CN101365693A

CN101365693A - Selected CGRP antagonists, methods for the production thereof and their use as medicaments

Info

Publication number: CN101365693A
Application number: CNA2006800317640A
Authority: CN
Inventors: 斯蒂芬·G·米勒; 克劳斯·鲁道夫; 菲利普·勒斯滕伯格; 格哈德·谢恩泽尔; 马科·桑塔戈斯蒂诺; 德克·斯滕坎普; 柯尔斯滕·阿恩特; 亨利·杜兹
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 2005-08-17
Filing date: 2006-08-15
Publication date: 2009-02-11
Also published as: ZA200711114B; UA90912C2

Abstract

The invention relates to the CGRP antagonists of general formula (I) in which R1, R2, R3 and R4 are defined as in claim 1, to their tautomers, isomers, diastereoisomers and enantiomers, hydrates, mixtures and their salts as well as the hydrates of the salts, particularly their physiologically compatible salts with inorganic or organic acids or bases, as well as to the compounds of general formula (I) in which one or more hydrogen atoms are exchanged for deuterium, to medicaments containing these compounds, the use thereof and to methods for the production thereof.

Description

The CGRP antagonist of selecting, its preparation method and as the purposes of medicine

The present invention relates to the CGRP antagonist of general formula I

R wherein ¹, R ², R ³And R ⁴All as the definition in the claim 1, its tautomer, isomer, diastereomer, enantiomer, hydrate, its mixture, and salt, and acceptable salt on the physiology that forms of the hydrate of this salt, particularly itself and inorganic or organic acid or alkali, and wherein one or more hydrogen atom by the compound of Formula I of deuterium exchange, the pharmaceutical composition that contains these compounds, its purposes and preparation method thereof.

Prior art

Being used for the treatment of migrainous CGRP antagonist has been described among international application PCT/EP97/04862 and the PCT/EP03/11762.

Detailed Description Of The Invention

In general formula I above, in first embodiment

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³Expression general formula I I group

Wherein

X represents N or C,

R ^3.1Expression H, C _1-3-alkyl or R ^3.1.1-O-C (O),

R ^3.1.1Expression H, C _1-6-alkyl, H ₂N-C _2-4-alkylidene group, (C _1-3-alkyl)-NH-C _2-4-alkylidene group, (C _1-3-alkyl) ₂N-C _2-4-alkylidene group, H ₂N-C (O)-C _1-3-alkylidene group, (C _1-3-alkyl)-NH-C (O)-C _1-3-alkylidene group, (C _1-3-alkyl) ₂N-C (O)-C _1-3-alkylidene group or R ^3.1.1.1-C _2-4-alkylidene group,

R ^3.1.1.1Expression is selected from following group,

With

If during X=N, R ^3.2Represent a pair of unbound electron, or

If during X=C, R ^3.2Expression H, C _1-3-alkyl or R ^3.2.1-O-C (O),

R ^3.2.1Expression H, C _1-6-alkyl, H ₂N-C _2-4-alkylidene group, (C _1-3-alkyl)-NH-C _2-4-alkylidene group, (C _1-3-alkyl) ₂N-C _2-4-alkylidene group, H ₂N-C (O)-C _1-3-alkylidene group, (C _1-3-alkyl)-NH-C (O)-C _1-3-alkylidene group, (C _1-3-alkyl) ₂N-C (O)-C _1-3-alkylidene group or R ^3.2.1.1-C _2-4-alkylidene group,

R ^3.2.1.1Expression is selected from following group,

With

R ⁴Expression general formula III group

Wherein

Y represents C, and

R ^4.1Expression H or C _1-3-alkyl, or

Y represents N, and

R ^4.1Represent a pair of unbound electron,

Condition is, X and Y do not represent N simultaneously,

R ^4.2Expression H, C _1-3-alkyl or R ^4.2.1-O-C (O),

R ^4.2.1Expression H, C _1-6-alkyl, H ₂N-C _2-4-alkylidene group, (C _1-3-alkyl)-NH-C _2-4-alkylidene group, (C _1-3-alkyl) ₂N-C _2-4-alkylidene group, H ₂N-C (O)-C _1-3-alkylidene group, (C _1-3-alkyl)-NH-C (O)-C _1-3-alkylidene group, (C _1-3-alkyl) ₂N-C (O)-C _1-3-alkylidene group or R ^4.2.1.1-C _2-4-alkylidene group,

R ^4.2.1.1Expression is selected from following group,

With

And

R ^4.3Expression H, C _1-6-alkyl, H ₂N-C _2-4-alkylidene group, (C _1-3-alkyl)-NH-C _2-4-alkylidene group, (C _1-3-alkyl) ₂N-C _2-4-alkylidene group, H ₂N-C (O)-C _1-3-alkylidene group, (C _1-3-alkyl)-NH-C (O)-C _1-3-alkylidene group, (C _1-3-alkyl) ₂N-C (O)-C _1-3-alkylidene group or R ^4.3.1-C _2-4-alkylidene group,

R ^4.3.1Expression is selected from following group,

With

R ^5.1Expression H, C _1-3-alkyl, R ^5.1.1-O-C (O), R ^5.1.1-O-C (O)-C _1-3-alkylidene group-NH, R ^5.1.1-O-C (O)-C _1-3-alkylidene group-N (C _1-3-alkyl), R ^5.1.1-O-C (O)-C _1-3-alkylidene group-O, R ^5.1.1-O-C (O)-C _1-3-alkylidene group, R ^5.1.1-O-C (O)-C (O), R ^5.1.1-O-C (O)-C (O)-O, R ^5.1.1-O-C (O)-C _1-3-alkylidene group-C (O) or R ^5.1.1-O-C (O)-C _1-3-alkylidene group-C (O)-O,

R ^5.1.1Expression H, C _1-8-alkyl, phenyl, indanyl, pyridyl-C _1-3-alkylidene group, HO-C _2-4-alkylidene group, C _1-6-alkyl-O-C _2-4-alkylidene group, H ₂N-C _2-4-alkylidene group, (C _1-6-alkyl)-NH-C _2-4-alkylidene group, (C _1-6-alkyl) ₂N-C _2-4-alkylidene group, H ₂N-C (O)-C _1-3-alkylidene group, (C _1-6-alkyl)-NH-C (O)-C _1-3-alkylidene group, (C _1-6-alkyl) ₂N-C (O)-C _1-3-alkylidene group, C _1-6-alkyl-C (O)-O-C _1-3-alkylidene group, C _1-6-alkyl-O-C (O)-O-C _1-3-alkylidene group, R ^5.1.1.1-C (O)-C _1-3-alkylidene group or R ^5.1.1.2-C _2-4-alkylidene group,

R ^5.1.1.1Expression is selected from following group,

R ^5.1.1.2Expression is selected from following group,

With

R ^5.2Expression H, C _1-3-alkyl, R ^5.2.1-O-C (O)-C _1-3-alkylidene group-NH, R ^5.2.1-O-C (O)-C _1-3-alkylidene group-O, R ^5.2.1-O-C (O)-C _1-3-alkylidene group, R ^5.2.1-O-C (O)-C (O) or R ^5.2.1-O-C (O)-C _1-3-alkylidene group-C (O),

R ^5.2.1Expression H, C _1-8-alkyl, phenyl, indanyl, pyridyl-C _1-3-alkylidene group, HO-C _2-4-alkylidene group, C _1-6-alkyl-O-C _2-4-alkylidene group, C _1-6-alkyl-O-C _2-4-alkylidene group-O-C _2-4-alkylidene group, H ₂N-C _2-4-alkylidene group, (C _1-6-alkyl)-NH-C _2-4-alkylidene group, (C _1-6-alkyl) ₂N-C _2-4-alkylidene group, H ₂N-C (O)-C _1-3-alkylidene group, (C _1-6-alkyl)-NH-C (O)-C _1-3-alkylidene group, (C _1-6-alkyl) ₂N-C (O)-C _1-3-alkylidene group, C _1-6-alkyl-C (O)-O-C _1-3-alkylidene group, C _1-6-alkyl-O-C (O)-O-C _1-3-alkylidene group, R ^5.2.1.1-C (O)-C _1-3-alkylidene group or R ^5.2.1.2-C _2-4-alkylidene group,

R ^5.2.1.1Expression is selected from following group,

With

R ^5.2.1.2Expression is selected from following group,

With

Perhaps

R ^5.2.1Expression following formula group

Condition is R ^3.1, R ^3.2, R ^4.2, R ^5.1Or R ^5.2In at least one group represent H or C _1-3Group beyond the-alkyl,

Its tautomer, diastereomer, enantiomer, hydrate, acceptable salt on the physiology that its mixture, and salt, and the hydrate of this salt, particularly itself and inorganic or organic acid or alkali form.

Preferred first embodiment of the present invention is a compound of Formula I above, wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³Expression general formula I I group

Wherein

X represents N or C,

R ^3.1Expression H, C _1-3-alkyl or HO-C (O),

If during X=N, R ^3.2Represent a pair of unbound electron, or

If during X=C, R ^3.2Expression H, C _1-3-alkyl or HO-C (O),

R ⁴Expression general formula III group

Wherein

Y represents C, and

R ^4.1Expression H or C _1-3-alkyl, or

Y represents N, and

R ^4.1Represent a pair of unbound electron,

Condition is, X and Y do not represent N simultaneously,

R ^4.2Expression H, C _1-3-alkyl or HO-C (O),

R ^5.1Expression H, C _1-3-alkyl, HO-C (O), HO-C (O)-C _1-3-alkylidene group-NH, HO-C (O)-C _1-3-alkylidene group-N (C _1-3-alkyl), HO-C (O)-C _1-3-alkylidene group-O, HO-C (O)-C _1-3-alkylidene group, HO-C (O)-C (O), HO-C (O)-C (O)-O, HO-C (O)-C _1-3-alkylidene group-C (O) or HO-C (O)-C _1-3-alkylidene group-C (O)-O,

R ^5.2Expression H, C _1-3-alkyl, HO-C (O)-C _1-3-alkylidene group-NH, HO-C (O)-C _1-3-alkylidene group-O, HO-C (O)-C _1-3-alkylidene group, HO-C (O)-C (O) or HO-C (O)-C _1-3-alkylidene group-C (O), condition is R ^3.1, R ^3.2, R ^4.2, R ^5.1Or R ^5.2In at least one group represent H or C _1-3Group beyond the-alkyl,

Second embodiment of the present invention is compound of Formula I above, wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³Expression general formula I I group

Wherein

X represents N or C,

R ^3.1Expression H, C _1-3-alkyl or R ^3.1.1-(O) C,

R ^3.1.1Expression HO, C _1-6-alkyl-O,

If during X=N, R ^3.2Represent a pair of unbound electron, or

If during X=C, R ^3.2Expression H or C _1-3-alkyl,

R ⁴Expression general formula III group

Perhaps

Wherein

Y represents C, and

R ^4.1Expression H or C _1-3-alkyl, or

Y represents N, and

R ^4.1Represent a pair of unbound electron,

Condition is, X and Y do not represent N simultaneously,

R ^4.2Expression H, C _1-3-alkyl or R ^4.2.1-(O) C,

R ^4.2.1Expression HO, C _1-6-alkyl-O, and

R ^4.3.1Expression is selected from following group,

With

R ^5.1Expression R ^5.1.1-O-C (O), R ^5.1.1-O-C (O)-C _1-3-alkylidene group-NH, R ^5.1.1-O-C (O)-C _1-3-alkylidene group-O, R ^5.1.1-O-C (O)-C _1-3-alkylidene group, R ^5.1.1-O-C (O)-C (O) or R ^5.1.1-O-C (O)-C _1-3-alkylidene group-C (O),

R ^5.1.1.1Expression is selected from following group,

R ^5.1.1.2Expression is selected from following group,

With

R ^5.2Expression R ^5.2.1-O-C (O)-C _1-3-alkylidene group-NH, R ^5.2.1-O-C (O)-C _1-3-alkylidene group-O, R ^5.2.1-O-C (O)-C _1-3-alkylidene group, R ^5.2.1-O-C (O)-C (O) or R ^5.2.1-O-C (O)-C _1-3-alkylidene group-C (O),

R ^5.2.1Expression H, C _1-8-alkyl, phenyl, indanyl, pyridyl-C _1-3-alkylidene group, HO-C _2-4-alkylidene group, C _1-6-alkyl-O-C _2-4-alkylidene group, H ₂N-C _2-4-alkylidene group, (C _1-6-alkyl)-NH-C _2-4-alkylidene group, (C _1-6-alkyl) ₂N-C _2-4-alkylidene group, H ₂N-C (O)-C _1-3-alkylidene group, (C _1-6-alkyl)-NH-C (O)-C _1-3-alkylidene group, (C _1-6-alkyl) ₂N-C (O)-C _1-3-alkylidene group, C _1-6-alkyl-C (O)-O-C _1-3-alkylidene group, C _1-6-alkyl-O-C (O)-O-C _1-3-alkylidene group, R ^5.2.1.1-C (O)-C _1-3-alkylidene group or R ^5.2.1.2-C _2-4-alkylidene group,

R ^5.2.1.1Expression is selected from following group,

With

R ^5.2.1.2Expression is selected from following group,

With

Preferred second embodiment of the present invention is compound of Formula I above, wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³Expression general formula I I group

Wherein

X represents N or C,

R ^3.1Expression H, C _1-3-alkyl or HO-C (O),

If during X=N, R ^3.2Represent a pair of unbound electron, or

If during X=C, R ^3.2Expression H or C _1-3-alkyl,

R ⁴Expression general formula III group

Perhaps

Wherein

Y represents C, and

R ^4.1Expression H or C _1-3-alkyl, or

Y represents N, and

R ^4.1Represent a pair of unbound electron,

Condition is, X and Y do not represent N simultaneously,

R ^4.2Expression H, C _1-3-alkyl or HO-C (O),

R ^5.1Expression HO-C (O), HO-C (O)-C _1-3-alkylidene group-NH, HO-C (O)-C _1-3-alkylidene group-O, HO-C (O)-C _1-3-alkylidene group, HO-C (O)-C (O) or HO-C (O)-C _1-3-alkylidene group-C (O),

R ^5.2Expression HO-C (O)-C _1-3-alkylidene group-NH, HO-C (O)-C _1-3-alkylidene group-O, HO-C (O)-C _1-3-alkylidene group, HO-C (O)-C (O) or HO-C (O)-C _1-3-alkylidene group-C (O),

The 3rd embodiment of the present invention is compound of Formula I above, wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³-R ⁴Represent general formula I V group together

Wherein

R ^3.1Expression H, H ₃C or R ^3.1.1-O-C (O),

R ^3.1.1Expression H, C _1-6-alkyl, (C _1-3-alkyl) ₂N-C _2-4-alkylidene group, (C _1-3-alkyl) ₂N-C (O)-C _1-3-alkylidene group or R ^3.1.1.1-C _2-4-alkylidene group,

R ^3.1.1.1Expression is selected from following group,

With

R ^3.2Expression H, C _1-3-alkyl or R ^3.2.1-O-C (O),

R ^3.2.1Expression H, C _1-6-alkyl, (C _1-3-alkyl) ₂N-C _2-4-alkylidene group, (C _1-3-alkyl) ₂N-C (O)-C _1-3-alkylidene group or R ^3.2.1.1-C _2-4-alkylidene group,

R ^3.2.1.1Expression is selected from following group,

With

R ^4.1Expression H or C _1-3-alkyl,

R ^4.2Expression H, C _1-3-alkyl or R ^4.2.1-O-C (O),

R ^4.2.1Expression H, C _1-6-alkyl, (C _1-3-alkyl) ₂N-C _2-4-alkylidene group, (C _1-3-alkyl) ₂N-C (O)-C _1-3-alkylidene group or R ^4.2.1.1-C _2-4-alkylidene group,

R ^4.2.1.1Expression is selected from following group,

With

R ^4.3.1Expression is selected from following group,

With

R ^5.1Expression H, H ₃C, R ^5.1.1-O-C (O), R ^5.1.1-O-C (O)-C _1-3-alkylidene group-NH, R ^5.1.1-O-C (O)-C _1-3-alkylidene group-N (C _1-3-alkyl), R ^5.1.1-O-C (O)-C _1-3-alkylidene group-O, R ^5.1.1-O-C (O)-C _1-3-alkylidene group, R ^5.1.1-O-C (O)-C (O), R ^5.1.1-O-C (O)-C (O)-O, R ^5.1.1-O-C (O)-C _1-3-alkylidene group-C (O) or R ^5.1.1-O-C (O)-C _1-3-alkylidene group-C (O)-O,

R ^5.1.1.1Expression is selected from following group,

R ^5.1.1.2Expression is selected from following group,

With

R ^5.2Expression H, H ₃C, R ^5.2.1-O-C (O)-C _1-3-alkylidene group-NH, R ^5.2.1-O-C (O)-C _1-3-alkylidene group-O, R ^5.2.1-O-C (O)-C _1-3-alkylidene group, R ^5.2.1-O-C (O)-C (O) or

R ^5.2.1-O-C (O)-C _1-3-alkylidene group-C (O),

R ^5.2.1.1Expression is selected from following group,

With

R ^5.2.1.2Expression is selected from following group,

With

Perhaps

R ^5.2.1Expression following formula group,

Condition is at least one radicals R ^3.1, R ^3.2, R ^4.2, R ^5.1Or R ^5.2Expression H or C _1-3Group beyond the-alkyl,

Preferred the 3rd embodiment of the present invention is compound of Formula I above, wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³-R ⁴Represent general formula I V group together

Wherein

R ^3.1Expression H, H ₃C or HO-C (O),

R ^3.2Expression H, C _1-3-alkyl or HO-C (O),

R ^4.1Expression H or C _1-3-alkyl,

R ^4.2Expression H, C _1-3-alkyl or HO-C (O),

R ^5.1Expression H, H ₃C, HO-C (O), HO-C (O)-C _1-3-alkylidene group-NH, HO-C (O)-C _1-3-alkylidene group-N (C _1-3-alkyl), HO-C (O)-C _1-3-alkylidene group-O, HO-C (O)-C _1-3-alkylidene group, HO-C (O)-C (O)-O, HO-C (O)-C (O)-O-, HO-C (O)-C _1-3-alkylidene group-C (O) or HO-C (O)-C _1-3-alkylidene group-C (O)-O,

R ^5.2Expression H, H ₃C, HO-C (O)-C _1-3-alkylidene group-NH, HO-C (O)-C _1-3-alkylidene group-O, HO-C (O)-C _1-3-alkylidene group, HO-C (O)-C (O) or HO-C (O)-C _1-3-alkylidene group-C (O),

Condition is R ^3.1, R ^3.2, R ^4.2, R ^5.1Or R ^5.2In at least one group represent H, H ₃C or C _1-3Group beyond the-alkyl,

The 4th embodiment of the present invention is compound of Formula I above, wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³-R ⁴Represent general formula I V group together

Wherein

R ^3.1Expression H,

R ^3.2Expression H or C _1-3-alkyl,

R ^4.1Expression H or C _1-3-alkyl,

R ^4.2Expression H,

R ^4.3.1Expression is selected from following group,

With

R ^5.1.1.1Expression is selected from following group,

R ^5.1.1.2Expression is selected from following group,

With

R ^5.2.1.1Expression is selected from following group,

With

R ^5.2.1.2Expression is selected from following group,

With

Preferred the 4th embodiment of the present invention is a compound of Formula I above, wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³-R ⁴Represent general formula I V group together

Wherein

R ^3.1Expression H,

R ^3.2Expression H or C _1-3-alkyl,

R ^4.1Expression H or C _1-3-alkyl,

R ^4.2Expression H,

R ^5.2Expression H-O-C (O)-C _1-3-alkylidene group-NH, HO-C (O)-C _1-3-alkylidene group-O, HO-C (O)-C _1-3-alkylidene group, HO-C (O)-C (O) or HO-C (O)-C _1-3-alkylidene group-C (O),

The 5th embodiment of the present invention is compound of Formula I above, wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³-R ⁴Represent general formula I V group together

Wherein

R ^3.1Expression H or R ^3.1.1-O-C (O),

R ^3.1.1.1The expression group

R ^3.2Expression H, H ₃C or R ^3.2.1-O-C (O),

R ^3.2.1.1The expression group

R ^4.2Expression H or H ₃C,

R ^4.3Expression H, C _1-6-alkyl, (C _1-3-alkyl) ₂N-C _2-4-alkylidene group, (C _1-3-alkyl) ₂N-C (O)-C _1-3-alkylidene group or R ^4.3.1-C _2-4-alkylidene group,

R ^4.3.1Expression is selected from following group,

With

R ^5.1Expression H, H ₃C, R ^5.1.1-O-C (O), R ^5.1.1-O-C (O)-C _1-3-alkylidene group-NH, R ^5.1.1-O-C (O)-C _1-3-alkylidene group-N (C _1-3-alkyl), R ^5.1.1-O-C (O)-C _1-3-alkylidene group-O, R ^5.1.1-O-C (O)-C _1-3-alkylidene group, R ^5.1.1-O-C (O)-C (O), R ^5.1.1-O-C (O)-C (O)-O-, R ^5.1.1-O-C (O)-C _1-3-alkylidene group-C (O) or R ^5.1.1-O-C (O)-C _1-3-alkylidene group-C (O)-O,

R ^5.1.1Expression H, C _1-8-alkyl, phenyl, indanyl, pyridyl-CH ₂, HO-C _2-4-alkylidene group, C _1-6-alkyl-O-C _2-4-alkylidene group, H ₂N-C _2-4-alkylidene group, (C _1-6-alkyl)-NH-C _2-4-alkylidene group, (C _1-6-alkyl) ₂N-C _2-4-alkylidene group, H ₂N-C (O)-C _1-3-alkylidene group, (C _1-6-alkyl)-NH-C (O)-C _1-3-alkylidene group, (C _1-6-alkyl) ₂N-C (O)-C _1-3-alkylidene group, C _1-6-alkyl-C (O)-O-C _1-3-alkylidene group, C _1-6-alkyl-O-C (O)-O-C _1-3-alkylidene group, R ^5.1.1.1-C (O)-C _1-3-alkylidene group or R ^5.1.1.2-C _2-4-alkylidene group,

R ^5.1.1.1Expression is selected from following group,

R ^5.1.1.2Expression is selected from following group,

With

R ^5.2Expression H, H ₃C, R ^5.2.1-O-C (O)-C _1-3-alkylidene group, R ^5.2.1-O-C (O)-C (O) or R ^5.2.1-O-C (O)-C _1-3-alkylidene group-C (O),

R ^5.2.1Expression H, C _1-8-alkyl, phenyl, indanyl, pyridyl-CH ₂, HO-C _2-4-alkylidene group, C _1-6-alkyl-O-C _2-4-alkylidene group, C _1-6-alkyl-O-C _2-4-alkylidene group-O-C _2-4-alkylidene group, H ₂N-C _2-4-alkylidene group, (C _1-6-alkyl)-NH-C _2-4-alkylidene group, (C _1-6-alkyl) ₂N-C _2-4-alkylidene group, H ₂N-C (O)-C _1-3-alkylidene group, (C _1-6-alkyl)-NH-C (O)-C _1-3-alkylidene group, (C _1-6-alkyl) ₂N-C (O)-C _1-3-alkylidene group, C _1-6-alkyl-C (O)-O-C _1-3-alkylidene group, C _1-6-alkyl-O-C (O)-O-C _1-3-alkylidene group, R ^5.2.1.1-C (O)-C _1-3-alkylidene group or R ^5.2.1.2-C _2-4-alkylidene group,

R ^5.2.1.1Expression is selected from following group,

R ^5.2.1.2Expression is selected from following group,

With

Perhaps

R ^5.2.1Expression following formula group

Preferred the 5th embodiment of the present invention is compound of Formula I above, wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³-R ⁴Represent general formula I V group together

Wherein

R ^3.1Expression H or HO-C (O),

R ^3.2Expression H, H ₃C or HO-C (O),

R ^4.2Expression H or H ₃C,

R ^5.1Expression HO-C (O), HO-C (O)-C _1-3-alkylidene group-NH, HO-C (O)-C _1-3-alkylidene group-N (C _1-3-alkyl), HO-C (O)-C _1-3-alkylidene group-O, HO-C (O)-C _1-3-alkylidene group, HO-C (O)-C (O), HO-C (O)-C (O)-O, HO-C (O)-C _1-3-alkylidene group-C (O) or HO-C (O)-C _1-3-alkylidene group-C (O)-O,

R ^5.2Expression HO-C (O)-C _1-3-alkylidene group, HO-C (O)-C (O) or HO-C (O)-C _1-3-alkylidene group-C (O),

The 6th embodiment of the present invention is compound of Formula I above, wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³-R ⁴Represent general formula I V group together

Wherein

R ^4.3.1Expression is selected from following group,

With

R ^5.1.1.1Expression is selected from following group,

R ^5.1.1.2Expression is selected from following group,

With

R ^5.2Expression R ^5.2.1-O-C (O)-C _1-3-alkylidene group, R ^5.2.1-O-C (O)-C (O) or R ^5.2.1-O-C (O)-C _1-3-alkylidene group-C (O),

R ^5.2.1Expression H, C _1-8-alkyl, phenyl, indanyl, pyridyl-CH ₂, HO-C _2-4-alkylidene group, C _1-6-alkyl-O-C _2-4-alkylidene group, H ₂N-C _2-4-alkylidene group, (C _1-6-alkyl)-NH-C _2-4-alkylidene group, (C _1-6-alkyl) ₂N-C _2-4-alkylidene group, H ₂N-C (O)-C _1-3-alkylidene group, (C _1-6-alkyl)-NH-C (O)-C _1-3-alkylidene group, (C _1-6-alkyl) ₂N-C (O)-C _1-3-alkylidene group, C _1-6-alkyl-C (O)-O-C _1-3-alkylidene group, C _1-6-alkyl-O-C (O)-O-C _1-3-alkylidene group, R ^5.2.1.1-C (O)-C _1-3-alkylidene group or R ^5.2.1.2-C _2-4-alkylidene group,

R ^5.2.1.1Expression is selected from following group,

R ^5.2.1.2Expression is selected from following group,

With

Preferred the 6th embodiment of the present invention is compound of Formula I above, wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³-R ⁴Represent general formula I V group together

The 7th embodiment of the present invention is compound of Formula I above, wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³-R ⁴Represent general formula I V group together

Also point out the above example of the most preferred compound of general formula I of following compounds conduct:

Used term and definition

Unless otherwise prescribed, otherwise all substituting groups are independently of one another.For example, if a group has a plurality of C _1-6-alkyl has three C as substituting group _1-6Under the situation of-alkyl substituent, each substituting group is independently of one another, but on behalf of n-propyl and one, a represent methylidene can represent the tertiary butyl for one.

In the scope of this specification sheets, in possible substituent definition, the form that these substituting groups also can structural formula is represented.If present, the asterisk in the substituent structural formula ( ^*) be interpreted as being connected to the tie point of molecule rest part.

Be also included within the theme of the present invention wherein one or more hydrogen atoms (for example, 1,2,3,4 or 5 hydrogen atom) by the deuterium alternate according to compound of the present invention, comprise its salt.

Term " C _1-3-alkyl " (also comprising its part as other group) refer to have the side chain and the straight chained alkyl of 1 to 3 carbon atom, term " C _1-6-alkyl " refer to have the side chain and the straight chained alkyl of 1 to 6 carbon atom, term " C _1-8-alkyl " refer to have the side chain and the straight chained alkyl of 1 to 8 carbon atom.Example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, hexyl, heptyl and octyl group.Also can be randomly with following simple pragmatic in above-mentioned group: Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu etc.Unless otherwise prescribed, this definition propyl group, butyl, amyl group, hexyl, heptyl and octyl group comprise all possible isomeric form of described group.Therefore, for example, propyl group comprises n-propyl and sec.-propyl, and butyl comprises isobutyl-, sec-butyl and the tertiary butyl etc.

Term " C _1-3-alkylidene group " (also be included as in other groups a part), be meant side chain and straight-chain alkyl-sub-, term " C with 1 to 3 carbon atom _2-4-alkylidene group " be meant to have

The side chain and the straight-chain alkyl-sub-of 2 to 4 carbon atoms.Example comprises: methylene radical, ethylidene, ethane-1,1-two bases, propylidene, propane-2,2-two bases, 1-methyl ethylidene, butylidene, 1-methyl propylidene, 1,1-dimethyl ethylidene, 1,2-dimethyl ethylidene.Unless address in addition, definition propylidene and butylidene comprise all possible isomeric form with same carbon number.Therefore, for example propylidene also comprises 1-methyl ethylidene, and butylidene comprises 1-methyl propylidene, 1,1-dimethyl ethylidene, 1,2-dimethyl ethylidene.

Also be to be noted that within the scope of the invention " alkylidene group " and " alkyl subunit " term are to use with the free burial ground for the destitute.

The compound of general formula I can have for example amido functional group of acidic-group (being mainly carboxyl) and/or basic group.Therefore the compound of general formula I can be used as inner salt, as with the Hydrogen bromide for example of available mineral acid pharmaceutically, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, tosic acid or organic acid be oxysuccinic acid for example, succsinic acid, acetate, fumaric acid, toxilic acid, amygdalic acid, lactic acid, tartrate, the formed salt of citric acid or as with the oxyhydroxide (for example sodium hydroxide or potassium hydroxide) of basic metal or alkaline-earth metal for example of available alkali pharmaceutically, or carbonate, ammoniacal liquor, zinc hydroxide or ammonium hydroxide or organic amine be diethylamine for example, triethylamine, thanomin, diethanolamine, trolamine, hexahydroaniline, the salt that dicyclohexyl amine forms.

The present invention relates to described compound, it is randomly with independent optical isomer, the separately mixture of enantiomer or the form of racemic modification, with the form of tautomer and with free alkali or with pharmacology on the form of the corresponding acid salt acid salt of haloid acid (for example hydrochloric acid or Hydrogen bromide) or organic acid (for example oxalic acid, fumaric acid, diethyl alkyd or methylsulfonic acid) (for example with) of acceptable acid.

The compounds of this invention can racemoid exists, if it has only a chiral element, then it also can be pure enantiomer, promptly obtains, preferably exists with racemoid or with (R)-form with (R)-or (S)-form.

But the application also comprise single diastereomer enantiomorph to or its mixture, when having more than a chiral element in the compound at general formula I, it exists above-mentioned situation and single optical activity enantiomorph, has the racemoid address thus.

Compound of the present invention is optional with independent optical isomer, the mixture of independent enantiomer or racemic object form, be tautomeric forms, and be free alkali form or with pharmacology on can accept acid respective acids additive salt-for example and halogen hydracid-as spirit of salt or Hydrogen bromide or organic acid, as the acid salt of oxalic acid, fumaric acid, diethyl alkyd or methanesulfonic.

The preparation method

Compound of Formula I is known method preparation on the principle.Following method has confirmed to be particularly useful for preparing the compound of the general formula I according to the present invention:

(a) in order to prepare compound of Formula I, wherein all groups all define as preamble: make general formula V carboxylic acid and the coupling of general formula VI amine

R among the formula V ¹With R ²All define as preamble,

H-R ³-R ⁴，

R wherein ³With R ⁴All as the preamble definition, binding is to pass through R ³Nitrogen-atoms carry out.

Before reacting, be present in formula H-R ³-R ⁴Any carboxylic-acid functional base, primary in the group of amine-or secondary amino group functional group or hydroxy functional group; can be protected by the protecting group of routine; and after reaction was carried out, employed protecting group can be carried out cracking again by the method that those of ordinary skill in the art is familiar with in case of necessity.

Coupling is preferably used by currently known methods in the chemistry of peptides and is undertaken (consulting, Houben-Weyl for example, Methoden der Organischen Chemie, the 15/2nd volume), for example use carbodiimide, for example dicyclohexylcarbodiimide (DCC), DIC (DIC) or ethyl-(3-dimethylamino-propyl)-carbodiimide, phosphofluoric acid O-(1H-benzotriazole-1-yl)-N, N-N ', N '-tetramethyl-urea (HBTU) or its a tetrafluoro borate (TBTU), or phosphofluoric acid 1H-benzotriazole-1-base-oxygen base-three-(dimethylamino)-Phosphonium (BOP).By interpolation I-hydroxybenzotriazole (HOBt) or 3-hydroxyl-4-oxo-3,4-dihydro-1,2,3-phentriazine (HOObt) can increase speed of response.Coupling is normally with the coupling composition and the coupling reagent of equimolar amount, in solvent, for example methylene dichloride, tetrahydrofuran (THF), acetonitrile, dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE (DMA), N-methyl tetrahydro pyrrolidine ketone (NMP) or its mixture, and in-30 ℃ and+carry out under the temperature between 30 ℃, be preferably-20 ℃ and+25 ℃ between.If necessary, preferably use N-ethyl-diisopropylamine (HunigShi alkali) as other auxiliary alkali.

Use so-called " acid anhydride method " as other other couling process, (can consult: M.Bodanszky, " Peptide Chemistry ", Springer-Verlag 1988, the 58-59 pages or leaves with synthetic compound of Formula I; M.Bodanszky, " Principles of Peptide Synthesis ", Springer-Verlag 1984, the 21-27 pages or leaves).Be preferably mixed anhydride method for making (J.R.Vaughan Jr.J.Amer.Chem.Soc.73 by the Vaughan variation method, 3547 (1951)), wherein use chlorine isobutyl carbonate butyl ester, obtain to want the general formula V carboxylic acid of coupling and the mixed anhydride of carbonic acid list isobutyl ester having in the presence of alkali such as 4-methylmorpholine or the 4-ethyl morpholine.The preparation of this mixed anhydride and with the coupling of general formula VI amine, be in single pot of method, use above-mentioned solvent, and in-20 ℃ with+temperature between 25 ℃ under carry out, be preferably 0 ℃ and+25 ℃.

(b) in order to prepare compound of Formula I, wherein all groups all define as preamble:

Make general formula VII compound

R wherein ¹With R ²All define as preamble; and Nu represents leaving group; halogen atom for example; chlorine for example; the bromine or iodine atom; the alkyl sulphonyl oxygen base that in moieties, has 1 to 10 carbon atom; phenyl sulfonyl oxygen base or naphthyl alkylsulfonyl oxygen base; it is optional by the chlorine or bromine atom; by methyl or nitro list-; two-or three replacements, wherein substituting group can be identical or different, 1H-imidazoles-1-base; choose wantonly in carbon skeleton by one or two methyl substituted 1H-pyrazol-1-yl; 1H-1,2, the 4-triazol-1-yl; 1H-1; 2; the 3-triazol-1-yl; 1H-1,2,3; 4-tetrazolium-1-base; vinyl; propargyl; right-nitrophenyl; 2; the 4-dinitrophenyl; trichlorophenyl; five chlorophenyl; pentafluorophenyl group; pyranyl or pyridyl; dimethylamino oxygen base (dimethylaminyloxy); 2 (1H)-oxo pyridine-1-base-oxygen base; 2,5-dioxo tetramethyleneimine-1-base oxygen base; phthalimide-based oxygen base; 1H-benzotriazole-1-base oxygen base or azido group is with the coupling of general formula VI amine

H-R ³-R ⁴，

Wherein all groups all define as preamble, and binding is through amine R ³Nitrogen-atoms carry out.

Before reacting; be present in any carboxylic-acid functional base, uncle or secondary amino group or hydroxyl in the group of general formula VI amine; can be protected by the protecting group of routine, and after reaction was carried out, the method that employed any protecting group can use those of ordinary skill in the art to be familiar with was carried out cracking again.

This reaction is to carry out under Schotten-Baumann or Einhorn condition, that is, each composition is existed down in the auxiliary alkali that has monovalent at least ,-50 ℃ with+120 ℃, preferably-10 ℃ and+temperature between 30 ℃ under, and choose wantonly in the presence of solvent and react.Used auxiliary alkali is preferably the oxyhydroxide of basic metal and alkaline-earth metal, sodium hydroxide for example, potassium hydroxide or hydrated barta, alkaline carbonate, yellow soda ash for example, salt of wormwood or cesium carbonate, alkali metal acetate, for example sodium acetate or potassium, and tertiary amine, pyridine for example, 2, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-diazabicyclo [2,2,2] octane or 1,8-diazabicyclo [5,4,0] 11-7-alkene, used solvent can be for example methylene dichloride, tetrahydrofuran (THF), 1, the 4-diox, acetonitrile, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-methyl-pyrrolidone or its mixture; If oxyhydroxide, alkaline carbonate or the alkali metal acetate of basic metal or alkaline-earth metal use as auxiliary alkali, then also water can be added in the reaction mixture as cosolvent.

Novel compound of Formula I according to the present invention contains one or more chiral centres.For example, if there are two chiral centres to exist, then compound can exist with two right forms of diastereo-isomerism of enantiomorph.The present invention includes independent isomer with and composition thereof.

Diastereomer can separate based on its different physical-chemical property, for example by the classified crystallization of appropriate solvent, through high pressure liquid chromatography or column chromatography, uses chirality, or is preferably the achirality stationary phase and carries out.

Can for example upward be separated by the racemoid that general formula I comprised through HPLC in suitable chiral stationary phase (for example chirality AGP, Chiralpak AD).The racemoid that contains alkalescence or acid functional groups also can separate through the diastereo-isomerism optically active salt; this salt be with optical activity acid; for example (+) or (-)-tartrate, (+) or (-)-diacetyl tartrate, (+) or (-)-tartrate mono-methyl or (+) or (-)-camphorsulfonic acid; or optical active alkali, for example or (S) with (R)-(+)-1-phenyl-ethyl amine, (S)-(-)-1-phenyl-ethyl amine-form during kind wooden huge legendary turtle alkali (brucine) reaction.

Ordinary method according to the separating isomerism body, be the racemoid that makes compound of Formula I,, in solvent, react with one of in the above-mentioned optical activity acid of equimolar amount or the alkali, and, utilize its different solubilities to separate with its resulting crystallinity diastereo-isomerism optically active salt.This reaction can be carried out in the solvent of any kind, as long as the solubleness of described salt is significantly different.Preferred methyl alcohol, ethanol or its mixture of using, for example its ratio is the 50:50 volume ratio.Then, make each optically active salt soluble in water, with alkali, for example yellow soda ash or salt of wormwood, or with suitable acid, for example with the dilute hydrochloric acid or the methanesulfonic aqueous solution, neutralization carefully, and obtain the compound of its corresponding free (+) or (-) form thus.

By only (R) or (S) enantiomer that general formula I comprised, or the mixture of two kinds of optical activity diastereo-isomerism compounds, also can be through above-mentioned synthetic and obtain to be (R) or (S) the appropriate reaction composition of configuration.

As the necessary general formula V of initial compounds hydroxycarboxylic acid, can be by making general formula VIII piperidines and general formula I X carbonic acid derivatives and obtaining with the reaction of general formula X compound

R among the formula VIII ¹As the preamble definition,

Y among the formula IX ¹With Y ²Expression nucleofugicity group, it can be identical or different, is preferably chlorine atom, right-nitro-phenoxy or trichlorine methoxyl group,

R among the formula X ²As the preamble definition, and Z ¹The protecting group of expression carboxyl, for example C _1-6Alkyl or optional substituted benzyl, wherein alkyl can be straight or branched, and benzyl can be replaced by one or two methoxyl group.

Z ¹Preferred expression methyl, ethyl, the tertiary butyl or benzyl.Before reacting, be present in the radicals R of formula (VI) compound ²In hydroxyl can be by the protecting group of routine protection, and after reaction was finished, employed protecting group can be carried out cracking again by the method that those skilled in the art were familiar with.

In a first step, make general formula VIII compound and general formula I X carbonic acid derivatives, in solvent, for example in methylene dichloride, THF, pyridine or its mixture, under the temperature between-20 ℃ to 50 ℃, at alkali, for example triethylamine, pyridine or ethyl diisopropyl amine react under existing.So the intermediate that forms can purified or further reaction, and need not purifying.The reaction of this intermediate and general formula X compound, also one of in mentioned solvent above in, and under above-mentioned specified temperature, for example carry out in the presence of triethylamine or the pyridine at alkali, add or do not add activating reagent, as the 4-Dimethylamino pyridine.For making its activation, the general formula X compound also can use metal hydride, as NaH or KH with deprotonation, yet, in this case, need not to exist alkali or activating reagent.

The initial compounds of formula VIII and IX or commercial getting known to document, maybe can be made by known method on the document.

A kind of approach that obtains the general formula X compound comprises making general formula X I aldehyde

(R wherein ²As the preamble definition), in diacetyl oxide, in the presence of alkali metal acetate, be preferably sodium acetate or potassium acetate as solvent, under proper temperature, preferably under 80 to 130 ℃, react with the N-acetyl-glycine.

The initial azalactones (azlactone) that forms is hydrolyzed to general formula X II compound without separation

R wherein ²Define as preamble.Exist down in the aqueous inorganic acid class,, but be preferably hydrochloric acid,, obtain general formula X III compound by further reaction as sulfuric acid, phosphoric acid or hydrochloric acid

R wherein ²Define as preamble.

Then, make it change into general formula X IV compound with suitable reductive agent

R wherein ²Define as preamble.

Suitable reductive agent is an alkali metal borohydride, as sodium borohydride or POTASSIUM BOROHYDRIDE.Other suitable reductive agents are the chloro Dialkylborane, as chloro dicyclohexyl borine.If use chirality chloro Dialkylborane, as B-chloro two different pinane pine base (pinocampheyl) borines, then general formula X IV compound can the enantiomeric pure isolated in form.The further reaction of general formula X IV compound is in the medium of alcohol to form the general formula X compound, is preferably in methyl alcohol or ethanol, carries out in the presence of suitable sour example hydrochloric acid.Alternatively, reaction can be preferably in the methyl alcohol in the solvent at alcohol, reacts with thionyl chloride.

All compound of Formula I that contain uncle or secondary amino group, hydroxyl or hydroxycarbonyl group functional group preferably can be obtained by the precursor with protecting group.The example of ammonia functional group protecting group comprises carbobenzoxy-(Cbz); 2-nitrobenzyl oxygen base carbonyl; 4-nitro-carbobenzoxy-(Cbz); 4-methoxyl group-carbobenzoxy-(Cbz); 2-chloro-carbobenzoxy-(Cbz); 3-chloro-carbobenzoxy-(Cbz); 4-chloro-carbobenzoxy-(Cbz); 4-xenyl-α; alpha-alpha-dimethyl-carbobenzoxy-(Cbz) or 3; 5-dimethoxy-α; alpha-alpha-dimethyl-carbobenzoxy-(Cbz); in moieties, has the carbalkoxy of 1 to 5 carbon atom altogether; methoxycarbonyl for example; ethoxycarbonyl; just-propoxycarbonyl; the different third oxygen carbonyl; just-butoxy carbonyl; 1-methyl-prop oxygen carbonyl; 2-methyl propoxy--carbonyl or tertbutyloxycarbonyl; allyloxy carbonyl; 2; 2; 2-three chloro-(1; 1-dimethyl oxyethyl group) carbonyl or 9-fluorenylmethyloxycarbonyl, or formyl radical; ethanoyl or trifluoroacetyl group.

The example of hydroxyl protecting group comprises trimethyl silyl, triethylsilyl, triisopropyl silyl, t-butyldimethylsilyl or t-butyldiphenylsilyl, the tertiary butyl, benzyl, 4-methoxy-benzyl or 3,4-dimethoxy-benzyl.

The example of hydroxycarbonyl group protecting group comprises having the alkyl of 1 to 5 carbon atom altogether, for example methyl, ethyl, just-propyl group, sec.-propyl, just-butyl, the tertiary butyl, allyl group, 2,2,2-three chloroethyls, benzyl or 4-methoxy-benzyl.

The compound of Formula I that is obtained if it contains suitable basic functional group, then can be converted into acceptable salt on the physiology of itself and inorganic or organic acid, particularly supplies medicinal use.Suitably acids for example comprises hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic, ethane sulfonic acid, Phenylsulfonic acid, right-toluenesulphonic acids, acetate, fumaric acid, succsinic acid, lactic acid, phenylglycollic acid, oxysuccinic acid, citric acid, tartrate or toxilic acid.

Moreover if it contains the carboxylic-acid functional base, then novel formula I compound can change into the additive salt of itself and inorganic or organic bases, particularly supplies medicinal use, changes into acceptable addition salt on its physiology.The alkali that this paper is suitable for comprises for example sodium hydroxide, potassium hydroxide, ammonia, hexahydroaniline, dicyclohexylamine, thanomin, diethanolamine and trolamine.

If compound of Formula I only has a chiral element, then the present invention relates to racemoid.But, the independent diastereo-isomerism that the application also comprises enantiomorph to or its mixture, if the chiral element of surpassing is arranged in compound of Formula I, then can exist above-mentioned diastereomer to and composition thereof, and indivedual optical activity enantiomers that constitute mentioned racemoid thus.

Be also contained in the theme of the present invention,, comprise its salt for compound according to the present invention, one or more hydrogen atom wherein, for example 1,2,3,4 or 5 hydrogen atom is by deuterium exchange.

Acceptable salt has valuable pharmacological character based on its selectivity CGRP-antagonist properties on novel compound of Formula I and the physiology thereof.The present invention is further about containing the medicine of this compound, its purposes and preparation thereof.

Acceptable salt on compounds referred to above and the physiology thereof has the CGRP-antagonist properties, and shows good affinity in the research of CGPR receptors bind.In the described hereinafter pharmacology test of these compounds system, show the CGRP-antagonist properties.

Carry out following experiment, to confirm avidity and the antagonist properties thereof of compound referred to above for human CGRP acceptor:

A. with the research that combines of SK-N-MC cell (expressing human CGRP acceptor)

The SK-N-MC cell is cultivated in " DulbeccoShi modification Eagle substratum ".From the culture that merges, remove substratum.Cell with PBS buffer reagent (Gibco 041-04190 M) washed twice, is dissolved with 0.02% EDTA blended PBS buffer reagent through adding, and by centrifugation.[BSS (representing with mM): NaCl 120, and KCl 5.4, NaHCO in 20 milliliters " balanced salt solutions " for resuspending ₃16.2, MgSO ₄0.8, NaHPO ₄1.0, CaCl ₂1.8 D-glucose 5.5, HEPES 30, pH 7.40] in after, make cell centrifugal twice under 100 * g, and resuspending is in BSS.After recording cell number, use Ultra-Turrax to make the cell homogenizing, and under 3000 * g centrifugal 10 minutes.Supernatant liquid is discarded, and make the precipitation grain contain Tutofusin tris (Tris) damping fluid (10mM Tris, 50mMNaCl, the 5mM MgCl of 1% bovine serum albumin and 0.1% bacitracin ₂, 1mM EDTA, pH 7.40) middle enrichment is centrifugal again, and resuspending (1 milliliter/1000000 cells).Make the homogenizing thing freezing down in-80 ℃.Cell membrane preparation is under this condition, and is stable above 6 weeks.

After thawing, with the homogenizing thing to detect damping fluid (50mM Tris, 150mM NaCl, 5mMMgCl ₂, 1mM EDTA, pH 7.40) and with the 1:10 dilution, and with Ultra-Turrax homogenizing 30 seconds.The homogenizing thing that makes 230 microlitres is under envrionment temperature, and with 50pM 125I-iodo tyrosyl-thyrocalcitonin-gene-related peptides (Amersham), and the test substance of the cumulative concentration in cumulative volume 250 microlitres was cultivated 180 minutes.Use cellular collector,, make to cultivate to stop by filtering fast with the GF/B-glass fibre filter that uses polymine (0.1%) to handle.Use gamma counter to measure bonded radioactivity on the protein.Non-specificity combination is to be defined as in the training period, back institute bonded radioactivity in the presence of the human CGRP-α of 1 μ M.

The concentration binding curve auxiliary non-linear curve fitting that uses a computer is analyzed.

In described test, compound exhibits IC referred to above ₅₀Value≤10000nM.

B. the CGRP antagonism in the SK-N-MC cell

SK-N-MC cell (100 ten thousand cells) is cultivated damping fluid (HEPES of Hanks, 1mM3-isobutyl--1-methyl xanthine, 1%BSA, pH7.4) washed twice and 37 ℃ of pre-down cultivations 15 minutes with 250 μ l.Adding conduct with cumulative concentration (10 ^-11To 10 ^-6Behind the CGRP of agonist M) (10 μ l) or other this material that adds with 3 to 4 kinds of different concns, this mixture was cultivated 15 minutes again.

Extract intracellular cAMP centrifugal then (2000 * g, went through 15 minutes by 4 ℃) by the 1M HCl that adds 20 μ l subsequently.Freezing supernatant liquor and storage under-20 ℃ in liquid nitrogen.

CAMP content in the sample is the pA by radioimmunoassay (Mess rs.Amersham) mensuration and antagonistic action material ₂Value is to be judged by graphic interpretation.

In described in vitro test model, compound of the present invention is 10 ^-12To 10 ^-5Show the CGRP-antagonist properties between the dosage range of M.

Indication

Because its pharmacological property, therefore according to compound of the present invention and with physiology on the salt of acceptable acid be applicable to acute and prophylactic treatment headache (especially, migraine, cluster headache and tension headache).In addition, compound according to the present invention also has active effect to following disease: non-insulin-dependent diabetes mellitus (NIDDM) (" NIDDM "), cardiovascular disorder, the morphine tolerance, the diarrhoea that causes by the clostridium toxin, (especially hot and radiation-induced skin injury comprises sunburn to dermatosis, lichen albus, pruigo, pruigo toxicodermatitis (pruritic toxidermies) and the serious stimulation of scratching where it itches), inflammatory diseases (for example, inflammatory diseases (the osteoarthritis in joint, rheumatoid arthritis, neurarthropathy), general soft tissue rheumatism (meat fiber pain), the nervosa inflammation of oral mucosa, the inflammatory lung disease, allergic rhinitis, asthma, COPD, along with excessive vasorelaxation and the blood supply that caused to tissue reduce and the disease that causes (for example, shock and Sepsis), chronic pain (for example, diabetic neuropathy), the neuropathy that causes because of chemotherapy, the neuropathy that HIV causes, neuropathy after the bleb, the neuropathy that causes because of tissue injury, trigeminal neuralgia, the temporomandibular joint dysfunction, CRPS (comprehensive regional pain), backache and viscera disease be irritable bowel syndrome (IBS) and inflammatory bowel for example.In addition, compound according to the present invention has general lenitive effect.Because of the blood flow of vasorelaxation and raising causes estrogen deficiency women's hot flush and the advantageously influence of using through the preventative and acute treatment of the CGRP of the application's case antagonist through the patients with prostate cancer and the castrating people of hormonotherapy, this therapeutic modality is different from hormone replacement owing to having no side effect.

Preferably be applicable to acute and prophylactic treatment migraine and cluster headache, be applicable to treatment irritable bowel syndrome (IBS) and be applicable to prevention and acute treatment estrogen deficiency women's hot flush according to The compounds of this invention.

When through intravenously or subcutaneous administration, reaching the required dosage of respective action is suitably 0.0001 to 3 milligram/kg body weight, is preferably 0.01 to 1 milligram/kg body weight, and be 0.01 to 10 milligram/kg body weight during when per os, intranasal or by inhalation, be preferably 0.1 to 10 milligram/kg body weight, in each situation, be all one day 1 to 3 time.

If to replenish conventional hormone replacement, then suggestion reduces above-mentioned specified dosage with the treatment of CGRP antagonist and/or CGRP release inhibitor, in this situation, dosage can be above-mentioned lower limit 1/5 until 1/1 of the specified upper limit.

CGRP is by being disengaged by sensory nerve, trigeminal nerve for example, and it is the part of innervation facial skin.Confirmed the stimulation of human gasserian ganglion, can cause increasing the CGRP plasma content, and cause face rubescent ([4]: people such as P.J.Goadsby, Annals of Neurology, the 23rd volume, the 2nd phase, 1988,193-196).

For confirming that hot flush can be successfully by helping the CGRP antagonist for treating of general formula I, it causes that through stimulating gasserian ganglion the increase of endogenous CGRP in the marmosets marmoset discharges, and causes increasing blood flow through skin heart.Validity is being feature by measuring given dose that intravenously is executed, and it can reduce the increase that causes because of endogenous CGRP and pass through blood flow of facial skin and reach 50%.The detailed description of this method is disclosed among European patent EP 1,207 884 B1.

According to CGRP antagonist of the present invention, also has activity in the visceral pain pattern in rodent.In this pattern, the supersensitivity of internal organ system is to use the instillation chemical substance, and for example butyrates, trinitro-benzene-sulfonic acid or acetate carry out through stimulating intestines.The supersensitivity of intestines is that the number of times that for example shrinks by belly is measured.This is to take place after the expansion of the balloon in introducing intestines, and increases (people such as Bourdu, Gastroenterology, 2005,128,1996-2008 in irritated intestines; People such as Diop, J.Phamacol.Exp.Ther.2002,302,1013-1022; People such as Plourde, Am.J.Physiol.1997,273, G191-G196).

Because of the supersensitivity of CGRP antagonist according to the present invention meeting reverse intestines in above-mentioned pattern, so it can be used for treating IBS (irritable bowel syndrome).

The invention further relates to The compounds of this invention as valuable adjuvant make and purifying (affinity chromatography) antibody and for example application of the tritiate (for example substituting halogen atom) by the precursor that is fit in RIA and ELISA detect after suitable radio-labeling with the catalytic hydrogenation of tritium or with tritium, and in neurotransmitter research as diagnosing or the analysis adjuvant.

Combination

The activated species that can be used for being used in combination comprises antiemetic, short gastrointestinal peristalsis agent (prokinetic), neuroplegic, antidepressive, neurokinin, spasmolytic, histamine-H1-receptor antagonist, beta blocker, α-agonist and alpha antagonist, Ergot alkaloids, gentle pain killer, non-steroid anti-inflammatory agent, reflunomide, calcium antagonist, 5-HT _1B/1DAgonist or other anti-migraine medicament, above-mentioned substance can with the carrier of one or more inertia routines and/or thinner (for example, with W-Gum, lactose, sucrose, Microcrystalline Cellulose, Magnesium Stearate, polyvinylpyrrolidone, citric acid, tartrate, water, water/ethanol, water/glycerine, water/Sorbitol Powder, water/polyoxyethylene glycol, propylene glycol, the hexadecyl Stearyl alcohol, carboxymethyl cellulose or fatty substance be the mixture that is fit to of solid fat or its for example) together allotment be processed into conventional Galenic formula (for example tablet or coated dose, capsule, pulvis, suspension, solution, aerosol or suppository through metering).

Therefore, other active substance that can be used in the aforesaid combination comprises (for example) non-steroid anti-inflammatory agent Aceclofenac, acemetacin, acetylsalicylic acid, ethanamide phenol (Paracetamol), azathioprine, diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, Ibuprofen BP/EP, indomethacin, Ketoprofen, leflunomide, lornoxicam, mefenamic acid, Naproxen Base, phenylbutazone, piroxicam, sulfasalazine, zomepirac or its pharmacologically acceptable salt and meloxicam and other selective COX-2 2-inhibitor, for example (for example) rofecoxib, valdecoxib, parecoxib, L-791456 and celecoxib, and suppress the material of the early stage or later stage of prostaglandin(PG) synthetic or prostaglandin receptor antagonist for example EP2-receptor antagonist and IP-receptor antagonist.

Also can use Ergotamine, dihydroergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, vigabatrin, timolol, isometheptene, Somigran, novain (botox), gabapentin, Pregabalin, duloxetine, topiramate, riboflavin (riboflavin), Singulair, lisinopril, telmisartan, promise peace life ingot (prochloroperazine), dexamethasone, flunarizine, Propoxyphene, Pethidine, metoprolol, Proprasylyte, nadolol, atenolol USP 23, clonidine, Indoramine, Carbamzepine, Phenytoin Sodium Salt, Sodium Valproate, amitriptyline (amitryptiline), imipramine, Venlafaxine, lignocaine or diltiazem

(and other 5-HT _1B/1D-agonist is almotriptan, avitriptan, Eletriptan, frovatriptan, naratriptan, Rizatriptan, sumatriptan and Zomitriptan for example.

In addition, can add CGRP-antagonist and following material: vanillin receptoroid antagonist is the VR-1 antagonist for example, glutamate receptor antagonists is the mGlu5-receptor antagonist for example, the mGlu1-receptor antagonist, the iGlu5-receptor antagonist, the AMPA-receptor antagonist, the purinoceptor blocker is the P2X3 antagonist for example, the NQ-synthetase inhibitors is the iNOS inhibitor for example, calcium ion channel blockor is PQ-type blocker for example, N-type blocker, potassium channel openers for example KCNQ passage is opened agent, Na-ion channel blocker is the PN3 channel blocker for example, the NMDA-receptor antagonist, the ionic channel antagonist of acid-sensitive sense is the ASIC3 antagonist for example, bradykinin receptor antagonists is the B1-receptor antagonist for example, the cannabinoid receptor agonist is the CB2 agonist for example, CB1 agonist, somatostatin receptor agonist be the sst2 receptor stimulant for example.

The dosage of these active substances be suitably minimum common recommended dose 1/5 to 1/1 of normal recommended dosage, refer to, for example 20 to 100mg sumatriptan.

Preparation

Compound prepared in accordance with the present invention can its separately or randomly with other be used for the treatment of migrainous active substance combination with approach in intravenously, subcutaneous, intramuscular, intraarticular, internal rectum, the nose, by suck, local, come administration through skin or per os, and aerosol formulation is particularly useful for sucking.Composition can while or administration in succession.

The form that is fit to administration maybe can suck powder or aerosol for for example tablet, capsule, solution, syrup, emulsion.Under various situations, the ratio of medicinal activity compound should account in the scope of 0.1 to 90 weight % of total composition, preferred 0.5 to 50 weight %, that is, and and to be enough to reach the amount of the dosage range of hereinafter mentioning.

Oral administration can tablet, the form of pulvis, the pulvis in capsule (for example, hard gelatine capsule) or give with solution or suspension.With inhalation the time, this active compound composition can be used as pulvis, water-based or water-based-ethanol solution or comes administration through the propellant gas preparation.

Therefore, preferred pharmaceutical preparation is characterised in that it contains one or more formula I compounds according to preferred embodiment mentioned above.

If the administration of formula I compound oral administration is then good especially, and if with once a day or twice administration also be particularly preferred.Corresponding tablet can (for example) by with active substance and known excipient (for example inert diluent for example lime carbonate, calcium phosphate or lactose), disintegrating agent for example W-Gum or alginic acid, tackiness agent for example starch or gelatin, lubricant for example the reagent that disengages of Magnesium Stearate or talcum powder and/or delay (for example carboxymethyl cellulose, ethyl phthalate Mierocrystalline cellulose or polyvinyl acetate mix and obtain.These tablets also can comprise multilayer.

Corresponding coating tablet can prepare by applying the nuclear that is similar to the tablet manufacturing with the material that generally is used for the tablet coating (but for example power ketone (collidone) or shellac, gum arabic, talcum powder, titanium dioxide or sugar).Postpone to discharge or the prevention uncompatibility for reaching, this nuclear also can be made up of multilayer.Similarly, can form by multilayer, can use the above-mentioned excipient that is used for tablet for reaching this tablet coating of delay release.

The syrup that contains this active substance or its composition according to the present invention can contain for example asccharin, cyclamate (cyclamate), glycerine or sugar and odorant (for example, for example vanillin food grade,1000.000000ine mesh or orange extract (orange extract) of perfume compound of sweeting agent in addition.It also can contain for example Xylo-Mucine, the wetting agent condensation product of Fatty Alcohol(C12-C14 and C12-C18) and oxyethane or sanitas p-Hydroxybenzoate for example for example of suspension adjuvant or thickening material in addition.

Contain the capsule of the composition of one or more active substances or active substance can (for example) by with this active substance and inert support lactose or Sorbitol Powder mixes and it is packaged in the gelatine capsule prepares for example.The suppository that is fit to can (for example) make by it is mixed with the carrier of being scheduled to (for example neutral fat or polyoxyethylene glycol or derivatives thereof).

Spendable excipient comprises (for example) water, for example paraffin is (for example for pharmaceutically acceptable organic solvent, petroleum cuts), vegetables oil (for example, peanut oil or sesame oil), unit alcohol or polyvalent alcohol are (for example, ethanol or glycerine), for example natural mineral powder is (for example for carrier, kaolin, clay, talcum powder, chalk), the synthetic mineral powder (for example, the silicic acid of high dispersing and silicate), sugar (for example, sucrose, lactose and glucose), emulsifying agent (for example, xylogen, sulfite waste lye, methylcellulose gum, starch and polyvinylpyrrolidone) and lubricant (for example, Magnesium Stearate, talcum powder, stearic acid and Sodium Lauryl Sulphate BP/USP).

For oral administration, these tablets can contain additive for example starch (being preferably potato starch), gelatin and the analogue thereof of Trisodium Citrate, lime carbonate and Lin Suanergai and various additive for example except the carrier of aforesaid regulation natch.In addition, when making tablet, can make with lubricator for example Magnesium Stearate, Sodium Lauryl Sulphate BP/USP and talcum powder.In the situation of waterborne suspension, active substance can mix with various odorants or tinting material except above-mentioned excipient.

If the compound of formula I is then same preferred by inhalation, if its be once a day or twice administration then good especially.For reaching this purpose, the compound of formula I must be made the formulation that can suck.But inhalant dosage form comprises can suck pulvis, contain propelling agent through the aerosol of metering or do not have the sucked solution of propelling agent, randomly it mixes with acceptable excipient on the physiology of routine.

Within the scope of the present invention, term the sucked solution that do not have a propelling agent also comprises spissated or aseptic the sucked solution that can use.The formulation that can use within the scope of the present invention will describe in detail in the next section of specification sheets.

Can suck pulvis

If formula I compound mixes with acceptable excipient on the physiology and exists, then can use on the following physiology acceptable excipient with preparation according to the powder that sucks of the present invention: single candy is (for example, glucose or pectinose), two candys (for example, lactose, sucrose, maltose), few candy and polysaccharide (for example, dextran), polyvalent alcohol (for example, Sorbitol Powder, mannitol, Xylitol), the mixture of salt (for example, sodium-chlor, lime carbonate) or these excipient.Preferred single candy or two candys of using wherein use the outstanding good use of lactose or glucose with its hydrate forms (but not exclusive).The particularly preferred use of the present invention, lactose, and lactose monohydrate is especially preferred.By milling and micronization and to mix the manufacturing method that sucks powder according to the present invention by this composition the most at last known in the prior art.

But the inhalation aerosol that contains propelling agent

The inhalation aerosol that contains propellant gas that can be used according to the invention can contain and is dissolved in the I that is discrete form in the propellant gas or therein.Can be used for preparing the propellant gas of inhalation aerosol by known in the state of the art.The propellant gas that is fit to is selected from hydro carbons, and for example n-propane, normal butane or Trimethylmethane and halogenated hydrocarbon for example are preferably the fluorinated derivatives of methane, ethane, propane, butane, pentamethylene or tetramethylene.Above-mentioned propellant gas can it use separately or use with its mixture.Preferred propellant gas is fluoridized the chain alkane derivatives for what be selected from TG134a (1,1,1, the 2-Tetrafluoroethane), TG227 (1,1,1,2,3,3, the 3-heptafluoro-propane) and composition thereof.The spendable inhalation aerosol that contains propellant gas of range of application also can contain other composition for example cosolvent, stablizer, tensio-active agent, antioxidant, lubricant and pH value conditioning agent according to the present invention.All these compositions are all known in the prior art.

The sucked solution of no propelling agent

Formula I application of compound of the present invention is preferred for preparing the sucked solution of no propelling agent and can sucking suspension.The solvent that is used for this purpose comprises water-based or alcohol, is preferably dealing with alcohol solution.This solvent can be independent water or be water and alcoholic acid mixture.Use suitable acid that the pH value of solution or suspension is adjusted to 2 to 7, is preferably 2 to 5.Can use and be selected from inorganic or the sour pH of the adjusting value of organic acid.Especially the representative examples of mineral pigments of Shi Heing comprises hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid and/or phosphoric acid.Especially the organic acid example of Shi Heing comprises xitix, citric acid, oxysuccinic acid, tartrate, toxilic acid, Succinic Acid, fumaric acid, acetate, formic acid and/or propionic acid etc.Preferred mineral acid is hydrochloric acid and sulfuric acid.Also may use the acid that forms acid salt with a kind of active substance.In organic acid, be preferably xitix, fumaric acid and citric acid.If need, then can use the mixture of above-mentioned acid, especially have other character except that its acidifying character (situation of) acid for example, as perfume compound, antioxidant or complexing agent, for example, citric acid or xitix.According to the present invention, You Jia uses hydrochloric acid to regulate the pH value.

The sucked solution that is used for no propelling agent of the present invention can add cosolvent and/or other excipient.Preferred cosolvent is the solvent that contains hydroxyl or other polar group, for example, and the Virahol of alcohols-especially, glycols-especially propylene glycol, polyoxyethylene glycol, polypropylene glycol, glycol ethers, glycerine, Volpo S 10 and polyoxyethylene fatty acid ester.Term excipient in this article and additive are interpreted as the acceptable material of medicine itself and inactive substance but can allocate character with the modified activity substance preparation in the solvent that pharmacology is fit to one or more active substances.Preferred this type of material does not have pharmacological effect or does not have or do not have at least a bad pharmacotoxicological effect to relevant treatment is noticeable.Excipient and additive comprise for example for example polysorbate, polyvinylpyrrolidone, other stablizer, complexing agent, assurance or prolong antioxidant and/or sanitas, perfume compound, VITAMIN and/or other additive well known in the prior art of staging life of the pharmaceutical preparation of finished product of soybean lecithin, oleic acid, sorbitan ester of (for example) tensio-active agent.These additives comprise that also acceptable salt on the pharmacology is for example as the sodium-chlor of isotonic agent.Preferred excipient comprises for example similar VITAMIN and the rovitamin that exist of xitix (for example, its restricted condition is not used for regulating the pH value for it), vitamin A, vitamin-E, tocopherol and human body of antioxidant.Can use sanitas to be used to protecting preparation to avoid the pollution of pathogenic agent.The sanitas that is fit to is well known in the prior art, especially cetylpyridinium chloride, benzalkonium chloride and phenylformic acid or the benzoate Sodium Benzoate of concentrated solution well known in the prior art for example.

Experimental section

Usually, obtained about made compound ¹H-NMR and mass spectrum.Unless address R in addition _fValue uses ready-made TLC silica-gel plate 60 F254 (E.Merck, Darmstadt, item number 1.05714) to record, and does not use chamber saturation.

With the measured R of title Polygram silica gel _fValue uses the ready-made Polygram SIL G/UV254 TLC film (applying with 0.2 millimeter silica gel) by Macherey-Nagel (Duren, item number 805 021) manufacturing to obtain.

With the measured Rf value of title Polygram Alox, use ready-made Polygram Alox N/UV254 TLC film (with 0.2 millimeter alumina coated) to obtain by Macherey-Nagel (Duren, item number 802 021) manufacturing.

For the ratio that eluent is given, relate to the ratio of the solvent volume unit that gives.To NH ₃The volume ratio unit that is given relates to NH ₃Strong solution in water.

Unless address in addition, be used for acid, alkali and the salts solution of processing reaction solution, be the aqueous system of giving concentration.

Silica gel (MATREX by the Millipore manufacturing ^TM, the 35-70 micron) and be to be used for chromatography purification.

The aluminum oxide of being made by ICN Biomedicals (Alox) (Eschwege, item number 02090) is to be used for chromatography purification.The needed active stage, (active Phase-III) was before using, and produces according to producer's specification sheets.

The HPLC data that provided are to measure under the parameter of listing in hereinafter:

Method A:

Analytical column: Merck Chromolith Speed ROD, RP18e; 4.6 * 50 millimeters; Column temperature: 30 ℃; Flow: 1.5 ml/min; Volume injected: 5 microlitres; Detect down in 254 millimicrons

Time [minute] volume ratio of the body acetonitrile (having 0.1% formic acid) of water (having 0.1% formic acid)

Long-pending per-cent per-cent

0 90 10

4.5 10 90

5 10 90

5.5 90 10

Method B:

Analytical column: Zorbax post (Agilent Technologies), SB (Stable Bond)-C18; 3.5 micron; 4.6 * 75 millimeters; Column temperature: 30 ℃; Flow: 1.6 ml/min; Volume injected: 5 microlitres; Detect down in 254 millimicrons

Long-pending per-cent per-cent

0 95 5

4.5 10 90

5.0 10 90

5.5 90 10

Method C:

Analytical column: Zorbax post (Agilent Technologies), SB (Stable Bond)-C18; 3.5 micron; 4.6 * 75 millimeters; Column temperature: 30 ℃; Flow: 0.8 ml/min; Volume injected: 5 microlitres; Detect down in 254 millimicrons

Time [minute] acetonitrile (having 0.1% formic acid) of water (having 0.1% formic acid)

The volume ratio per-cent of volume percent

0 95 5

9 10 90

10 10 90

11 90 10

In preparation property HPLC purifying, use usually with in order to obtain the identical gradient liquid of analysis HPLC data.

Product is to collect under mass spectrum control, and the wash-out that will contain product partly merges, and freeze-drying.

About any more multidata of configuration not in the presence of, be not understand whether relate to pure enantiomer, or part or even whole racemization do not occur.

Following abbreviation is used in the test explanation:

The Boc tertbutyloxycarbonyl

The Cyc hexanaphthene

The DCM methylene dichloride

The DIPE Di Iso Propyl Ether

DMF N, dinethylformamide

The EtOAc ethyl acetate

EtOH ethanol

H hour

HCl hydrochloric acid

HOAc acetate

I.vac. in a vacuum (under vacuum)

Min minute

MeOH methyl alcohol

MTBE methyl-tertbutyl ether

NaOH sodium hydroxide

The PE sherwood oil

The RT envrionment temperature

TBTU Tetrafluoroboric acid 2-(1H-benzotriazole-1-yl)-1,1,3, the 3-tetramethyl-urea

The TFA trifluoroacetic acid

The THF tetrahydrofuran (THF)

The preparation of initial compounds is to be described in down:

Amine 1

3-[4,4 '] connection piperidines-1-base-ethyl propionate

A1a) join piperidyl-1-carboxylic acid tert-butyl ester 1 '-(2-ethoxycarbonyl-ethyl)-[4,4 ']

4.4 milliliters of (40.6 mmole) ethyl propenoates are added in the solution of 10.0 gram (37.3 mmole) [4,4 '] connection piperidyl-1-carboxylic acid tert-butyl esters in 100 milliliters of EtOH, and made reaction mixture refluxed 2 hours.For finishing reaction, add 1 milliliter of (9.2 mmole) ethyl propenoate again, mixture was refluxed 1 hour, and at room temperature place and spend the night.Remove solvent in a vacuum, and crude product is further reacted, need not to make its purifying.

Output: 14.0 grams (theoretical value 100%)

ESI-MS：(M+H) ⁺＝369

A1b) 3-[4,4 '] connection piperidines-1-base-ethyl propionate

28 milliliters of TFA are dropped in the solution of crude product in 250 milliliters of DCM of 14.0 gram embodiment A 1a, and reaction mixture was at room temperature stirred 4 hours.The evaporate to dryness mixture is dissolved among 200 milliliters of DCM residue in a vacuum, and with this solution portion-wise addition to 20 gram Na ₂CO ₃In the solution in 120 ml waters.Isolate organic phase, with DCM extracting twice again, and the organic phase that makes merging is with Na with water ₂SO ₄Dry.After removing siccative and solvent, make residue dried, and react and need not to be further purified.

Output: 8.8 grams (theoretical value 88%)

ESI-MS：(M+H) ⁺＝269

Amine 2

3-(4-piperazine-1-base-piperidines-1-yl)-ethyl propionate

A2a) 3-[4-(4-benzyl-piperazine-1-yl)-piperidines-1-yl]-ethyl propionate

5.5 milliliters of (50.8 mmole) ethyl propenoates are added in 11.7 gram (44.9 mmole) 1-benzyl-solution of 4-piperidin-4-yl-piperazine in 120 milliliters of anhydrous EtOH, and made reaction mixture refluxed 1 hour, at room temperature stir then and spend the night.Remove solvent in a vacuum, and make residue under the oil pump vacuum dry 1 hour.Crude product is further reacted, need not purifying.

Output: 16.5 grams (theoretical value 99%)

ESI-MS：(M+H) ⁺＝360

A2b) 3-(4-piperazine-1-base-piperidines-1-yl)-ethyl propionate

Make the crude products of 16.5 gram embodiment A 2a restrain the suspension of 10%Pd/C in 200 milliliters of EtOH with 1.6, hydrogenation is 4 hours under 50 ℃ and 50psi hydrogen pressure.Remove catalyzer by suction filtration, make filtrate be concentrated into about 120 milliliters, and mix with the ethanolic soln (1.3M) of 72 milliliters of HCl.With formed throw out suction filtration, and dry in a vacuum.Obtain product, be two-hydrochloride.

Output: 12.6 grams (theoretical value 83%)

ESI-MS：(M+H) ⁺＝270

Amine 3

3-(4-piperidin-4-yl-piperazine-1-yl)-ethyl propionate

A3a) 3-[4-(1-benzyl-piperidines-1-yl)-piperazine-1-yl]-ethyl propionate

12.5 milliliters of (73.0 mmole) ethyl diisopropyl amines and 5.0 milliliters of (46.1 mmole) ethyl propenoates are added in the solution of 11.0 gram (33.2 mmole) 1-(1-benzyl-piperidin-4-yl)-piperazines (using with two-hydrochloride) in 40 milliliters of EtOH, and reaction mixture is heated to 90 ℃ (bathe temperature), went through 3 hours.After cooling, mix with water, mixture is thoroughly extracted with EtOAc, and the organic phase that makes merging is with Na ₂SO ₄Dry.Behind siccative and removal of solvents, make residue pass through chromatography (silica gel, DCM/EtOH/NH ₃100:10:1) purifying.

Output: 6.8 grams (theoretical value 56%)

ESI-MS：(M+H) ⁺＝360

R _f=0.64 (silica gel, DCM/MeOH/NH ₃90:9:1)

A3b) 3-(4-piperidin-4-yl-piperazine-1-yl)-ethyl propionate

Make 5.13 gram (14.3 mmole) 3-[4-(1-benzyl-piperidin-4-yl)-piperazine-1-yls]-ethyl propionate and 1.0 restrains the suspension of 10%Pd/C in 100 milliliters of EtOH, and hydrogenation is 2 hours under 50 ℃ and 50psi hydrogen pressure.Leach catalyzer, and evaporated filtrate is to doing.Oily product is further reacted, need not purifying.

Output: 3.6 grams (theoretical value 93%)

ESI-MS：(M+H) ⁺＝270

Amine 4

[4,4 '] connection piperidines-1-base-oxo-acetic acids ethyl ester

A4a) join piperidyl-1-carboxylic acid tert-butyl ester 1 '-oxyethyl group oxalyl group-[4,4 ']

1.68 milliliters of (15.0 mmole) chloro-oxo-acetic acids ethyl esters dropwise are added into 4.0 gram (14.9 mmoles) [4,4 '] triethylamine of connection piperidyl-1-carboxylic acid tert-butyl ester and 2.15 milliliters (15.4 mmoles) is in 80 milliliters of DCM, is cooled in 0 ℃ the solution.After interpolation has stopped, remove cooling bath, and mixture was at room temperature stirred 1 hour.Reaction mixture is mixed with water, isolate organic phase, and with Na ₂SO ₄Dry.Behind siccative and removal of solvents, residue is dissolved among the EtOAc, make solution through filtered through silica gel, and evaporate to dryness in a vacuum.

Output: 3.1 grams (theoretical value 57%)

ESI-MS：(M+H) ⁺＝386

A4b) [4,4 '] connection piperidines-1-base-oxo-acetic acids ethyl ester

5.0 milliliters of TFA are dropped in the solution of connection piperidyl-1-carboxylic acid tert-butyl ester 1 '-oxyethyl group oxalyl group-[4,4 '] in 40 milliliters of DCM of 3.1 grams (8.36 mmole), and reaction mixture was at room temperature stirred 4 hours.The evaporate to dryness mixture is dissolved among 50 milliliters of DCM residue in a vacuum, and with this solution portion-wise addition to 4.0 gram Na ₂CO ₃In the ice-cooled solution in 20 ml waters.Isolate organic phase, with DCM extracting twice again, and the organic phase that makes merging is with Na with water ₂SO ₄Dry.Behind siccative and removal of solvents, obtain product, be oil, make its further reaction, need not purifying.

Output: 2.3 grams (theoretical value 84%)

ESI-MS：(M+H) ⁺＝269

Amine 5

4-[4,4 '] connection piperidines-1-base-4-oxo-ethyl butyrate

A5a) join piperidyl-1-carboxylic acid tert-butyl ester 1 '-(3-carboxyl-propionyl)-[4,4 ']

With the solution of 4.1 gram (40.7 mmole) succinyl oxides in 50 milliliters of THF, at room temperature drop to 10.0 gram (37.3 mmoles) [4,4 '] in the connection solution of piperidyl-1-carboxylic acid tert-butyl ester in 100 milliliters of THF, and reaction mixture at room temperature stirred spend the night.For finishing reaction, add 2.0 gram (19.9 mmole) succinyl oxides again, mixture was stirred 4 hours down in 50 ℃, and at room temperature stir and spend the night.Add 200 milliliters of 7.5%K ₂CO ₃Solution, and with 200 milliliters of EtOAc washing waters.With 200 milliliters of 7.5%K ₂CO ₃The solution extraction organic phase, and make the aqueous phase as acidified of merging with citric acid.Mixture is thoroughly extracted with EtOAc, and the organic phase that merges of evaporate to dryness in a vacuum.

Output: 11.7 grams (theoretical value 85%)

ESI-MS：(M+H) ⁺＝369

A5b) 4-[4,4 '] connection piperidines-1-base-4-oxo-ethyl butyrate

The solution of connection piperidyl-1-carboxylic acid tert-butyl ester 1 '-(3-carboxyl-propionyl)-[4,4 '] in the ethanolic soln (1.25M) of 250 milliliters of HCl with 11.7 grams (31.7 mmole) at room temperature stirs and spends the night.Remove solvent in a vacuum, and obtain product, be hydrochloride, make its further reaction, need not purifying.

Output: 4.3 grams (theoretical value 46%)

ESI-MS：(M+H) ⁺＝297

Amine 6

([1,4 '] connection piperidin-4-yl-tertbutyloxycarbonyl-amino)-ethyl acetate

A6a) (connection piperidin-4-yl 1 '-benzyl-[1,4 '])-t-butyl carbamate

With 5.0 gram (25.0 mmole) piperidin-4-yl-t-butyl carbamate and the solution of 4.46 milliliters of (25.0 mmole) 1-benzyl-piperidin-4-one-s in 150 milliliters of THF, be adjusted to pH value 5 with AcOH, restrain (26.5 mmole) NaBH (OAc) with 5.61 down ice-cooled then ₃, batch mixing in 3 hours.Reaction mixture at room temperature stirred spend the night, then with 500 milliliters of 30%K ₂CO ₃Solution makes it be alkalescence, at room temperature stirs 1 hour, and with each 100 milliliters of EtOAc extraction three times, and the organic phase that makes merging is with Na ₂SO ₄Dry.Behind siccative and removal of solvents, residue is further reacted, need not purifying.

Output: 7.0 grams (theoretical value 75%)

A6b) join piperidin-4-yl amine 1 '-benzyl-[1,4 ']

7.0 grams (18.7 mmole) (connection piperidin-4-yl 1 '-benzyl-[1,4 '])-t-butyl carbamate and the solution of 14.3 milliliters of (185 mmole) TFA in 80 milliliters of DCM are refluxed to spend the night.Evaporate to dryness mixture in a vacuum is with residue and 200 milliliters of 30%K ₂CO ₃Solution mixes, and with each 100 milliliters of EtOAc extraction three times, discards first part 100 milliliters collection liquid.The organic phase that makes merging is with Na ₂SO ₄Drying is filtered, and evaporate to dryness.Product is further reacted, need not purifying.

Output: 5.1 grams (theoretical value 100%)

A6c) (connection piperidin-4-yl amino 1 '-benzyl-[1,4 '])-ethyl acetate

With 2.79 gram (13.17 mmole) NaBH (OAc) ₃Portion-wise addition is to the 1 '-benzyl-[1 that is cooled to 0 ℃ 1.8 grams (6.58 mmole), 4 '] in connection piperidin-4-yl amine, 2.69 milliliters of (13.0 mmole) oxo-acetic acids ethyl esters (using) and the solution of 1 milliliter of (17.45 mmole) AcOH in 250 milliliters of THF, and reaction mixture at room temperature stirred spend the night with 50% solution in the toluene.Make its evaporate to dryness in a vacuum, residue is dissolved among the EtOAc, with saturated K ₂CO ₃The solution washing organic phase, and with Na ₂SO ₄Dry.Behind siccative and removal of solvents, make residue through the HPLC purifying.Merge the fraction contain product, remove organic solvent (acetonitrile) in a vacuum, moist residue is thoroughly extracted with DCM, and the organic phase that makes merging is with MgSO ₄Dry.Behind siccative and removal of solvents, obtain product, be yellow oil.

Output: 1.25 grams (theoretical value 53%)

ESI-MS：(M+H) ⁺＝360

R _f=0.35 (silica gel, DCM/MeOH/NH ₃90:10:1)

A6d) [(connection piperidin-4-yl 1 '-benzyl-[1,4 '])-tertbutyloxycarbonyl-amino]-ethyl acetate

The triethylamine of 3.34 milliliters (30.0 mmoles) is dropped to 1.20 gram (3.34 mmole) (1 '-benzyls-[1,4 '] connection piperidin-4-yl amino)-solution of ethyl acetate in 15 milliliters of DCM in, portion-wise addition 0.73 gram (3.34 mmole) Boc-acid anhydride then.Reaction mixture was at room temperature stirred 70 hours, then evaporate to dryness in vacuum.Residue is dissolved among the EtOAc, with 15%K ₂CO ₃Solution washing, and with Na ₂SO ₄Dry.Behind siccative and removal of solvents, residue is further reacted, need not purifying.

Output: 1.3 grams (theoretical value 85%)

A6e) ([1,4 '] connection piperidin-4-yl-tertbutyloxycarbonyl-amino)-ethyl acetate

Make 1.30 grams (2.83 mmole) [(1 '-benzyl-[1,4 '] connection piperidin-4-yl)-tertbutyloxycarbonyl-amino]-ethyl acetate restrain the suspension of 10%Pd/C in 25 milliliters of EtOH with 0.16, hydrogenation is 5 hours under 50 ℃ and 50psi hydrogen pressure.Filter the removal catalyzer through bleeding, and evaporated filtrate is to doing.Obtain product, be water white oil, make its further reaction, need not purifying.

Output: 1.00 grams (theoretical value 96%)

ESI-MS：(M+H) ⁺＝370

Amine 7

(4-methyl-4-piperazine-1-base-piperidines-1-yl)-ethyl acetate

A7a) 1-benzyl-4-piperazine-1-base-piperidines-4-nitrile

11.0 gram (49.8 mmole) 1-benzyl-4-hydroxy-piperdine-4-nitriles and the mixture of 22.0 gram (255 mmole) piperazines in 200 milliliters of MeOH were refluxed 2 hours.The filtering precipitate of bleeding, evaporate to dryness filtrate is dissolved in the less water residue in a vacuum, thoroughly extract with DCM, and the organic phase that makes merging is with Na ₂SO ₄Dry.Behind siccative and removal of solvents, make residue through chromatography (Alox, DCM/MeOH 30:1) purifying.

Output: 2.38 grams (theoretical value 16%)

ESI-MS：(M+H) ⁺＝285

R _f＝0.37(Polygram-Alox，DCM/MeOH?25:1)

A7b) 1-(1-benzyl-4-methyl-piperidin-4-yl)-piperazine

With 15 milliliters of methyl chloride magnesium solutions (45 mmoles, 3M is in THF), at room temperature be added in the gram of 2.37 among 100 milliliters of anhydrous THF (7.92 mmole) 1-benzyl-4-piperazine-1-base-piperidines-4-nitrile, and reaction mixture was stirred 3 hours.With saturated NH ₄Cl solution mixes, and with mixture restir 10 minutes, with EtOAc washing water, mixes with 4M NaOH solution, till the react acid thing, thoroughly extract with DCM, and the organic phase that makes merging is with Na ₂SO ₄Dry.Behind siccative and removal of solvents, residue is further reacted, and do not carry out purifying.

Output: 0.64 gram (theoretical value 30%)

ESI-MS：(M+H) ⁺＝274

A7c) 4-(1-benzyl-4-methyl-piperidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester

1.35 gram (6.00 mmole) Boc-acid anhydrides are added in the gram of 1.63 among 50 milliliters of THF (5.66 mmole) 1-(1-benzyl-4-methyl-piperidin-4-yl)-piperazine, and reaction mixture was at room temperature stirred 3 hours.It is dried that it is evaporated in a vacuum, and residue is further reacted, and need not purifying.

Output: 2.10 grams (theoretical value 100%)

ESI-MS：(M+H) ⁺＝374

A7d) 4-(4-methyl-piperidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester

Make 4-(1-benzyl-4-methyl-piperidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester and the suspension of 300 milligrams of 10%Pd/C in 50 milliliters of MeOH of 2.28 grams (5.62 mmole), hydrogenation is 3 hours under 50 ℃ and 3447hPa hydrogen pressure.For finishing reaction, add 0.47 milliliter of dense HCl, and make mixture hydrogenation 3 hours under 50 ℃ and 3447hPa hydrogen pressure.Leach catalyzer, evaporate to dryness filtrate is stirred residue with ether in a vacuum, the filtration of bleeding, and dry.

Output: 1.54 grams (theoretical value 86%)

ESI-MS：(M+H) ⁺＝284

A7e) 4-(1-ethoxycarbonylmethyl group-4-methyl-piperidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester

4-(4-methyl-piperidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester and the mixture of 1.1 milliliters of (5.55 mmole) oxo-acetic acids ethyl esters (50%, in toluene) in 50 milliliters of THF with 1.53 grams (4.78 mmole) at room temperature stirred 1 hour.Make reaction mixture be cooled to 0 ℃, the sodium triacetoxy borohydride of portion-wise addition 1.25 gram (5.90 mmole), and after cooling bath is removed at room temperature stirs mixture and to spend the night.With itself and 10 milliliters of 20%NaHCO ₃Solution mixes, and thoroughly extract with EtOAc, and the organic phase that makes merging is with Na ₂SO ₄Dry.Behind siccative and removal of solvents, make residue through chromatography (Alox, DCM/EtOH 100:1) purifying.

Output: 0.47 gram (theoretical value 27%)

ESI-MS：(M+H) ⁺＝370

A7f) (4-methyl-4-piperazine-1-base-piperidines-1-yl)-ethyl acetate

Under 0 ℃, 2 milliliters of TFA are added in 4-(1-ethoxycarbonylmethyl group-4-methyl-piperidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester of the grams of 0.46 among 5 milliliters of DCM (1.25 mmole), and reaction mixture was at room temperature stirred 2 hours.Make its evaporate to dryness in a vacuum, and the crude product that has obtained with two-trifluoroacetate is further reacted, and need not purifying.

Output: 0.65 gram (theoretical value 100%)

ESI-MS：(M+H) ⁺＝270

Amine 8

[4-(4-methyl-piperidin-4-yl)-piperazine-1-yl]-ethyl acetate

A8a) [4-(1-benzyl-4-methyl-piperidin-4-yl)-piperazine-1-yl]-ethyl acetate

Similar embodiment A7e is by 0.62 gram (2.27 mmole) 1-(1-benzyl-4-methyl-piperidin-4-yl)-piperazine (embodiment A 7b) and 0.55 milliliter of (2.77 mmole) oxo-acetic acids ethyl ester (50%, in toluene) preparation.Make crude product through chromatography (Alox, gradient liquid PE/EtOAc 2:1 to 1:1) purifying.

Output: 0.45 gram (theoretical value 50%)

ESI-MS：(M+H) ⁺＝360

R _f＝0.56(Polygram-Alox，PE/EtOAc?1:1)

A8b) [4-(4-methyl-piperidin-4-yl)-piperazine-1-yl]-ethyl acetate

Make 0.44 gram (1.10 mmole) [4-(1-benzyl-4-methyl-piperidin-4-yl)-piperazine-1-yl]-ethyl acetate and the suspension of 100 milligrams of 10%Pd/C in 20 milliliters of EtOH, hydrogenation is 12 hours under 50 ℃ and 3447hPa hydrogen pressure.Leach catalyzer, and evaporated filtrate is to doing.Product is further reacted, need not purifying.

Output: 0.29 gram (theoretical value 97%)

ESI-MS：(M+H) ⁺＝270

Amine 9

(S)-4-methyl isophthalic acid-piperidin-4-yl-piperazine-2-carboxylic acid's ethyl ester

A9a) (S)-and piperazine-1,2, the 4-tricarboxylic acid 1-benzyl ester-4-tertiary butyl-2-ethyl ester

With the triethylamines of 11.2 gram (34.9 mmole) TBTU and 5.5 milliliters (39.6 mmoles) be added into be cooled to 0 ℃ 12.2 restrain (32.8 mmole) (S)-piperazine-1,2, in 4-tricarboxylic acid 1-benzyl ester-4-tert-butyl ester and the mixture of 30 milliliters of EtOH in 150 milliliters of THF, restir is 30 minutes under this temperature, stirs 68 hours under room temperature then.600 milliliters of ether are added in the reaction mixture, with itself and 200 milliliters of saturated NaHCO ₃Solution mixes, and isolates water, with saturated NaCl solution washing organic phase, and with Na ₂SO ₄Dry.Behind siccative and removal of solvents, make residue through chromatography (silica gel, gradient liquid PE/EtOAc 4:1 to 7:3) purifying.

Output: 11.35 grams (theoretical value 88%)

ESI-MS：(M+H) ⁺＝393

R _f=0.38 (Polygram-silica gel, PE/EtOAc 3:1)

A9b) (S)-and piperazine-1,2-dicarboxylic acid 1-benzyl ester-2-ethyl ester

With 10 milliliters of TFA be added into be cooled to 0 ℃ 3.27 the gram (8.33 mmole) (S)-piperazine-1,2, in the mixture of the 4-tricarboxylic acid 1-benzyl ester-4-tert-butyl ester-2-ethyl ester and 30 milliliters of DCM, down mixture was stirred 10 minutes ice-cooled, and at room temperature stirred 2 hours.In vacuum, at 30 ℃ of following evaporate to dryness mixtures, residue is dissolved among the EtOAc again, and evaporate to dryness in vacuum again.The crude product that obtains with trifluoroacetate is further reacted, need not purifying.

A9c) (S)-and 4-methyl-piperazine-1,2-dicarboxylic acid 1-benzyl ester-2-ethyl ester

With 1.00 gram (12.2 mmole) NaOAc and 10 mol sieve A3 be added into 4.4 restrain derive from A9b) crude product and 1.2 milliliters of (16.0 mmole) formaldehyde (37%, in water) in the mixture in 80 milliliters of THF, and reaction mixture at room temperature stirred 2 hours.After being cooled to 0 ℃, the sodium triacetoxy borohydride of portion-wise addition 3.39 grams (16.0 mmole) stirs mixture 30 minutes under this temperature, and stirs 68 hours under room temperature.Leach insoluble fluidity composition, with saturated K ₂CO ₃Solution is added in the filtrate, and it was stirred 15 minutes, mixes with EtOAc, isolates organic phase, and with Na ₂SO ₄Dry.Behind siccative and removal of solvents, make residue through chromatography (Alox, PE/EtOAc 2:1) purifying.

Output: 2.04 grams (theoretical value 81%)

ESI-MS：(M+H) ⁺＝307

R _f＝0.73(Polygram-Alox，PE/EtOAc?1:1)

A9d) (S)-4-methyl-piperazine-2-carboxylic acid's ethyl ester

Make 2.04 grams (6.66 mmole) (S)-4-methyl-piperazine-1,2-dicarboxylic acid 1-benzyl ester-2-ethyl ester and the suspension of 200 milligrams of 10%Pd/C in 100 milliliters of EtOH, hydrogenation is 6 hours under 50 ℃ and 3447hPa hydrogen pressure.Leach catalyzer, evaporated filtrate is extremely done in a vacuum, and residue is further reacted, and need not purifying.

Output: 1.06 grams (theoretical value 92%)

ESI-MS：(M+H) ⁺＝173

A9e) (S)-1-(1-tertbutyloxycarbonyl-piperidin-4-yl)-4-methyl-piperazine-2-carboxylic acid's ethyl ester

With 0.90 gram (5.23 mmole) (S)-4-methyl-piperazine-2-carboxylic acid's ethyl ester and 1.20 restrains the mixture of 4-oxo-piperidines-1-carboxylic acid tert-butyl ester in 20 milliliters of EtOH of (6.02 mmole), mix with 50 microlitre formic acid and 3 mol sieve A3, and reaction mixture was at room temperature placed 66 hours.Leach molecular sieve, mixture is mixed with 100 milligrams of 10%Pd/C, and hydrogenation 4 hours under 50 ℃ and 3447hPa hydrogen pressure.Filter the removal catalyzer through bleeding, evaporated filtrate makes residue through chromatography (silica gel, gradient liquid DCM/EtOH 98:2 to 75:25) purifying in a vacuum.

Output: 0.35 gram (theoretical value 19%)

ESI-MS：(M+H) ⁺＝356

R _f＝0.5(Polygram-Alox，DCM/MeOH?50:1)

A9f) (S)-4-methyl isophthalic acid-piperidin-4-yl-piperazine-2-carboxylic acid's ethyl ester

Make 0.34 gram (0.96 mmole) (S)-mixture of 1-(1-tertbutyloxycarbonyl-piperidin-4-yl)-4-methyl-piperazine-2-carboxylic acid's ethyl ester in the ethanolic soln (1.25M) of 6 milliliters of HCl refluxed 1 hour.After the reaction mixture cooling, the filtering precipitate of bleeding, and dry.Obtaining product, is three-hydrochloride.

Output: 0.33 gram (theoretical value 95%)

ESI-MS：(M+H) ⁺＝256

Amine 10

(S)-1-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylic acid's ethyl ester

A10a) (S)-and piperazine-1, the 3-dicarboxylic acid 1-tert-butyl ester-3-ethyl ester

Make 4.00 grams (10.2 mmole) (S)-piperazine-1,2, the 4-tricarboxylic acid-1-benzyl ester-4-tert-butyl ester-2-ethyl ester (embodiment A 9a) and the suspension of 200 milligrams of 10%Pd/C in 100 milliliters of EtOH, hydrogenation is 2 hours under 50 ℃ and 3447hPa hydrogen pressure.Leach catalyzer, evaporate to dryness filtrate in a vacuum, and residue is further reacted, and need not purifying.

Output: 2.61 grams (theoretical value 98%)

ESI-MS：(M+H) ⁺＝259

A10b) (S)-and 4-(1-methyl-piperidin-4-yl)-piperazine-1, the 3-dicarboxylic acid 1-tert-butyl ester-3-ethyl ester

With 2.65 the gram (10.05 mmole) (S)-piperazine-1, the 3-dicarboxylic acid-1-tert-butyl ester-3-ethyl ester and the mixture of 1.36 milliliters of (11.06 mmole) 1-methyl-piperidin-4-one-s in 100 milliliters of THF at room temperature stirred 1 hour.After being cooled to 0 ℃, the sodium triacetoxy borohydride of portion-wise addition 3.00 gram (14.16 mmole), and reaction mixture at room temperature stirred spend the night.For finishing reaction, add sodium triacetoxy borohydride and 0.3 milliliter of AcOH of 1.00 grams (4.72 mmole) again, and with mixture restir 48 hours at room temperature.Add 40 milliliters of saturated K ₂CO ₃Solution stirs mixture 15 minutes, thoroughly extract with EtOAc, and the organic phase that makes merging is with Na ₂SO ₄Dry.Behind siccative and removal of solvents, make residue through chromatography (Alox, DCM/EtOH 100:1) purifying.

Output: 1.93 grams (theoretical value 53%)

ESI-MS：(M+H) ⁺＝356

A10c) (S)-1-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylic acid's ethyl ester

With 1.88 grams (5.18 mmole) (S)-4-(1-methyl-piperidin-4-yl)-piperazine-1, the mixture of the ethanolic soln (1.25M) of the 3-dicarboxylic acid-1-tert-butyl ester-3-ethyl ester, 3 milliliters of EtOH and 15 milliliters of HCl at room temperature stirs and spends the night.For finishing reaction, mixture was refluxed 1 hour.After the reaction mixture cooling, the filtering precipitate of bleeding, and dry.Obtain product, be two-hydrochloride.

Output: 1.35 grams (theoretical value 79%)

ESI-MS：(M+H) ⁺＝256

Amine 11

(S)-4-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylic acid's ethyl ester

A11a) (S)-and 4-(1-methyl-piperidin-4-yl)-piperazine-1,2-dicarboxylic acid 1-benzyl ester-2-ethyl ester

With 4.20 grams (10.13 mmole) (S)-piperazine-1,2-dicarboxylic acid 1-benzyl ester-2-ethyl ester (embodiment 49b, with trifluoroacetate use) and the mixture of 1.37 milliliters of 1-methyl-piperidin-4-one-s in 100 milliliters of THF at room temperature stirred 1 hour.After being cooled to 0 ℃, the sodium triacetoxy borohydride of portion-wise addition 3.00 gram (14.16 mmole), and reaction mixture at room temperature stirred spend the night.With itself and 40 milliliters of saturated K ₂CO ₃Solution mixes, and restir 15 minutes thoroughly extracts with EtOAc, and the organic phase that makes merging is with Na ₂SO ₄Dry.Behind siccative and removal of solvents, make residue through chromatography (Alox, DCM/EtOH 100:1) purifying.

Output: 2.17 grams (theoretical value 55%)

ESI-MS：(M+H) ⁺＝390

R _f＝0.43(Polygram-Alox，DCM/MeOH?50:1)

A11b) (S)-4-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylic acid's ethyl ester

Make 2.15 grams (5.52 mmole) (S)-4-(1-methyl-piperidin-4-yl)-piperazine-1,2-dicarboxylic acid 1-benzyl ester-2-ethyl ester and the suspension of 100 milligrams of 10%Pd/C in 50 milliliters of EtOH, hydrogenation is 2 hours under 50 ℃ and 3447hPa hydrogen pressure.Leach catalyzer, and evaporated filtrate is to doing.Product is further reacted, need not purifying.

Output: 1.35 grams (theoretical value 96%)

ESI-MS：(M+H) ⁺＝256

Amine 12

(3-piperazine-1-base-8-aza-bicyclo [3.2.1] suffering-8-yl)-ethyl acetate

A12a) 3-(4-carbobenzoxy-(Cbz)-piperazine-1-yl)-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

With 5.00 gram (22.2 mmole) 3-oxo-8-aza-bicyclo [3.2.1] suffering-8-carboxylic acid tert-butyl ester and the mixtures of piperazine-1-benzyl carboxylate in 60 milliliters of THF, be adjusted to pH value 5 with AcOH, and at room temperature stirred 1 hour.Ice-cooled down with mixture with the 5.64 sodium triacetoxy borohydride batch mixing that restrain (26.6 mmole), and reaction mixture at room temperature stirred spends the night.With itself and 150 milliliters of 15%K ₂CO ₃Solution mixes, and isolates organic phase, and with the thorough aqueous phase extracted of EtOAc, and the organic phase that makes merging is with Na ₂SO ₄Dry.Behind siccative and removal of solvents, make residue through chromatography (silica gel, EtOAc) purifying.

Can isolate 2 kinds of isomerized products:

Isomer A:

Output: 2.10 grams (theoretical value 22%)

ESI-MS：(M+H) ⁺＝430

R _f=0.55 (silica gel, EtOAc)

Retention time (HPLC): 3.2 minutes (method B)

Isomer B:

Output: 2.20 grams (theoretical value 23%)

ESI-MS：(M+H) ⁺＝430

R _f=0.68 (silica gel, EtOAc)

A12b) 4-(8-aza-bicyclo [3.2.1] oct-3-yl)-piperazine-1-benzyl carboxylate

6.01 milliliters of (78.0 mmole) TFA slowly are added in 2.10 gram (4.89 mmole) 3-(4-carbobenzoxy-(Cbz)-piperazine-1-yl)-8-aza-bicyclo [3.2.1] octane-mixtures of 8-carboxylic acid tert-butyl ester (isomer A) in 60 milliliters of DCM, and reaction mixture was at room temperature stirred 2 hours.Make its evaporate to dryness in a vacuum, make residue be dissolved in 15%K ₂CO ₃In the solution, thoroughly extract, and the organic phase that makes merging is with Na with DCM ₂SO ₄Dry.Behind siccative and removal of solvents, product is further reacted, and need not purifying.

Output: 1.50 grams (theoretical value 93%)

ESI-MS：(M+H) ⁺＝330

R _f=0.16 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

A12c) 4-(8-ethoxycarbonylmethyl group-8-aza-bicyclo [3.2.1] oct-3-yl)-piperazine-1-benzyl carboxylate

With 1.29 gram (9.30 mmole) K ₂CO ₃Be added in 4-(8-aza-bicyclo [3.2.1] oct-3-yl)-piperazine-1-benzyl carboxylate (A12b) of the grams of 1.50 among 10 milliliters of DMF (4.55 mmole), slowly drip 0.56 milliliter of (5.00 mmole) ethyl bromoacetate then, and with reaction mixture restir 4 hours at room temperature.Leach insoluble composition, mix with EtOAc, with organic phase with saturated NaHCO ₃Solution washing twice, and with Na ₂SO ₄Dry.Behind siccative and removal of solvents, residue is further reacted, and need not purifying.

Output: 1.75 grams (theoretical value 92%)

ESI-MS：(M+H) ⁺＝416

R _f=0.72 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

A12d) (3-piperazine-1-base-8-aza-bicyclo [3.2.1] suffering-8-yl) ethyl acetate

Make 4-(8-ethoxycarbonylmethyl group-8-aza-bicyclo [3.2.1] oct-3-yl)-piperazine-1-benzyl carboxylate (A12c) and the suspension of 200 milligrams of 10%Pd/C in 30 milliliters of EtOH of 1.70 grams (4.09 mmole), vibration is 3 hours under room temperature and 3000hPa hydrogen pressure.Filter the removal catalyzer through bleeding, and evaporated filtrate is to doing.Product is further reacted, need not purifying.

Output: 1.10 grams (theoretical value 96%)

ESI-MS：(M+H) ⁺＝282

R _f=0.21 (silica gel, DCM/MeOH/NH ₃80:20:2)

Amine 13

([1,4 '] connection piperidin-4-yl oxygen base)-ethyl acetate

A13a) join piperidines-1 '-benzyl carboxylate 4-tertiary butyloxycarbonyl ylmethoxy-[1,4 ']

4-oxo-piperidines-1-the benzyl carboxylates of sodium triacetoxy borohydride portion-wise addition to 2.58 gram (11.06 mmole) of 2.90 grams (13.27 mmole) are restrained in (12.36 mmole) (piperidin-4-yl oxygen base)-mixtures of tert.-butyl acetate in 30 milliliters of THF with 2.80, and reaction mixture at room temperature stirred spend the night.It is mixed with 50 milliliters of 1M NaOH, mixture was at room temperature stirred 1 hour, mix, isolate organic phase with EtOAc, and with Na ₂SO ₄Dry.Behind siccative and removal of solvents, make residue through chromatography (Alox, DCM/MeOH 100:1) purifying.

Output: 3.10 grams (theoretical value 65%)

ESI-MS：(M+H) ⁺＝433

A13b) ([1,4 '] connection piperidin-4-yl oxygen base)-tert.-butyl acetate

Make 4-tertiary butyloxycarbonyl ylmethoxy-[1,4 '] connection piperidines-the 1 '-benzyl carboxylate and the suspension of 300 milligrams of 10%Pd/C in 60 milliliters of MeOH of 3.08 grams (7.12 mmole), hydrogenation is 2 hours under 50 ℃ and 3447hPa hydrogen pressure.Filter the removal catalyzer through bleeding, and evaporated filtrate is to doing.Product is further reacted, need not purifying.

Output: 2.15 grams (theoretical value 99%)

ESI-MS：(M+H) ⁺＝299

A13c) ([1,4 '] connection piperidin-4-yl oxygen base)-ethyl acetate

The ethanolic soln (1.25M) of 20 milliliters of HCl is added in the grams of 2.02 among 20 milliliters of EtOH (6.63 mmole) ([1,4 '] connection piperidin-4-yl oxygen base)-tert.-butyl acetate, and made reaction mixture refluxed 3 hours.After being cooled to 0 ℃, bleed and filter formed throw out, and dry under high vacuum.Make with two-product that hydrochloride was obtained and further react, need not purifying.

Output: 1.74 grams (theoretical value 76%)

ESI-MS：(M+H) ⁺＝271

Amine 14

[1,4 '] connection piperidin-4-yl-ethyl acetate

A14a) (connection piperidin-4-yl 1 '-benzyl-[1,4 '])-ethyl acetate

50 milliliters of DCM and 11.7 milliliters of (62.5 mmole) 1-benzyl-piperidin-4-one-s are added in the gram of 11.8 among 100 milliliters of THF (56.8 mmole) piperidin-4-yl-ethyl acetate, and reaction mixture was at room temperature stirred 2 hours.With the sodium triacetoxy borohydride batch mixing of mixture and 13.7 grams (62.5 mmole), and under room temperature restir 36 hours.100 milliliters of 10%NaOH are added in the reaction mixture, and with each 100 milliliters of MTBE extracting twice, and the organic phase that makes merging is with Na with it ₂SO ₄Dry.Behind siccative and removal of solvents, make residue through the HPLC purifying.

Output: 3.27 grams (theoretical value 17%)

ESI-MS：(M+H) ⁺＝345

R _f=0.55 (silica gel, EtOAc/MeOH/NH ₃90:10:1)

A14b) [1,4 '] connection piperidin-4-yl-ethyl acetate

Make 3.24 grams (9.41 mmole) (connection piperidin-4-yl 1 '-benzyl-[1,4 '])-ethyl acetate and the suspension of 300 milligrams of 10%Pd/C in 50 milliliters of EtOA, hydrogenation under room temperature and 3000hPa hydrogen pressure is till the hydrogen of theoretical amount has been absorbed.Filter the removal catalyst through bleeding, evaporated filtrate mixes residue to doing with the ethanolic soln (1.25M) of 50 milliliters of EtOH and HCl.It is dried that mixture is evaporated in a vacuum, and residue is stirred with 100 milliliters of DIPE/ Virahols (2:1), leaches throw out, and under 35 ℃, dry in the drying by circulating air case.Obtain product, be two-hydrochloride.

Output: 2.90 grams (theoretical value 94%)

ESI-MS：(M+H) ⁺＝255

R _f=0.05 (silica gel, EtOAc/MeOH/NH ₃70:30:3)

Amine 15

3-[1,4 '] connection piperidin-4-yl-ethyl propionate

A15a) 4-(2-methoxycarbonyl-ethyl)-[1,4 '] connection piperidines-1 '-carboxylic acid tert-butyl ester

Under nitrogen atmosphere, the mixture of 4-oxo-piperidines-1-carboxylic acid tert-butyl ester in 50 milliliters of THF with 4.00 gram (19.3 mmole) 3-piperidin-4-yl-methyl propionates and 3.85 grams (19.3 mmole), be adjusted to pH value 5 with AcOH, and mixture was at room temperature stirred 1 hour.After being cooled to 0 ℃,, and reaction mixture at room temperature being stirred spend the night the sodium triacetoxy borohydride batch mixing of mixture and 5.15 grams (24.3 mmole).In 10 minutes, drip 90 milliliters of 30%K ₂CO ₃Solution, with EtOAc extraction three times, and the organic phase that makes merging is with Na with mixture ₂SO ₄Dry.Behind siccative and removal of solvents, residue is further reacted, need not purifying.

Output: 5.40 grams (theoretical value 79%)

ESI-MS：(M+H) ⁺＝355

R _f=0.63 (silica gel, DCM/MeOH/NH ₃80:20:2)

A15b) 3-[1,4 '] connection piperidin-4-yl-ethyl propionate

With 5.40 in the ethanolic soln (1.25M) of 150 milliliters of HCl gram (15.2 mmole) 4-(2-methoxycarbonyl-ethyl)-([1,4 '] connection piperidines-1 '-carboxylic acid tert-butyl ester at room temperature stirs and spends the night.The solvent major part is removed in a vacuum, leached formed throw out, and dry.The product that obtains with two-hydrochloride is further reacted, need not purifying.

Output: 2.30 grams (theoretical value 79%)

ESI-MS：(M+H) ⁺＝269

Retention time (HPLC): 1.2 minutes (method B)

Amine 16

4-(4-piperazine-1-base-piperidines-1-yl)-ethyl butyrate

A16a) 4-[4-(4-benzyl-piperazine-1-yl)-piperidines-1-yl]-ethyl butyrate

Under nitrogen atmosphere, with 3.11 gram (12.0 mmole) 1-benzyl-4-piperidin-4-yl-piperazines and 7.50 milliliters (12.0 mmoles, 15%, in the water) mixture of 4-oxo-butyric acid in 70 milliliters of THF, be adjusted to pH value 5 with AcOH, and at room temperature stirred 1 hour.After being cooled to 0 ℃, the sodium triacetoxy borohydride of portion-wise addition 5.35 gram (24.0 mmole), and reaction mixture at room temperature stirred spend the night.In 15 minutes, drip 80 milliliters of 30%K ₂CO ₃Solution, with water with the EtOAc washed twice, and in a vacuum the evaporation drop to half.Add 1M KHSO ₄Solution filters the formed throw out of removal through bleeding, with the EtOAc wash filtrate, and it is dried that water is evaporated in a vacuum.Residue is dissolved in the ethanolic soln (1.25M) of 150 milliliters of HCl, and reaction mixture is at room temperature stirred spend the night.Make its evaporate to dryness in a vacuum, make residue be dissolved in a small amount of 15%K ₂CO ₃In the solution, thoroughly extract, and the organic phase that makes merging is with Na with EtOAc ₂SO ₄Dry.Behind siccative and removal of solvents, residue is further reacted, and need not purifying.

Output: 2.90 grams (theoretical value 65%)

ESI-MS：(M+H) ⁺＝374

A16b) 4-(4-piperazine-1-base-piperidines-1-yl)-ethyl butyrate

2.90 4-[4-(4-benzyl-piperazine-1-yl)-piperidines-1-yl of gram (7.76 mmole)]-ethyl butyrate and the suspension of 300 milligrams of 10%Pd/C in 60 milliliters of MeOH, hydrogenation is 24 hours under room temperature and 3447hPa hydrogen pressure.Filter the removal catalyzer through bleeding, evaporated filtrate is dissolved in DIPE and a small amount of Virahol residue to doing, and with 1, the 4M HCl mixing in the 4-diox.The filtering precipitate of bleeding, and dry.Obtain product, be two-hydrochloride.

Output: 2.50 grams (theoretical value 90%)

ESI-MS：(M+H) ⁺＝284

Retention time (HPLC): 0.7 minute (method B)

Amine 17

4-piperazine-1-base-piperidines-1-benzyl carboxylate

A17a) 4-(1-carbobenzoxy-(Cbz)-piperidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester

With the solution of 7.18 milliliters of (48.0 mmole) chloroformic acid benzyl esters in 50 milliliters of DCM, in the ice-cooled 4-piperidin-4-yl-piperazine-1-carboxylic acid tertiary butyl ester that drops to down the grams of 12.3 among 200 milliliters of DCM (45.7 mmole) and 8.2 milliliters of (50 mmole) N-ethyl diisopropyl amines, and reaction mixture at room temperature stirred spend the night.With it with 200 milliliters of 15%K ₂CO ₃Solution washing is isolated organic phase, and with Na ₂SO ₄Dry.Behind siccative and removal of solvents, residue is further reacted, and need not purifying.

Output: 16.0 grams (theoretical value 87%)

A17b) 4-piperazine-1-base-piperidines-1-benzyl carboxylate

Under room temperature, 25 milliliters of TFA are added in 4-(1-carbobenzoxy-(Cbz)-piperidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester of 16.0 among 200 milliliters of DCM gram (39.7 mmole), and reaction mixture are at room temperature stirred spend the night.Make its evaporate to dryness in a vacuum, residue is dissolved among 200 ml waters and the 200 milliliters of EtOAc, isolate water, with 50 milliliters of 15%K ₂CO ₃Solution mixes, each 200 milliliters of EtOAc extracting twice, and the organic phase that makes merging is with Na ₂SO ₄Dry.Behind siccative and removal of solvents, make the residue reaction, and need not purifying.

Output: 4.00 grams (theoretical value 33%)

ESI-MS：(M+H) ⁺＝304

The preparation of final compound is to be described in down:

Embodiment 1

1 '-(R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl }-1,4 '-Lian piperidyl-4-carboxylic acid, ethyl ester

1a) (Z, E)-2-acetylaminohydroxyphenylarsonic acid 3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-vinylformic acid

39.7 gram (335 mmole) N-acetyl-glycines are added in the 4-amino-3-chloro-5-trifluoromethyl-phenyl aldehyde and the suspension of 27.5 gram (335 mmole) NaOAc in 202 ml acetic anhydride of 50.0 grams (224 mmole); and with reaction mixture at 115 ℃, heated 1 hour.After being cooled to 80 ℃, drip 100 ml waters, the temperature of mixture is remained under 80 ℃.This suspension is heated to 95 ℃,, is added into then in the mixture of 250 milliliters of toluene and 500 ml waters again through 40 minutes.This suspension is at room temperature stirred, the filtering precipitate of bleeding, and under 60 ℃, dry in the drying by circulating air case.

Output: 48.8 grams (theoretical value 68%)

ESI-MS：(M+H) ⁺＝321/323(Cl)

R _f=0.37 (silica gel, DCM/MeOH/AcOH 90:10:1)

1b) 3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-oxo-propionic acid

(Z, E)-2-acetylaminohydroxyphenylarsonic acid 3-(4-amino-3-chloro-5-three-fluorine-based methyl-phenyl)-vinylformic acid is at 900 milliliter 1, the suspension among 4-diox and the 1050 milliliters of 4M HCl is heated to 100 ℃, goes through 8 hours with 97.0 grams (300 mmole).Mixture is evaporated in a vacuum drop to about 600 milliliters, be cooled to room temperature, leach sedimentary material, with each 100 ml water washed twice, and dry down in 50 ℃.Residue is dissolved in 850 milliliters of toluene, and the heating down that refluxes is cooled off in ice bath then.Filter formed throw out, with the PE washing, and in the drying by circulating air case, dry down at 50 ℃.

Output: 63.0 grams (theoretical value 74%)

ESI-MS：(M-H) ^-＝280/282(Cl)

R _f=0.21 (silica gel, DCM/MeOH/NH ₃80:20:2)

1c) (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-hydroxyl-propionic acid

With 100.0 the gram (312 mmole) (1R)-solution of B-chloro diisopinocampheylchloroborane base borine in 150 milliliters of THF, drop in the solution of triethylamine in 300 milliliters of THF of 63.0 gram (224 mmole) 3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-oxo-propionic acid of being cooled to approximately-30 ℃ and 31.2 milliliters (224 mmoles), and reaction mixture was kept 1.5 hours, under this temperature then room temperature heating one hour.When being added into 80 milliliters of 4M NaOH in the reaction mixture, it was stirred 5 minutes, be cooled to 0 ℃, mix with 300 milliliters of MTBE, restir is 20 minutes under this temperature, then separates liquid phase.With the thorough extracted organic phase of water, make the aqueous phase as acidified of merging with 4M HCl, thoroughly extract with MTBE, and the organic phase that makes merging is with Na ₂SO ₄Dry.With 4M HCl acidifying THF/MTBE/NaOH phase, separate liquid phase, and evaporate to dryness organic phase in a vacuum.Two parts of residues are merged, and the single step reaction of going forward side by side need not purifying.

R _f=0.20 (silica gel, DCM/MeOH/NH ₃80:20:2)

1d) (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-hydroxyl-methyl propionate

The crude product (62 gram) of embodiment 1c is dissolved among 300 milliliters of MeOH, and slowly drips 3.65 milliliters of (50 mmole) SOCl ₂So far in the solution.With reaction mixture restir 3 hours at room temperature, evaporate to dryness in a vacuum is dissolved among the DCM residue then, and through filtered through silica gel.Evaporate to dryness solution in a vacuum, and make residue through chromatography (silica gel, DCM/MeOH/NH ₃80:20:2)) purifying.Merge the part that contains product, evaporate to dryness mixes residue with PE in a vacuum, the filtration of bleeding, and dry.

Output: 43.1 grams (65% of theoretical value is through 2 steps)

ESI-MS：(M+H) ⁺＝298/300(Cl)

R _f=0.86 (silica gel, DCM/MeOH/NH ₃80:20:2)

1e) 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine leather-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-methoxycarbonyl-ethyl ester

Under nitrogen atmosphere, with the solution of 13.5 gram (65.0 mmole) chloroformic acid 4-nitro phenyl esters in 40 milliliters of THF, under 60 ℃ (bathing temperature), in 10 minutes, be metered in 100 milliliters of pyridines, mixture was stirred 10 minutes, drip then 18.0 grams (60.5 mmole) (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-solution of 2-hydroxyl-methyl propionate in 50 milliliters of pyridines, and reaction mixture kept 1.5 hours under this temperature.Then portion-wise addition 15.9 restrains (65.0 mmole) 3-piperidin-4-yls-1,3,4,5-tetrahydrochysene-1,3-benzodiazepine

-2-ketone.The temperature of reaction mixture is increased to 100 ℃, and mixture kept 6 hours under this temperature, stirred under room temperature then and spent the night.The evaporate to dryness mixture is dissolved among 200 milliliters of EtOAc residue in a vacuum, with organic phase with each 10 milliliters of 1M KHSO ₄Solution washing twice is with each 50 milliliters of 15%K ₂CO ₃Solution ten times, and with Na ₂SO ₄Dry.Behind siccative and removal of solvents, residue is further reacted, need not purifying.

Output: 33.1 grams (theoretical value 96%)

ESI-MS：(M+H) ⁺＝569/571(Cl)

R _f=0.72 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

1f) 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxyl-ethyl ester

With the solution of 2.11 gram (88.0 mmole) LiOH in 100 ml waters, be added into 33.0 gram (58.0 mmole) 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepines

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-solution of 1-methoxyl group-carbonyl-ethyl ester in 200 milliliters of THF in, and reaction soln stirred under room temperature 3.5 hours.Remove THF in a vacuum, moist residue with the MTBE washed twice, with 2M HCl acidifying, is thoroughly extracted with DCM, and the organic phase that makes merging is with Na ₂SO ₄Dry.Behind siccative and removal of solvents, residue is dissolved under 65 ℃ in 80 milliliters of Virahols, and slowly is cooled to ambient temperature overnight.This suspension is cooled off in ice bath, the filtration of bleeding, with a small amount of Virahol and DIPE washing, and dry.

Output: 26.2 grams (theoretical value 81%)

ESI-MS：(M+H) ⁺＝555/557(Cl)

R _f=0.18 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

Retention time (HPLC): 4.0 minutes (method B)

1g) 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-oxo-2-(4-oxo-piperidines-1-yl)-ethyl ester

The triethylamine of 7.40 gram (23.0 mmole) TBTU and 5.84 milliliters (40.0 mmoles) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 10.0 grams (18.0 mmole)

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-solution of 1-carboxyl-ethyl ester in 50 milliliters of DMF in, and under room temperature, stirred 10 minutes.2.77 gram (18.0 mmole) piperidin-4-one-s (using with the hydrate of its hydrochloride) are added in the reaction mixture, and it are at room temperature stirred spend the night.Reaction soln is poured over 1 liter of 7%K ₂CO ₃On the solution, leach settled material, with water washing, and following dry 6 hours in 60 ℃.(silica gel EtOAc) is further purified through column chromatography.

Output: 7.5 grams (theoretical value 65%)

ESI-MS：(M+H) ⁺＝636/638(Cl)

R _f=0.25 (silica gel, EtOAc)

1h) 1 '-and (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

62.9 milligrams of (0.4 mmole) piperidines-4-carboxylic acid, ethyl esters and 11 microlitres (0.2 mmole) AcOH are added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 127 milligrams (0.2 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-(oxo-piperidines-1-the yl)-solution of ethyl ester in 2 milliliters of THF/MeOH (2:1) in, and reaction mixture at room temperature stirred 2 hours.Make it be cooled to 0 ℃ then, after 2 hours, with 10.6 milligrams of (0.16 mmole) NaBH ₃CN mixes, and stirs under 0 ℃ and spend the night.Make solvent evaporation, residue is dissolved among 2 milliliters of DMF, and through HPLC purifying crude product.Merge the wash-out part that contains product, and freeze-drying.

Output: 68 milligrams (theoretical value 44%)

ESI-MS：(M+H) ⁺＝777/779(Cl)

Retention time (HPLC): 7.0 minutes (method C)

Embodiment 1.1

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl }-1,4 '-Lian piperidyl-4-carboxylic acid

With the solution of 7.2 milligrams of (0.3 mmole) LiOH in 1 ml water, be added into 140 milligrams (0.18 mmoles) 1 '-(R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl }-1, in the solution of 4 '-Lian piperidyl-4-carboxylic acid, ethyl ester in 1 milliliter of THF, and reaction mixture at room temperature stirred 3 hours.Add 1 milliliter of HCl (1M), and make crude product through the HPLC purifying.Merge the drip washing part that contains product, and freeze-drying.

Output: 53 milligrams (theoretical value 39%)

ESI-MS：(M+H) ⁺＝749/751(Cl)

Retention time (HPLC): 3.4 minutes (method B)

Embodiment 2

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(ethoxycarbonylmethyl group-amino)-1,4 '-Lian piperidines-1 '-yl]-2-oxo-ethyl ester

2a) 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(ethoxycarbonyl ethoxycarbonyl-methylamino)-1,4 '-Lian piperidines-1 '-yl]-2-oxo-ethyl ester

The triethylamine of 128 milligrams of (0.40 mmole) TBTU and 56 microlitres (0.40 mmole) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 200 milligrams (0.36 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-solution of 1-carboxyl-ethyl ester in 2 milliliters of DMF in, and under room temperature, stirred 10 minutes.148 milligrams (0.40 mmoles) ([1,4 '] connection piperidin-4-yl-tertbutyloxycarbonyl-amino)-ethyl acetate (amine A6) is added in the reaction mixture, and it is at room temperature stirred spend the night.The evaporate to dryness reaction soln is dissolved among the EtOAc residue in a vacuum, and bleed and filter formed throw out, and dry.Product is further reacted, need not purifying.

Output: 330 milligrams (theoretical value 100%)

2b) 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

0.5 milliliter of TFA is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 330 milligrams (0.36 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(tertbutyloxycarbonyl-ethoxycarbonyl-methylamino)-1,4 '-Lian piperidines-1 '-yl]-2-oxo-ethyl ester being cooled in 0 ℃ the solution in 5 milliliters of DCM, and reaction mixture at room temperature stirred spend the night.Make its evaporate to dryness in a vacuum, and make residue through the HPLC purifying.Merge the wash-out part that contains product, and freeze-drying.

Output: 263 milligrams (theoretical value 90%)

ESI-MS：(M+H) ⁺＝806/808(Cl)

Retention time (HPLC): 2.6 minutes (method A)

Embodiment 2.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(carboxymethyl-amino)-1,4 '-Lian piperidines-1 '-yl]-2-oxo-ethyl ester

9.4 milligrams of (0.39 mmole) LiOH solution are added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 212 milligrams (0.26 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(ethoxy carbonyl-methylamino-)-1,4 '-Lian piperidines-1 '-yl]-solution of 2-oxo-ethyl ester in 9 milliliters of THF in, and reaction mixture at room temperature stirred spends the night.For finishing reaction, add 6.3 milligrams of (0.26 mmole) LiOH again, and mixture stirred under room temperature again spend the night.Make reaction mixture through the HPLC purifying, need not further processing.Merge the wash-out part that contains product, and freeze-drying, the product that is obtained is a trifluoroacetate.

Output: 130 milligrams (theoretical value 55%)

ESI-MS：(M+H) ⁺＝778/780(Cl)

Retention time (HPLC): 2.7 minutes (method A)

Embodiment 3

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-ethoxycarbonylmethyl group-4,4 '-Lian piperidines-1-yl)-2-oxo-ethyl ester

632 milligrams of (1.97 mmole) TBTU and 0.34 milliliter of (1.97 mmole) ethyl diisopropyl amine are added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 1.0 grams (1.80 mmole)

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-solution of 1-carboxyl-ethyl ester in 10 milliliters of THF in, and mixture at room temperature stirred 10 minutes.500 milligrams (1.97 mmole) [4,4 '] connection piperidines-1-base-ethyl acetate is added in the reaction mixture, and it is at room temperature stirred spend the night.The evaporate to dryness mixture is dissolved among the DCM residue, with 1M KHSO in a vacuum ₄Solution and 15%K ₂CO ₃The solution washing organic phase, and with Na ₂SO ₄Dry.Behind siccative and removal of solvents, make residue through the HPLC purifying.Merge the wash-out part that contains product, evaporate to dryness is developed residue with DIPE in a vacuum, the filtration of bleeding, and dry.

Output: 150 milligrams (theoretical value 11%)

ESI-MS：(M+H) ⁺＝791/793(Cl)

R _f=0.46 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

Embodiment 3.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-carboxymethyl-4,4 '-Lian piperidines-1-yl)-2-oxo-ethyl ester

With the solution of 1 milligram of (0.04 mmole) LiOH in 1 ml water, be added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 30 milligrams (0.04 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-ethoxy carbonyl methyl-4,4 '-Lian piperidines-1-yl)-solution of 2-oxo-ethyl ester in 2 milliliters of THF in, and reaction mixture at room temperature stirred spends the night.The evaporate to dryness mixture mixes residue with less water and 1M HCl in a vacuum, till obtaining acid reactant.Bleed and filter formed throw out, and dry.

Output: 20 milligrams (theoretical value 66%)

ESI-MS：(M+H) ⁺＝763/765(Cl)

R _f=0.31 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

Embodiment 3.2

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-methoxycarbonyl methyl-4,4 '-Lian piperidines-1-yl)-2-oxo-ethyl ester

100 milligrams of (0.31 mmole) TBTU and 0.06 milliliter of (0.34 mmole) ethyl diisopropyl amine are added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 200 milligrams (0.26 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-carboxymethyl-4,4 '-Lian piperidines-1-the yl)-solution of 2-oxo-ethyl ester in 15 milliliters of THF in, and mixture at room temperature stirred 10 minutes.1 milliliter of (24.6 mmole) MeOH is added in the reaction mixture, and it is at room temperature stirred spend the night.Make its evaporate to dryness in a vacuum, residue is dissolved among 2 milliliters of DMF, and through HPLC purifying crude product.Merge the wash-out part that contains product, and freeze-drying.

Output: 80 milligrams (theoretical value 39%)

ESI-MS：(M+H) ⁺＝777/779(Cl)

R _f=0.60 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

Following compounds is to make from 200 milligrams of 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine in each situation in a similar manner

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-carboxymethyl-4,4 '-Lian piperidines-1-yl)-2-oxo-ethyl ester and 1 milliliter of alcohol separately:

Embodiment 3.7

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-(1 '-phenyloxycarbonyl methyl-4,4 '-Lian piperidines-1-yl)-ethyl ester

The triethylamine of 50 milligrams of (0.16 mmole) TBTU and 37 microlitres (0.26 mmole) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 100 milligrams (0.13 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-carboxymethyl-4,4 '-Lian piperidines-1-the yl)-solution of 2-oxo-ethyl ester in 1.5 milliliters of THF in, and under room temperature, stirred 1 hour.Add 14.8 milligrams of (0.16 mmole) phenol, and reaction mixture at room temperature stirred spend the night.Reaction soln is filtered through the injection filter, and make crude product through the HPLC purifying.Merge the wash-out part that contains product, and freeze-drying.Residue is dissolved among the DCM, and evaporate to dryness is developed with DIPE in a vacuum, the filtration of bleeding, and dry.

Output: 48 milligrams (theoretical value 44%)

ESI-MS：(M+H) ⁺＝839/841(Cl)

R _f=0.47 (silica gel, DCM/MeOH/NH ₃90:10:1)

Retention time (HPLC): 3.2 minutes (method B)

Following compounds is 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of making in each situation in a similar manner from 100 milligrams (embodiment 3.8 to 3.12), 120 milligrams (embodiment 3.13) or 90 milligrams (embodiment 3.14 and 3.15)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-carboxymethyl-4,4 '-Lian piperidines-1-yl)-2-oxo-ethyl ester becomes deal with necessary alcohol in each situation:

Embodiment 3.16

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1 '-(2,2-dimethyl propylene acyloxy-methoxycarbonyl-methyl)-4,4 '-Lian piperidines-1-yl]-2-oxo-ethyl ester

With 27 milligrams of (0.20 mmole) K ₂CO ₃With 28 microlitres (0.20 mmole) 2,2-dimethyl-propionic acid chloromethyl ester is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 100 milligrams (0.13 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-carboxymethyl-4,4 '-Lian piperidines-1-the yl)-solution of 2-oxo-ethyl ester in 2 milliliters of DMF in, and reaction mixture at room temperature stirred 2 hours.The evaporate to dryness mixture is dissolved among 50 milliliters of DCM residue in a vacuum, with 20 ml waters washing organic phase, and with Na ₂SO ₄Dry.Behind siccative and removal of solvents, make residue through chromatography (silica gel, DCM/MeOH/NH ₃97:3:0.3) purifying.Merge the wash-out part that contains product, the evaporate to dryness residue, with a small amount of ether/DIPE development, the filtration of bleeding, and dry.

Output: 38 milligrams (theoretical value 34%)

ESI-MS：(M+H) ⁺＝877/879(Cl)

R _f=0.47 (silica gel, DCM/MeOH/NH ₃90:10:1)

Retention time (HPLC): 3.3 minutes (method B)

Embodiment 3.17

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-dimethylamino formyl radical methoxyl group-carbonyl methyl-4,4 '-Lian piperidines-1-yl)-2-oxo-ethyl ester

Triethylamine and 15 milligrams of (0.15 mmole) 2-hydroxy-ns with 48 milligrams of (0.15 mmole) TBTU, 21 microlitres (0.15 mmole), N-dimethyl-ethanamide is added into 4-(2-oxo-1,2,4 of 100 milligrams (0.13 mmoles), 5-tetrahydrochysene-1, the 3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-carboxymethyl-4,4 '-Lian piperidines-1-the yl)-solution of 2-oxo-ethyl ester in 1 milliliter of DMF in, and reaction mixture at room temperature stirred spends the night.Reaction soln is filtered through the injection filter, and make crude product through the HPLC purifying.Merge the wash-out part contain product, and evaporate to dryness in a vacuum.

Output: 23 milligrams (theoretical value 21%)

ESI-MS：(M+H) ⁺＝848/850(Cl)

Retention time (HPLC): 2.9 minutes (method B)

Embodiment 4

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-ethoxycarbonylmethyl group-piperidin-4-yl)-piperazine-1-yl]-2-oxo-ethyl ester

0.52 gram (1.62 mmole) TBTU and 0.28 milliliter of (1.61 mmole) ethyl diisopropyl amine are added into 0.80 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine that restrains (1.44 mmole)

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-solution of 1-carboxyl-ethyl ester in 30 milliliters of THF in, and under room temperature, stirred 10 minutes.0.40 gram (1.57 mmole) (4-piperazine-1-base-piperidines-1-yl)-ethyl acetate is added in the reaction mixture, and it is at room temperature stirred spend the night.Add 40 milliliters of EtOAc, with 15%K ₂CO ₃The solution washing organic phase, and with MgSO ₄Dry.Behind siccative and removal of solvents, make residue through chromatography (silica gel, gradient liquid DCM to DCM/EtOH/NH ₃70:30:3) purifying.

Output: 0.68 gram (theoretical value 60%)

ESI-MS：(M+H) ⁺＝792/794(Cl)

R _f=0.70 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

Embodiment 4.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazine-1-yl]-2-oxo-ethyl ester

With the solution of 25 milligrams of (1.02 mmole) LiOH in 20 ml waters, be added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 380 milligrams (0.48 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-ethoxycarbonylmethyl group-piperidin-4-yl)-piperazine-1-yl]-solution of 2-oxo-ethyl ester in 20 milliliters of THF in, and reaction mixture at room temperature stirred spends the night.Remove organic solvent in a vacuum, and mix with 1.1 milliliters of 1M HCl with 20 ml waters.The evaporate to dryness mixture is dissolved among 5 milliliters of DMF residue, and makes crude product through the HPLC purifying in a vacuum.Merge the wash-out part that contains product, and freeze-drying.

Output: 114 milligrams (theoretical value 31%)

ESI-MS：(M+H) ⁺＝764/766(Cl)

R _f=0.07 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

Embodiment 4.2

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-butoxy carbonyl methyl-piperidin-4-yl)-piperazine-1-yl]-2-oxo-ethyl ester

The triethylamine of 51 milligrams of (0.16 mmole) TBTU and 29 microlitres (0.34 mmole) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 80 milligrams (0.11 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazine-1-yl]-solution of 2-oxo-ethyl ester in 1.5 milliliters of DMF in, and mixture was at room temperature vibrated 30 minutes.100 microlitres (1.09 mmole) 1-butanols is added in the reaction mixture, and makes its shaken overnight at room temperature.Through behind the syringe filtering, make crude product through the HPLC purifying.Merge the wash-out part that contains product, and freeze-drying.

Output: 46 milligrams (theoretical value 54%)

ESI-MS：(M+H) ⁺＝820/822(Cl)

R _f=0.67 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

Following compounds is to make from 80 milligrams of 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine in each situation in a similar manner

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazine-1-yl]-2-oxo-ethyl ester and 100 microlitres pure composition separately:

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazine-1-yl]-2-oxo-ethyl ester and 1.5 equivalents (embodiment 4.5 and 4.6) and 1.6 equivalents (embodiment 4.7 and 4.8) pure composition separately:

Embodiment 4.9

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(2-morpholine-4-base-ethoxycarbonylmethyl group)-piperidin-4-yl]-piperazine-1-yl }-2-oxo-ethyl ester

The triethylamine of 50 milligrams of (0.16 mmole) TBTU and 37 microlitres (0.34 mmole) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 100 milligrams (0.13 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazine-1-yl]-solution of 2-oxo-ethyl ester in 5 milliliters of THF in, and under room temperature, stirred 30 minutes.19 microlitres (0.16 mmole) 2-morpholine-4-base-ethanol is added in the reaction mixture, and this suspension was at room temperature stirred 1.5 hours.Add 3 milliliters of DMF, and with mixture restir 4 hours at room temperature.The evaporate to dryness reaction mixture is dissolved among 1.5 milliliters of MeOH residue in a vacuum, filter through the injection filter, and through the HPLC purifying.Make the wash-out part evaporate to dryness in a vacuum that contains product, with DIPE development residue, filtrations of bleeding, and under 50 ℃, drying in a vacuum.

Output: 47 milligrams (theoretical value 41%)

ESI-MS：(M+H) ⁺＝877/879(Cl)

R _f=0.31 (silica gel, DCM/MeOH/NH ₃90:10:1)

Retention time (HPLC): 2.7 minutes (method B)

Embodiment 4.10

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-(4-{1-[2-(2-oxo-tetramethyleneimine-1-yl)-ethoxycarbonylmethyl group]-piperidin-4-yl }-piperazine-1-yl)-ethyl ester

Similar embodiment 4.9, system is from the 4-of 80 milligrams (0.11 mmoles) (2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazine-1-yl]-2-oxo-ethyl ester and 18 microlitres (0.16 mmole) 1-(2-hydroxyl-ethyl)-pyrrolidin-2-one, use 1.5 milliliters of DMF as solvent.

Output: 39 milligrams (theoretical value 43%)

ESI-MS：(M+H) ⁺＝875/877(Cl)

R _f=0.40 (silica gel, DCM/MeOH/NH ₃90:10:1)

Retention time (HPLC): 2.9 minutes (method B)

Embodiment 4.11

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(3-morpholine-4-base-third oxygen carbonyl-methyl)-piperidin-4-yl]-piperazine-1-yl }-2-oxo-ethyl ester

Similar embodiment 4.9, system is from the 4-of 90 milligrams (0.12 mmoles) (2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazine-1-yl]-2-oxo-ethyl ester and 22 milligrams of (0.15 mmole) 3-morpholine-4-base-third-1-alcohol, use 1.5 milliliters of DMF as solvent.Behind the HPLC purifying, product is dissolved among the DCM, with 5%NaHCO ₃The solution extraction organic phase, and with Na ₂SO ₄Dry.Behind siccative and removal of solvents, residue is stirred with DIPE, the filtration of bleeding, and in air drying.

Output: 48 milligrams (theoretical value 46%)

ESI-MS：(M+H) ⁺＝891/893(Cl)

R _f=0.17 (silica gel, DCM/MeOH/NH ₃90:10:1)

Retention time (HPLC): 2.7 minutes (method B)

Embodiment 4.12

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(2,2-dimethyl-propionyloxy methoxycarbonyl-methyl)-piperidin-4-yl]-piperazine-1-yl }-2-oxo-ethyl ester

With 42 milligrams of (0.30 mmole) K ₂CO ₃With 43 microlitres (0.30 mmole) 2,2-dimethyl-propionic acid chloromethyl ester is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 150 milligrams (0.20 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazine-1-yl]-solution of 2-oxo-ethyl ester in 5 milliliters of DMF in, and reaction mixture at room temperature stirred spends the night.Make its evaporate to dryness in a vacuum, with residue and 30 milliliters of 15%K ₂CO ₃Solution mixes, and bleed and filter sedimentary product, and through column chromatography (silica gel, gradient liquid DCM to DCM/MeOH/NH ₃50:47:3) purifying.

Output: 50 milligrams (theoretical value 29%)

ESI-MS：(M+H) ⁺＝878/880(Cl)

R _f=0.63 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

Embodiment 4.13

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(1-ethoxycarbonyl-oxygen base-ethoxycarbonyl-methyl)-piperidin-4-yl]-piperazine-1-yl }-2-oxo-ethyl ester

Similar embodiment 4.12, system is from the 4-of 150 milligrams (0.20 mmoles) (2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazine-1-yl]-2-oxo-ethyl ester and 40 microlitres (0.30 mmole) 1-chloroethyl-ethyl-carbonate.

Output: 50 milligrams (theoretical value 29%)

ESI-MS：(M+H) ⁺＝880/882(Cl)

R _f=0.68 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

Embodiment 4.14

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-diethyl amino formyl radical methoxyl group-carbonyl methyl-piperidin-4-yl)-piperazine-1-yl]-2-oxo-ethyl ester

Triethylamine and 30 milligrams of (0.23 mmole) N with 50 milligrams of (0.16 mmole) TBTU, 25 microlitres (0.18 mmole), N-diethyl-2-hydroxyl-ethanamide is added into 4-(2-oxo-1,2,4 of 100 milligrams (0.13 mmoles), 5-tetrahydrochysene-1, the 3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-three fluoro-methyl-benzyls)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazine-1-yl]-solution of 2-oxo-ethyl ester in 1 milliliter of DMF in, and reaction mixture at room temperature stirred 20 hours.Reaction soln is poured over saturated NaHCO ₃On the solution, bleed and filter formed throw out, and dry.Make crude product through the HPLC purifying.Merge the wash-out part that contains product, and freeze-drying.

Output: 36 milligrams (theoretical value 31%)

ESI-MS：(M+H) ⁺＝877/879(Cl)

Retention time (HPLC): 3.2 minutes (method B)

Following compounds is to make from 100 milligrams of 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine in each situation in a similar manner

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazine-1-yl]-each pure composition of 2-oxo-ethyl ester and its respective amount:

Embodiment 5

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-ethoxycarbonylmethyl group-piperazine-1-yl)-piperidines-1-yl]-2-oxo-ethyl ester

The triethylamine of 64 milligrams of (0.20 mmole) TBTU and 28 microlitres (0.20 mmole) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 100 milligrams (0.18 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-solution of 1-carboxyl-ethyl ester in 1 milliliter of DMF in, and under room temperature, stirred 10 minutes.51 milligrams (0.20 mmoles) (4-piperidin-4-yl-piperazine-1-yl)-ethyl acetate is added in the reaction mixture, and makes its shaken overnight at room temperature.After filtering through the injection filter, make reaction soln through the HPLC purifying, need not further processing.Merge the wash-out part that contains product, and freeze-drying.

Output: 91 milligrams (theoretical value 64%)

ESI-MS：(M+H) ⁺＝792/794(Cl)

R _f=0.48 (silica gel, DCM/MeOH/NH ₃90:10:1)

Embodiment 5.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-carboxymethyl-piperazine-1-yl)-piperidines-1-yl]-2-oxo-ethyl ester

With the solution of 3.6 milligrams of (0.15 mmole) LiOH in 1 ml water, be added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 70 milligrams (0.09 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-ethoxy carbonyl methyl-piperazine-1-yl)-piperidines-1-yl]-solution of 2-oxo-ethyl ester in 10 milliliters of DTH in, and reaction mixture at room temperature stirred spends the night.In nitrogen gas stream, remove THF,, then add formic acid, till obtaining acid reactant, add acetonitrile then, and make product stand lyophilize then with mixes with small amount of water.

Output: 52 milligrams (theoretical value 76%)

ESI-MS：(M-H) ^-＝762/764(Cl)

R _f=0.14 (silica gel, DCM/MeOH/NH ₃90:10:1)

Embodiment 5.2

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-dimethylamino formyl radical methoxycarbonyl-methyl-piperazine-1-yl)-piperidines-1-yl]-2-oxo-ethyl ester

Triethylamine and 29 milligrams of (0.28 mmole) 2-hydroxy-ns with 90 milligrams of (0.28 mmole) TBTU, 39 microlitres (0.15 mmole), N-dimethyl-ethanamide is added into 4-(2-oxo-1,2,4 of 190 milligrams (0.25 mmoles), 5-tetrahydrochysene-1, the 3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-carboxymethyl-piperazine-1-yl)-piperidines-1-yl]-solution of 2-oxo-ethyl ester in 5 milliliters of DMF in, and reaction mixture at room temperature stirred spends the night.Reaction soln is filtered through the injection filter, and make crude product through the HPLC purifying.Merge the wash-out part that contains product, and freeze-drying.

Output: 106 milligrams (theoretical value 50%)

ESI-MS：(M+H) ⁺＝849/851(Cl)

Retention time (HPLC): 3.3 minutes (method B)

Embodiment 6

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1 '-(2-ethoxycarbonyl-ethyl)-4,4 '-Lian piperidines-1-yl]-2-oxo-ethyl ester

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-solution of 1-carboxyl-ethyl ester in 1 milliliter of DMF in, and under room temperature, stirred 10 minutes.With 54 milligrams of (0.20 mmole) 3-[4,4 '] connection piperidines-1-base-ethyl propionate (amine A1) is added in the reaction mixture, and makes its shaken overnight at room temperature.After filtering through the injection filter, make reaction soln through the HPLC purifying, need not further processing.Merge the wash-out part that contains product, and freeze-drying.

Output: 42 milligrams (theoretical value 29%)

ESI-MS：(M+H) ⁺＝805/807(Cl)

R _f=0.58 (silica gel, DCM/MeOH/NH ₃90:10:1)

Embodiment 6.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1 '-(2-carboxyl-ethyl)-4,4 '-Lian piperidines-1-yl]-2-oxo-ethyl ester

With the solution of 1.4 milligrams of (0.06 mmole) LiOH in 1 ml water, be added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 30 milligrams (0.04 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1 '-(2-ethoxy carbonyl-ethyl)-4,4 '-Lian piperidines-1-yl]-solution of 2-oxo-ethyl ester in 10 milliliters of THF in, and reaction mixture at room temperature stirred spends the night.In nitrogen gas stream, remove THF, add less water then, then add formic acid, till obtaining acid reactant, then add acetonitrile, and make crude product through the HPLC purifying.Merge the wash-out part that contains product, and freeze-drying.

Output: 28 milligrams (theoretical value 97%)

ESI-MS：(M+H) ⁺＝777/779(Cl)

R _f=0.15 (silica gel, DCM/MeOH/NH ₃90:10:1)

Embodiment 7

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(2-ethoxycarbonyl-ethyl)-piperidin-4-yl]-piperazine-1-yl }-2-oxo-ethyl ester

The triethylamine of 64 milligrams of (0.20 mmole) TBTU and 111 microlitres (0.80 mmole) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 100 milligrams (0.18 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-solution of 1-carboxyl-ethyl ester in 1 milliliter of DMF in, and under room temperature, stirred 10 minutes.122 milligrams of (0.20 mmole) 3-(4-piperazine-1-base-piperidines-1-yl)-ethyl propionate (amine A2 uses with three-trifluoroacetate) is added in the reaction mixture, and makes its shaken overnight at room temperature.After filtering through the injection filter, make reaction soln through the HPLC purifying, need not further processing.Merge the wash-out part that contains product, and freeze-drying.

Output: 45 milligrams (theoretical value 31%)

ESI-MS：(M+H) ⁺＝806/808(Cl)

R _f=0.57 (silica gel, DCM/MeOH/NH ₃90:10:1)

Embodiment 7.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(2-carboxyl-ethyl)-piperidin-4-yl]-piperazine-1-yl }-2-oxo-ethyl ester

Similar embodiment 6.1, system is from the 4-of 30 milligrams (0.04 mmoles) (2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(2-ethoxycarbonyl-ethyl)-piperidin-4-yl]-piperazine-1-yl }-2-oxo-ethyl ester and 1.4 milligrams of (0.06 mmole) LiOH.

Output: 15 milligrams (theoretical value 51%)

ESI-MS：(M-H) ^-＝776/778(Cl)

R _f=0.13 (silica gel, DCM/MeOH/NH ₃90:10:1)

Embodiment 7.2

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(4-{1-[2-(2-dimethylin-ethoxycarbonyl)-ethyl]-piperidin-4-yl }-piperazine-1-yl)-2-oxo-ethyl ester

The triethylamine of 48 milligrams of (0.15 mmole) TBTU and 21 microlitres (0.15 mmole) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 100 milligrams (0.13 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(2-carboxyl-ethyl)-piperidin-4-yl]-piperazine-1-yl-solution of 2-oxo-ethyl ester in 1 milliliter of DMF in, and at room temperature stirred 10 minutes.15 microlitres (0.15 mmole) 2-dimethylamino-ethanol is added in the reaction mixture, and makes its shaken overnight at room temperature.After filtering through the injection filter, make reaction soln through the HPLC purifying, need not further processing.Merge the wash-out part that contains product, and freeze-drying.

Output: 22 milligrams (theoretical value 20%)

ESI-MS：(M+H) ⁺＝849/851(Cl)

Retention time (HPLC): 2.8 minutes (method B)

Following compounds is to make from the 4-of 100 milligrams (embodiment 7.3 and 7.4) or 95 milligrams (embodiment 7.5) (2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine in each situation in a similar manner

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(2-carboxyl-ethyl)-piperidin-4-yl]-piperazine-1-yl }-each pure composition of 2-oxo-ethyl ester and its respective amount:

Embodiment 8

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[4-(2-ethoxycarbonyl-ethyl)-piperazine-1-yl]-piperidines-1-yl }-2-oxo-ethyl ester

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-solution of 1-carboxyl-ethyl ester in 1 milliliter of DMF in, and under room temperature, stirred 10 minutes.54 milligrams of (0.20 mmole) 3-(4-piperidin-4-yl-piperazine-1-yl)-ethyl propionate (amine A3) is added in the reaction mixture, and makes its shaken overnight at room temperature.After filtering through the injection filter, make reaction soln through the HPLC purifying, need not further processing.Merge the wash-out part that contains product, and freeze-drying.

Output: 77 milligrams (theoretical value 53%)

ESI-MS：(M+H) ⁺＝806/808(Cl)

R _f=0.58 (silica gel, DCM/MeOH/NH ₃90:10:1)

Embodiment 8.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[4-(2-carboxyl-ethyl)-piperazine-4-yl]-piperidines-1-yl }-2-oxo-ethyl ester

Similar embodiment 6.1, system is from the 4-of 60 milligrams (0.07 mmoles) (2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[4-(2-ethoxycarbonyl-ethyl)-piperazine-1-yl]-piperidines-1-yl }-2-oxo-ethyl ester and 2.9 milligrams of (0.12 mmole) LiOH.

Output: 40 milligrams (theoretical value 70%)

ESI-MS：(M-H) ^-＝776/778(Cl)

R _f=0.14 (silica gel, DCM/MeOH/NH ₃90:10:1)

Embodiment 9

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((R)-2-ethoxycarbonyl-tetramethyleneimine-1-yl)-piperidines-1-yl]-2-oxo-ethyl ester

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-solution of 1-carboxyl-ethyl ester in 1 milliliter of DMF in, and under room temperature, stirred 10 minutes.With 45 milligrams (0.20 mmoles) (R)-1-piperidin-4-yl-tetramethyleneimine-2-carboxylic acid, ethyl ester is added in the reaction mixture, and makes its shaken overnight at room temperature.After filtering through the injection filter, make reaction soln through the HPLC purifying, need not further processing.Merge the wash-out part that contains product, and freeze-drying.

Output: 77 milligrams (theoretical value 56%)

ESI-MS：(M+H) ⁺＝763/765(Cl)

Retention time (HPLC): 3.4 minutes (method B)

Embodiment 9.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((R)-2-carboxyl-tetramethyleneimine-1-yl)-piperidines-1-yl]-2-oxo-ethyl ester

Similar embodiment 6.1, system is from the 4-of 60 milligrams (0.08 mmoles) (2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((R)-2-ethoxycarbonyl-tetramethyleneimine-1-yl)-piperidines-1-yl]-2-oxo-ethyl ester and 2.9 milligrams of (0.12 mmole) LiOH.

Output: 42 milligrams (theoretical value 73%)

ESI-MS：(M+H) ⁺＝735/737(Cl)

Retention time (HPLC): 3.3 minutes (method B)

Embodiment 9.2

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((R)-2-dimethylamino formyl radical methoxycarbonyl-tetramethyleneimine-1-yl)-piperidines-1-yl]-2-oxo-ethyl ester

The triethylamine of 25 milligrams of (0.08 mmole) TBTU and 11 microlitres (0.08 mmole) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 50 milligrams (0.07 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((R)-2-carboxyl-tetramethyleneimine-1-yl)-pyridine-1-yl]-solution of 2-oxo-ethyl ester in 1 milliliter of DMF in, and under room temperature, stirred 10 minutes.With 8.1 milligrams of (0.08 mmole) 2-hydroxy-ns, N-dimethyl-ethanamide is added in the reaction mixture, and makes its shaken overnight at room temperature.After filtering through the injection filter, make reaction soln through the HPLC purifying, need not further processing.Merge the wash-out part that contains product, and freeze-drying.

Output: 38 milligrams (theoretical value 68%)

ESI-MS：(M+H) ⁺＝820/822(Cl)

Retention time (HPLC): 2.9 minutes (method A)

Embodiment 9.3

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[(R)-2-(2-morpholine-4-base-ethoxycarbonyl)-tetramethyleneimine-1-yl]-piperidines-1-yl }-2-oxo-ethyl ester

Similar embodiment 9.2, system is from the 4-of 50 milligrams (0.07 mmoles) (2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((R)-2-carboxyl-tetramethyleneimine-1-yl)-piperidines-1-yl]-2-oxo-ethyl ester and 10.3 milligrams of (0.08 mmole) 2-morpholine-4-base-ethanol.

Output: 35 milligrams (theoretical value 61%)

ESI-MS：(M+H) ⁺＝848/850(Cl)

Retention time (HPLC): 2.6 minutes (method A)

Embodiment 10

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((S)-2-methoxycarbonyl-tetramethyleneimine-1-yl)-piperidines-1-yl]-2-oxo-ethyl ester

Similar embodiment 9, system is from the 4-of 100 milligrams (0.18 mmoles) (2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxyl-ethyl ester and 42 milligrams (0.20 mmole) (S)-1-piperidin-4-yl-pyridine alkane-2-carboxylate methyl ester.

Output: 80 milligrams (theoretical value 59%)

ESI-MS：(M+H) ⁺＝749/751(Cl)

Retention time (HPLC): 3.3 minutes (method B)

Embodiment 10.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((S)-2-carboxyl-tetramethyleneimine-1-yl)-piperidines-1-yl]-2-oxo-ethyl ester

With the solution of 2.9 milligrams of (0.12 mmole) LiOH in 1 ml water, be added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 60 milligrams (0.08 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((S)-2-methoxycarbonyl-tetramethyleneimine-1-yl)-piperidines-1-yl]-solution of 2-oxo-ethyl ester in 3 milliliters of THF in, and reaction mixture at room temperature stirred spends the night.In nitrogen gas stream, remove solvent, residue is dissolved in 1 ml water, add formic acid, till obtaining acid reactant, and thoroughly extract mixture with EtOAc.The organic collection liquid that makes merging is with Na ₂SO ₄Drying is filtered, and evaporate to dryness in a vacuum.Residue is dissolved in less water and the acetonitrile, and freeze-drying.

Output: 51 milligrams (theoretical value 87%)

ESI-MS：(M+H) ⁺＝735/737(Cl)

Retention time (HPLC): 3.3 minutes (method B)

Embodiment 10.2

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((S)-2-dimethylamino formyl radical methoxycarbonyl-tetramethyleneimine-1-yl)-piperidines-1-yl]-2-oxo-ethyl ester

Similar embodiment 9.2, system is from the 4-of 70 milligrams (0.10 mmoles) (2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((S)-2-carboxyl-tetramethyleneimine-1-yl)-piperidines-1-yl]-2-oxo-ethyl ester and 11 milligrams of (0.11 mmole) 2-hydroxy-ns, N-dimethyl-ethanamide.

Output: 45 milligrams (theoretical value 58%)

ESI-MS：(M+H) ⁺＝820/822(Cl)

Retention time (HPLC): 3.0 minutes (method A)

Embodiment 10.3

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[(S)-2-(morpholine-4-base-ethoxycarbonyl)-tetramethyleneimine-1-yl]-piperidines-1-yl }-2-oxo-ethyl ester

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((S)-2-carboxyl-tetramethyleneimine-1-yl)-piperidines-1-yl]-2-oxo-ethyl ester and 13.2 milligrams of (0.11 mmole) 2-morpholine-4-base-ethanol.

Output: 54 milligrams (theoretical value 59%)

ESI-MS：(M+H) ⁺＝848/850(Cl)

Retention time (HPLC): 2.6 minutes (method A)

Embodiment 11

(R)-1 '-and (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl }-1,4 '-Lian piperidyl-2-carboxylate methyl ester

The triethylamine of 64 milligrams of (0.20 mmole) TBTU and 56 microlitres (0.40 mmole) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 100 milligrams (0.18 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-solution of 1-carboxyl-ethyl ester in 1 milliliter of DMF in, and at room temperature stirred 10 minutes.57 milligrams (0.20 mmoles) (R)-[1,4 '] are joined piperidyl-2-carboxylate methyl ester (using with acetate) be added in the reaction mixture, and make its shaken overnight at room temperature.After filtering through the injection filter, make reaction soln through the HPLC purifying, need not further processing.Merge the wash-out part that contains product, and freeze-drying.

Output: 59 milligrams (theoretical value 43%)

ESI-MS：(M+H) ⁺＝763/765(Cl)

R _f=0.50 (silica gel, DCM/MeOH/NH ₃90:10:1)

Embodiment 11.1

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl }-1,4 '-Lian piperidyl-2-carboxylic acid

Similar embodiment 6.1, the system from 40 milligrams (0.05 mmoles) (R)-1 '-(R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl }-1,4 '-Lian piperidyl-2-carboxylate methyl ester and 1.9 milligrams of (0.08 mmole) LiOH.

Output: 10 milligrams (theoretical value 25%)

ESI-MS：(M-H) ^-＝747/749(Cl)

R _f=0.27 (silica gel, DCM/MeOH/NH ₃90:10:1)

Embodiment 12

(S)-1 '-and (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

Similar embodiment 11, system is from the 4-of 100 milligrams (0.18 mmoles) (2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine leather-3-yl)-(S)-[1,4 '] two pyridyl-2-carboxylate methyl ester of piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxyl-ethyl ester and 45 milligrams (0.20 mmole).

Output: 33 milligrams (theoretical value 24%)

ESI-MS：(M+H) ⁺＝763/765(Cl)

R _f=0.44 (silica gel, DCM/MeOH/NH ₃90:10:1)

Embodiment 12.1

Similar embodiment 6.1, the system from 20 milligrams (0.03 mmoles) (S)-1 '-(R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl }-1,4 '-Lian piperidyl-2-carboxylate methyl ester and 1.2 milligrams of (0.05 mmole) LiOH.

Output: 3 milligrams (theoretical value 15%)

ESI-MS：(M-H) ^-＝747/749(Cl)

Rf=0.29 (silica gel, DCM/MeOH/NH ₃90:10:1)

Embodiment 13

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-oxyethyl group oxalyl group-4,4 '-Lian piperidines-1-yl)-2-oxo-ethyl ester

The triethylamine of 64 milligrams of (0.20 mmole) TBTU and 70 microlitres (0.50 mmole) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 100 milligrams (0.18 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-solution of 1-carboxyl-ethyl ester in 2 milliliters of DMF in, and under room temperature, stirred 10 minutes.54 milligrams (0.20 mmole) [4,4 '] connection piperidines-1-base-oxo-acetic acids ethyl ester (amine A4) is added in the reaction mixture, and makes its shaken overnight at room temperature.After filtering through the injection filter, make reaction soln through the HPLC purifying, need not further processing.Merge the wash-out part that contains product, and freeze-drying.

Output: 88 milligrams (theoretical value 61%)

ESI-MS：(M+H) ⁺＝805/807(Cl)

Retention time (HPLC): 4.5 minutes (method B)

Embodiment 13.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-oxalyl group-4,4 '-Lian piperidines-1-yl)-2-oxo-ethyl ester

Similar embodiment 6.1, system is from the 4-of 40 milligrams (0.05 mmoles) (2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-oxyethyl group oxalyl group-4,4 '-Lian piperidines-1-yl)-2-oxo-ethyl ester will with 3.6 milligrams of (0.15 mmole) LiOH.

Output: 26 milligrams (theoretical value 67%)

ESI-MS：(M+H) ⁺＝777/779(Cl)

Retention time (HPLC): 5.0 minutes (method C)

Embodiment 13.2

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-dimethylamino formyl radical-methoxyl group oxalyl group-4,4 '-Lian piperidines-1-yl)-2-oxo-ethyl ester

Similar embodiment 7.2, system is from the 4-of 100 milligrams (0.13 mmoles) (2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-oxalyl group-4,4 '-Lian piperidines-1-yl)-2-oxo-ethyl ester and 15 milligrams of (0.15 mmole) 2-hydroxy-ns, N-dimethyl-ethanamide.

Output: 70 milligrams (theoretical value 63%)

ESI-MS：(M+H) ⁺＝862/864(Cl)

Retention time (HPLC): 4.1 minutes (method B)

Embodiment 13.3

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1 '-(2-morpholine-4-base-oxyethyl group oxalyl group)-4,4 '-Lian piperidines-1-yl]-2-oxo-ethyl ester

Similar embodiment 9.2, system is from the 4-of 100 milligrams (0.13 mmoles) (2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-oxalyl group-4,4 '-Lian piperidines-1-yl)-2-oxo-ethyl ester and 18 microlitres (0.15 mmole) 2-morpholine-4-base-ethanol.

Output: 69 milligrams (theoretical value 60%)

ESI-MS：(M+H) ⁺＝890/892(Cl)

Retention time (HPLC): 3.6 minutes (method B)

Embodiment 14

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1 '-(3-ethoxycarbonyl-propionyl)-4,4 '-Lian piperidines-1-yl]-2-oxo-ethyl ester

The triethylamine of 64 milligrams of (0.20 mmole) TBTU and 28 microlitres (0.50 mmole) is added into 4-(the 2-oxo-1 of 100 milligrams (0.18 mmoles), 2,4,5-tetrahydrochysene-1,3-benzodiazepine leather-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-solution of 1-carboxyl-ethyl ester in 1 milliliter of DMF in, and under room temperature, stirred 10 minutes.With the 4-[4 of 59 milligrams (0.20 mmoles), 4 '] connection piperidines-1-base-4-oxo-ethyl butyrate (amine A5) is added in the reaction mixture, and makes its shaken overnight at room temperature.After filtering through the injection filter, make reaction soln through the HPLC purifying, need not further processing.Merge the wash-out part that contains product, and freeze-drying.

Output: 61 milligrams (theoretical value 41%)

ESI-MS：(M+H) ⁺＝833/835(Cl)

R _f=0.61 (silica gel, DCM/MeOH/NH ₃90:10:1)

Embodiment 14.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1 '-(3-carboxyl-propionyl)-4,4 '-Lian piperidines-1-yl]-2-oxo-ethyl ester

With the solution of 1.9 milligrams of (0.08 mmole) LiOH in 1 ml water, be added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 40 milligrams (0.05 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1 '-(3-ethoxy carbonyl-propionyl)-4; 4 '-Lian piperidines-1-yl]-solution of 2-oxo-ethyl ester in 10 milliliters of THF in, and reaction mixture at room temperature stirred spends the night.In nitrogen gas stream, remove solvent, residue is dissolved in 1 ml water, mix, till obtaining acid reactant, and mixes, reach freeze-drying with 1 milliliter of acetonitrile with formic acid.Residue is dissolved among 1 milliliter of DMF, and through the HPLC purifying.Merge the wash-out part that contains product, and freeze-drying.

Output: 19 milligrams (theoretical value 39%)

ESI-MS：(M+H) ⁺＝805/807(Cl)

Rf=0.16 (silica gel, DCM/MeOH/NH ₃90:10:1)

Embodiment 14.2

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{1 '-[3-(2-morpholine-4-base-ethoxycarbonyl)-propionyl]-4,4 '-Lian piperidines-1-yl }-2-oxo-ethyl ester

Similar embodiment 9.2, system is from the 4-of 100 milligrams (0.12 mmoles) (2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1 '-(3-carboxyl-propionyl)-4,4 '-Lian piperidines-1-yl]-2-oxo-ethyl ester and 17 microlitres (0.14 mmole) 2-morpholine-4-base-ethanol.

Output: 16 milligrams (theoretical value 14%)

ESI-MS：(M+H) ²⁺＝459/460(Cl)

Retention time (HPLC): 3.7 minutes (method B)

Embodiment 15

4-(7-methoxyl group-2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

15a) 4-(7-methoxyl group-2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-ethoxycarbonyl-ethyl ester

1.29 gram (6.42 mmole) chloroformic acid 4-nitro phenyl esters are added in the solution of 0.79 gram (6.42 mmole) DMAP in 50 milliliters of pyridines, and at room temperature stirred 1 hour.Drip 2.00 grams (6.42 mmole) (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-solution of 2-hydroxyl-ethyl propionate in 15 milliliters of pyridines, and reaction mixture at room temperature stirred 2 hours.Portion-wise addition 1.77 restrains (6.42 mmole) 7-methoxyl group-3-piperidin-4-yls-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine then

-2-ketone.This suspension was at room temperature stirred 72 hours, follow evaporate to dryness in a vacuum.Residue is mixed with 200 milliliters of EtOAc, with 200 milliliters of 15%K ₂CO ₃Solution washing is isolated organic phase, and evaporate to dryness in a vacuum.Make residue through chromatography (silica gel, gradient liquid DCM to MeOH/NH ₃95:5) purifying.

Output: 1.80 grams (theoretical value 46%)

ESI-MS：(M+H) ⁺＝613/615(Cl)

Rf=0.50 (silica gel, DCM/MeOH9:1)

15b) 4-(7-methoxyl group-2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

With the solution of 0.11 gram (4.50 mmole) LiOH in 50 ml waters, be added into 4-(7-methoxyl group-2-oxo-1,3,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 1.80 grams (2.94 mmole)

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-solution of 1-ethoxycarbonyl-ethyl ester in 50 milliliters of THF in, and reaction mixture at room temperature stirred 3 hours.Remove THF in a vacuum, with the dilution of 100 ml waters, and with 1M HCl acidifying.Bleed and filter sedimentary material, with the washing of 50 ml waters, and in vacuum drying oven, dry down at 65 ℃.

Output: 1.60 milligrams (theoretical value 93%)

ESI-MS：(M+H) ⁺＝585/587(Cl)

15c) 4-(7-methoxyl group-2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

Similar embodiment 9, system is from the 4-of 100 milligrams (0.17 mmoles) (7-methoxyl group-2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxyl-ethyl ester and 48 milligrams (0.19 mmole) [4,4 '] connection piperidines-1-base-ethyl acetate.

Output: 58 milligrams (theoretical value 41%)

ESI-MS：(M+H) ⁺＝821/823(Cl)

Retention time (HPLC): 3.0 minutes (method B)

Embodiment 15.1

4-(7-methoxyl group-2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

With the solution of 1 milligram of (0.04 mmole) LiOH in 1 ml water, be added into 4-(7-methoxyl group-2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 20 milligrams (0.02 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-ethoxycarbonylmethyl group-4,4 '-Lian piperidines-1-yl)-solution of 2-oxo-ethyl ester in 1 milliliter of THF in, and reaction mixture at room temperature stirred spends the night.For finishing reaction, thus the solution of 1 milligram of LiOH in 1 ml water added again, and with mixture restir 3 hours at room temperature.In nitrogen gas stream, remove solvent, residue is dissolved in the mixture of acetonitrile and water, and makes product stand lyophilize.

Output: 14 milligrams (theoretical value 72%)

ESI-MS：(M+H) ⁺＝793/795(Cl)

Retention time (HPLC): 2.6 minutes (method B)

Embodiment 15.2

4-(7-methoxyl group-2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1 '-(2-morpholine-4-base-ethoxycarbonyl-methyl)-4,4 '-Lian piperidines-1-yl]-2-oxo-ethyl ester

The triethylamine of 113 milligrams of (0.35 mmole) TBTU, 84 microlitres (0.60 mmole) and 39 milligrams of (0.30 mmole) 2-morpholine-4-base-ethanol are added into 4-(the 7-methoxyl group-2-oxo-1 of 230 milligrams (0.29 mmoles), 2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-carboxymethyl-4,4 '-Lian piperidines-1-the yl)-solution of 2-oxo-ethyl ester in 5 milliliters of DMF in, and reaction mixture at room temperature stirred spends the night.Reaction soln is poured over saturated NaHCO ₃On the solution, bleed and filter sedimentary product, and dry down at 40 ℃.Crude product is dissolved in 25 milliliters of anhydrous isopropyl alcohols, and is precipitated as salt with the 0.5M HCl in the Virahol.Leach throw out, with 5 milliliters of Virahols and 30 milliliters of DIPE washings, and in vacuum drying oven, 30 ℃ of following dried overnight.

Output: 90 milligrams (theoretical value 34%)

ESI-MS：(M+H) ⁺＝906/908(Cl)

Retention time (HPLC): 3.1 minutes (method B)

Embodiment 16

4-(7-methoxyl group-2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxyl-ethyl ester and 49 milligrams (0.19 mmole) (4-piperidin-4-yl-piperazine-1-yl)-ethyl acetate.

Output: 62 milligrams (theoretical value 44%)

ESI-MS：(M+H) ⁺＝822/824(Cl)

Retention time (HPLC): 2.9 minutes (method B)

Embodiment 16.1

4-(7-methoxyl group-2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

Similar embodiment 15.1, system is from the 4-of 20 milligrams (0.02 mmoles) (7-methoxyl group-2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-ethoxycarbonylmethyl group-piperazine-1-yl)-piperidines-1-yl]-2-oxo-ethyl ester and 2 milligrams of (0.08 mmole) LiOH.

Output: 19 milligrams (theoretical value 99%)

ESI-MS：(M+H) ⁺＝794/796(Cl)

Retention time (HPLC): 2.6 minutes (method B)

Embodiment 17

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-methyl-benzyl)-2-(1 '-ethoxycarbonylmethyl group-4,4 '-Lian piperidines-1-yl)-2-oxo-ethyl ester

17a) (Z, E)-2-acetylaminohydroxyphenylarsonic acid 3-(4-amino-3-chloro-5-methyl-phenyl)-methyl acrylate

Under nitrogen atmosphere, with the three-neighbour-tolyl-phosphine and 11.0 gram (49.0 mmole) Pd (OAc) of 15.4 grams (49.1 mmole) ₂The 4-bromo-2-chloro-6-methyl-aniline that are added into 72.8 grams (330 mmole) and 58.0 gram (397 mmole) 2-acetylaminohydroxyphenylarsonic acid methyl acrylates and descend stirring 18 hours with reaction mixture in 80 ℃ in the mixture in 970 milliliters of triethylamines and the 1.2 liters of acetonitriles.After the reaction cooling, filtering solution, evaporate to dryness stirs residue with 350 ml waters and 350 milliliters of EtOAc in a vacuum.Decant goes out solvent, residue stirred with 300 milliliters of EtOAc again, and the filtration of bleeding, with a small amount of EtOAc and MTBE washing, and dry down in 60 ℃.

Output: 40.6 grams (theoretical value 44%)

ESI-MS：(M+H) ⁺＝283/285(Cl)

R _f=0.47 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

17b) 3-(4-amino-3-chloro-5-methyl-phenyl)-2-oxo-propionic acid

Under nitrogen atmosphere, (Z, E)-2-acetylaminohydroxyphenylarsonic acid 3-(4-amino-3-chloro-5-methyl-phenyl)-methyl acrylate is at 250 milliliter 1, the solution among 4-diox and the 125 milliliters of HCl (4M) is 80 ℃ of stirrings 6 hours down with 28.0 grams (99.0 mmole).Remove solvent in a vacuum,, bleed to filter and remove throw out with Virahol and DIPE development residue, and dry down in 60 ℃.Obtain product, be its hydrochloride, make its further reaction, need not purifying.

Output: 26.0 grams (theoretical value 99%)

ESI-MS：(M-H) ^-＝226/228(Cl)

R _f=0.15 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

17c) (R)-3-(4-amino-3-chloro-5-methyl-phenyl)-2-hydroxyl-methyl propionate

Under nitrogen atmosphere, with 27.0 grams (84.2 mmole) (1R)-the B-chlorine two-solution of different loose pinane phenylborinane in 75 milliliters of THF, in 15 minutes, drop in the solution of triethylamine in 175 milliliters of THF of 13.0 gram (49.2 mmole) 3-(4-amino-3-chloro-5-methyl-phenyl)-2-oxo-propionic acid of being cooled to approximately-30 ℃ and 17.0 milliliters (122.3 mmoles).After interpolation stops, removing cooling bath, and reaction mixture at room temperature stirred spend the night.Down 150 milliliters of 1M NaOH are dropped in the reaction mixture ice-cooled.Add 200 milliliters of EtOAc,, isolate water mixture restir 15 minutes, and with organic phase with each 50 milliliters of 1M NaOH washed twice, with 40 milliliters of washings once, and be adjusted to acidity with 4MHCl.Isolate organic phase, with MgSO ₄Drying, and evaporate to dryness in a vacuum.Residue is mixed with 250 ml methanol HCl (1.25M), and at room temperature stir and spend the night.The evaporate to dryness reaction mixture is dissolved among a small amount of PE and the EtOAc residue in a vacuum, be placed on the silica gel, and with PE/EtOAc (2:1) wash-out.Merge the wash-out part that contains product, and evaporate to dryness.

Output: 6.0 grams (theoretical value 50%)

ESI-MS：(M+H) ⁺＝244/246(Cl)

R _f=0.74 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

17d) 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-methyl-phenyl)-1-carboxyl-ethyl ester

Similar embodiment 1e, system from 6.0 grams (24.6 mmole) (R)-3-(4-amino-3-chloro-5-methyl-phenyl)-2-hydroxyl-methyl propionate and 6.1 restrains (24.9 mmole) 3-piperidin-4-yls-1,3,4,5-tetrahydrochysene-1,3-benzodiazepine

-2-ketone.Rough methyl esters product is dissolved among 100 milliliters of THF, and mixes with the solution of 1.0 gram (40.9 mmole) LiOH in 50 ml waters.Reaction mixture was at room temperature stirred 15 hours,, and remove organic solvent in a vacuum with the water dilution.With 60 milliliters of EtOAc washing waters,, and at room temperature stirred 15 minutes with 21 milliliters of 4M HCl acidifying.With each 150 milliliters of DCM extraction three times, and the organic phase that makes merging is with MgSO with mixture ₄Dry.Behind siccative and removal of solvents, make residue through chromatography (silica gel, gradient liquid DCM to DCM/MeOH/NH ₃70:27:3) purifying.

Output: 0.88 gram (theoretical value 7%)

ESI-MS：(M+H) ⁺＝501/503(Cl)

R _f=0.17 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

17e) 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

Similar embodiment 5, system is from the 4-of 100 milligrams (0.20 mmoles) (2-oxo-1,3,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-methyl-phenyl)-1-carboxyl-ethyl ester and 56 milligrams (0.22 mmole) [4,4 '] connection piperidines-1-base-ethyl acetate.

Output: 19 milligrams (theoretical value 13%)

ESI-MS：(M+H) ⁺＝737/739(Cl)

R _f=0.72 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

Embodiment 17.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-methyl-benzyl)-2-(1 '-carboxymethyl-4,4 '-Lian piperidines-1-yl)-2-oxo-ethyl ester

With the solution of 7.0 milligrams of (0.29 mmole) LiOH in 5 ml waters, be added into 80 milligrams of (0.11 mmole) 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepines

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-methyl-benzyl)-2-(1 '-ethoxycarbonyl-methyl-4,4 '-Lian piperidines-1-the yl)-solution of 2-oxo-ethyl ester in 10 milliliters of THF in, and reaction mixture at room temperature stirred spends the night.Remove THF in a vacuum, moist residue is mixed with 0.35 milliliter of 1M HCl, and evaporate to dryness in a vacuum.Make residue through the HPLC purifying.Merge the wash-out part that contains product, and freeze-drying.

Output: 8 milligrams (theoretical value 10%)

ESI-MS：(M+H) ⁺＝709/711(Cl)

R _f=0.21 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

Embodiment 18

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(3-chloro-4-hydroxy-5-methyl base-benzyl)-2-(1 '-ethoxycarbonylmethyl group-4,4 '-Lian piperidines-1-yl)-2-oxo-ethyl ester

18a) 2-benzyloxy-5-bromo-1-chloro-3-methyl-benzene

7.0 milliliters of (57.7 mmole) cylites are added into 4-bromo-2-chloro-6-methyl-phenol and 30.0 gram (217 mmole) K of 10.2 grams (46.1 mmole) ₂CO ₃In the suspension in 130 milliliters of DMF, and reaction mixture at room temperature stirred spend the night.Leach insoluble composition, evaporate to dryness filtrate is mixed with water, and is thoroughly extracted with EtOAc in a vacuum.The organic phase that makes merging is with Na ₂SO ₄Drying is filtered, and evaporate to dryness.Product is further reacted, need not purifying.

Output: 14.0 grams (theoretical value 98%)

R _f=0.91 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

18b) (Z, E)-2-acetylaminohydroxyphenylarsonic acid 3-(4-benzyloxy-3-chloro-5-methyl-phenyl)-methyl acrylate

Under nitrogen atmosphere, with the three-neighbour-tolyl-phosphine and 3.2 gram (14.3 mmole) Pd (OAc) of 4.4 grams (14.0 mmole) ₂Be added into 28.0 gram (89.9 mmole) 2-benzyloxy-5-bromo-1-chloro-3-methyl-benzene and 15.0 gram (103 mmole) 2-acetylaminohydroxyphenylarsonic acid methyl acrylates in the mixture in 260 milliliters of triethylamines and the 400 milliliters of acetonitriles, and reaction mixture is descended stirring 18 hours in 80 ℃.After cooling, the evaporate to dryness reaction soln stirs residue, and filters out insoluble composition with 100 ml waters, 50 milliliters of EtOAc and 50 milliliters of PE in a vacuum.Residue is dissolved among the DCM/MeOH (5:1), mixes, filter with gac, and evaporate to dryness in a vacuum.Crude product is further reacted, need not purifying.

Output: 12.5 grams (theoretical value 37%)

ESI-MS：(M+H) ⁺＝374/376(Cl)

R _f=0.67 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

18c) 3-(4-benzyloxy-3-chloro-5-methyl-phenyl)-2-oxo-propionic acid

With 75 milliliters of 4M HCl be added into 18.4 grams (49.2 mmole) (Z, E)-2-acetylaminohydroxyphenylarsonic acid 3-(4-benzyloxy-3-chloro-5-aminomethyl phenyl)-methyl acrylate is at 150 milliliter 1, in the solution in the 4-diox, and reaction mixture refluxed spent the night.Remove 1 in a vacuum, the 4-diox leaches precipitated product, be dissolved among the DIPE again, and with MgSO ₄Dry.Behind siccative and removal of solvents, residue is further reacted, need not purifying.

Output: 15.5 grams (theoretical value 99%)

ESI-MS：(M-H) ^-＝317/319(Cl)

R _f=0.20 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

18d) (R)-3-(4-benzyloxy-3-chloro-5-methyl-phenyl)-2-hydroxyl-methyl propionate

Under nitrogen atmosphere, with 27.6 grams (86.0 mmole) (1R)-solution of B-chlorine diisopinocampheylchloroborane phenylborinane in 100 milliliters of THF, in 15 minutes, drop in the solution of triethylamine in 200 milliliters of THF of 15.5 gram (48.6 mmole) 3-(4-benzyloxy-3-chloro-5-methyl-phenyl)-2-oxo-propionic acid of being cooled to approximately-30 ℃ and 9.2 milliliters (66.2 mmoles).In add stopped after, remove cooling bath, and reaction mixture at room temperature stirred spend the night.Under ice-cooled, 240 milliliters of 1M NaOH are dropped in the reaction mixture.Add 400 milliliters of EtOAc, mixture stirred 15 minutes, isolate water, and with organic phase with each 100 milliliters of 1M NaOH washed twice, and once with 100 ml waters.The water that makes merging is with half dense HCl acidifying, and with each 150 milliliters of EtOAc extracting twice, and the organic phase that makes merging is with MgSO ₄Dry.Behind siccative and removal of solvents, the oily residue is mixed with 150 ml methanol HCl (1.25M), and reaction mixture at room temperature stirred spend the night.Make its evaporate to dryness in a vacuum, with residue and 70 milliliters of 15%K ₂CO ₃Solution mixes, and with each 50 milliliters of EtOAc extracting twice.The organic phase that makes merging is with MgSO ₄Drying is filtered, and evaporate to dryness in a vacuum.Product is further reacted, need not purifying.

Output: 7.0 grams (theoretical value 43%)

ESI-MS：(M+NH ₄) ⁺＝352/354(Cl)

R _f=0.87 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

18e) 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-benzyloxy-3-chloro-5-methyl-phenyl)-1-carboxyl-ethyl ester

Similar embodiment 1e, system from 7.0 grams (20.9 mmole) (R)-3-(4-benzyloxy-3-chloro-5-methyl-phenyl)-2-hydroxyl-methyl propionate and 5.2 restrains (21.2 mmole) 3-piperidin-4-yls-1,3,4,5-tetrahydrochysene-1,3-benzodiazepine

-2-ketone.Rough methyl esters product is dissolved among 150 milliliters of THF, and mixes with the solution of 0.5 gram (20.7 mmole) LiOH in 50 ml waters.Reaction mixture at room temperature stirred spend the night,, and remove organic solvent in a vacuum with the water dilution.With water with each 60 milliliters of EtOAc washed twice, with 21 milliliters of 4M HCl acidifying, and with the thorough oil that so forms of extraction of EtOAc.The organic phase that makes merging is with MgSO ₄Drying is filtered, and solvent evaporated in a vacuum.With DIPE development residue, and the filtration of bleeding.

Output: 3.3 grams (theoretical value 26%)

ESI-MS：(M+H) ⁺＝592/594(Cl)

R _f=0.35 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

18f) 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-carboxyl-2-(3-chloro-4-hydroxy-5-methyl base-phenyl)-ethyl ester

Make 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 2.75 grams (4.65 mmole)

-3-yl)-and piperidines-1-carboxylic acid (R)-2-(4-benzyloxy-3-chloro-5-methyl-phenyl)-1-carboxyl-ethyl ester and rhodium the suspension among 150 milliliter MeOHs of 1.0 grams on the aluminum oxide, hydrogenation is 18 hours under 40 ℃ and 50psi hydrogen pressure.For finishing reaction, thus rhodium on the 0.5 gram aluminum oxide added again, and make mixture hydrogenation 6 hours again.Filter to remove catalyzer through bleeding, and evaporate to dryness filtrate in a vacuum.The residue that is polluted by about 50% its corresponding methyl esters is dissolved among 25 milliliters of THF, and mixes, and reaction mixture was at room temperature stirred 3 hours with the solution of 250 milligrams of (10.23 mmole) LiOH in 15 ml waters.Remove THF in a vacuum, mix, bleed and filter sedimentary product, then it is washed with less water with water and 10.5 milliliters of 1M HCl, and dry down in 60 ℃.

Output: 2.1 grams (theoretical value 90%)

ESI-MS：(M+H) ⁺＝502/504(Cl)

R _f=0.12 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

18g) 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-carboxyl-2-(3-chloro-4-hydroxy-5-methyl base-phenyl)-ethyl ester and 51 milligrams (0.20 mmole) [4,4 '] connection piperidines-1-base-ethyl acetate.

Output: 14 milligrams (theoretical value 9%)

ESI-MS：(M+H) ⁺＝738/740(Cl)

Retention time (HPLC): 3.2 minutes (method B)

Embodiment 18.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-2-(1 '-carboxymethyl-4,4 '-Lian piperidines-1-yl)-1-(3-chloro-4-hydroxy-5-methyl base-benzyl)-2-oxo-ethyl ester

With the solution of 2.0 milligrams of (0.08 mmole) LiOH in 1 ml water, be added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 38 milligrams (0.05 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(3-chloro-4-hydroxy-5-methyl base-benzyl)-2-(1 '-ethoxy carbonyl methyl-4,4 '-Lian piperidines-1-the yl)-solution of 2-oxo-ethyl ester in 1 milliliter of THF in, and reaction mixture was at room temperature vibrated 3 hours.Make the reaction soln acidifying with 1M HCl, and through the HPLC purifying.Merge the wash-out part that contains product, and freeze-drying.

Output: 30 milligrams (theoretical value 82%)

ESI-MS：(M+H) ⁺＝710/712(Cl)

R _f=0.20 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

Embodiment 19

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-ethoxycarbonylmethyl group-4-methyl-piperidin-4-yl)-piperazine-1-yl]-2-oxo-ethyl ester

The triethylamine of 0.25 milliliter (1.18 mmole) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 250 milligrams (0.45 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxyl-ethyl ester (embodiment 1f), 250 milligrams (0.50 mmole) (4-methyl-4-piperazine-1-base-piperidines-1-yl)-ethyl acetate (embodiment A 7f) and the mixture of 160 milligrams of (0.50 mmole) TBTU in 2 milliliters of DMF in, and reaction mixture at room temperature stirred 4 hours.Make its evaporate to dryness in a vacuum, and make residue through the HPLC purifying; Merge the wash-out part that contains product, and freeze-drying.

Output: 225 milligrams (theoretical value 62%)

ESI-MS：(M+H) ⁺＝806/808(Cl)

Retention time (HPLC): 3.2 minutes (method B)

Embodiment 19.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-carboxymethyl-4-methyl-piperidin-4-yl)-piperazine-1-yl]-2-oxo-ethyl ester

With the solution of 10.0 milligrams of (0.42 mmole) LiOH in 5 ml waters, be added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 100 milligrams (0.12 mmoles) among 10 milliliters of THF

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-ethoxy carbonyl-methyl-4-methyl-piperidin-4-yl)-piperazine-1-yl]-2-oxo-ethyl ester in, and reaction mixture at room temperature stirred 3 hours.Mix with 0.42 milliliter of (0.42 mmole) 1M HCl, and evaporate to dryness mixture in a vacuum.Residue is dissolved among a small amount of DCM/MeOH (1:1), through a small amount of filtered through silica gel, and with DCM/MeOH (1:1) wash-out.Evaporate to dryness filtrate in a vacuum, and dry under high vacuum.

Output: 95 milligrams (theoretical value 98%)

ESI-MS：(M+H) ⁺＝778/780(Cl)

Retention time (HPLC): 2.9 minutes (method B)

Embodiment 20

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-ethoxycarbonylmethyl group-piperazine-1-yl)-4-methyl-piperidines-1-yl]-2-oxo-ethyl ester

The triethylamine of 0.10 milliliter (0.72 mmole) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 250 milligrams (0.45 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxyl-ethyl ester (embodiment 1f), 140 milligrams (0.49 mmole) [4-(4-methyl-piperidin-4-yl)-piperazine-1-yl]-ethyl acetate (embodiment A 8b) and the mixture of 160 milligrams of (0.50 mmole) TBTU in 2 milliliters of DMF in, and reaction mixture at room temperature stirred 18 hours.Make its evaporate to dryness in a vacuum, and make residue through chromatography (Alox, gradient liquid DCM/MeOH 40:1 to 30:1) purifying.Merge the wash-out part contain product, evaporate to dryness in a vacuum, and through the HPLC purifying; Merge the wash-out part that contains product, and freeze-drying.

Output: 178 milligrams (theoretical value 49%)

ESI-MS：(M+H) ⁺＝806/808(Cl)

Retention time (HPLC): 3.8 minutes (method B)

Embodiment 20.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-carboxymethyl-piperazine-1-yl)-4-methyl-piperidin-4-yl]-2-oxo-ethyl ester

Similar embodiment 19.1, system is from the 4-of 100 milligrams (0.12 mmoles) (2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-ethoxycarbonylmethyl group-piperazine-1-yl)-4-methyl-piperidines-1-yl]-2-oxo-ethyl ester and 10.0 milligrams of (0.42 mmole) LiOH.

Output: 42 milligrams (theoretical value 44%)

ESI-MS：(M+H) ⁺＝778/780(Cl)

Retention time (HPLC): 3.3 minutes (method B)

Embodiment 21

(S)-1-(1-{ (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl }-piperidin-4-yl)-4-methyl-piperazine-2-carboxylic acid's ethyl ester

The triethylamine of 0.40 milliliter (2.88 mmole) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 260 milligrams (0.46 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxyl-ethyl ester (embodiment 1f), 210 milligrams (0.58 mmole) (S)-4-methyl isophthalic acid-piperidin-4-yl-piperazine-2-carboxylic acid's ethyl ester (embodiment A 9f) and the mixture of 170 milligrams of (0.53 mmole) TBTU in 2.4 milliliters of DMF in, and reaction mixture at room temperature stirred 18 hours.Make reaction mixture through the HPLC purifying, need not further processing; Merge the wash-out part that contains product, and freeze-drying.

Output: 227 milligrams (theoretical value 61%)

ESI-MS：(M+H) ⁺＝792/794(Cl)

Retention time (HPLC): 3.4 minutes (method B)

Embodiment 21.1

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl }-piperidin-4-yl)-4-methyl-piperazine-2-carboxylic acid

With 0.5 milligram of (1.00 mmole) 2M LiOH solution be added among 1 milliliter of THF 80.0 milligrams (0.10 mmoles) (S)-1-(1-{ (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl-piperidin-4-yl)-4-methyl-piperazine-2-carboxylic acid's ethyl ester in, and reaction mixture at room temperature stirred 20 hours.Make it through the HPLC purifying, and need not to handle; Merge the wash-out part that contains product, and freeze-drying.

Output: 50 milligrams (theoretical value 65%)

ESI-MS：(M+H) ⁺＝764/766(Cl)

Retention time (HPLC): 3.0 minutes (method B)

Embodiment 22

(S)-4-{ (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl }-1-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylic acid's ethyl ester

The triethylamine of 0.25 milliliter (2.88 mmole) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 200 milligrams (0.36 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxyl-ethyl ester (embodiment 1f), 150 milligrams (0.58 mmole) (S)-1-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylic acid's ethyl ester (embodiment A 10c) and the mixture of 140 milligrams of (0.44 mmole) TBTU in 2.0 milliliters of DMF in, and reaction mixture at room temperature stirred 5 hours.Make it through the HPLC purifying, need not further processing; Merge the wash-out part that contains product, and freeze-drying.

Output: 84 milligrams (theoretical value 29%)

ESI-MS：(M+H) ⁺＝792/794(Cl)

Retention time (HPLC): 3.5 minutes (method B)

Embodiment 22.1

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl }-1-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylic acid

With 0.26 milliliter of (0.13 mmole) 0.5M LiOH solution be added among 0.8 milliliter of THF 50.0 milligrams (0.06 mmoles) (S)-4-{ (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl-1-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylic acid's ethyl ester in, and reaction mixture at room temperature stirred spends the night.For finishing reaction,,, make reaction mixture through the HPLC purifying then, and need not to handle its restir 4 hours under room temperature so add 50 microlitres (0.1 mmole) 0.5M LiOH solution again; Merge the wash-out part that contains product, and freeze-drying.

Output: 22 milligrams (theoretical value 46%)

ESI-MS：(M+H) ⁺＝764/766(Cl)

Retention time (HPLC): 2.9 minutes (method B)

Embodiment 23

(S)-1-{ (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl }-4-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylic acid's ethyl ester

The triethylamine of 0.30 milliliter (2.16 mmole) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 700 milligrams (1.26 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxyl-ethyl ester (embodiment 1f), 430 milligrams (1.41 mmole) (S)-4-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylic acid's ethyl ester (embodiment A 11b) and the mixture of 450 milligrams of (1.40 mmole) TBTU in 7 milliliters of DMF in, and reaction mixture at room temperature stirred 18 hours.Make its evaporate to dryness in a vacuum, with residue and saturated NaHCO ₃Solution stirs together, thoroughly extract with EtOAc, and the organic phase that makes merging is with Na ₂SO ₄Dry.Behind siccative and removal of solvents, make residue through the HPLC purifying; Merge the wash-out part that contains product, and freeze-drying.

Output: 670 milligrams (theoretical value 67%)

ESI-MS：(M+H) ⁺＝792/794(Cl)

Retention time (HPLC): 3.4 minutes (method B)

Embodiment 23.1

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl }-4-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylic acid

Similar embodiment 22.1, the system from 80.0 milligrams (0.10 mmoles) (S)-1-{ (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl }-4-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylic acid's ethyl ester and 0.46 milliliter of (0.23 mmole) 0.5M LiOH solution.

Output: 53 milligrams (theoretical value 69%)

ESI-MS：(M+H) ⁺＝764/766(Cl)

Retention time (HPLC): 2.9 minutes (method B)

Embodiment 24

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(8-ethoxycarbonylmethyl group-8-aza-bicyclo [3.2.1] oct-3-yl)-piperazine-1-yl]-2-oxo-ethyl ester

113 milligrams (0.40 mmoles) (3-piperazine-1-base-8-aza-bicyclo [3.2.1] suffering-8-yl)-ethyl acetate (embodiment A 12d) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 200 milligrams (0.45 mmoles)

-3-yl)-mixture of triethylamine in 2 milliliters of DMF of piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxyl-ethyl ester (embodiment 1f), 128 milligrams of (0.40 mmole) TBTU and 56 microlitres (0.40 mmole) in, and reaction mixture at room temperature stirred 2 hours.Make it through the HPLC purifying, need not further processing; Merge the wash-out part contain product, and evaporate to dryness in a vacuum.

Output: 156 milligrams (theoretical value 53%)

ESI-MS：(M+H) ⁺＝818/820(Cl)

Retention time (HPLC): 3.1 minutes (method B)

Embodiment 24.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(8-carboxymethyl-8-aza-bicyclo [3.2.1] oct-3-yl)-piperazine-1-yl]-2-oxo-ethyl ester

With the solution of 1.92 milligrams of (0.08 mmole) LiOH in 1 ml water, be added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 40.0 milligrams (0.05 mmoles) among 1 milliliter of THF

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(8-ethoxycarbonyl-methyl-8-aza-bicyclo [3.2.1] oct-3-yl)-piperazine-1-yl]-2-oxo-ethyl ester in, and with reaction mixture shaken overnight at room temperature.In nitrogen gas stream, remove solvent, and make residue through the HPLC purifying; Merge the wash-out part that contains product, and freeze-drying.

Output: 13 milligrams (theoretical value 34%)

ESI-MS：(M+H) ⁺＝790/792(Cl)

Retention time (HPLC): 2.7 minutes (method B)

Embodiment 25

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(4-ethoxycarbonyl methoxyl group-1,4 '-Lian piperidines-1 '-yl)-2-oxo-ethyl ester

The triethylamine of 0.30 milliliter (2.16 mmole) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 300 milligrams (0.54 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxyl-ethyl ester (embodiment 1f), 220 milligrams of (0.64 mmoles) ([1,4 '] connection piperidin-4-yl oxygen base)-ethyl acetate (embodiment A 13c) and the mixture of 200 milligrams of (0.62 mmole) TBTU in 3 milliliters of DMF in, and reaction mixture at room temperature stirred 4 hours.With ice and saturated NaHCO ₃Solution mixes, and leaches throw out.It is dissolved among DCM and a small amount of EtOH, and with Na ₂SO ₄Dry.Behind siccative and removal of solvents, make residue through the HPLC purifying; Merge the wash-out part that contains product, and freeze-drying.

Output: 170 milligrams (theoretical value 39%)

ESI-MS：(M+H) ⁺＝807/809(Cl)

Retention time (HPLC): 3.7 minutes (method B)

Embodiment 25.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(4-carboxyl methoxyl group-1,4 '-Lian piperidines-1 '-yl)-2-oxo-ethyl ester

With the solution of 8.00 milligrams of (0.33 mmole) LiOH in 2.5 ml waters, be added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 100 milligrams (0.12 mmoles) among 8 milliliters of THF

-3-yl)-(4-ethoxycarbonyl-methoxyl group-1 in 4 '-Lian piperidines-1 '-yl)-2-oxo-ethyl ester, and at room temperature stirred reaction mixture 3 hours piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-.Add 0.34 milliliter of (0.34 mmole) 1M HCl, and evaporate to dryness mixture in a vacuum.Residue is dissolved among the DCM/MeOH, through a small amount of filtered through silica gel, and with DCM/MeOH (7:3) wash-out.Make its evaporate to dryness in a vacuum, and make residue dry under high vacuum.

Output: 61 milligrams (theoretical value 63%)

ESI-MS：(M+H) ⁺＝779/781(Cl)

Retention time (HPLC): 3.2 minutes (method B)

Embodiment 26

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(4-ethoxycarbonylmethyl group-1,4 '-Lian piperidines-1 '-yl)-2-oxo-ethyl ester

The triethylamine of 200 microlitres (1.43 mmole) and 414 milligrams of (1.29 mmole) TBTU are added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 650 milligrams (1.17 mmoles) among 30 milliliters of THF and the 5 milliliters of DMF

-3-yl)-piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxyl-ethyl ester (embodiment 1f) in, and reaction mixture at room temperature stirred 30 minutes.Then, add 422 milligrams (1.29 mmole) [1,4 '] connection piperidin-4-yl-ethyl acetate (embodiment A 14b) and the triethylamine of 330 microlitres (2.38 mmole) among 10 milliliters of DCM, and with mixture restir 18 hours at room temperature.Add 50 milliliters of semi-saturation NaHCO ₃Solution, with mixture with each 50 milliliters of EtOAc extracting twice, the organic phase that merges with 50 milliliters of saturated NaCl solution washings, and with Na ₂SO ₄Dry.Behind siccative and removal of solvents, make residue through chromatography (silica gel, EtOAc/MeOH/NH ₃95:5:0.5) purifying.Merge the wash-out part that contains product, evaporate to dryness is developed residue with DIPE in a vacuum, the filtration of bleeding, and dry.

Output: 646 milligrams (theoretical value 70%)

ESI-MS：(M+H) ⁺＝791/793(Cl)

R _f=0.33 (silica gel, EtOAc/MeOH/NH ₃90:10:1)

Embodiment 26.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(4-carboxymethyl-1,4 '-Lian piperidines-1 '-yl)-2-oxo-ethyl ester

With the solution of 5.00 milligrams of (0.21 mmole) LiOH in 3 ml waters, be added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 100 milligrams (0.13 mmoles) among 10 milliliters of THF

-3-yl)-(4-ethoxycarbonyl-methyl isophthalic acid in 4 '-Lian piperidines-1 '-yl)-2-oxo-ethyl ester, and at room temperature stirred reaction mixture 2 days piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-.Make mixture evaporate to dryness in a vacuum, residue is dissolved among 1 milliliter of DMF, and through the HPLC purifying; Merge the wash-out part that contains product, and freeze-drying.

Output: 22 milligrams (theoretical value 22%)

ESI-MS：(M+H) ⁺＝763/765(Cl)

Retention time (HPLC): 3.2 minutes (method B)

Embodiment 27

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(2-ethoxycarbonyl-ethyl)-1,4 '-Lian piperidines-1 '-yl]-2-oxo-ethyl ester

Similar embodiment 24, system is from the 4-of 500 milligrams (0.90 mmoles) (2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxyl-ethyl ester (embodiment 1f) and 341 milligrams of (1.00 mmole) 3-[1,4 '] connection piperidin-4-yl-ethyl propionate (embodiment A 15b).

Output: 340 milligrams (theoretical value 47%)

ESI-MS：(M+H) ⁺＝805/807(Cl)

Retention time (HPLC): 3.6 minutes (method B)

Embodiment 27.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(2-carboxyl-ethyl)-1,4 '-Lian piperidines-1 '-yl]-2-oxo-ethyl ester

With the solution of 2.40 milligrams of (0.10 mmole) LiOH in 1 ml water, be added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 50 milligrams (0.06 mmoles) among 3 milliliters of THF

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(2-ethoxycarbonyl-ethyl)-1,4 '-Lian piperidines-1 '-yl]-2-oxo-ethyl ester in, and reaction mixture at room temperature stirred 4 hours.In nitrogen gas stream, remove THF, residue is dissolved in the less water, and through the HPLC purifying; Merge the wash-out part that contains product, and freeze-drying.

Output: 38 milligrams (theoretical value 79%)

ESI-MS：(M+H) ⁺＝777/779(Cl)

Retention time (HPLC): 3.4 minutes (method B)

Embodiment 28

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(3-ethoxycarbonyl-propyl group)-piperidin-4-yl]-piperazine-1-yl }-2-oxo-ethyl ester

4-(4-piperazine-1-base-piperidines-1-the yl)-ethyl butyrate (embodiment A 16b) of 283 milligrams (1.00 mmoles) is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 500 milligrams (0.90 mmoles)

-3-yl)-mixture of triethylamine in 10 milliliters of DMF of piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxyl-ethyl ester (embodiment 1f), 321 milligrams of (1.00 mmole) TBTU and 0.14 milliliter (1.00 mmole) in, and reaction mixture at room temperature stirred 2 hours.Make it through the HPLC purifying, need not further processing; Merge the wash-out part contain product, evaporate to dryness in a vacuum is with residue and saturated NaHCO ₃Solution stirs together, filters, and dry.

Output: 165 milligrams (theoretical value 22%)

ESI-MS：(M+H) ⁺＝820/822(Cl)

Retention time (HPLC): 3.1 minutes (method B)

Embodiment 28.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(3-carboxyl-propyl group)-piperidin-4-yl]-piperazine-1-yl }-2-oxo-ethyl ester

Similar embodiment 27.1, system is from the 4-of 50 milligrams (0.06 mmoles) (2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(3-ethoxycarbonyl-propyl group)-piperidin-4-yl]-piperazine-1-yl }-2-oxo-ethyl ester and 2.40 milligrams of (0.10 mmole) LiOH.

Output: 29 milligrams (theoretical value 60%)

ESI-MS：(M+H) ⁺＝792/794(Cl)

Retention time (HPLC): 3.0 minutes (method B)

Embodiment 29

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(1-ethoxycarbonyl-ethyl)-piperidin-4-yl]-piperazine-1-yl }-2-oxo-ethyl ester

29a) 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazine-1-yl)-ethyl ester

With 1.00 gram (1.80 mmole) 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepines

-3-yl)-and the mixture of triethylamine in 10 milliliters of DMF of piperidines-1-carboxylic acid (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxyl-ethyl ester (embodiment 1f), the 4-piperazine-1-base-piperidines-1-benzyl carboxylate (embodiment A 17b) of 546 milligrams (1.80 mmoles), 643 milligrams of (2.00 mmole) TBTU and 0.35 milliliter (2.50 mmole), at room temperature stir and spend the night.With itself and 150 milliliters of 15%K ₂CO ₃Solution mixes, and filters through bleeding and removes throw out, with the washing of 30 ml waters, and makes crude product under 40 ℃, and is dry in loft drier.

Output: 1.50 grams (theoretical value 99%)

ESI-MS：(M+H) ⁺＝840/842(Cl)

Retention time (HPLC): 3.7 minutes (method B)

Make 750 milligrams of (0.89 mmole) above-mentioned products and the suspension of 600 milligrams of Raney nickels in 50 milliliters of MeOH, hydrogenation is 30 hours under room temperature and 3447hPa.Filter to remove catalyzer through bleeding, evaporate to dryness in a vacuum, and make residue through the HPLC purifying.Merge the wash-out part that contains product, evaporate to dryness makes residue with 15%K in a vacuum ₂CO ₃Solution transfers to alkalescence, with 100 milliliters of EtOAc extractions, isolates organic phase, and with Na ₂SO ₄Dry.Behind siccative and removal of solvents, with 30 milliliters of DIPE development residues, the filtration of bleeding, and dry.

Output: 280 milligrams (theoretical value 44%)

ESI-MS：(M+H) ⁺＝706/708(Cl)

Retention time (HPLC): 2.8 minutes (method B)

29b) 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

Make 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 140 milligrams (0.20 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazine-1-yl)-ethyl ester, 60.8 milligrams of (0.44 mmole) K ₂CO ₃And the mixture of 29 microlitres (0.22 mmole) 2 bromopropionic acid ethyl ester in 1.8 milliliters of DMF, vibrated 2 hours down at 50 ℃.Make reaction mixture through the HPLC purifying, and need not to handle; Merge the wash-out part that contains product, and freeze-drying.

Output: 111 milligrams (theoretical value 69%)

ESI-MS：(M+H) ⁺＝806/808(Cl)

Retention time (HPLC): 3.1 minutes (method B)

Embodiment 29.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(1-carboxyl-ethyl)-piperidin-4-yl]-piperazine-1-yl }-2-oxo-ethyl ester

With the solution of 2.4 milligrams of (0.10 mmole) LiOH in 0.8 ml water, be added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 50 milligrams (0.06 mmoles) among 1 milliliter of THF

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(1-ethoxycarbonyl-ethyl)-piperidin-4-yl]-piperazine-1-yl-2-oxo-ethyl ester in, and reaction mixture was at room temperature vibrated 2 hours, and vibrated 4 hours down at 50 ℃.Make it through the HPLC purifying then, and need not to handle; Merge the wash-out part that contains product, and freeze-drying.

Output: 42 milligrams (theoretical value 87%)

ESI-MS：(M+H) ⁺＝778/780(Cl)

Retention time (HPLC): 3.0 minutes (method B)

Embodiment 30

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(1-ethoxycarbonyl-1-methyl-ethyl)-piperidin-4-yl]-piperazine-1-yl }-2-oxo-ethyl ester

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazine-1-yl)-ethyl ester (embodiment 29a), 60.8 milligrams of (0.44 mmole) K ₂CO ₃And the mixture of 45 microlitres (0.30 mmole) 2-bromo-2-methyl-ethyl propionate in 1.8 milliliters of DMF, vibrated 12 hours down at 50 ℃, then under room temperature, vibrated 48 hours.Leach throw out, and make filtrate, and need not to handle through the HPLC purifying; Merge the wash-out part that contains product, evaporate to dryness makes residue with saturated NaHCO in a vacuum ₃Solution is adjusted to alkalescence, the filtering precipitate of bleeding, and with the washing of 20 ml waters, and dry down in 40 ℃.

Output: 85 milligrams (theoretical value 52%)

ESI-MS：(M+H) ⁺＝820/822(Cl)

Retention time (HPLC): 3.0 minutes (method B)

Embodiment 31

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl }-the 4-methyl isophthalic acid, 4 '-Lian piperidyl-4-carboxylic acid, ethyl ester

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine with 127 milligrams (0.20 mmoles)

-3-yl)-the 4-methyl-piperidines-4-carboxylic acid, ethyl ester and the mixture of 11 microlitres (0.2 mmole) AcOH in 2 milliliters of DCM of piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-(4-oxo-piperidines-1-yl)-ethyl ester (embodiment 1g), 68.5 milligrams (0.40 mmoles), at room temperature stirred 2 hours, be cooled to 0 ℃, stirred 2 hours, sodium triacetoxy borohydride with 57.7 milligrams (0.26 mmoles) mixes then, and stirs under 0 ℃ and spend the night.Make reaction mixture through the HPLC purifying, and need not to handle; Merge the wash-out part that contains product, and freeze-drying.

Output: 85 milligrams (theoretical value 54%)

ESI-MS：(M+H) ⁺＝791/793(Cl)

Retention time (HPLC): 7.7 minutes (method B)

Following compounds be in a similar manner in each situation by 127 milligrams of 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-(4-oxo-piperidines-1-yl)-ethyl ester (embodiment 1g) with in each situation the amount of needed amine composition make:

Embodiment 32

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl }-the 4-methyl isophthalic acid, 4 '-Lian piperidyl-4-carboxylic acid

With the solution of 2.99 milligrams of (0.08 mmole) LiOH in 1 ml water, be added into 40 milligrams (0.05 mmoles) among 0.8 milliliter of THF 1 '-(R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine

-3-yl)-piperidines-1-ketonic oxygen base]-propionyl }-the 4-methyl isophthalic acid, in 4 '-Lian piperidyl-4-carboxylic acid, ethyl ester, and reaction mixture at room temperature stirred 1 hour, and stirred 8 hours down at 50 ℃.Make it through the HPLC purifying, and need not to handle; Merge the wash-out part that contains product, and freeze-drying.

Output: 18 milligrams (theoretical value 47%)

ESI-MS：(M+H) ⁺＝763/765(Cl)

Retention time (HPLC): 3.5 minutes (method B)

Following compounds is to be prepared by 40 milligrams of its corresponding ethyl esters in each situation in a similar manner, and hydrolytic action only needs at room temperature 1 hour:

Embodiment 33

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(5-methyl-2-oxo-1,3-Dioxol-4-yl methoxycarbonyl methyl)-piperidin-4-yl]-piperazine-1-yl }-2-oxo-ethyl ester

Make 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 185 milligrams (0.24 mmoles)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazine-1-yl]-KHCO of 2-oxo-ethyl ester (embodiment 4.1), 25 milligrams (0.25 mmoles) ₃And the 4-brooethyl-5-methyl isophthalic acid of 50 milligrams (0.26 mmoles), the mixture of 3-dioxole-2-ketone in 1 milliliter of DMF, at room temperature shaken overnight.Reaction mixture is filtered through the injection filter, and through the HPLC purifying; Merge the wash-out part that contains product, and freeze-drying.

Output: 14 milligrams (theoretical value 7%)

ESI-MS：(M+H) ⁺＝876/878(Cl)

R _f=0.54 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

Embodiment 33.1

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine leather-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1 '-(5-methyl-2-oxo-1,3-Dioxol-4-yl methoxycarbonyl methyl)-4,4 '-Lian piperidines-1-yl]-2-oxo-ethyl ester

Similar embodiment 33, system is from 150 milligrams of (0.20 mmole) 4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepines

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-carboxymethyl-4,4 '-Lian piperidines-1-yl)-and the 4-brooethyl-5-methyl isophthalic acid of 2-oxo-ethyl ester (embodiment 3.1) and 50 milligrams (0.26 mmoles), 3-dioxole-2-ketone.

Output: 8 milligrams (theoretical value 5%)

ESI-MS：(M+H) ⁺＝875/877(Cl)

R _f=0.74 (silica gel, DCM/Cyc/MeOH/NH ₃70:15:15:2)

Embodiment 34

4-(2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(4-{1-[2-(2-methoxyl group-oxyethyl group)-ethoxycarbonylmethyl group]-piperidin-4-yl }-piperazine-1-yl)-2-oxo-ethyl ester

13 microlitres (0.11 mmole) 2-(2-methoxyl group-oxyethyl group)-ethanol is added into 4-(2-oxo-1,2,4,5-tetrahydrochysene-1, the 3-benzodiazepine of 75 millis (0.10 mmole)

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazine-1-yl]-mixture of triethylamine in 1 milliliter of DMF of 2-oxo-ethyl ester (embodiment 4.1), 35 milligrams of (0.11 mmole) TBTU and 28 microlitres (0.20 mmole) in, and reaction mixture at room temperature stirred 1 hour.Make it through the HPLC purifying, and need not to handle; Merge the wash-out part that contains product, and freeze-drying.

Output: 22 milligrams (theoretical value 26%)

ESI-MS：(M+H) ⁺＝866/868(Cl)

Retention time (HPLC): 3.2 minutes (method B)

Embodiment 35

4-(7-methoxyl group-2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepine

-3-yl)-and piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1 '-(2-morpholine-4-base-ethoxycarbonylmethyl group)-4,4 '-Lian piperidines-1-yl]-2-oxo-ethyl ester

With 230 milligrams of (0.29 mmole) 4-(7-methoxyl group-2-oxo-1,2,4,5-tetrahydrochysene-1,3-benzodiazepines

-3-yl)-piperidines-1-carboxylic acid (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1 '-carboxymethyl-4,4 '-Lian piperidines-1-yl)-and triethylamine and 39.3 milligrams of (0.30 mmole) 2-morpholine-4-base-ethanol mixtures in 5 milliliters of DMF of 2-oxo-ethyl ester (embodiment 15.1), 113 milligrams of (0.35 mmole) TBTU, 84 microlitres (0.60 mmole), at room temperature stir and spend the night.Reaction mixture is poured over saturated NaHCO ₃On the solution, bleed and filter sedimentary product, and dry down in 40 ℃.It is dissolved in 25 milliliters of Virahols, and the 0.5M HCl in adding Virahol, it is precipitated with hydrochloride.With its filtration of bleeding, with 5 milliliters of Virahols and 30 milliliters of DIPE washings, and under 30 ℃, dry in vacuum drying oven.

Output: 90 milligrams (theoretical value 34%)

ESI-MS：(M+H) ⁺＝906/908(Cl)

Retention time (HPLC): 3.1 minutes (method B)

Hereinafter embodiment is the preparation of describing medicinal preparations, and it contains any compound of Formula I as active substance:

Example I

For the inhalant capsule of powder, contain 1 milligram of active substance

Composition:

1 inhalant capsule of powder contains:

1.0 milligrams of active substances

20.0 milligrams of lactose

Hard gelatin capsule 50.0 milligram

71.0 milligram

The preparation method:

Active substance is ground to form the needed size of particles of inhaled material.Active substance through grinding mixes with lactose equably.Mixture is charged in the hard gelatin capsule.

Example II

Supply

With sucked solution, contain 1 milligram of active substance

Composition:

1 spraying contains:

1.0 milligrams of active substances

0.002 milligram of benzalkonium chloride

0.0075 milligram of disodium ethylene diamine tetraacetate

Pure water adds 15.0 microlitres

The preparation method:

Make active substance and benzalkonium chloride soluble in water, and be packed into In the cartridge case.

EXAMPLE III

Sucked solution for spraying gun is used contains 1 milligram of active substance

Composition:

1 little glass bottle contains:

Active substance 0.1 gram

Sodium-chlor 0.18 gram

Benzalkonium chloride 0.002 gram

Pure water adds 20.0 milliliters

The preparation method:

Make active substance, sodium-chlor and benzalkonium chloride soluble in water.

EXAMPLE IV

The aerosol of the metering of propellant gas-operation contains 1 milligram of active substance

Composition:

1 spraying contains:

1.0 milligrams of active substances

Yelkin TTS 0.1%

Propellant gas adds 50.0 microlitres

The preparation method:

Micronized active substance evenly is suspended in the mixture of Yelkin TTS and propellant gas.This suspension is filled in the pressurizing vessel with metering valve.

EXAMPLE V

The nasal spray that contains 1 milligram of active substance

Composition:

1.0 milligrams of active substances

0.9 milligram in sodium-chlor

0.025 milligram of benzalkonium chloride

0.05 milligram of disodium ethylene diamine tetraacetate

Pure water adds 0.1 milliliter

The preparation method:

Make active substance and vehicle soluble in water, and be filled in the appropriate containers.

Example VI

Per 5 milliliters of injection solutions that contain 5 milligrams of active substances

Composition:

5 milligrams of active substances

250 milligrams of glucose

10 milligrams of human serum albumin

250 milligrams in sugar furfural

Water for injection adds to 5 milliliters

Preparation:

Sugared furfural (glycofurol) and glucose are dissolved in the water for injection (WfI); Add human serum albumin; Lytic activity material under heating; Complement to specified volume with WfI; Under nitrogen, be transferred in the ampoule.

Example VII A

Per 20 milliliters of injection solutions that contain 100 milligrams of active substances

Composition:

100 milligrams of active substances

Potassium primary phosphate=KH ₂PO ₄12 milligrams

Sodium phosphate dibasic=Na ₂HPO ₄2H ₂12 milligrams of O

180 milligrams in sodium-chlor

50 milligrams of human serum albumin

20 milligrams of tween 80s

Water for injection adds 20 milliliters

Preparation:

Tween 80, sodium-chlor, biphosphate list potassium and Sodium phosphate dibasic are dissolved in the water for injection (WfI); Add human serum albumin; Lytic activity material under heating; Complement to specified volume with WfI; Be transferred in the ampoule.

Example VII A I

The lyophilized products that contains 10 milligrams of active substances

Composition:

10 milligrams of active substances

300 milligrams in N.F,USP MANNITOL

20 milligrams of human serum albumin

Water for injection adds to 2 milliliters

Preparation:

N.F,USP MANNITOL is dissolved in the water for injection (WfI); Add human serum albumin; Lytic activity material under heating; Complement to specified volume with WfI; Be transferred in the little glass bottle; Freeze-drying.

The solvent that lyophilized products is used:

80 20 milligrams of tween 80=Tween

200 milligrams in N.F,USP MANNITOL

Water for injection adds 10 milliliters

Preparation:

Tween 80 and N.F,USP MANNITOL are dissolved in the water for injection (WfI); Be transferred in the ampoule.

Example I X

The tablet that contains 20 milligrams of active substances

Composition:

20 milligrams of active substances

120 milligrams of lactose

40 milligrams of W-Gums

2 milligrams of Magnesium Stearates

18 milligrams of Povidone K25

Preparation:

With active substance, lactose and W-Gum uniform mixing; With the granulation of the Povidone aqueous solution; Mix with Magnesium Stearate; In tabletting machine, suppress; 200 milligrams of tablet weight.

Embodiment X

The capsule that contains 20 milligrams of active substances

Composition:

20 milligrams of active substances

80 milligrams of W-Gums

5 milligrams of the silicic acid of high dispersing

2.5 milligrams of Magnesium Stearates

Preparation:

Active substance, W-Gum and silicic acid are mixed equably; Mix with Magnesium Stearate; Mixture is filled in the hard gelatin capsule of No. 3 sizes in the capsule packing machine.

Embodiment XI

The suppository that contains 50 milligrams of active substances

Composition:

50 milligrams of active substances

Hard butter (solid Tallow, beef) capacity to 1700 milligram

Preparation:

Make hard butter in about 38 ℃ of following fusions; Active substance through grinding is scattered in the molten state hard butter equably; After being cooled to about 35 ℃, be poured in the mould of precooling.

Embodiment XII

Per 1 milliliter of Injectable solution that contains 10 milligrams of active substances

Composition:

10 milligrams of active substances

50 milligrams in N.F,USP MANNITOL

10 milligrams of human serum albumin

Water for injection adds 1 milliliter

Preparation:

N.F,USP MANNITOL is dissolved in the water for injection (WfI); Add human serum albumin; Lytic activity material under heating; Complement to specified volume with WfI; Under nitrogen, be transferred in the ampoule.

Claims

1. the CGRP antagonist of general formula I

Wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³Expression general formula I I group

Wherein

X represents N or C,

R ^3.1Expression H, C _1-3-alkyl or R ^3.1.1-O-C (O),

R ^3.1.1.1Expression is selected from following group,

With

R ^3.2If during X=N, represent a pair of unbound electron, or

R ^3.2If during X=C, expression H, C _1-3-alkyl or R ^3.2.1-O-C (O),

R ^3.2.1.1Expression is selected from following group,

With

R ⁴Expression general formula III group

Wherein

Y represents C, and

R ^4.1Expression H or C _1-3-alkyl, or

Y represents N, and

R ^4.1Represent a pair of unbound electron,

Condition is, X and Y do not represent N simultaneously,

R ^4.2Expression H, C _1-3-alkyl or R ^4.2.1-O-C (O),

R ^4.2.1.1Expression is selected from following group,

With

And

R ^4.3Expression H, C _1-6-alkyl, H ₂N-C _2-4-alkylidene group, (C _1-3-alkyl)-NH-C _2-4-alkylidene group, (C _1-3-alkyl) ₂N-C _2-4-alkylidene group, H ₂N-C (O)-C _1-3-alkylidene group, (C _1-3-alkyl)-NH-C (O)-C _1-3-alkylidene group, (C _1-3-alkyl) ₂N-C (O)-C _1-3-alkylidene group or R ^4.3.1-C _2-4-alkylidene group, and

R ^4.3.1Expression is selected from following group,

With

R ^5.1.1.1Expression is selected from following group,

R ^5.1.1.2Expression is selected from following group,

With

R ^5.2.1.1Expression is selected from following group,

With

R ^5.2.1.2Expression is selected from following group,

With

Perhaps

R ^5.2.1Expression following formula group

2. compound of Formula I as claimed in claim 1, wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³Expression general formula I I group

Wherein

X represents N or C,

R ^3.1Expression H, C _1-3-alkyl or R ^3.1.1-(O) C,

R ^3.1.1Expression HO, C _1-6-alkyl-O,

R ^3.2If during X=N, represent a pair of unbound electron, or

R ^3.2If during X=C, expression H or C _1-3-alkyl,

R ⁴Expression general formula III group

Perhaps

Wherein

Y represents C, and

R ^4.1Expression H or C _1-3-alkyl, or

Y represents N, and

R ^4.1Represent a pair of unbound electron,

Condition is, X and Y do not represent N simultaneously,

R ^4.2Expression H, C _1-3-alkyl or R ^4.2.1-(O) C,

R ^4.2.1Expression HO, C _1-6-alkyl-O, and

R ^4.3.1Expression is selected from following group,

With

R ^5.1.1.1Expression is selected from following group,

R ^5.1.1.2Expression is selected from following group,

With

R ^5.2.1.1Expression is selected from following group,

With

R ^5.2.1.2Expression is selected from following group,

With

3. compound of Formula I as claimed in claim 1, wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³-R ⁴Represent general formula I V group together

Wherein

R ^3.1Expression H, H ₃C or R ^3.1.1-O-C (O),

R ^3.1.1.1Expression is selected from following group,

With

R ^3.2Expression H, C _1-3-alkyl or R ^3.2.1-O-C (O),

R ^3.2.1.1Expression is selected from following group,

With

R ^4.1Expression H or C _1-3-alkyl,

R ^4.2Expression H, C _1-3-alkyl or R ^4.2.1-O-C (O),

R ^4.2.1.1Expression is selected from following group,

With

R ^4.3.1Expression is selected from following group,

With

R ^5.1Expression H, H ₃C, R ^5.1.1-O-C (O), R ^5.1.1-O-C (O)-C _1-3-alkylidene group-NH, R ^5.1.1-O-C (O)-C _1-3-alkylidene group-N (C _1-3-alkyl), R ^5.1.1-O-C (O)-C _1-3-alkylidene group-O, R ^5.1.1-O-C (O)-C _1-3-alkylidene group, R ^5.1.1-O-C (O)-C (O), R ^5.1.1-O-C (O)-C (O)-O, R ^5.1.1-O-C (O)-C _1-3-alkylidene group-C (O) or

R ^5.1.1-O-C (O)-C _1-3-alkylidene group-C (O)-O,

R ^5.1.1.1Expression is selected from following group,

R ^5.1.1.2Expression is selected from following group,

With

R ^5.2Expression H, H ₃C, R ^5.2.1-O-C (O)-C _1-3-alkylidene group-NH, R ^5.2.1-O-C (O)-C _1-3-alkylidene group-O, R ^5.2.1-O-C (O)-C _1-3-alkylidene group, R ^5.2.1-O-C (O)-C (O) or R ^5.2.1-O-C (O)-C _1-3-alkylidene group-C (O),

R ^5.2.1.1Expression is selected from following group,

With

R ^5.2.1.2Expression is selected from following group,

With

Perhaps

R ^5.2.1Expression following formula group,

4. compound of Formula I as claimed in claim 1, wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³-R ⁴Represent general formula I V group together

Wherein

R ^3.1Expression H,

R ^3.2Expression H or C _1-3-alkyl,

R ^4.1Expression H or C _1-3-alkyl,

R ^4.2Expression H,

R ^4.3.1Expression is selected from following group,

With

R ^5.1.1.1Expression is selected from following group,

R ^5.1.1.2Expression is selected from following group,

With

R ^5.2.1.1Expression is selected from following group,

With

R ^5.2.1.2Expression is selected from following group,

With

5. compound of Formula I as claimed in claim 1, wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³-R ⁴Represent general formula I V group together

Wherein

R ^3.1Expression H or R ^3.1.1-O-C (O),

R ^3.1.1.1The expression group

R ^3.2Expression H, H ₃C or R ^3.2.1-O-C (O),

R ^3.2.1.1The expression group

R ^4.2Expression H or H ₃C,

R ^4.3Expression H, C _1-6-alkyl, (C _1-3-alkyl) ₂N-C _2-4-alkylidene group, (C _1-3-alkyl) ₂N-C (O)-C _1-3-alkylidene group or R ^4.3.1-C _2-4-alkylidene group, and

R ^4.3.1Expression is selected from following group,

With

R ^5.1Expression H, H ₃C, R ^5.1.1-O-C (O), R ^5.1.1-O-C (O)-C _1-3-alkylidene group-NH, R ^5.1.1-O-C (O)-C _1-3-alkylidene group-N (C _1-3-alkyl), R ^5.1.1-O-C (O)-C _1-3-alkylidene group-O, R ^5.1.1-O-C (O)-C _1-3-alkylidene group, R ^5.1.1-O-C (O)-C (O), R ^5.1.1-O-C (O)-C (O)-O-R ^5.1.1-O-C (O)-C _1-3-alkylidene group-C (O) or R ^5.1.1-O-C (O)-C _1-3-alkylidene group-C (O)-O,

R ^5.1.1Expression H, C _1-8-alkyl, phenyl, indanyl, pyridyl-methyl, HO-C _2-4-alkylidene group, C _1-6-alkyl-O-C _2-4-alkylidene group, H ₂N-C _2-4-alkylidene group, (C _1-6-alkyl)-NH-C _2-4-alkylidene group, (C _1-6-alkyl) ₂N-C _2-4-alkylidene group, H ₂N-C (O)-C _1-3-alkylidene group, (C _1-6-alkyl)-NH-C (O)-C _1-3-alkylidene group, (C _1-6-alkyl) ₂N-C (O)-C _1-3-alkylidene group, C _1-6-alkyl-C (O)-O-C _1-3-alkylidene group, C _1-6-alkyl-O-C (O)-O-C _1-3-alkylidene group, R ^5.1.1.1-C (O)-C _1-3-alkylidene group or R ^5.1.1.2-C _2-4-alkylidene group,

R ^5.1.1.1Expression is selected from following group,

R ^5.1.1.2Expression is selected from following group,

With

R ^5.2.1Expression H, C _1-8-alkyl, phenyl, indanyl, pyridyl-methyl, HO-C _2-4-alkylidene group, C _1-6-alkyl-O-C _2-4-alkylidene group, C _1-6-alkyl-O-C _2-4-alkylidene group-O-C _2-4-alkylidene group, H ₂N-C _2-4-alkylidene group, (C _1-6-alkyl)-NH-C _2-4-alkylidene group, (C _1-6-alkyl) ₂N-C _2-4-alkylidene group, H ₂N-C (O)-C _1-3-alkylidene group, (C _1-6-alkyl)-NH-C (O)-C _1-3-alkylidene group, (C _1-6-alkyl) ₂N-C (O)-C _1-3-alkylidene group, C _1-6-alkyl-C (O)-O-C _1-3-alkylidene group, C _1-6-alkyl-O-C (O)-O-C _1-3-alkylidene group, R ^5.2.1.1-C (O)-C _1-3-alkylidene group or R ^5.2.1.2-C _2-4-alkylidene group,

R ^5.2.1.1Expression is selected from following group,

With

R ^5.2.1.2Expression is selected from following group,

With

Perhaps

R ^5.2.1Expression following formula group

6. compound of Formula I as claimed in claim 1, wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³-R ⁴Represent general formula I V group together

Wherein

R ^4.3.1Expression is selected from following group,

With

R ^5.1.1.1Expression is selected from following group,

R ^5.1.1.2Expression is selected from following group,

With

R ^5.2.1.1Expression is selected from following group,

R ^5.2.1.2Expression is selected from following group,

With

7. compound of Formula I as claimed in claim 1, wherein

R ¹Expression is selected from following group,

With

Wherein

R ^1.1Expression H or H ₃C-O,

R ²Expression is selected from following group,

With

R ³-R ⁴Represent general formula I V group together

8. compound of Formula I as claimed in claim 1 is selected from

9. acceptable salt on the physiology that forms as the compound of each general formula I in the claim 1 to 8 and inorganic or organic acid or alkali.

10. pharmaceutical composition contains just like at least one compound in the claim 1 to 8, and perhaps acceptable salt on the physiology according to claim 9 randomly also contains one or more inert supports and/or thinner.

11. be used for acute and prophylactic treatment headache as at least one compound in the claim 1 to 9 in preparation, especially the purposes in the pharmaceutical composition used of migraine, cluster headache and tension headache.

12. be used for the treatment of purposes in the pharmaceutical composition of non-insulin-dependent diabetes mellitus (NIDDM) in preparation as at least one compound in the claim 1 to 9.

13. be used for the treatment of purposes in the pharmaceutical composition of following disease as at least one compound in the claim 1 to 9 in preparation: cardiovascular disorder, the morphine tolerance, the diarrhoea that causes by the clostridium toxin, dermatosis, especially hot and radiation-induced damage comprises sunburn, lichen albus, pruigo, pruigo toxicodermatitis and serious scratching where it itches, inflammatory diseases, arthritis disease osteoarthritis for example for example, rheumatoid arthritis or neurarthropathy, general soft tissue rheumatism (meat fiber pain), oral mucosa nervosa inflammation, the inflammatory lung disease, allergic rhinitis, asthma and COPD, the disease of following excessive vasorelaxation and the vascular flow that causes thus to descend and causing, for example suffer a shock or Sepsis, chronic pain is diabetic neuropathy for example, the neuropathy that chemotherapy causes, the neuropathy that HIV causes, neuropathy after the bleb, the neuropathy that causes because of tissue injury, trigeminal neuralgia, the temporomandibular joint dysfunction, CRPS, backache and viscera disease be IBS (irritable bowel syndrome) or inflammatory bowel for example; Be used for alleviating pain generally speaking or be used for menopausal women estrogen deficiency women that preventative or acute treatment processing causes because of vasorelaxation and blood flow increase and through the patients with prostate cancer of hormonotherapy and castrating people patient's hot flush syndromes.

14. as in the claim 1 to 9 one of at least described compound be used for the treatment of purposes in the pharmaceutical composition of irritable bowel syndrome (IBS) in preparation.

15. as in the claim 1 to 9 one of at least described compound be used for preventing handling the women's of estrogen deficiency the purposes of pharmaceutical composition of hot flush with acute treatment in preparation.

16. a method for preparing as the pharmaceutical composition of claim 10 is characterized in that will being incorporated in one or more inert supports and/or the thinner as at least one compound in the claim 1 to 9 by method non-chemically.

17. a method for preparing as the compound of Formula I one of in the claim 1 to 9 is characterized in that

(a) make general formula V carboxylic acid

R among the formula V ¹With R ²All as definition in the claim 1, with the coupling of general formula VI amine

H-R ³-R ⁴，

R among the formula VI ³With R ⁴All, wherein connect through R as definition in the claim 1 ³Nitrogen-atoms form, and before reacting, be present in any carboxylic-acid functional base, primary amino or secondary amino group or hydroxyl in the group of general formula VI amine, protected base protection, and after reaction finished, employed protecting group was cleaved again, or

(b) make general formula VII compound

R wherein ¹With R ²As definition in the claim 1, and Nu represents leaving group, with general formula VI amine coupling H-R ³-R ⁴,

Wherein all groups all as definition in the claim 1, wherein connect through amine R ³Nitrogen-atoms form, and before reacting, be present in any carboxylic-acid functional base, uncle's ammonia or parahelium functional group or hydroxyl in the group of general formula VI amine, protected base protection, and after reaction finished, employed any protecting group was cleaved again, wherein

As the hydroxycarboxylic acid of the needed general formula V of initial compounds, be through general formula VIII piperidines

R wherein ¹As definition in the claim 1, with the carbonic acid derivatives of general formula I X

Y wherein ¹With Y ²Expression nucleofugicity group, it can be identical or different,

And with general formula X compound reaction and obtain

R wherein ²As definition in the claim 1, and Z ¹The expression carboxyl-protecting group, and before reacting, may be present in the radicals R of formula VI compound ²In the protected base protection of any hydroxyl, and after reaction finished, employed any protecting group was cleaved again, and

Reach the approach of general formula X compound, comprise making general formula X I aldehyde

R wherein ²As definition in the claim 1, with the N-acetyl-glycine, in diacetyl oxide, in the presence of alkali metal acetate, react as solvent, and/or

Randomly then make the compound of Formula I of acquisition like this split into its steric isomer, and/or

Make the compound of Formula I of acquisition like this change into its salt, particularly change into for acceptable salt on the physiology of medicinal use.