, pyrimidyl, pyrazinyl, [1,2; 3] triazinyl, [1; 3,5] triazinyl, [1,2; 4] triazinyl, pyrryl, imidazolyl, [1; 2,4] triazolyl, [1,2; 3] triazolyl, tetrazyl, furyl, different

azoles base, azoles base, [1; 2,3]

di azoly, [1,2; 4]

di azoly, furazan base, thienyl, thiazolyl, isothiazolyl, [1; 2,3] thiadiazolyl group, [1,2; 4] thiadiazolyl group or [1; 2,5] thiadiazolyl group

And be contained in alkyl and the alkoxyl group that have in the above-mentioned definition more than two carbon atoms, except as otherwise noted, for straight or branched, and the alkyl in aforementioned dialkyl amido can be identical or different,

And tautomer, enantiomer and salt.

2. according to the substituted carboxylic acid amide of the general formula I of claim 1, wherein

A represents the group of following general formula

Wherein m represents numeral 1 or 2,

R ^6aRepresent hydrogen or fluorine atom, C independently of one another _1-3-alkyl, hydroxyl, amino, C _1-3-alkylamino, two-(C _1-3-alkyl)-amino, aminocarboxyl, C _1-3-alkyl amino-carbonyl, two-(C _1-3-alkyl)-aminocarboxyl or C _1-3-alkyl-carbonyl-amino reaches

The group of following general formula

Wherein

M represents numeral 1 or 2,

X ¹Represent methylene radical ,-NR ^6b-, carbonyl or alkylsulfonyl,

X ²Represention oxygen atom or-NR ^6bGroup,

X ³Represent methylene radical, carbonyl or alkylsulfonyl,

X ⁴Represent oxygen or sulphur atom ,-NR ^6bOr carbonyl,

X ⁵Represent carbonyl or alkylsulfonyl,

X ⁸Represent carbonyl,

X ⁹Represent carbonyl,

R ²Represent hydrogen, fluorine, chlorine or bromine atom or C _1-3-alkyl,

R ³Represent C _2-3-thiazolinyl or C _2-3The C of-alkynyl or straight or branched _1-6-alkyl, wherein Wasserstoffatoms can be whole or in part replaced by fluorine atom, and randomly by nitrile, hydroxyl, wherein Wasserstoffatoms can be whole or in part by the substituted C of fluorine atom _1-5-alkoxyl group, allyloxy, alkynes propoxy-, benzyloxy, C _1-5-alkyl-carbonyl oxygen base, C _1-5-alkoxy-carbonyl oxy, carboxyl-C _1-3-alkoxyl group, C _1-5-alkoxy carbonyl-C _1-3-alkoxyl group, C _1-8-alkoxycarbonyl amino, sulfydryl, C _1-3-alkylthio, C _1-3-alkyl sulphinyl, C _1-3-alkyl sulphonyl, C _1-3-alkyl-carbonyl-amino-C _1-3-alkylthio, C _1-3-alkyl-carbonyl-amino-C _1-3-alkyl sulphinyl, C _1-3Alkyl-carbonyl-amino-C _1-3-alkyl sulphonyl, carboxyl, C _1-3-alkoxy carbonyl, allyloxy carbonyl, alkynes propoxycarbonyl, benzyloxycarbonyl, aminocarboxyl, C _1-3-alkyl amino-carbonyl, two-(C _1-3-alkyl)-aminocarboxyl, C _3-6-cycloalkylidene imino-carbonyl, amino-sulfonyl, C _1-3-alkyl amino sulfonyl, two-(C _1-3-alkyl)-amino-sulfonyl, C _3-6-cycloalkylidene imino-alkylsulfonyl, amino, C _1-3-alkylamino, two-(C _1-3-alkyl)-amino, C _1-5-alkyl-carbonyl-amino, C _1-3-alkyl sulfonyl-amino, N-(C _1-3-alkyl sulphonyl)-C _1-3-alkylamino, C _3-6-cycloalkyl amino carbonyl, amino carbonyl amino, C _1-3-alkyl amino-carbonyl is amino, two-(C _1-3-alkyl)-amino carbonyl amino, 4-to 7-member cycloalkylidene imino-carbonylamino, benzyloxycarbonyl are amino, phenylcarbonyl group is amino or guanidine radicals replaces,

R ⁴Represent Wasserstoffatoms or C _1-3-alkyl,

R ⁵Represent Wasserstoffatoms or C _1-3-alkyl,

B represents the group of following formula

Wherein

N represents numeral 1 or 2,

R ⁷Represent Wasserstoffatoms, C _1-3-alkyl, hydroxyl, C _1-5-alkoxy carbonyl, carboxyl-C _1-3-alkyl, C _1-3-alkoxy carbonyl-C _1-3-alkyl, amino or C _1-3-alkylamino reaches

R ⁸Represent hydrogen, fluorine, chlorine, bromine or iodine atom independently of one another, wherein Wasserstoffatoms can be whole or in part by the substituted C of fluorine atom _1-3-alkyl, C _2-3-thiazolinyl or C _2-3-alkynyl, hydroxyl, C _1-3-alkoxyl group, trifluoromethoxy, amino, nitro or nitrile group,

And except as otherwise noted; The term of in the preamble definition, being mentioned " heteroaryl " means and is selected from following monocycle 5-or 6-person's heteroaryl: pyridyl, N-oxo-pyridyl, pyrazolyl, pyridazinyl, pyrimidyl, pyrazinyl, [1; 2,3] triazinyl, [1,3; 5] triazinyl, [1; 2,4] triazinyl, pyrryl, imidazolyl, [1,2; 4] triazolyl, [1; 2,3] triazolyl, tetrazyl, furyl, different

azoles base,

azoles base, [1,2; 3]

di azoly, [1; 2,4]

di azoly, furazan base, thienyl, thiazolyl, isothiazolyl, [1,2; 3] thiadiazolyl group, [1; 2,4] thiadiazolyl group or [1,2; 5] thiadiazolyl group

And tautomer, enantiomer and salt.

3. according to the substituted carboxylic acid amide of the general formula I of claim 1, wherein

A represents the group of following general formula

Wherein m represents numeral 1 or 2,

R ^6aRepresent hydrogen or fluorine atom, C independently of one another _1-3-alkyl, hydroxyl, amino, C _1-3-alkylamino, two-(C _1-3Alkyl)-amino, aminocarboxyl, C _1-3-alkyl amino-carbonyl, two-(C _1-3-alkyl)-aminocarboxyl or C _1-3-alkyl-carbonyl-amino, and

The group of following general formula

Wherein

M represents numeral 1 or 2,

X ¹Represent methylene radical ,-NR ^6b-, carbonyl or alkylsulfonyl,

X ²Represention oxygen atom or-NR ^6bGroup,

X ³Represent methylene radical, carbonyl or alkylsulfonyl,

X ⁴Represent oxygen or sulphur atom or-NR ^6bGroup,

X ⁵Represent carbonyl or alkylsulfonyl,

R ¹Represent fluorine, chlorine or bromine atom, wherein Wasserstoffatoms can be whole or in part by the substituted C of fluorine atom _1-3-alkyl, nitro, C _1-3-alkoxyl group, list-, two-or trifluoromethoxy,

R ²Represent Wasserstoffatoms,

R ³Represent the C of straight or branched _1-6-alkyl, wherein Wasserstoffatoms can be whole or in part replaced by fluorine atom, and randomly by nitrile, hydroxyl, benzyloxy, wherein Wasserstoffatoms can be whole or in part by the substituted C of fluorine atom _1-5-alkoxyl group, allyloxy, C _1-5-alkyl-carbonyl oxygen base, C _1-5-alkoxy-carbonyl oxy, carboxyl-C _1-3-alkoxyl group, C _1-5-alkoxy carbonyl-C _1-3-alkoxyl group, C _1-8-alkoxycarbonyl amino, C _1-3-alkylthio, C _1-3-alkyl sulphonyl, carboxyl, C _1-3Alkoxy carbonyl, C _1-3-alkyl amino-carbonyl, two-(C _1-3-alkyl)-aminocarboxyl, C _3-6-cycloalkylidene imino-carbonyl, amino carbonyl amino, C _1-3Amino or the two-(C of-alkyl amino-carbonyl _1-3-alkyl)-the amino carbonyl amino replacement,

3-to 7-member naphthenic base, wherein the methylene radical in circular part can be by randomly by C _1-3-alkyl or C _1-3-alkyl-carbonyl is substituted-NH group replacement or by the Sauerstoffatom replacement,

R ⁴Represent Wasserstoffatoms,

R ⁵Represent Wasserstoffatoms,

B represents the group of following formula

Wherein

N represents numeral 1,

R ⁷Represent Wasserstoffatoms to reach

azoles base,

azoles base, [1,2; 3] di azoly, [1; 2,4]

And tautomer, enantiomer and salt.

4. according to the substituted carboxylic acid amide of the general formula I of claim 3, wherein

A, R ¹, R ², R ⁴, R ⁵And B reaches according to definition in the claim 3

R ³Represent the C of straight or branched _1-6-alkyl, wherein Wasserstoffatoms can be whole or in part replaced by fluorine atom, and randomly by nitrile, hydroxyl, benzyloxy, wherein Wasserstoffatoms can be whole or in part by the substituted C of fluorine atom _1-5-alkoxyl group, allyloxy, C _1-5-alkyl-carbonyl oxygen base, C _1-5-alkoxy-carbonyl oxy, carboxyl-C _1-3-alkoxyl group, C _1-5-alkoxy carbonyl-C _1-3-alkoxyl group, C _1-8-alkoxycarbonyl amino, C _1-3-alkylthio, C _1-3-alkyl sulphonyl, carboxyl, C _1-3-alkoxy carbonyl, C _1-3-alkyl amino-carbonyl, two-(C _1-3-alkyl)-aminocarboxyl, C _3-6-cycloalkylidene imino-carbonyl, amino carbonyl amino, C _1-3Amino or the two-(C of-alkyl amino-carbonyl _1-3-alkyl)-the amino carbonyl amino replacement,

And tautomer, enantiomer and salt.

5. according to the substituted carboxylic acid amide of the general formula I of claim 3, wherein

A, R ¹, R ², R ⁴, R ⁵According to definition in the claim 3, and

R ³Represent phenyl or heteroaryl, phenyl-C _1-3-alkyl or heteroaryl-C _1-3-alkyl, its randomly in phenyl or heteroaryl moieties by fluorine, chlorine or bromine atom, C _1-3-alkyl, amino, C _1-3-alkylamino, two-(C _1-3-alkyl)-amino, hydroxyl, C _1-4-alkoxyl group, list-, two-or trifluoromethoxy, carboxyl, C _1-3-alkoxy carbonyl list-or polysubstituted,

azoles base,

azoles base, [1,2; 3]

di azoly, [1; 2,4] di azoly, furazan base, thienyl, thiazolyl, isothiazolyl, [1,2; 3] thiadiazolyl group, [1; 2,4] thiadiazolyl group or [1,2; 5] thiadiazolyl group

And tautomer, enantiomer and salt.

6. according to the substituted carboxylic acid amide of the general formula I of claim 1, wherein

A represents the group of following general formula

Wherein m represents numeral 1 or 2,

R ^6bCan be Wasserstoffatoms or C _1-3-alkyl, its restricted condition does

The group of following general formula

Wherein

M represents numeral 1 or 2,

X ¹Represent methylene radical ,-NR ^6b-, carbonyl or alkylsulfonyl,

X ²Represention oxygen atom or-NR ^6bGroup,

X ³Represent methylene radical, carbonyl or alkylsulfonyl,

X ⁴Represent oxygen or sulphur atom or-NR ^6bGroup,

X ⁵Represent carbonyl or alkylsulfonyl,

R ²Represent Wasserstoffatoms,

R ³Represent the C of straight or branched _1-4-alkyl, wherein Wasserstoffatoms can be whole or in part replaced by fluorine atom, and randomly by hydroxyl, wherein Wasserstoffatoms can be whole or in part by the substituted C of fluorine atom _1-4-alkoxyl group, C _1-3-alkylthio, C _1-3-alkyl sulphonyl, carboxyl or C _1-3Alkoxy carbonyl replaces,

Phenyl or heteroaryl, phenyl-C _1-3-alkyl or heteroaryl-C _1-3-alkyl, its randomly in phenyl or heteroaryl moieties by fluorine, chlorine or bromine atom, C _1-3-alkyl, C _1-4-alkoxyl group, list-, two-or trifluoromethoxy, carboxyl or C _1-3-alkoxy carbonyl list-or polysubstituted,

R ⁴Represent Wasserstoffatoms,

R ⁵Represent Wasserstoffatoms, and

B represents the group of following formula

Wherein

N represents numeral 1,

R ⁷Represent Wasserstoffatoms to reach

R ⁸Represent chlorine or bromine atom or ethynyl,

azoles base,

azoles base, [1,2; 3]

di azoly, [1; 2,4]

And be contained in the alkyl that has in the above-mentioned definition more than two carbon atoms, except as otherwise noted, for straight or branched, and the alkyl in aforementioned dialkyl amido can be identical or different,

And tautomer, enantiomer and salt.

7. according to the substituted carboxylic acid amide of the general formula I of claim 6, wherein

A, R ¹, R ², R ⁴, R ⁵And B is according to defining in the claim 6, reaching

R ³Represent the C of straight or branched _1-4-alkyl, wherein Wasserstoffatoms can be whole or in part replaced by fluorine atom, and randomly by hydroxyl, wherein Wasserstoffatoms can be whole or in part by the substituted C of fluorine atom _1-4-alkoxyl group, C _1-3-alkylthio, C _1-3-alkyl sulphonyl, carboxyl or C _1-3-alkoxy carbonyl replaces,

And tautomer, enantiomer and salt.

8. according to the substituted carboxylic acid amide of the general formula I of claim 6, wherein

azoles base,

azoles base, [1,2; 3]

di azoly, [1; 2,4]

And tautomer, enantiomer and salt.

9. according to the substituted carboxylic acid amide of the general formula I of claim 1, wherein

A represents the group of following formula

Wherein m represents numeral 1 or 2,

R ²Represent Wasserstoffatoms,

Furyl, thienyl, pyrryl, pyrazolyl, imidazolyl,

Azoles base, different Azoles base, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridyl-C _1-2-alkyl or imidazolyl-C _1-2-alkyl, its randomly in heteroaryl moieties by one or two C _1-3-alkyl, C _1-3-alkoxyl group, carboxyl or C _1-3-alkoxy carbonyl replaces,

R ⁴Represent Wasserstoffatoms,

R ⁵Represent Wasserstoffatoms, and

B represents the group of following formula

Wherein

N represents numeral 1,

R ⁷Represent Wasserstoffatoms, and

R ⁸Represent chlorine or bromine atom or ethynyl,

azoles base,

azoles base, [1,2; 3] di azoly, [1; 2,4]

And tautomer, enantiomer and salt.

10. according to the substituted carboxylic acid amide of the general formula I of claim 9, wherein

A, R ¹, R ², R ⁴, R ⁵And B is according to defining in the claim 9, reaching

And tautomer, enantiomer and salt.

11. according to the substituted carboxylic acid amide of the general formula I of claim 9, wherein

R ³Represent furyl, thienyl, pyrryl, pyrazolyl, imidazolyl,

Azoles base, different

Azoles base, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridyl-C _1-2-alkyl or imidazolyl-C _1-2-alkyl, randomly wherein Wasserstoffatoms can be whole or in part by the substituted C of fluorine atom by one or two in heteroaryl moieties for it _1-3-alkyl, wherein Wasserstoffatoms can be whole or in part by the substituted C of fluorine atom _1-3-alkoxyl group, carboxyl or C _1-3-alkoxy carbonyl replaces, and

azoles base,

azoles base, [1,2; 3]

di azoly, [1; 2,4]

And tautomer, enantiomer and salt.

12. according to the substituted carboxylic acid amide of each general formula I in the claim 1 to 8, wherein radicals X ¹Represent methylene radical.

13. according to the substituted carboxylic acid amide of each general formula I in the claim 1 to 8, wherein radicals X ¹Represent carbonyl.

14. according to the substituted carboxylic acid amide of each general formula I in the claim 1 to 8, wherein radicals X ³Represent methylene radical.

15. according to the substituted carboxylic acid amide of the general formula I of claim 12, wherein radicals X ³Represent methylene radical.

16. according to the substituted carboxylic acid amide of the general formula I of claim 13, wherein radicals X ³Represent methylene radical.

17. according to the substituted carboxylic acid amide of each general formula I in the claim 1 to 8, wherein radicals X ³Represent carbonyl.

18. according to the substituted carboxylic acid amide of the general formula I of claim 12, wherein radicals X ³Represent carbonyl.

19. according to the substituted carboxylic acid amide of the general formula I of claim 13, wherein radicals X ³Represent carbonyl.

20. according to the substituted carboxylic acid amide of each general formula I in the claim 1 to 8, wherein radicals X ⁴Represention oxygen atom.

21. according to the substituted carboxylic acid amide of the general formula I of claim 12, wherein radicals X ⁴Represention oxygen atom.

22. according to the substituted carboxylic acid amide of the general formula I of claim 13, wherein radicals X ⁴Represention oxygen atom.

23. according to the substituted carboxylic acid amide of the general formula I of claim 14, wherein radicals X ⁴Represention oxygen atom.

24. according to the substituted carboxylic acid amide of the general formula I of claim 17, wherein radicals X ⁴Represention oxygen atom.

25. according to the substituted carboxylic acid amide of each general formula I in the claim 1 to 11, wherein group B is represented following groups

R wherein ⁷, R ⁸With n in the claim 1 to 11 each definition.

26. according to the substituted carboxylic acid amide of the general formula I of claim 12, wherein group B is represented following groups

R wherein ⁷, R ⁸With n in the claim 1 to 12 each definition.

27. according to the substituted carboxylic acid amide of the general formula I of claim 13, wherein group B is represented following groups

R wherein ⁷, R ⁸With n in the claim 1 to 13 each definition.

28. according to the substituted carboxylic acid amide of the general formula I of claim 14, wherein group B is represented following groups

R wherein ⁷, R ⁸With n in the claim 1 to 14 each definition.

29. according to the substituted carboxylic acid amide of the general formula I of claim 17, wherein group B is represented following groups

R wherein ⁷, R ⁸With n in the claim 1 to 17 each definition.

30. according to the substituted carboxylic acid amide of the general formula I of claim 20, wherein group B is represented following groups

R wherein ⁷, R ⁸With n in the claim 1 to 20 each definition.

31. according to the substituted carboxylic acid amide of each general formula I in the claim 1 to 11, wherein group B is represented following groups

R wherein ⁷, R ⁸With n in the claim 1 to 11 each definition.

32. according to the substituted carboxylic acid amide of the general formula I of claim 12, wherein group B is represented following groups

R wherein ⁷, R ⁸With n in the claim 1 to 12 each definition.

33. according to the substituted carboxylic acid amide of the general formula I of claim 13, wherein group B is represented following groups

R wherein ⁷, R ⁸With n in the claim 1 to 13 each definition.

34. according to the substituted carboxylic acid amide of the general formula I of claim 14, wherein group B is represented following groups

R wherein ⁷, R ⁸With n in the claim 1 to 14 each definition.

35. according to the substituted carboxylic acid amide of the general formula I of claim 17, wherein group B is represented following groups

R wherein ⁷, R ⁸With n in the claim 1 to 17 each definition.

36. according to the substituted carboxylic acid amide of the general formula I of claim 20, wherein group B is represented following groups

R wherein ⁷, R ⁸With n in the claim 1 to 20 each definition.

37. according to the substituted carboxylic acid amide of each general formula I in the claim 1 to 11, wherein group B is represented following groups

R wherein ⁸With n in the claim 1 to 11 each definition.

38. according to the substituted carboxylic acid amide of the general formula I of claim 12, wherein group B is represented following groups

R wherein ⁸With n in the claim 1 to 12 each definition.

39. according to the substituted carboxylic acid amide of the general formula I of claim 13, wherein group B is represented following groups

R wherein ⁸With n in the claim 1 to 13 each definition.

40. according to the substituted carboxylic acid amide of the general formula I of claim 14, wherein group B is represented following groups

R wherein ⁸With n in the claim 1 to 14 each definition.

41. according to the substituted carboxylic acid amide of the general formula I of claim 17, wherein group B is represented following groups

R wherein ⁸With n in the claim 1 to 17 each definition.

42. according to the substituted carboxylic acid amide of the general formula I of claim 20, wherein group B is represented following groups

R wherein ⁸With n in the claim 1 to 20 each definition.

43. according to the substituted carboxylic acid amide of each general formula I in the claim 1 to 11, wherein radicals R ⁸Represent the chlorine atom.

44. according to the substituted carboxylic acid amide of the general formula I of claim 12, wherein radicals R ⁸Represent the chlorine atom.

45. according to the substituted carboxylic acid amide of the general formula I of claim 13, wherein radicals R ⁸Represent the chlorine atom.

46. according to the substituted carboxylic acid amide of the general formula I of claim 14, wherein radicals R ⁸Represent the chlorine atom.

47. according to the substituted carboxylic acid amide of the general formula I of claim 17, wherein radicals R ⁸Represent the chlorine atom.

48. according to the substituted carboxylic acid amide of the general formula I of claim 20, wherein radicals R ⁸Represent the chlorine atom.

49. according to the substituted carboxylic acid amide of the general formula I of claim 25, wherein radicals R ⁸Represent the chlorine atom.

50. according to the substituted carboxylic acid amide of the general formula I of claim 31, wherein radicals R ⁸Represent the chlorine atom.

51. according to the substituted carboxylic acid amide of the general formula I of claim 37, wherein radicals R ⁸Represent the chlorine atom.

52. according to the substituted carboxylic acid amide of each general formula I in the claim 1 to 11, wherein radicals R ⁸Represent bromine atoms.

53. according to the substituted carboxylic acid amide of the general formula I of claim 12, wherein radicals R ⁸Represent bromine atoms.

54. according to the substituted carboxylic acid amide of the general formula I of claim 13, wherein radicals R ⁸Represent bromine atoms.

55. according to the substituted carboxylic acid amide of the general formula I of claim 14, wherein radicals R ⁸Represent bromine atoms.

56. according to the substituted carboxylic acid amide of the general formula I of claim 17, wherein radicals R ⁸Represent bromine atoms.

57. according to the substituted carboxylic acid amide of the general formula I of claim 20, wherein radicals R ⁸Represent bromine atoms.

58. according to the substituted carboxylic acid amide of the general formula I of claim 25, wherein radicals R ⁸Represent bromine atoms.

59. according to the substituted carboxylic acid amide of the general formula I of claim 31, wherein radicals R ⁸Represent bromine atoms.

60. according to the substituted carboxylic acid amide of the general formula I of claim 37, wherein radicals R ⁸Represent bromine atoms.

61. according to the substituted carboxylic acid amide of each general formula I in the claim 1 to 11, wherein radicals R ⁸Represent ethynyl.

62. according to the substituted carboxylic acid amide of the general formula I of claim 12, wherein radicals R ⁸Represent ethynyl.

63. according to the substituted carboxylic acid amide of the general formula I of claim 13, wherein radicals R ⁸Represent ethynyl.

64. according to the substituted carboxylic acid amide of the general formula I of claim 14, wherein radicals R ⁸Represent ethynyl.

65. according to the substituted carboxylic acid amide of the general formula I of claim 17, wherein radicals R ⁸Represent ethynyl.

66. according to the substituted carboxylic acid amide of the general formula I of claim 20, wherein radicals R ⁸Represent ethynyl.

67. according to the substituted carboxylic acid amide of the general formula I of claim 25, wherein radicals R ⁸Represent ethynyl.

68. according to the substituted carboxylic acid amide of the general formula I of claim 31, wherein radicals R ⁸Represent ethynyl.

69. according to the substituted carboxylic acid amide of the general formula I of claim 37, wherein radicals R ⁸Represent ethynyl.

70. according to the substituted carboxylic acid amide of each general formula I in the claim 1 to 11, it is equivalent to general formula I a

R wherein ¹, R ², R ³, R ⁴, R ⁵, A and B in the claim 1 to 11 each definition.

71. according to the substituted carboxylic acid amide of the general formula I of claim 12, it is equivalent to general formula I a

R wherein ¹, R ², R ³, R ⁴, R ⁵, A and B in the claim 1 to 12 each definition.

72. according to the substituted carboxylic acid amide of the general formula I of claim 13, it is equivalent to general formula I a

R wherein ¹, R ², R ³, R ⁴, R ⁵, A and B in the claim 1 to 13 each definition.

73. according to the substituted carboxylic acid amide of the general formula I of claim 14, it is equivalent to general formula I a

R wherein ¹, R ², R ³, R ⁴, R ⁵, A and B in the claim 1 to 14 each definition.

74. according to the substituted carboxylic acid amide of the general formula I of claim 17, it is equivalent to general formula I a

R wherein ¹, R ², R ³, R ⁴, R ⁵, A and B in the claim 1 to 17 each definition.

75. according to the substituted carboxylic acid amide of the general formula I of claim 20, it is equivalent to general formula I a

R wherein ¹, R ², R ³, R ⁴, R ⁵, A and B in the claim 1 to 20 each definition.

76. according to the substituted carboxylic acid amide of the general formula I of claim 25, it is equivalent to general formula I a

R wherein ¹, R ², R ³, R ⁴, R ⁵, A and B in the claim 1 to 25 each definition.

77. according to the substituted carboxylic acid amide of the general formula I of claim 31, it is equivalent to general formula I a

R wherein ¹, R ², R ³, R ⁴, R ⁵, A and B in the claim 1 to 31 each definition.

78. according to the substituted carboxylic acid amide of the general formula I of claim 37, it is equivalent to general formula I a

R wherein ¹, R ², R ³, R ⁴, R ⁵, A and B in the claim 1 to 37 each definition.

79. according to the substituted carboxylic acid amide of the general formula I of claim 43, it is equivalent to general formula I a

R wherein ¹, R ², R ³, R ⁴, R ⁵, A and B in the claim 1 to 43 each definition.

80. according to the substituted carboxylic acid amide of the general formula I of claim 52, it is equivalent to general formula I a

R wherein ¹, R ², R ³, R ⁴, R ⁵, A and B in the claim 1 to 52 each definition.

81. according to the substituted carboxylic acid amide of the general formula I of claim 61, it is equivalent to general formula I a

R wherein ¹, R ², R ³, R ⁴, R ⁵, A and B in the claim 1 to 61 each definition.

82. following compounds according to the general formula I of claim 1

(34) 3-bromo-N-[(1R)-1-(5-chloro-1H-benzimidazolyl-2 radicals-yl)-2-methoxyl group-ethyl]-4-(piperidines-2-ketone-1-yl)-BM, and

And tautomer, enantiomer and salt.

83. physiologically acceptable salt according to each compound in the claim 1 to 82.

84. pharmaceutical composition contains in the with good grounds claim 1 to 82 at least one compound or 3 physiologically acceptable salt according to Claim 8, randomly with one or more inert support and/or thinner.

85. according at least one the compound or the purposes of 3 physiologically acceptable salt according to Claim 8 in the claim 1 to 82, it is inhibited and/or relevant Tryase had inhibiting medicine to Xa factor to be used for preparation.

86. preparation is the method for 4 pharmaceutical composition according to Claim 8, it is characterized by with according in the claim 1 to 82 at least one compound or according to Claim 83 physiologically acceptable salt be mixed in one or more inert support and/or the thinner through method non-chemically.