CN101405263A

CN101405263A - Cannibinoid receptor modulators

Info

Publication number: CN101405263A
Application number: CNA2007800093729A
Authority: CN
Inventors: S·查克拉曼尼尔; M·V·契里亚; M·C·克拉斯比; K·A·伊刚; J·D·史考特; 王永刚; 夏岩; W·J·格林里
Original assignee: Schering Corp
Current assignee: Merck Sharp and Dohme Corp
Priority date: 2006-01-18
Filing date: 2007-01-16
Publication date: 2009-04-08
Also published as: ZA200806237B

Abstract

A compound having the general structure of Formula (I): Chemical formula should be inserted here as it appears on the abstract in paper form. or a pharmaceutically acceptable salt, solvate, or ester thereof, is useful in treating diseases, disorders, or conditions such as obesity, metabolic disorders, addiction, diseases of the central nervous system, cardiovascular disorders, respiratory disorders, and gastrointestinal disorders.

Description

Cannibinoid receptor modulators

Invention field

The present invention relates to be used for the treatment of the Cannibinoid receptor modulators (CB especially of obesity, metabolism disorder, addiction, central nervous system disease, cardiovascular disorder, respiratory disease and gastrointestinal dysfunction ₁The antagonist of acceptor or inverse agonists), the pharmaceutical composition that comprises this compounds, and with described compound and the combination treatment treatment of conditions method of obesity, metabolism disorder, addiction, central nervous system disease, cardiovascular disorder, respiratory disease and gastrointestinal dysfunction for example.

Background of invention

CB ₁Acceptor is one of neuroregulation acceptor the abundantest in the brain, and in hippocampus, cortex, cerebellum and basal ganglion high level expression (for example, people such as Wilson, Science, 2002, vol.296,678-682).Selectivity CB ₁Receptor antagonist, pyrazole derivatives for example, (for example United States Patent (USP) 6,432 as Li Monaban, 984), can be used for treating various illnesss, as obesity and metabolism syndrome (people such as Bensaid for example, Molecular Pharmacology, 2003 vol.63, no.4, pp.908-914; People such as Trillou, Am.J.Physiol.Regul.Integr.Comp.Physiol.2002 vol.284, R345-R353; Kirkham, Am.J.Physiol.Regul.Integr.Comp.Physiol.2002 vol.284, R343-R344), neuritis sexual disorder (for example, people such as Adam, Expert Opin.Ther.Patents, 2002, vol.12, no.10,1475-1489; U.S.6,642,258), cognitive disorder and psychosis (for example, people such as Adam, Expert Opin.Ther.Pat, 2002, vol.12, pp.1475-1489), addiction (for example, smoking cessation (smoking cessation); U.S. Patent Publication 2003/0087933), gastrointestinal dysfunction (for example, people such as Lange, J.Med.Chem.2004, vol.47,627-643) and cardiovascular disorder (people such as Porter for example, Pharmacology and Therapeutics, 2001 vol.90,45-60; Sanofi-AventisPublication, Bear Steams Conference, New York, September 14,2004, pages 19-24).

Yet still need less side effect and improve improvement cannaboid medicament, especially Cannibinoid receptor modulators (for example, the CB of effect ₁The antagonist of acceptor or inverse agonists).Therefore, the purpose of this invention is to provide and be used for the treatment of by the disease of Cannabined receptor mediation or the condensed-bicyclic and the volution Cannibinoid receptor modulators of illness.

Summary of the invention

In one embodiment, the present invention relates to the compound of formula (I):

Or its pharmacy acceptable salt, solvate or ester, wherein:

M is 0 or 1, and n is 1 or 2, and m+n is 1 or 2;

Dotted line in the formula (I)

The expression valency requires singly-bound or two key of permission;

R ¹Be selected from-C (O)-N (R ¹⁰) ₂,-C (O)-O-alkyl and-C (O)-R ¹⁴

R ²The alkyl that is selected from H, unsubstituted alkyl, replaces with one or more U groups and-alkylidene group-N (R ¹⁰) ₂

Perhaps R ¹And R ²Being presented at the middle bonded carbon atom of formula (I) with them forms suc as formula the group Q shown in (IA):

Wherein Q is selected from:

Y ¹For-O-or-N (R ⁷)-;

Y ²For-O-or-N (R ⁸)-;

R ³, R ⁴, R ⁵And R ⁶Independently be selected from respectively H ,-O-R ⁹, R ¹¹With-N (R ¹⁶) ₂

R ⁷Be selected from H, alkyl, arylalkyl, thiazolinyl ,-alkylidene group-N (R ⁹) ₂,-alkylidene group-O-R ⁹,-alkylidene group-R ¹²,-C (O)-R ¹⁴,-alkylidene group-C (O) H ,-C (O)-O-R ¹¹And Boc;

R ⁸Be selected from H ,-alkylidene group-R ¹²,-C (O)-R ¹⁷,-S (O ₂)-R ¹¹,-S (O ₂)-R ¹⁴,-C (O)-N (R ¹⁸) ₂, R ¹⁴And Boc;

Its condition is wherein said group-N (R ¹⁸) ₂Two R ¹⁸Group forms unsubstituted Heterocyclylalkyl, uses one or more X with their bonded N atoms ³The Heterocyclylalkyl that group replaces, perhaps described replacement or unsubstituted Heterocyclylalkyl and aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl condense;

R ⁹Be selected from H, TBS, TIPS, Tf and R ¹¹

Each R ¹⁰The alkyl that independently is selected from H, unsubstituted alkyl, replaces with one or more U groups ,-alkylidene group-R ¹²,-alkylidene group-R ¹³,-alkylidene group-R ¹⁴,-C (O)-R ¹⁴,-alkylidene group-O-R ⁹, R ¹⁴, unsubstituted Heterocyclylalkyl, use one or more X ³Heterocyclylalkyl that group replaces and benzo-fused cycloalkyl;

R ¹¹The alkyl that is selected from unsubstituted alkyl, replaces with one or more U groups ,-alkylidene group-O-alkyl ,-alkylidene group-O-aryl, unsubstituted aryl and use one or more X ¹The aryl that group replaces;

R ¹²Be selected from unsubstituted aryl and use one or more X ¹The aryl that group replaces;

R ¹³Be selected from unsubstituted heteroaryl and use one or more X ²The heteroaryl that group replaces;

R ¹⁴Be selected from unsubstituted cycloalkyl, use one or more X ⁴The cycloalkyl that group replaces, unsubstituted alkyl and the alkyl that replaces with one or more U groups;

Each R ¹⁵Independently be selected from H ,-N ₃, halogen, thiazolinyl ,-alkylidene group-R ¹²,-alkylidene group-O-R ⁹,-alkylidene group-N (R ¹⁸) ₂,-alkylidene group-C (O) H ,-OH ,-CN ,-the O-alkyl ,-C (O) N (R ¹⁸) ₂,-N (R ¹⁸) ₂,-NR ¹⁸C (O) R ¹⁸,-NR ¹⁸C (O) ₂R ¹⁸,-NR ¹⁸C (O) N (R ¹⁸) ₂,-NR ¹⁸S (O) ₂R ¹⁸,-O-thiazolinyl ,-C (O) ₂R ¹⁸, unsubstituted alkyl, the alkyl that replaces with one or more U groups ,-O-alkylidene group-C (O) R ¹⁸Or-C (O) R ¹⁸

R ¹⁶Be selected from R ⁹With-C (O)-R ¹²

R ¹⁷Be selected from unsubstituted Heterocyclylalkyl, use one or more X ³The Heterocyclylalkyl that group replaces ,-alkylidene group-R ¹²,-O-R ⁹And R ¹²

Each R ¹⁸Independently be selected from H, unsubstituted Heterocyclylalkyl, use one or more X ³Heterocyclylalkyl, R that group replaces ¹², R ¹³And R ¹⁴

Its condition is, works as R ¹⁸When being attached to N, each R ¹⁸Independently be selected from H, unsubstituted Heterocyclylalkyl, use one or more W ³The Heterocyclylalkyl that group replaces ,-C (O) R ²¹, R ¹², R ¹³And R ¹⁴

R ¹⁹Be selected from H, TBS, TIPS, Tf and R ²¹

Each R ²⁰The alkyl that independently is selected from H, unsubstituted alkyl, replaces with one or more U groups ,-alkylidene group-R ²²,-alkylidene group-R ²³,-alkylidene group-R ²⁴,-C (O)-R ²⁴,-alkylidene group-O-R ¹⁹, R ²⁴, unsubstituted Heterocyclylalkyl, use one or more W ³Heterocyclylalkyl that group replaces and benzo-fused cycloalkyl;

R ²¹The alkyl that is selected from unsubstituted alkyl, replaces with one or more U groups ,-alkylidene group-O-alkyl ,-alkylidene group-O-aryl, unsubstituted aryl, use one or more W ¹Aryl, the unsubstituted heteroaryl that group replaces, use one or more W ²Heteroaryl, the unsubstituted cycloalkyl that group replaces, use one or more W ⁴Cycloalkyl, the unsubstituted Heterocyclylalkyl that group replaces, use one or more W ³The Heterocyclylalkyl that group replaces ,-O-alkylidene group-O-R ²⁴,-C (O)-O-alkylidene group-O-R ²⁴,-C (O)-alkylidene group-R ²³,-C (O)-R ²²,-C (O)-R ²⁴,-C (O)-O-R ²²,-C (O)-O-R ²⁴,-NHR ²²,-NHR ²⁴,-S (O) ₂-R ²⁴With-alkylidene group-O-alkylidene group-O-R ²⁴, its condition is for can not use R ²¹With described R ²¹Bonded atom formation-O-O-;

R ²²Be selected from unsubstituted aryl and use one or more W ¹The aryl that group replaces;

R ²³Be selected from unsubstituted heteroaryl and use one or more W ²The heteroaryl that group replaces;

R ²⁴Be selected from alkyl, unsubstituted cycloalkyl, use one or more W ⁴The cycloalkyl that group replaces, unsubstituted alkyl and the alkyl that replaces with one or more U groups;

Each R ²⁵Independently be selected from H, R ²², R ²³, unsubstituted alkyl, the alkyl, the unsubstituted cycloalkyl that replace with one or more U groups, use one or more W ⁴The cycloalkyl that group replaces ,-alkylidene group-OR ¹⁹,-alkylidene group-NR ¹⁹R ¹⁹,-alkylidene group-SR ¹⁹,-alkylidene group-R ²³,-alkylidene group-R ²², unsubstituted Heterocyclylalkyl, use one or more W ³The Heterocyclylalkyl that group replaces ,-the alkylidenyl-heterocyclic alkyl, use one or more W ³The group replacement-the alkylidenyl-heterocyclic alkyl ,-C (O)-R ²⁴,-C (O)-R ²²,-C (O)-R ²⁴,-C (O)-O-R ²²,-C (O)-O-R ²⁴,-NHR ²²,-NHR ²⁴,-S (O) ₂-R ²⁴,-C (O)-NH-R ²²With-C (O)-NH-R ²⁴

Its condition is wherein said group-N (R ²⁵) ₂Two R ²⁵Group forms unsubstituted Heterocyclylalkyl, uses one or more X with their bonded N atoms ³The Heterocyclylalkyl that group replaces, perhaps described replacement or unsubstituted Heterocyclylalkyl and aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl condense;

Each W ¹Independently be selected from halogen ,-CN ,-OH ,-O-S (O) ₂-haloalkyl, unsubstituted aryl, the aryl that replaces with one or more Z groups, unsubstituted heteroaryl, with the heteroaryl of one or more Z groups replacements and-the O-alkyl;

Each W ²The aryl that independently is selected from halogen, unsubstituted aryl and replaces with one or more Z groups;

Each W ³Independently be selected from-OH, alkyl ,-alkylidene group-OH ,-the O-alkyl ,-C (O)-alkyl ,-C (O) NH ₂,-NHC (O) alkyl ,-NHC (O) H ,-NHC (O)-O-alkyl and-C (O)-O-alkyl; Perhaps

Two W ³Group forms carbonyl with their bonded ring carbon atoms;

Each W ⁴Independent is halogen or alkyl;

Ar ¹And Ar ²Independently be selected from R ¹²And R ¹³

Each X ¹Independently be selected from halogen ,-CN ,-O-R ¹⁹,-OH ,-O-S (O) ₂-haloalkyl, unsubstituted aryl, the aryl that replaces with one or more Z groups, unsubstituted heteroaryl, with the heteroaryl of one or more Z groups replacements ,-the O-cycloalkyl ,-the O-cycloalkylalkyl ,-O-alkylidene group-OR ¹⁹,-O-alkylidene group-C (O) N (R ²⁰) ₂,-O-alkylidene group-O-R ¹⁹, unsubstituted alkyl, the alkyl that replaces with one or more U groups, unsubstituted-the O-alkyl, with one or more U groups replacements-the O-alkyl ,-the O-thiazolinyl ,-O-alkylidene group-O-alkylidene group-OR ¹⁹,-O-alkylidene group-C (O) R ²⁴,-O-alkylidene group-C (O) OR ¹⁹,-O-alkyl ,-N (R ²⁵) ₂,-C (O) alkyl ,-C (O) OH ,-C (O) O-alkyl ,-C (O) O-cycloalkyl ,-C (O) N (R ²⁵) ₂,-O-alkylidenyl-heterocyclic alkyl, use one or more W ³Group replaces-O-alkylidenyl-heterocyclic alkyl, unsubstituted Heterocyclylalkyl, use one or more W ³The Heterocyclylalkyl that group replaces ,-O-alkenylene-O-alkylidene group-O-R ²⁴,-O-alkylidene group-N (R ²⁵) ₂,-O-alkylidene group-C (O) N (R ²⁵) ₂, unsubstituted cycloalkyl, use one or more W ⁴The cycloalkyl that group replaces ,-S (O)-R ²⁴,-S (O) ₂-R ²⁴And thiazolinyl;

Its condition is wherein said group-N (R ²⁰) ₂Or-N (R ²⁵) ₂Two R ²⁰Or R ²⁵Group forms unsubstituted Heterocyclylalkyl, uses one or more X with their bonded N atoms ³The Heterocyclylalkyl that group replaces, perhaps described replacement or unsubstituted Heterocyclylalkyl and aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl condense;

Each X ²Independently be selected from halogen ,-CN ,-O-R ¹⁹,-OH ,-O-S (O) ₂-haloalkyl, unsubstituted aryl, the aryl that replaces with one or more Z groups, unsubstituted heteroaryl, with the heteroaryl of one or more Z groups replacements ,-the O-cycloalkyl ,-the O-cycloalkylalkyl ,-O-alkylidene group-OR ¹⁹,-O-alkylidene group-C (O) N (R ²⁰) ₂,-O-alkylidene group-O-R ¹⁹, unsubstituted alkyl, the alkyl that replaces with one or more U groups, unsubstituted-the O-alkyl, with one or more U groups replacements-the O-alkyl ,-the O-thiazolinyl ,-O-alkylidene group-O-alkylidene group-OR ¹⁹,-O-alkylidene group-C (O) R ²⁴,-O-alkylidene group-C (O) OR ¹⁹,-O-alkyl ,-N (R ²⁵) ₂,-C (O) alkyl ,-C (O) OH ,-C (O) O-alkyl ,-C (O) O-cycloalkyl ,-C (O) N (R ²⁵) ₂,-O-alkylidenyl-heterocyclic alkyl, use one or more W ³Group replaces-O-alkylidenyl-heterocyclic alkyl, unsubstituted Heterocyclylalkyl, use one or more W ³The Heterocyclylalkyl that group replaces ,-O-alkenylene-O-alkylidene group-O-R ²⁴,-O-alkylidene group-N (R ²⁵) ₂,-O-alkylidene group-C (O) N (R ²⁵) ₂, unsubstituted cycloalkyl, use one or more W ⁴The cycloalkyl that group replaces ,-S (O)-R ²⁴,-S (O) ₂-R ²⁴And thiazolinyl;

Each X ³Independently be selected from-OH, alkyl ,-alkylidene group-OH ,-the O-alkyl ,-C (O)-alkyl ,-C (O) NH ₂,-NHC (O) alkyl ,-NHC (O) H ,-NHC (O)-O-alkyl and-C (O)-O-alkyl; Perhaps

Two X ³Group forms carbonyl with their bonded ring carbon atoms;

Each X ⁴Independent is halogen or alkyl;

Each U independently is selected from-OH ,-the O-alkyl ,-the O-aryl ,-O-alkylidene group-aryl ,-O-alkylidene group-O-alkyl ,-O-alkylidene group-O-haloalkyl ,-O-alkylidene group-O-aryl, halogen ,-CN, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, OTBS, OTIPS and OTf; And

Each Z independently is selected from-OH ,-O-alkyl, halogen, alkyl ,-CN ,-CF ₃, cycloalkyl ,-alkylidene group-OH ,-alkylidene group-O-alkyl, with one or more being selected from-OH ,-O-alkyl, halogen ,-group of CN, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl replaces-alkylidene group-O-alkyl ,-alkylidene group-O-alkylidene group-O-alkyl ,-alkylidene group-O-alkylidene group-O-aryl ,-alkylidene group-O-aryl and with one or more be selected from halogen ,-CN ,-OH ,-O-S (O) ₂-haloalkyl, aryl, heteroaryl and-group of O-alkyl replaces-alkylidene group-O-aryl; Perhaps

Two Z groups form carbonyl with their bonded ring carbon atoms.

In another embodiment, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition comprises compound or its pharmacy acceptable salt, solvate or ester and at least a pharmaceutically acceptable carrier of at least a formula (I) for the treatment of significant quantity.

In another embodiment, the present invention also provides a kind of by compound or its pharmacy acceptable salt, solvate, ester or the steric isomer treatment that needs at least a formula of patient's significant quantity (I), the method that alleviates or improve metabolism syndrome, obesity, waistline, fat distribution, insulin sensitivity, neuritis sexual disorder, cognitive disorder, psychosis, addiction behavior, gastrointestinal dysfunction and cardiovascular disorder are arranged.

In another embodiment, the present invention relates to a kind of treatment, alleviate or improve the method for disease of patient or illness, as metabolism syndrome, obesity, waistline, fat distribution, insulin sensitivity, neuritis sexual disorder, cognitive disorder, psychosis, addiction behavior, gastrointestinal dysfunction and cardiovascular disorder.Described method comprises the compound of at least a formula (I) that gives patient's significant quantity or the combination of its pharmacy acceptable salt, solvate or ester and one or more cholesterol-lowering agents.

Detailed Description Of The Invention

In one embodiment, the present invention relates to compound or its pharmacy acceptable salt, solvate, ester or the steric isomer of formula as herein described (I).

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester and steric isomer have with following formula (I):

Wherein

M is 0 or 1, and n is 1 or 2, and m+n is 1 or 2;

Dotted line in the formula (I) (

) represent that valency requires singly-bound or the two key that allows;

R ¹Be selected from-C (O)-N (R ¹⁰) ₂,-C (O)-O-(C ₁-C ₆) alkyl and-C (O)-R ¹⁴

R ²Be selected from H, unsubstituted (C ₁-C ₆) the alkyl, (C that replaces with one or more U groups ₁-C ₆) alkyl and-(C ₁-C ₆) alkylidene group-N (R ¹⁰) ₂

Wherein Q is selected from:

Y ¹For-O-or-N (R ⁷)-;

Y ²For-O-or-N (R ⁸)-;

R ⁷Be selected from H, (C ₁-C ₆) alkyl, (C ₆-C ₁₂) aryl (C ₁-C ₆) alkyl, (C ₂-C ₆) thiazolinyl ,-(C ₁-C ₆) alkylidene group-N (R ⁹) ₂,-(C ₁-C ₆) alkylidene group-O-R ⁹,-(C ₁-C ₆) alkylidene group-R ¹²,-C (O)-R ¹⁴,-(C ₁-C ₆) alkylidene group-C (O) H ,-C (O)-O-R ¹¹And Boc;

R ⁸Be selected from H ,-(C ₁-C ₆) alkylidene group-R ¹²,-C (O)-R ¹⁷,-S (O ₂)-R ¹¹,-S (O ₂)-R ¹⁴,-C (O)-N (R ¹⁸) ₂, R ¹⁴And Boc;

Its condition is wherein said group-N (R ¹⁸) ₂Two R ¹⁸Group forms unsubstituted (C with their bonded N atoms ₃-C ₅) Heterocyclylalkyl, use one or more X ³(the C that group replaces ₃-C ₅) Heterocyclylalkyl, perhaps described replacement or unsubstituted (C ₃-C ₅) Heterocyclylalkyl and (C ₆-C ₁₂) aryl, (C ₂-C ₁₀) heteroaryl, (C ₃-C ₇) cycloalkyl or (C ₃-C ₅) Heterocyclylalkyl condenses;

R ⁹Be selected from H, TBS, TIPS, Tf and R ¹¹

Each R ¹⁰Independently be selected from H, unsubstituted (C ₁-C ₆) the alkyl, (C that replaces with one or more U groups ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-R ¹²,-(C ₁-C ₆) alkylidene group-R ¹³,-(C ₁-C ₆) alkylidene group-R ¹⁴,-C (O)-R ¹⁴,-(C ₁-C ₆) alkylidene group-O-R ⁹, R ¹⁴, unsubstituted (C ₃-C ₅) Heterocyclylalkyl, use one or more X ³(the C that group replaces ₃-C ₅) Heterocyclylalkyl and benzo-fused (C ₃-C ₇) cycloalkyl;

R ¹¹Be selected from unsubstituted (C ₁-C ₆) the alkyl, (C that replaces with one or more U groups ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-O-(C ₆-C ₁₂) aryl, unsubstituted (C ₆-C ₁₂) aryl and use one or more X ¹(the C that group replaces ₆-C ₁₂) aryl;

R ¹²Be selected from unsubstituted (C ₆-C ₁₂) aryl and use one or more X ¹(the C that group replaces ₆-C ₁₂) aryl;

R ¹³Be selected from unsubstituted (C ₂-C ₁₀) heteroaryl and use one or more X ²(the C that group replaces ₂-C ₁₀) heteroaryl;

R ¹⁴Be selected from unsubstituted (C ₃-C ₇) cycloalkyl, use one or more X ⁴(the C that group replaces ₃-C ₇) cycloalkyl, unsubstituted (C ₁-C ₆) alkyl and the (C that replaces with one or more U groups ₁-C ₆) alkyl;

Each R ¹⁵Independently be selected from H ,-N ₃, halogen, (C ₂-C ₆) thiazolinyl ,-(C ₁-C ₆) alkylidene group-R ¹²,-(C ₁-C ₆) alkylidene group-O-R ⁹,-(C ₁-C ₆) alkylidene group-N (R ¹⁸) ₂,-(C ₁-C ₆) alkylidene group-C (O) H ,-OH ,-CN ,-O-(C ₁-C ₆) alkyl ,-C (O) N (R ¹⁸) ₂,-N (R ¹⁸) ₂,-NR ¹⁸C (O) R ¹⁸,-NR ¹⁸C (O) ₂R ¹⁸,-NR ¹⁸C (O) N (R ¹⁸) ₂,-NR ¹⁸S (O) ₂R ¹⁸,-O-(C ₂-C ₆) thiazolinyl ,-C (O) ₂R ¹⁸, unsubstituted (C ₁-C ₆) the alkyl, (C that replaces with one or more U groups ₁-C ₆) alkyl ,-O-(C ₁-C ₆) alkylidene group-C (O) R ¹⁸Or-C (O) R ¹⁸

R ¹⁶Be selected from R ⁹With-C (O)-R ¹²

R ¹⁷Be selected from unsubstituted (C ₃-C ₅) Heterocyclylalkyl, use one or more X ³(the C that group replaces ₃-C ₅) Heterocyclylalkyl ,-(C ₁-C ₆) alkylidene group-R ¹²,-O-R ⁹And R ¹²

Each R ¹⁸Independently be selected from H, unsubstituted (C ₃-C ₅) Heterocyclylalkyl, use one or more X ³(the C that group replaces ₃-C ₅) Heterocyclylalkyl, R ¹², R ¹³And R ¹⁴

Its condition is, works as R ¹⁸When being attached to N, each R ¹⁸Independently be selected from H, unsubstituted (C ₃-C ₅) Heterocyclylalkyl, use one or more W ³(the C that group replaces ₃-C ₅) Heterocyclylalkyl ,-C (O) R ²¹, R ¹², R ¹³And R ¹⁴

R ¹⁹Be selected from H, TBS, TIPS, Tf and R ²¹

Each R ²⁰Independently be selected from H, unsubstituted (C ₁-C ₆) the alkyl, (C that replaces with one or more U groups ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-R ²²,-(C ₁-C ₆) alkylidene group-R ²³,-(C ₁-C ₆) alkylidene group-R ²⁴,-C (O)-R ²⁴,-(C ₁-C ₆) alkylidene group-O-R ¹⁹, R ²⁴, unsubstituted (C ₃-C ₅) Heterocyclylalkyl, use one or more W ³(the C that group replaces ₃-C ₅) Heterocyclylalkyl and benzo-fused (C ₃-C ₇) cycloalkyl;

R ²¹Be selected from unsubstituted (C ₁-C ₆) the alkyl, (C that replaces with one or more U groups ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-O-(C ₆-C ₁₂) aryl, unsubstituted (C ₆-C ₁₂) aryl, use one or more W ¹(the C that group replaces ₆-C ₁₂) aryl, unsubstituted (C ₂-C ₁₀) heteroaryl, use one or more W ²(the C that group replaces ₂-C ₁₀) heteroaryl, unsubstituted (C ₃-C ₇) cycloalkyl, use one or more W ⁴(the C that group replaces ₃-C ₇) cycloalkyl, unsubstituted (C ₃-C ₅) Heterocyclylalkyl, use one or more W ³(the C that group replaces ₃-C ₅) Heterocyclylalkyl ,-O-(C ₁-C ₆) alkylidene group-O-R ²⁴,-C (O)-O-(C ₁-C ₆) alkylidene group-O-R ²⁴,-C (O)-(C ₁-C ₆) alkylidene group-R ²³,-C (O)-R ²²,-C (O)-R ²⁴,-C (O)-O-R ²²,-C (O)-O-R ²⁴,-NHR ²²,-NHR ²⁴,-S (O) ₂-R ²⁴With-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkylidene group-O-R ²⁴, its condition is for can not use R ²¹With described R ²¹Bonded atom formation-O-O-;

R ²²Be selected from unsubstituted (C ₆-C ₁₂) aryl and use one or more W ¹(the C that group replaces ₆-C ₁₂) aryl;

R ²³Be selected from unsubstituted (C ₂-C ₁₀) heteroaryl and use one or more W ²(the C that group replaces ₂-C ₁₀) heteroaryl;

R ²⁴Be selected from unsubstituted (C ₃-C ₇) cycloalkyl, use one or more X ⁴(the C that group replaces ₃-C ₇) cycloalkyl, unsubstituted (C ₁-C ₆) alkyl and the (C that replaces with one or more U groups ₁-C ₆) alkyl;

Each R ²⁵Independently be selected from H, R ²², R ²³, unsubstituted (C ₁-C ₆) the alkyl, (C that replaces with one or more U groups ₁-C ₆) alkyl, unsubstituted (C ₃-C ₇) cycloalkyl, use one or more W ⁴(the C that group replaces ₃-C ₇) cycloalkyl ,-(C ₁-C ₆) alkylidene group-OR ¹⁹,-(C ₁-C ₆) alkylidene group-NR ¹⁹R ¹⁹,-(C ₁-C ₆) alkylidene group-SR ¹⁹,-(C ₁-C ₆) alkylidene group-R ²³,-(C ₁-C ₆) alkylidene group-R ²², unsubstituted (C ₃-C ₅) Heterocyclylalkyl, use one or more W ³(the C that group replaces ₃-C ₅) Heterocyclylalkyl ,-(C ₁-C ₆) alkylidene group-(C ₃-C ₅) Heterocyclylalkyl, use one or more W ³Group replaces-(C ₁-C ₆) alkylidene group-(C ₃-C ₅) Heterocyclylalkyl ,-C (O)-R ²⁴,-C (O)-R ²²,-C (O)-R ²⁴,-C (O)-O-R ²²,-C (O)-O-R ²⁴,-NHR ²²,-NHR ²⁴,-S (O) ₂-R ²⁴,-C (O)-NH-R ²²With-C (O)-NH-R ²⁴

Its condition is wherein said group-N (R ²⁵) ₂Two R ²⁵Group forms unsubstituted (C with their bonded N atoms ₃-C ₅) Heterocyclylalkyl, use one or more X ³(the C that group replaces ₃-C ₅) Heterocyclylalkyl, perhaps described replacement or unsubstituted (C ₃-C ₅) Heterocyclylalkyl and (C ₆-C ₁₂) aryl, (C ₂-C ₁₀) heteroaryl, (C ₃-C ₇) cycloalkyl or (C ₃-C ₅) Heterocyclylalkyl condenses;

Each W ¹Independently be selected from halogen ,-CN ,-OH ,-O-S (O) ₂-(C ₁-C ₆) haloalkyl, unsubstituted (C ₆-C ₁₂) the aryl, (C that replaces with one or more Z groups ₆-C ₁₂) aryl, unsubstituted (C ₂-C ₁₀) the heteroaryl, (C that replaces with one or more Z groups ₂-C ₁₀) heteroaryl and-O-(C ₁-C ₆) alkyl;

Each W ²Independently be selected from halogen, unsubstituted (C ₆-C ₁₂) aryl and the (C that replaces with one or more Z groups ₆-C ₁₂) aryl;

Each W ³Independently be selected from-OH, (C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-OH ,-O-(C ₁-C ₆) alkyl ,-C (O)-(C ₁-C ₆) alkyl ,-C (O) NH ₂,-NHC (O) (C ₁-C ₆) alkyl ,-NHC (O) H ,-NHC (O)-O-(C ₁-C ₆) alkyl and-C (O)-O-(C ₁-C ₆) alkyl; Perhaps

Two W ³Group forms carbonyl with their bonded ring carbon atoms;

Each W ⁴Independent is halogen or (C ₁-C ₆) alkyl;

Ar ¹And Ar ²Independently be selected from R ¹²And R ¹³

Each X ¹Independently be selected from halogen ,-CN ,-O-R ¹⁹,-OH ,-O-S (O) ₂-(C ₁-C ₆) haloalkyl, unsubstituted (C ₆-C ₁₂) the aryl, (C that replaces with one or more Z groups ₆-C ₁₂) aryl, unsubstituted (C ₂-C ₁₀) the heteroaryl, (C that replaces with one or more Z groups ₂-C ₁₀) heteroaryl ,-O-(C ₃-C ₇) cycloalkyl ,-O-(C ₃-C ₇) cycloalkyl (C ₁-C ₆) alkyl ,-O-(C ₁-C ₆) alkylidene group-OR ¹⁹,-O-(C ₁-C ₆) alkylidene group-C (O) N (R ²⁰) ₂,-O-(C ₁-C ₆) alkylidene group-O-R ¹⁹, unsubstituted (C ₁-C ₆) the alkyl, (C that replaces with one or more U groups ₁-C ₆) alkyl, unsubstituted-O-(C ₁-C ₆) alkyl, with one or more U groups replace-O-(C ₁-C ₆) alkyl ,-O-(C ₂-C ₇) thiazolinyl ,-O-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkylidene group-OR ¹⁹,-O-(C ₁-C ₆) alkylidene group-C (O) R ²⁴,-O-(C ₁-C ₆) alkylidene group-C (O) OR ¹⁹,-O-(C ₁-C ₆) alkyl ,-N (R ²⁵) ₂,-C (O) (C ₁-C ₆) alkyl ,-C (O) OH ,-C (O) O-(C ₁-C ₆) alkyl ,-C (O) O-(C ₃-C ₇) cycloalkyl ,-C (O) N (R ²⁵) ₂,-O-(C ₁-C ₆) alkylidene group-(C ₃-C ₅) Heterocyclylalkyl, use one or more W ³Group replaces-O-(C ₁-C ₆) alkylidene group-(C ₃-C ₅) Heterocyclylalkyl, unsubstituted (C ₃-C ₅) Heterocyclylalkyl, use one or more W ³Group replaces-(C ₃-C ₅) Heterocyclylalkyl ,-O-(C ₂-C ₇) alkenylene-O-(C ₁-C ₆) alkylidene group-O-R ²⁴,-O-(C ₁-C ₆) alkylidene group-N (R ²⁵) ₂,-O-(C ₁-C ₆) alkylidene group-C (O) N (R ²⁵) ₂, unsubstituted (C ₃-C ₇) cycloalkyl, use one or more W ⁴(the C that group replaces ₃-C ₇) cycloalkyl ,-S (O)-R ²⁴,-S (O) ₂-R ²⁴(C ₂-C ₇) thiazolinyl;

Its condition is wherein said group-N (R ²⁰) ₂Or-N (R ²⁵) ₂Two R ²⁰Or R ²⁵Group forms unsubstituted (C with their bonded N atoms ₃-C ₅) Heterocyclylalkyl, use one or more X ³(the C that group replaces ₃-C ₅) Heterocyclylalkyl, perhaps described replacement or unsubstituted (C ₃-C ₅) Heterocyclylalkyl and (C ₆-C ₁₂) aryl, (C ₂-C ₁₀) heteroaryl, (C ₃-C ₇) cycloalkyl or (C ₃-C ₅) Heterocyclylalkyl condenses;

Each X ²Independently be selected from halogen ,-CN ,-O-R ¹⁹,-OH ,-O-S (O) ₂-(C ₁-C ₆) haloalkyl, unsubstituted (C ₆-C ₁₂) the aryl, (C that replaces with one or more Z groups ₆-C ₁₂) aryl, unsubstituted (C ₂-C ₁₀) the heteroaryl, (C that replaces with one or more Z groups ₂-C ₁₀) heteroaryl ,-O-(C ₃-C ₇) cycloalkyl ,-O-(C ₃-C ₇) cycloalkyl (C ₁-C ₆) alkyl ,-O-(C ₁-C ₆) alkylidene group-OR ¹⁹,-O-(C ₁-C ₆) alkylidene group-C (O) N (R ²⁰) ₂,-O-(C ₁-C ₆) alkylidene group-O-R ¹⁹, unsubstituted (C ₁-C ₆) the alkyl, (C that replaces with one or more U groups ₁-C ₆) alkyl, unsubstituted-O-(C ₁-C ₆) alkyl, with one or more U groups replace-O-(C ₁-C ₆) alkyl ,-O-(C ₂-C ₇) thiazolinyl ,-O-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkylidene group-OR ¹⁹,-O-(C ₁-C ₆) alkylidene group-C (O) R ²⁴,-O-(C ₁-C ₆) alkylidene group-C (O) OR ¹⁹,-O (C ₁-C ₆) alkyl ,-N (R ²⁵) ₂,-C (O) (C ₁-C ₆) alkyl ,-C (O) OH ,-C (O) O-(C ₁-C ₆) alkyl ,-C (O) O-(C ₃-C ₇) cycloalkyl ,-C (O) N (R ²⁵) ₂,-O-(C ₁-C ₆) alkylidene group-(C ₃-C ₅) Heterocyclylalkyl, use one or more W ³Group replaces-O-(C ₁-C ₆) alkylidene group-(C ₃-C ₅) Heterocyclylalkyl, unsubstituted (C ₃-C ₅) Heterocyclylalkyl, use one or more W ³Group replaces-(C ₃-C ₅) Heterocyclylalkyl ,-O-(C ₂-C ₇) alkenylene-O-(C ₁-C ₆) alkylidene group-O-R ²⁴,-O-(C ₁-C ₆) alkylidene group-N (R ²⁵) ₂,-O-(C ₁-C ₆) alkylidene group-C (O) N (R ²⁵) ₂, unsubstituted (C ₃-C ₇) cycloalkyl, use one or more W ⁴(the C that group replaces ₃-C ₇) cycloalkyl ,-S (O)-R ²⁴,-S (O) ₂-R ²⁴(C ₂-C ₇) thiazolinyl;

Each X ³Independently be selected from-OH, (C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-OH ,-O-(C ₁-C ₆) alkyl ,-C (O)-(C ₁-C ₆) alkyl ,-C (O) NH ₂,-NHC (O) (C ₁-C ₆) alkyl ,-NHC (O) H ,-NHC (O)-O-(C ₁-C ₆) alkyl and-C (O)-O-(C ₁-C ₆) alkyl; Perhaps

Two X ³Group forms carbonyl with their bonded ring carbon atoms;

Each X ⁴Independent is halogen or (C ₁-C ₆) alkyl;

Each U independently is selected from-OH ,-O-(C ₁-C ₆) alkyl ,-O-(C ₆-C ₁₂) aryl ,-O-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₂) aryl ,-O-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkyl ,-O-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) haloalkyl ,-O-(C ₁-C ₆) alkylidene group-O-(C ₆-C ₁₂) aryl, halogen ,-CN, (C ₃-C ₇) cycloalkyl, (C ₃-C ₅) Heterocyclylalkyl, (C ₆-C ₁₂) aryl, (C ₂-C ₁₀) heteroaryl, OTBS, OTIPS and OTf; And

Each Z independently is selected from-OH ,-O-(C ₁-C ₆) alkyl, halogen, (C ₁-C ₆) alkyl ,-CN ,-CF ₃, (C ₃-C ₇) cycloalkyl ,-(C ₁-C ₆) alkylidene group-OH ,-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkyl, with one or more being selected from-OH ,-O-(C ₁-C ₆) alkyl, halogen ,-CN, (C ₃-C ₇) cycloalkyl, (C ₃-C ₅) Heterocyclylalkyl, (C ₆-C ₁₂) aryl, (C ₂-C ₁₀) group of heteroaryl replaces-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkylidene group-O-(C ₆-C ₁₂) aryl ,-(C ₁-C ₆) alkylidene group-O-(C ₆-C ₁₂) aryl and with one or more be selected from halogen ,-CN ,-OH ,-O-S (O) ₂-(C ₁-C ₆) haloalkyl, (C ₆-C ₁₂) aryl, (C ₂-C ₁₀) heteroaryl and-O-(C ₁-C ₆) group of alkyl replaces-(C ₁-C ₆) alkylidene group-O-(C ₆-C ₁₂) aryl; Perhaps

Two Z groups form carbonyl with their bonded ring carbon atoms.

Dotted line in the formula (I)

Expression can independently be the key of singly-bound or two keys.Ring in the formula (I) can not contain two keys, or contains one or more pairs of keys (being one or two pair key), and its condition is stable for the gained compound.The unrestricted example of formula (I) compound can have one of following general formula, wherein R ¹, R ², R ¹⁵, Ar ¹And Ar ²As defined herein:

When existing, each R of formula (I) ¹⁵Group can be attached to any carbon atom of the formula (I) that can replace.As unrestricted example, below general structure:

Comprise wherein radicals R when existing ¹⁵Can be attached to the following structure of any ring carbon atom.For example,

When there being a R ¹⁵During group, more than general structure comprise following:

When there being two R ¹⁵During group, more than general structure comprise following:

When the six-ring of formula (I) comprises one or more pairs of keys, each R when existing then ¹⁵Can be attached to these and replace possible any ring carbon atom.

The similar compound of imagining formula (I) comprises all possible stable steric isomer.As unrestricted example, below general structure (each R wherein ¹⁵Be H):

Comprise following steric isomer:

In another embodiment of the compound of formula (I) or its pharmacy acceptable salt, solvate, ester or steric isomer, R ¹And R ²Being presented at the middle bonded carbon atom of formula (I) with them forms suc as formula the group Q shown in (IA):

Wherein group Q is selected from:

Therefore, the compound of formula of the present invention (IA) comprises following general formula:

Those skilled in the art will appreciate that formula (VII-1), (VII-2), (VIII-1) and (VIII-2) same compound can be described be equal to tautomeric form (for example, at formula (VIII-1) or R (VIII-2) ⁵For-NHR ¹⁶, and formula (VII-1) or R (VII-2) ⁷During for H).Therefore, can think that following structural formula is equal to:

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have with following formula (II):

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have with following formula (IIA):

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (IIA), wherein:

Ar ¹And Ar ²Independently be selected from R ¹²And R ¹³

R ⁷Be selected from H, alkyl, thiazolinyl ,-alkylidene group-N (R ⁹) ₂,-alkylidene group-O-R ⁹,-alkylidene group-R ¹²,-C (O)-R ¹⁴With-C (O)-O-R ¹¹

R ⁹Be selected from H and alkyl;

R ¹²Be selected from unsubstituted phenyl and use one or more X ¹The phenyl that group replaces;

R ¹³Be selected from the unsubstituted pyridine base and use one or more X ²The pyridyl that group replaces;

R ¹⁴Be selected from alkyl, unsubstituted cycloalkyl or use one or more X ⁴The cycloalkyl that group replaces; And

R ¹⁵Be selected from H, alkyl, thiazolinyl ,-alkylidene group-R ¹²With-the O-thiazolinyl.

Ar ¹For using one or more X ¹The phenyl that group replaces;

Ar ²For using one or more X ¹The phenyl that group replaces or use one or more X ²The pyridyl that group replaces;

R ⁷Be H; And

R ¹⁵Be alkyl.

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have with following formula (III):

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have with following formula (IIIA):

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (IIIA), wherein:

Ar ¹And Ar ²Independently be selected from R ¹²And R ¹³

R ³And R ⁴Independent respectively is H or alkyl;

R ¹²Be selected from unsubstituted phenyl and use one or more X ¹The phenyl that group replaces; And

R ¹³Be selected from the unsubstituted pyridine base and use one or more X ²The pyridyl that group replaces.

R ³And R ⁴Respectively independent be H or-CH ₃

Ar ¹Be unsubstituted phenyl or the phenyl that replaces with one or more halogens; And

Ar ²Phenyl, the unsubstituted pyridine base that is selected from unsubstituted phenyl, replaces with one or more halogens and use one or more X ²The pyridyl that group replaces.

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have with following formula (IV):

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have with following formula (IVA):

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (IVA), wherein:

Ar ¹And Ar ²Independently be selected from R ¹²And R ¹³

R ⁸Be selected from-alkylidene group-R ¹²,-C (O)-R ¹⁷,-S (O ₂)-R ¹⁴,-C (O)-N (R ¹⁸) ₂And R ¹⁴

R ⁹Be selected from H and alkyl;

R ¹⁷Be selected from unsubstituted Heterocyclylalkyl, use one or more X ³The Heterocyclylalkyl that group replaces ,-alkylidene group-R ¹²,-O-R ⁹And R ¹²And

Each R ¹⁸Independently be selected from H, R ¹²And R ¹⁴

R ⁸Be selected from-CH ₂-R ¹²,-CH (CH ₃)-R ¹²,-C (O)-R ¹⁷,-S (O ₂)-R ¹⁴,-C (O)-N (R ¹⁸) ₂And R ¹⁴

R ⁹Be selected from H and alkyl;

R ¹⁷Be selected from unsubstituted Heterocyclylalkyl, use one or more X ³The Heterocyclylalkyl that group replaces ,-CH ₂-R ¹²,-CH (CH ₃)-R ¹²,-O-R ⁹And R ¹²And

Each R ¹⁸Independent be H, unsubstituted cycloalkyl, use one or more X ⁴Cycloalkyl, the unsubstituted aryl that group replaces and use one or more X ¹The aryl that group replaces.

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have following formula V:

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have with following formula (VA):

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (VA), wherein:

R ⁷For H or-alkylidene group-R ¹²And

R ¹²Be selected from unsubstituted phenyl and use one or more X ¹The phenyl that group replaces.

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have with following formula (VI):

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have with following formula (VIA):

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (VIA), wherein:

R ³, R ⁵And R ⁶Independently be selected from respectively H ,-O-R ⁹And R ¹¹

R ⁹Be H or alkyl;

R ¹¹Be selected from alkyl, unsubstituted phenyl and use one or more X ¹The phenyl that group replaces;

R ¹³Be selected from the unsubstituted pyridine base and use one or more X ²The pyridyl that group replaces; And

Ar ²Be selected from R ¹²And R ¹³

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have with following formula (VII):

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have with following formula (VIIA):

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (VIIA), wherein:

R ¹⁶For-C (O)-R ¹²And

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have with following formula (VIII):

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have with following formula (VIIIA):

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (VIIIA), wherein:

R ³, R ⁴And R ⁵Respectively independent be H or-N (R ¹⁶) ₂

R ⁹Be selected from H and R ¹¹

R ¹¹Be selected from alkyl, unsubstituted aryl and use one or more X ¹The aryl that group replaces;

R ¹⁶Be selected from R ⁹With-C (O)-R ¹²

In another embodiment of the compound of formula (I) or its pharmacy acceptable salt, solvate, ester or steric isomer, R ¹Be selected from-C (O)-N (R ¹⁰) ₂,-C (O)-O-alkyl and-C (O)-R ¹⁴And R ²The alkyl that is selected from H, alkyl, replaces with one or more-OH group and-alkylidene group-N (R ¹⁰) ₂

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have with following formula (IB):

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (IB), wherein:

R ⁹Be selected from H and alkyl;

Each R ¹⁰The alkyl that independently is selected from H, replaces with one or more-OH group ,-alkylidene group-R ¹²,-alkylidene group-R ¹³,-alkylidene group-R ¹⁴,-alkylidene group-O-R ⁹, R ¹⁴With benzo-fused cycloalkyl;

R ¹³Be selected from unsubstituted heteroaryl and use one or more X ²The heteroaryl that group replaces; And

R ¹⁴Be selected from alkyl, unsubstituted cycloalkyl or use one or more X ⁴The cycloalkyl that group replaces.

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have with following formula (IC):

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (IC), wherein:

R ¹For-C (O)-N (R ¹⁰) ₂Or-C (O)-O-alkyl;

R ²The alkyl that is selected from H, alkyl, replaces with one or more-OH group and-alkylidene group-N (R ¹⁰) ₂

Each R ¹⁰Independently be selected from H ,-alkylidene group-R ¹²With-C (O)-R ¹⁴

R ¹⁵For H or-OH.

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have with following formula (ID):

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have with following formula (IE):

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (ID), wherein:

Y ¹Be NH or N-Boc;

R ³Be H or alkyl;

R ⁴Be H or alkyl;

R ¹⁵Be alkyl; And

Ar ¹And Ar ²Be selected from unsubstituted phenyl and use one or more X ¹The phenyl that group replaces.

Each X ¹Independently be selected from halogen ,-CN ,-OH ,-the O-cycloalkyl ,-the O-cycloalkylalkyl ,-O-alkylidene group-OR ¹⁹,-O-alkylidene group-C (O) N (R ²⁰) ₂,-O-alkylidene group-O-R ¹⁹, unsubstituted alkyl, the alkyl that replaces with one or more U groups, unsubstituted-the O-alkyl, with one or more U groups replacements-the O-alkyl ,-O-thiazolinyl-O-alkylidene group-O-alkylidene group-OR ¹⁹,-O-alkylidene group-C (O) R ²⁴,-O-alkylidene group-C (O) OR ¹⁹With-the O-alkyl.

Each X ¹Independently be selected from-OCH ₃,-OH ,-OTf ,-CN ,-OCH ₂CH ₃,-OCH (CH ₃) ₂,

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (ID),

Or its pharmacy acceptable salt, solvate or ester, wherein:

Y ¹Be NH or N-Boc;

R ³Be H or alkyl;

R ⁴Be H or alkyl;

R ¹⁵Be alkyl;

Ar ¹And Ar ²Be selected from unsubstituted phenyl and use one or more X ¹The phenyl that group replaces; And

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (IE),

Or its pharmacy acceptable salt, solvate or ester, wherein:

Y ¹Be NH or N-Boc;

R ³Be H or alkyl;

R ⁴Be H or alkyl;

R ¹⁵Be alkyl; And

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (I), wherein each R ¹⁵Independently be selected from H ,-N ₃, halogen, thiazolinyl ,-alkylidene group-R ¹²,-alkylidene group-O-R ⁹,-alkylidene group-N (R ¹⁸) ₂,-alkylidene group-C (O) H ,-OH ,-CN ,-the O-alkyl ,-C (O) N (R ¹⁸) ₂,-N (R ¹⁸) ₂,-NHC (O) R ¹⁸,-NHC (O) ₂R ¹⁸,-NR ¹⁸C (O) N (R ¹⁸) ₂,-NHS (O) ₂R ¹⁸,-O-thiazolinyl ,-C (O) ₂R ¹⁸, unsubstituted alkyl, the alkyl that replaces with one or more U groups ,-O-alkylidene group-C (O) R ¹⁸Or-C (O) R ¹⁸, its condition is wherein said group-N (R ¹⁸) ₂Two R ¹⁸Group forms unsubstituted Heterocyclylalkyl, uses one or more X with their bonded N atoms ³The Heterocyclylalkyl that group replaces, perhaps described replacement or unsubstituted Heterocyclylalkyl and aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl condense.

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (I), wherein each R ¹⁵Independently be selected from H ,-OH ,-OCH ₃,-OCH ₂CH ₃,-CH ₃,-CH ₂CH ₃,-CH ₂CH ₂CH ₃,-N ₃,-NH ₂,-CO ₂H ,-CO ₂CH ₃,-CH ₂OH ,-CH ₂CH ₂OH ,-CH ₂CH ₂OTBS ,-CH ₂OCH ₃,-OCH ₂CH ₂OH,

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (I), wherein: R ³And R ⁴Independently be selected from respectively H ,-O-R ⁹, R ¹¹With-N (R ¹⁶) ₂

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (I), wherein each R ³And R ⁴Independently be selected from H ,-CH ₃,-CH ₂OH ,-CH ₂OCH ₂CH ₂OCH ₃,-CH ₂OCH ₃,-CH ₂OCH ₂CH ₃,-CH ₂OCH ₂CH ₂CH ₃,-CH ₂CH ₂OH,

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (I), wherein R ⁷Be selected from H, alkyl, arylalkyl, thiazolinyl ,-alkylidene group-N (R ⁹) ₂,-alkylidene group-O-R ⁹,-alkylidene group-R ¹²,-C (O)-R ¹⁴,-alkylidene group-C (O) H ,-C (O)-O-R ¹¹And Boc.

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (I), wherein R ⁷For H ,-CH ₃, Boc,

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (I), wherein Ar ¹For using one or more X ¹The phenyl that group replaces; And each X ¹Independently be selected from halogen ,-CN ,-O-R ¹⁹,-OH ,-O-S (O) ₂-haloalkyl, unsubstituted aryl, the aryl that replaces with one or more Z groups, unsubstituted heteroaryl, with the heteroaryl of one or more Z groups replacements ,-the O-cycloalkyl ,-the O-cycloalkylalkyl ,-O-alkylidene group-OR ¹⁹,-O-alkylidene group-C (O) N (R ²⁰) ₂,-O-alkylidene group-O-R ¹⁹, unsubstituted alkyl, the alkyl that replaces with one or more U groups, unsubstituted-the O-alkyl, with one or more U groups replacements-the O-alkyl ,-the O-thiazolinyl ,-O-alkylidene group-O-alkylidene group-OR ¹⁹,-O-alkylidene group-C (O) R ²⁴,-O-alkylidene group-C (O) OR ¹⁹,-O-alkyl ,-N (R ²⁵) ₂,-C (O) alkyl ,-C (O) OH ,-C (O) O-alkyl ,-C (O) O-cycloalkyl ,-C (O) N (R ²⁵) ₂,-O-alkylidenyl-heterocyclic alkyl, use one or more W ³Group replaces-O-alkylidenyl-heterocyclic alkyl, unsubstituted Heterocyclylalkyl, use one or more W ³The group replacement-Heterocyclylalkyl ,-O-alkenylene-O-alkylidene group-O-R ²⁴,-O-alkylidene group-N (R ²⁵) ₂,-O-alkylidene group-C (O) N (R ²⁵) ₂, unsubstituted cycloalkyl, use one or more W ⁴The cycloalkyl that group replaces ,-S (O)-R ²⁴,-S (O) ₂-R ²⁴And thiazolinyl; Its condition is wherein said group-N (R ²⁰) ₂Or-N (R ²⁵) ₂Two R ²⁰Or R ²⁵Group forms unsubstituted Heterocyclylalkyl, uses one or more X with their bonded N atoms ³The Heterocyclylalkyl that group replaces, perhaps described replacement or unsubstituted Heterocyclylalkyl and aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl condense.

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (I), wherein each X ¹Independently be selected from Cl, F ,-CH ₃,-OCH ₃,-OCH ₂CH ₃,-OH ,-OTf ,-CN ,-OCH ₂CH ₃,-OCH (CH ₃) ₂,

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (I), wherein Ar ²For using one or more X ¹The phenyl that group replaces or use one or more X ²The pyridyl that group replaces; X ¹Be selected from-OH ,-CN, halogen ,-OTIPS ,-OTf, alkyl ,-the O-alkyl ,-O-alkyl-OH and heteroaryl; And X ²Be selected from halogen and cycloalkyl.

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure of formula (I), wherein Ar ²For using one or more X ¹The phenyl that group replaces or use one or more X ²The pyridyl that group replaces; X ¹Be selected from-OH ,-CN, Cl ,-OTIPS ,-CH ₃,-OCH ₃,-OCH ₂CH ₃,-OTf and And X ²Be selected from Cl, Br and

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have with following formula (IF) or structure (IFa):

In another embodiment, compound of the present invention or its pharmacy acceptable salt, solvate, ester or steric isomer have the structure with following formula (IH):

Other embodiments of formula I are the compound with following structure:

Compound of the present invention, for example the compound of formula (I) preferably is purified to the purity that is suitable as pharmaceutically active substance.That is to say, the compound of formula (I) can have 95% weight or higher purity (does not comprise auxiliary material, as pharmaceutically acceptable carrier, solvent etc., these are used for the compound of formula (I) is mixed with regular dosage form, as are suitably for pill, capsule, IV solution of patient's administration etc.).Purity is 97% weight or bigger more preferably, even more preferably 99% weight or bigger.The purifying compounds of formula (I) comprises having 95% weight or bigger, 97% weight or bigger or 99% weight or the bigger above individual isomer that purity is discussed.For example, the purifying compounds of formula (I) can have 95% weight or bigger, 97% weight or bigger or 99% weight or bigger purity.

Perhaps, the purifying compounds of formula (I) can comprise the mixture of isomers that has formula (I) structure respectively, and wherein the amount of impurity (that is the compound or other pollutents that, do not comprise above discussion auxiliary material) is 5% weight or littler, 3% weight or littler, or 1% weight or littler.For example, the purifying compounds of formula (I) can be the isomer mixture of formula (I) compound, and wherein the ratio of the amount of two kinds of isomer is about 1: 1, and the combined amount of two kinds of isomer is 95% weight or bigger, 97% weight or bigger or 99% weight or bigger.

Variable m and n can represent integer O or 1 and 1 or 2 respectively, and its condition is that m and n sum (being m+n) are 1 or 2.Therefore, in an embodiment of formula (I) compound, m is 0, and n is 2, for example:

And

In another embodiment of formula (I) compound, m is 1, and n is 1, for example:

R ¹Be selected from-C (O)-N (R ¹⁰) ₂,-C (O)-O-alkyl and-C (O)-R ¹⁴Substituent R ¹⁰And R ¹⁴As defined herein." alkyl " of term-C (O)-O-alkyl comprises for example low alkyl group, as-CH ₃,-CH ₂CH ₃,-CH ₂CH ₂CH ₃(n-propyl) ,-CH (CH ₃) ₂(sec.-propyl) ,-CH ₂CH ₂CH ₂CH ₃(normal-butyl) ,-C (CH ₃) ₃(tertiary butyl) ,-CH (CH ₃)-CH ₂CH ₃(sec-butyl) ,-CH ₂CH (CH ₃) ₂(isobutyl-) ,-CH ₂CH ₂CH ₂CH ₂CH ₃(n-pentyl) ,-CH ₂C (CH ₃) ₃(neo-pentyl) etc.Therefore ,-C (O)-O-alkyl for example comprises-C (O)-O-CH ₃,-C (O)-O-CH ₂CH ₃,-C (O)-O-CH ₂CH ₂CH ₃,-C (O)-O-CH (CH ₃) ₂,-C (O)-O-CH ₂CH ₂CH ₂CH ₃,-C (O)-O-C (CH ₃) ₃,-C (O)-O-CH (CH ₃)-CH ₂CH ₃,-C (O)-O-CH ₂CH (CH ₃) ₂,-C (O)-O-CH ₂CH ₂CH ₂CH ₂CH ₃,-C (O)-O-CH ₂C (CH ₃) ₃Deng.Equally ,-C (O)-N (R ¹⁰) ₂Comprise-C (O)-NH ₂,-C (O)-NH (alkyl) ,-C (O)-N (alkyl) ₂,-C (O)-NH (alkyl-OH) ,-C (O)-N (alkyl-OH) ₂.-C (O)-NH-alkylidene group-R ¹²,-C (O)-N (alkyl)-alkylidene group-R ¹²,-C (O)-NH-alkylidene group-R ¹³,-C (O)-N (alkyl)-alkylidene group-R ¹³,-C (O)-NH-alkylidene group-R ¹⁴,-C (O)-N (alkyl)-alkylidene group-R ¹⁴,-C (O)-NH-C (O)-R ¹⁴,-C (O)-N (alkyl)-C (O)-R ¹⁴,-C (O)-NH-alkylidene group-O-R ⁹,-C (O)-N (alkyl)-alkylidene group-O-R ⁹, choose wantonly and on Heterocyclylalkyl, use one or more X ³Group replaces-and C (O)-NH-Heterocyclylalkyl, choose wantonly and on Heterocyclylalkyl, use one or more X ³Replace-C (O)-N (alkyl)-Heterocyclylalkyl ,-C (O)-NH-(benzo-fused cycloalkyl) and-C (O)-N (alkyl)-(benzo-fused cycloalkyl).Term " alkyl ", " alkylidene group ", " benzo-fused cycloalkyl " and " Heterocyclylalkyl " as defined herein.Above term " alkyl-OH " refers to that the alkyl that replaces with one or more-OH is (for example following to R ²Described group).-C (O)-N (R ¹⁰) ₂Each R ¹⁰Comprise that independently this paper is to R ¹⁰Any group of definition, and be not limited to above concrete group and combination.

R ²The alkyl that is selected from H, alkyl, replaces with one or more-OH group and-alkylidene group-N (R ¹⁰) ₂Alkyl comprises for example above to R ¹Described low alkyl group.The alkyl that replaces with one or more-OH group for example comprises-CH ₂-OH ,-CH ₂CH ₂-OH ,-CH (OH) CH ₃,-CH (OH) CH ₂CH ₃,-CH ₂CH (OH) CH ₃,-CH ₂CH ₂CH ₂-OH ,-CH (OH) CH ₂CH ₂-OH ,-CH (OH) CH (OH) CH ₂-OH ,-C (OH) (CH ₃) ₂,-CH (CH ₃) CH ₂-OH ,-CH (OH) CH ₂CH ₂CH ₃,-CH ₂CH (OH) CH ₂CH ₃,-CH ₂CH ₂CH (OH) CH ₃,-CH ₂CH ₂CH ₂CH ₂-OH ,-CH (OH) CH ₂CH (OH) CH ₃Deng.-alkylidene group-N (R ¹⁰) ₂" alkylidene group " part unrestricted example comprise-CH ₂-,-CH ₂CH ₂-,-CH ₂CH ₂CH ₂-,-CH ₂CH ₂CH ₂CH ₂-,-CH ₂CH ₂CH ₂CH ₂CH ₂-,-CH ₂CH ₂CH ₂CH ₂CH ₂CH ₂-,-CH (CH ₃)-,-CH (CH ₃) CH ₂-,-CH ₂CH (CH ₃)-,-CH (CH ₂CH ₃)-,-CH (CH ₃) CH ₂CH ₂-,-CH ₂CH (CH ₃) CH ₂-,-CH ₂CH ₂CH (CH ₃)-,-CH (CH ₂CH ₃) CH ₂-,-CH ₂CH (CH ₂CH ₃)-,-CH (CH ₂CH ₂CH ₃)-,-CH (CH ₃) CH (CH ₃)-etc.R ¹⁰As defined herein, and-alkylidene group-N (R ¹⁰) ₂Each R ¹⁰The independent selection, and can be independently and any alkylidene group of defining of this paper make up with any array mode.

In a embodiment for choosing, R ¹And R ²Being presented in the formula (I) the bonded carbon atom with them forms and is selected from following group Q:

Y wherein ¹, Y ², R ³, R ⁴, R ⁵, R ⁶, R ⁷And R ¹⁶As defined herein.So the various possible twin nuclei that forms as defined above.

R ³, R ⁴, R ⁵And R ⁶Independently be selected from respectively H ,-O-R ⁹, R ¹¹With-N (R ¹⁶) ₂R ⁹And R ¹¹As defined herein.For example ,-O-R ⁹Can comprise-OH and-O-R ¹¹-O-R ¹¹For example can comprise-O-CH ₃,-O-CH ₂CH ₃,-O-CH ₂CH ₂CH ₃,-O-CH (CH ₃) ₂,-O-CH ₂CH ₂CH ₂CH ₃,-O-C (CH ₃) ₃,-O-CH (CH ₃) CH ₂CH ₃,-O-CH ₂CH (CH ₃) ₂,-O-CH ₂CH ₂CH ₂CH ₂CH ₃,-O-CH ₂C (CH ₃) ₃,-O-phenyl ,-the O-naphthyl ,-O-xenyl etc., wherein said phenyl, naphthyl and xenyl do not replace or use one or more X ¹Group replaces, wherein said X ¹As defined herein.Equally, R ¹¹Unrestricted example comprise above to R ¹The alkyl of definition and not replacing or X ¹The aryl that replaces, for example phenyl, naphthyl and xenyl etc.R ¹⁶As defined herein, and-N (R ¹⁶) ₂Each R ¹⁶Can independently select.Therefore ,-N (R ¹⁶) ₂Unrestricted example for example comprise-N (R ⁹) ₂, each R wherein ⁹Independent select and as defined herein, and can comprise H, alkyl, unsubstituted aryl and use one or more W ¹The aryl that group replaces with any combination; And-N (R ⁹)-C (O)-R ¹², R wherein ⁹And R ¹²Independent select and as defined herein.Therefore, N (R ⁹The unrestricted example of)-C (O)-aryl comprises-NH-C (O)-aryl ,-N (alkyl)-C (O)-aryl ,-N (aryl)-C (O)-aryl, wherein each " aryl " be not for for example replacing or X ¹The phenyl that replaces, naphthyl, xenyl etc., and each " alkyl " is selected from above to R ¹Described low alkyl group.

R ⁷Be selected from H, arylalkyl, alkyl, thiazolinyl ,-alkylidene group-N (R ⁹) ₂,-alkylidene group-O-R ⁹,-alkylidene group-R ¹²,-C (O)-R ¹⁴,-alkylidene group-C (O) H and-C (O)-O-R ¹¹Term " alkyl " comprises for example above to R ¹Described low alkyl group.Term " arylalkyl " comprises for example replacing or unsubstituted arylalkyl of this paper definition.Term " thiazolinyl " for example comprises-CH=CH ₂,-CH ₂-CH=CH ₂,-CH=CH-CH ₃,-CH ₂-C (CH ₃)=CH ₂With-CH ₂-CH=CHCH ₃Term " alkylidene group-R ¹²" comprise the R of " alkylidene group " of above definition and this paper definition ¹²The combination of group." alkylidene group-R for example ¹²" for example comprise-CH ₂-aryl ,-CH ₂CH ₂-aryl ,-CH ₂CH ₂CH ₂-aryl ,-CH ₂CH ₂CH ₂CH ₂-aryl ,-CH ₂CH ₂CH ₂CH ₂CH ₂-aryl ,-CH ₂CH ₂CH ₂CH ₂CH ₂CH ₂-aryl ,-CH (CH ₃)-aryl ,-CH (CH ₃) CH ₂-aryl ,-CH ₂CH (CH ₃)-aryl ,-CH (CH ₂CH ₃)-aryl ,-CH (CH ₃) CH ₂CH ₂-aryl ,-CH ₂CH (CH ₃) CH ₂-aryl ,-CH ₂CH ₂CH (CH ₃)-aryl ,-CH (CH ₂CH ₃) CH ₂-aryl ,-CH ₂CH (CH ₂CH ₃)-aryl ,-CH (CH ₂CH ₂CH ₃)-aryl ,-CH (CH ₃) CH (CH ₃)-aryl etc., wherein " aryl " for example comprises and can not replace or use one or more X ¹Phenyl, naphthyl or xenyl that group replaces.-alkylidene group-N (R ⁹) ₂" alkylidene group " part unrestricted example comprise-CH ₂-,-CH ₂CH ₂-,-CH ₂CH ₂CH ₂-,-CH ₂CH ₂CH ₂CH ₂-,-CH ₂CH ₂CH ₂CH ₂CH ₂-,-CH ₂CH ₂CH ₂CH ₂CH ₂CH ₂-,-CH (CH ₃)-,-CH (CH ₃) CH ₂-,-CH ₂CH (CH ₃)-,-CH (CH ₂CH ₃)-,-CH (CH ₃) CH ₂CH ₂-,-CH ₂CH (CH ₃) CH ₂-,-CH ₂CH ₂CH (CH ₃)-,-CH (CH ₂CH ₃) CH ₂-,-CH ₂CH (CH ₂CH ₃)-,-CH (CH ₂CH ₂CH ₃)-,-CH (CH ₃) CH (CH ₃)-etc.R ⁹As defined herein, and-alkylidene group-N (R ⁹) ₂Each R ⁹The independent selection, and can be independently and any alkylidene group of defining of this paper make up with any array mode.Term " alkylidene group-O-R ⁹" for example comprise-CH ₂-O-R ⁹,-CH ₂CH ₂-O-R ⁹,-CH ₂CH ₂CH ₂-O-R ⁹,-CH ₂CH ₂CH ₂CH ₂-O-R ⁹,-CH ₂CH ₂CH ₂CH ₂CH ₂-O-R ⁹,-CH ₂CH ₂CH ₂CH ₂CH ₂CH ₂-O-R ⁹,-CH (CH ₃)-O-R ⁹,-CH (CH ₃) CH ₂-O-R ⁹,-CH ₂CH (CH ₃)-O-R ⁹,-CH (CH ₂CH ₃)-O-R ⁹,-CH (CH ₃) CH ₂CH ₂-O-R ⁹,-CH ₂CH (CH ₃) CH ₂-O-R ⁹,-CH ₂CH ₂CH (CH ₃)-O-R ⁹,-CH (CH ₂CH ₃) CH ₂-O-R ⁹,-CH ₂CH (CH ₂CH ₃)-O-R ⁹,-CH (CH ₂CH ₂CH ₃)-O-R ⁹,-CH (CH ₃) CH (CH ₃)-O-R ⁹,-CH (OR ⁹) CH ₂-etc.-alkylidene group-R ¹²Unrestricted example for example comprise-CH ₂-aryl ,-CH ₂CH ₂-aryl ,-CH ₂CH ₂CH ₂-aryl ,-CH ₂CH ₂CH ₂CH ₂-aryl ,-CH ₂CH ₂CH ₂CH ₂CH ₂-aryl ,-CH ₂CH ₂CH ₂CH ₂CH ₂CH ₂-aryl ,-CH (CH ₃)-aryl ,-CH (CH ₃) CH ₂-aryl ,-CH ₂CH (CH ₃)-aryl ,-CH (CH ₂CH ₃)-aryl ,-CH (CH ₃) CH ₂CH ₂-aryl ,-CH ₂CH (CH ₃) CH ₂-aryl ,-CH ₂CH ₂CH (CH ₃)-aryl ,-CH (CH ₂CH ₃) CH ₂-aryl ,-CH ₂CH (CH ₂CH ₃)-aryl ,-CH (CH ₂CH ₂CH ₃)-aryl ,-CH (CH ₃) CH (CH ₃)-aryl etc., wherein " aryl " for example comprises and can not replace or use one or more X ¹Phenyl, naphthyl or xenyl that group replaces.-C (O)-R ¹⁴Unrestricted example comprise-C (O)-cyclopropyl ,-C (O)-cyclobutyl ,-C (O)-cyclopentyl ,-C (O)-cyclohexyl ,-C (O)-suberyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl part do not replace or use one or more X ⁴Group replaces.-C (O)-O-R ¹¹Unrestricted example comprise-C (O)-OH ,-C (O)-O-CH ₃,-C (O)-O-CH ₂CH ₃,-C (O)-O-CH ₂CH ₂CH ₃,-C (O)-O-CH (CH ₃) ₂,-C (O)-O-C (CH ₃) ₃,-C (O)-O-CH ₂CH ₂CH ₂CH ₃,-C (O)-O-CH (CH ₃) CH ₂CH ₃,-C (O)-O-CH ₂CH (CH ₃) ₂,-C (O)-O-phenyl ,-C (O)-O-naphthyl ,-C (O)-O-xenyl etc., wherein said phenyl, naphthyl and xenyl can not replace or use X ¹Replace.

R ⁸Be selected from H ,-alkylidene group-R ¹²,-C (O)-R ¹⁷,-S (O ₂)-R ¹¹,-S (O ₂)-R ¹⁴,-C (O)-N (R ¹⁸) ₂And R ¹⁴Term " thiazolinyl " and " alkylidene group-R ¹²" for example as defined herein.Term " C (O)-R ¹⁷" for example comprise-C (O)-Heterocyclylalkyl ,-C (O)-alkylidene group-R ¹²,-C (O)-O-R ⁹With-C (O)-R ¹²Therefore ,-C (O)-R ¹⁷For example comprise-C (O)-morpholinyl ,-C (O)-piperazinyl ,-C (O)-piperidyl ,-C (O)-pyrrolidyl ,-C (O)-tetrahydrofuran base ,-C (O)-tetrahydrofuran base ,-C (O)-thiazolinyl ,-C (O)-THP trtrahydropyranyl etc.;-C (O)-CH ₂-aryl ,-C (O)-CH ₂CH ₂-aryl ,-C (O)-CH ₂CH ₂CH ₂-aryl ,-C (O)-CH ₂CH ₂CH ₂CH ₂-aryl ,-C (O)-CH ₂CH ₂CH ₂CH ₂CH ₂-aryl ,-C (O)-CH ₂CH ₂CH ₂CH ₂CH ₂CH ₂-aryl ,-C (O)-CH (CH ₃)-aryl ,-C (O)-CH (CH ₃) CH ₂-aryl ,-C (O)-CH ₂CH (CH ₃)-aryl ,-C (O)-CH (CH ₂CH ₃)-aryl ,-C (O)-CH (CH ₃) CH ₂CH ₂-aryl ,-C (O)-CH ₂CH (CH ₃) CH ₂-aryl ,-C (O)-CH ₂CH ₂CH (CH ₃)-aryl ,-C (O)-CH (CH ₂CH ₃) CH ₂-aryl ,-C (O)-CH ₂CH (CH ₂CH ₃)-aryl ,-C (O)-CH (CH ₂CH ₂CH ₃)-aryl ,-C (O)-CH (CH ₃) CH (CH ₃)-aryl etc., wherein said " aryl " for example comprise and can not replace or use one or more X ¹Phenyl, naphthyl or xenyl that group replaces;-C (O)-O-H ,-C (O)-O-CH ₃,-C (O)-O-CH ₂CH ₃,-C (O)-O-CH ₂CH ₂CH ₃,-C (O)-O-CH (CH ₃) ₂,-C (O)-O-CH ₂CH ₂CH ₂CH ₃,-C (O)-O-C (CH ₃) ₃,-C (O)-O-CH (CH ₃)-CH ₂CH ₃,-C (O)-O-CH ₂CH (CH ₃) ₂,-C (O)-O-CH ₂CH ₂CH ₂CH ₂CH ₃,-C (O)-O-CH ₂C (CH ₃) ₃Deng ,-C (O)-O-phenyl ,-C (O)-O-naphthyl ,-C (O)-O-xenyl, wherein said phenyl, naphthyl and xenyl part can not replace or use one or more X ¹Group replaces; With-C (O)-phenyl ,-C (O)-naphthyl ,-C (O)-xenyl, wherein said phenyl, naphthyl and xenyl part can not replace or use one or more X ¹Group replaces.-S (O ₂)-R ¹¹Unrestricted example for example comprise-S (O ₂)-CH ₃,-S (O ₂)-CH ₂CH ₃,-S (O ₂)-CH ₂CH ₂CH ₃,-S (O ₂)-CH (CH ₃) ₂,-S (O ₂)-CH ₂CH ₂CH ₂CH ₃,-S (O ₂)-C (CH ₃) ₃,-S (O ₂)-CH (CH ₃)-CH ₂CH ₃,-S (O ₂)-CH ₂CH (CH ₃) ₂,-S (O ₂)-CH ₂CH ₂CH ₂CH ₂CH ₃,-S (O ₂)-CH ₂C (CH ₃) ₃Deng ,-S (O ₂)-phenyl ,-S (O ₂)-naphthyl ,-S (O ₂)-xenyls etc., wherein said phenyl, naphthyl and xenyl part can not replace or use one or more X ¹Group replaces.-S (O ₂)-R ¹⁴Unrestricted example for example comprise-S (O ₂)-CH ₃,-S (O ₂)-CH ₂CH ₃,-S (O ₂)-CH ₂CH ₂CH ₃,-S (O ₂)-CH (CH ₃) ₂,-S (O ₂)-CH ₂CH ₂CH ₂CH ₃,-S (O ₂)-C (CH ₃) ₃,-S (O ₂)-CH (CH ₃)-CH ₂CH ₃,-S (O ₂)-CH ₂CH (CH ₃) ₂,-S (O ₂)-CH ₂CH ₂CH ₂CH ₂CH ₃,-S (O ₂)-CH ₂C (CH ₃) ₃Deng and-S (O ₂)-cyclopropyl ,-S (O ₂)-cyclobutyl ,-S (O ₂)-cyclopentyl ,-S (O ₂)-cyclohexyl ,-S (O ₂)-suberyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl part can not replace or use one or more X ⁴Group replaces.R ⁸Also comprise the R that this paper defines ¹⁴, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl, each group can not replace or use one or more X ⁴Group replaces.Term-C (O)-N (R ¹⁸) ₂For example comprise-C (O)-NHR ¹⁸, R wherein ¹⁸As following definition.

R ⁹Be selected from H and R ¹¹, R wherein ¹¹As defined herein.

R ¹⁰The alkyl that is selected from H, replaces with one or more-OH group ,-alkylidene group-R ¹²,-alkylidene group-R ¹³,-alkylidene group-R ¹⁴,-C (O)-R ¹⁴,-alkylidene group-O-R ⁹, R ¹⁴, unsubstituted Heterocyclylalkyl, use one or more X ³Heterocyclylalkyl that group replaces and benzo-fused cycloalkyl.Term " with the alkyl of one or more-OH group replacement ", " alkylidene group-R ¹²" and " C (O)-R ¹⁴" as defined herein.-alkylidene group-R ¹³Unrestricted example comprise-alkylidene group-heteroaryl that wherein its " alkylidene group " part for example comprises-CH ₂-,-CH ₂CH ₂-,-CH ₂CH ₂CH ₂-,-CH ₂CH ₂CH ₂CH ₂-,-CH ₂CH ₂CH ₂CH ₂CH ₂-,-CH ₂CH ₂CH ₂CH ₂CH ₂CH ₂-,-CH (CH ₃)-,-CH (CH ₃) CH ₂-,-CH ₂CH (CH ₃)-,-CH (CH ₂CH ₃)-,-CH (CH ₃) CH ₂CH ₂-,-CH ₂CH (CH ₃) CH ₂-,-CH ₂CH ₂CH (CH ₃)-,-CH (CH ₂CH ₃) CH ₂-,-CH ₂CH (CH ₂CH ₃)-,-CH (CH ₂CH ₂CH ₃)-,-CH (CH ₃) CH (CH ₃)-, and its " heteroaryl " part comprises for example azaindole base, benzimidazolyl-, benzofuryl, benzo azaindole base, benzothienyl, cinnolines base, furyl, furazan base, indyl, isoquinolyl, 2,3-phthalazinyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, quinolyl, quinoxalinyl, quinazolyl, thienyl, isoxazolyl, triazolyl, thiazolyl, thiadiazolyl group etc., each group can not replace or use one or more X ²Group replaces.-alkylidene group-R ¹⁴Unrestricted example comprise-alkylidene group-cycloalkyl-, wherein its " alkylidene group " part comprises for example CH ₂-,-CH ₂CH ₂-,-CH ₂CH ₂CH ₂-,-CH ₂CH ₂CH ₂CH ₂-,-CH ₂CH ₂CH ₂CH ₂CH ₂-,-CH ₂CH ₂CH ₂CH ₂CH ₂CH ₂-,-CH (CH ₃)-,-CH (CH ₃) CH ₂-,-CH ₂CH (CH ₃)-,-CH (CH ₂CH ₃)-,-CH (CH ₃) CH ₂CH ₂-,-CH ₂CH (CH ₃) CH ₂-,-CH ₂CH ₂CH (CH ₃)-,-CH (CH ₂CH ₃) CH ₂-,-CH ₂CH (CH ₂CH ₃)-,-CH (CH ₂CH ₂CH ₃)-,-CH (CH ₃) CH (CH ₃)-, and its cycloalkyl moiety comprise for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two ring [2.2.1] heptyl, adamantyl etc., and each group can not replace or use one or more X ⁴Group replaces.At R ¹⁰Be R ¹⁴The time, unrestricted example comprises for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two ring [2.2.1] heptyl, adamantyl etc., each group can not replace or use one or more X ⁴Group replaces.Work as R ¹⁰For unsubstituted Heterocyclylalkyl or use one or more X ³During Heterocyclylalkyl that group replaces, described Heterocyclylalkyl can comprise morpholinyl, piperazinyl, piperidyl, pyrrolidyl, tetrahydrofuran base, tetrahydrofuran base, thiazolinyl, THP trtrahydropyranyl etc.The unrestricted example of benzo-fused cycloalkyl comprises following structure:

Deng.Though above structure shows benzo-fused cycloalkyl and is attached to precursor structure from the cycloalkyl moiety of group, also can imagine benzo-fused cycloalkyl and be attached to precursor structure (promptly from saturated or sp from cycloalkyl moiety ³Ring carbon) or from " benzo " part be attached to precursor structure (promptly from unsaturated or sp ²Ring carbon).

R ¹¹The alkyl that is selected from unsubstituted alkyl, replaces with one or more-OH group ,-alkylidene group-O-alkyl ,-alkylidene group-O-aryl, unsubstituted aryl and use one or more X ¹The aryl that group replaces.Term " alkyl ", " alkylidene group " and " aryl " are as defined herein.

R ¹²Be selected from unsubstituted aryl and use one or more X ¹The aryl that group replaces, wherein " aryl " as defined herein.

R ¹³Be selected from unsubstituted heteroaryl and use one or more X ²The heteroaryl that group replaces.Be fit to R ¹³The unrestricted example of group comprises for example azaindole base, benzimidazolyl-, benzofuryl, benzo azaindole base, benzothienyl, cinnolines base, furyl, furazan base, indyl, isoquinolyl, 2,3-phthalazinyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, quinolyl, quinoxalinyl, quinazolyl, thienyl, isoxazolyl, triazolyl, thiazolyl, thiadiazolyl group etc., each group can not replace or use one or more X ²Group replaces.

R ¹⁴Be selected from alkyl, unsubstituted cycloalkyl or use one or more X ⁴The cycloalkyl that group replaces.The unrestricted example that is fit to " alkyl " comprises those alkyl of above definition.The unrestricted example that is fit to cycloalkyl comprises for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two ring [2.2.1] heptyl, adamantyl etc., and each group can not replace or use one or more X ⁴Group replaces.

Each R ¹⁵Independently be selected from H, alkyl, thiazolinyl ,-alkylidene group-R ¹²,-OH and-the O-thiazolinyl.Be fit to alkyl, thiazolinyl and-alkylidene group-R ¹²Unrestricted example comprise those groups of above definition.The unrestricted example of suitable-O-thiazolinyl for example comprises-O-CH=CH ₂,-O-CH ₂-CH=CH ₂,-O-CH=CH-CH ₃,-O-CH ₂-C (CH ₃)=CH ₂,-O-CH ₂-CH=CHCH ₃Deng.In formula (I) compound, can there be 0,1 or 2 R ¹⁵Group.

R ¹⁶Be selected from R ⁹With-C (O)-R ¹²Be fit to R ⁹With-C (O)-R ¹²The unrestricted example of group as defined herein.

R ¹⁷Be selected from unsubstituted Heterocyclylalkyl, use one or more X ³The Heterocyclylalkyl that group replaces ,-alkylidene group-R ¹²,-O-R ⁹And R ¹²Suitable Heterocyclylalkyl ,-alkylidene group-R ¹²,-O-R ⁹And R ¹²The unrestricted example of group as defined herein.

Each R ¹⁸Independently be selected from H, R ¹²And R ¹⁴, R wherein ¹²And R ¹⁴As defined herein.

Each R ¹⁹Be selected from H and R ²¹, R wherein ²¹As defined herein.

Each R ²⁰Be selected from H, with one or more-OH or-alkyl that the O-alkyl replaces ,-alkylidene group-R ²²,-alkylidene group-R ²³,-alkylidene group-R ²⁴,-C (O)-R ²⁴,-alkylidene group-O-R ¹⁹, R ²⁴, unsubstituted Heterocyclylalkyl, use one or more W ³Heterocyclylalkyl that group replaces and benzo-fused cycloalkyl.With one or more-OH or-alkyl that the O-alkyl replaces ,-alkylidene group-R ²²,-alkylidene group-R ²³,-alkylidene group-R ²⁴,-C (O)-R ²⁴,-alkylidene group-O-R ¹⁹, R ²⁴, unsubstituted Heterocyclylalkyl, use one or more W ³The unrestricted example of Heterocyclylalkyl that group replaces and benzo-fused cycloalkyl as defined herein.

R ²¹The alkyl that is selected from unsubstituted alkyl, replaces with one or more-OH group ,-alkylidene group-O-alkyl ,-alkylidene group-O-aryl, unsubstituted aryl and use one or more W ¹The aryl that group replaces.Be fit to unsubstituted alkyl, with the alkyl of one or more-OH group replacement ,-alkylidene group-O-alkyl ,-alkylidene group-O-aryl, unsubstituted aryl and use one or more W ¹The unrestricted example of the aryl that group replaces as defined herein.

R ²²Be selected from unsubstituted aryl and use one or more W ¹The aryl that group replaces.Be fit to unsubstituted aryl and use one or more W ¹The unrestricted example of the aryl that group replaces as defined herein.

R ²³Be selected from unsubstituted heteroaryl and use one or more W ²The heteroaryl that group replaces.Be fit to unsubstituted heteroaryl and use one or more W ²The unrestricted example of the heteroaryl that group replaces as defined herein.

R ²⁴Be selected from alkyl, unsubstituted cycloalkyl or use one or more W ⁴The cycloalkyl that group replaces.Be fit to alkyl, unsubstituted cycloalkyl or use one or more W ⁴The unrestricted example of the cycloalkyl that group replaces as defined herein.

W ¹Independently be selected from halogen ,-CN ,-OH ,-O-S (O) ₂-haloalkyl, unsubstituted aryl, the aryl that replaces with one or more Z groups, unsubstituted heteroaryl, with the heteroaryl of one or more Z groups replacements and-the O-alkyl.Suitable halogen ,-CN ,-OH ,-O-S (O) ₂-haloalkyl, unsubstituted aryl, the aryl that replaces with one or more Z groups, unsubstituted heteroaryl, with the heteroaryl of one or more Z groups replacements and-the unrestricted example of O-alkyl as defined herein.

W ²The aryl that independently is selected from halogen, unsubstituted aryl and replaces with one or more Z groups.The unrestricted example that is fit to halogen comprises F, Cl and Br.The suitable example of aryl comprises those aryl for example as herein described.

W ³For-C (O)-O-alkyl.The unrestricted example of suitable-C (O)-O-alkyl comprises those groups that this paper defines.In addition, two W ³Group forms carbonyl with their bonded ring carbon atoms.Can imagine Heterocyclylalkyl independently with one or more-C (O)-O-alkyl and/or one or more carbonyl substituted (for example one, two, three, four or five W ³Group).

W ⁴Independent is halogen or alkyl.The unrestricted example that is fit to halogen comprises F, Cl and Br.The unrestricted example that is fit to alkyl comprises those alkyl as herein described.

Ar ¹And Ar ²Independently be selected from R ¹²And R ¹³Be fit to R ¹²And R ¹³The unrestricted example of group as defined herein.

Use one or more X ¹The aryl that group replaces comprises for example single replacement, two replacements, three replacements, quaternary aryl etc., and wherein each substituting group independently is selected from X ¹Unrestricted example comprises for example chloro-phenyl-, dichlorophenyl, bromophenyl, dibromo phenyl, bromochlorophene base, fluorophenyl, difluorophenyl, chlorofluorobenzene base, bromofluoro benzene base, cyano-phenyl, xenyl, askarel base, DCBP base etc.Similarly use one or more X ²The heteroaryl that group replaces comprises single replacement, two replacements, three replacements, quaternary heteroaryl etc., and wherein each substituting group independently is selected from X ²The aryl and the heteroaryl that are fit to comprise any aryl as herein described and heteroaryl.

X ¹Independently be selected from halogen ,-CN ,-OH ,-O-S (O) ₂-haloalkyl, unsubstituted aryl, the aryl that replaces with one or more Z groups, unsubstituted heteroaryl, with the heteroaryl of one or more Z groups replacements ,-the O-cycloalkyl ,-the O-cycloalkylalkyl ,-O-alkylidene group-OR ¹⁹,-O-alkylidene group-C (O) N (R ²⁰) ₂,-O-alkylidene group-O-R ¹⁹, unsubstituted alkyl, the alkyl that replaces with one or more U groups, unsubstituted-the O-alkyl, with one or more U groups replacements-the O-alkyl ,-the O-thiazolinyl ,-O-alkylidene group-O-alkylidene group-OR ¹⁹,-O-alkylidene group-C (O) R ²⁴,-O-alkylidene group-C (O) OR ¹⁹With-the O-alkyl.The unrestricted example that is fit to halogen comprises for example F, Cl and Br.Be fit to-O-S (O) ₂The unrestricted example of-haloalkyl comprises-O-S (O) ₂-CH ₂F ,-O-S (O) ₂-CHF ₂,-O-S (O) ₂-CF ₃,-O-S (O) ₂-CH ₂CF ₃,-O-S (O) ₂-CF ₂CF ₃,-O-S (O) ₂-CH ₂Cl ,-O-S (O) ₂-CH ₂Br etc.The unrestricted example of suitable-O-alkyl comprises those groups as herein described.

Be fit to X ¹The unrestricted example of group independently is selected from-OCH ₃,-OH ,-OTf ,-CN ,-OCH ₂CH ₃,-OCH (CH ₃) ₂,

Similar X ²Be selected from halogen ,-CN, unsubstituted aryl and the aryl that replaces with one or more Z groups.The unrestricted example that is fit to halogen comprises F, Cl and Br.The suitable example of aryl comprises those aryl for example as herein described.

X ³For-C (O)-O-alkyl.The unrestricted example of suitable-C (O)-O-alkyl comprises those groups that this paper defines.In addition, two X ³Group forms carbonyl with their bonded ring carbon atoms.Can imagine Heterocyclylalkyl independently with one or more-C (O)-O-alkyl and/or one or more carbonyl substituted (for example one, two, three, four or five X ³Group).

X ⁴Independent is halogen or alkyl.The unrestricted example that is fit to halogen comprises F, Cl and Br.The unrestricted example that is fit to alkyl comprises those alkyl as herein described.

U independently is selected from-OH ,-O-alkyl and halogen.The unrestricted example that is fit to alkyl and halogen comprises those groups as herein described.

Z be selected from halogen, alkyl and-CN.The unrestricted example of halogen and alkyl comprises those groups of above definition.

As above reach in the whole specification sheets usedly, except as otherwise noted, following term should be interpreted as have following implication:

" patient " comprises humans and animals.

" Mammals " refers to people and other Mammalss.

" alkyl " is meant and can be straight chain or branching and comprise about 1 aliphatic hydrocarbyl to about 20 carbon atoms in chain.Preferred alkyl comprises about 1 to about 12 carbon atoms in chain.Preferred alkyl comprises about 1 to about 6 carbon atoms in chain.Branching refers to that one or more low alkyl groups (as methyl, ethyl or propyl group) are attached to linear alkyl chain." low alkyl group " be meant can be straight chain or branching in chain, have about 1 a group to about 6 carbon atoms.Term " alkyl of replacement " is meant that alkyl can be replaced by one or more substituting groups that can be identical or different, each substituting group independently be selected from halogen, alkyl, aryl, cycloalkyl, cyano group, hydroxyl, alkoxyl group, alkylthio, amino ,-NH (alkyl) ,-NH (cycloalkyl) ,-N (alkyl) ₂, carboxyl and-C (O) O-alkyl.The unrestricted example that is fit to alkyl comprises methyl, ethyl, n-propyl, sec.-propyl and the tertiary butyl.

" alkylidene group " is meant from the alkyl of above definition and removes the divalent group that a hydrogen atom obtains.The unrestricted example of alkylidene group comprise methylene radical, ethylidene (promptly-CH ₂CH ₂-or-CH (CH ₃)-) and propylidene (for example comprise-CH ₂CH ₂CH ₂-and-CH (CH ₃) CH ₂-).

" thiazolinyl " is meant and comprises at least one carbon-to-carbon double bond, can be straight chain or branching and comprise about 2 aliphatic hydrocarbyls to about 15 carbon atoms in chain.Preferred thiazolinyl has about 2 to about 12 carbon atoms in chain, more preferably have about 2 to about 6 carbon atoms in chain.Branching is meant that one or more low alkyl groups (as methyl, ethyl or propyl group) are attached to linear alkenylene chain." low-grade alkenyl " be meant can be straight chain or branching in chain, have about 2 thiazolinyls to about 6 carbon atoms.Term " thiazolinyl of replacement " is meant that thiazolinyl can be replaced by one or more substituting groups that can be identical or different, each substituting group independently be selected from halogen, alkyl, aryl, cycloalkyl, cyano group, alkoxyl group and-S (alkyl).The unrestricted example that is fit to thiazolinyl comprises vinyl, propenyl, n-butene base, 3-methyl but-2-ene base, positive pentenyl, octenyl and decene base.

" alkenylene " is meant from the thiazolinyl of above definition and removes the divalent group that a hydrogen atom obtains.The unrestricted example of " alkenylene " comprises-CH=CH-,-C (CH ₃)=CH-and-CH=CHCH ₂-.

" alkynyl " is meant and comprises at least one carbon-to-carbon three key, can be straight chain or branching and comprise about 2 aliphatic hydrocarbyls to about 15 carbon atoms in chain.Preferred alkynyl has about 2 to about 12 carbon atoms in chain, more preferably have about 2 to about 4 carbon atoms in chain.Branching is meant that one or more low alkyl groups (as methyl, ethyl or propyl group) are attached to linear alkynyl chain." low-grade alkynyl " be meant can be straight chain or branching in chain, have about 2 alkynyls to about 6 carbon atoms.The unrestricted example that is fit to alkynyl comprises ethynyl, proyl, 2-butyne base and 3-methyl butynyl.Term " alkynyl of replacement " is meant that alkynyl can be replaced by one or more substituting groups that can be identical or different, and each substituting group independently is selected from alkyl, aryl and cycloalkyl.

" alkynylene " is meant from the alkynyl of above definition and removes two functional groups that a hydrogen atom obtains.The unrestricted example of alkynylene comprises-C ≡ C-and-CH ₂C ≡ C-.

" aryl " be meant and comprise about 6 to about 14 carbon atoms, and preferred about 6 to the aromatic monocyclic of about 10 carbon atoms or encircle loop systems more.Aryl can choose wantonly with one or more can be identical or different and as defined herein " loop systems substituting group " replace.The unrestricted example that is fit to aryl comprises phenyl and naphthyl.

" heteroaryl " be meant and comprise about 5 to about 14 annular atomses, and preferred about 5 to the aromatic monocyclic of about 10 annular atomses or encircle loop systems more, and wherein one or more annular atomses are the element that is different from carbon, and for example nitrogen, oxygen or sulphur are separately or its combination.Preferred heteroaryl comprises about 5 to about 6 annular atomses." heteroaryl " can choose wantonly with one or more can be identical or different and as defined herein " loop systems substituting group " replace.Prefix azepine (a word used for translation), oxa-(Evil before the heteroaryl root name) or thia (thiophene) be meant that at least one nitrogen, oxygen or sulphur atom exist as an annular atoms respectively.The nitrogen-atoms that can choose wantonly heteroaryl is oxidized to corresponding N-oxide compound.The unrestricted example that is fit to heteroaryl comprises pyridyl, pyrazinyl, furyl, thienyl, pyrimidyl, pyridone (comprising the pyridone that N-replaces) isoxazolyl, isothiazolyl oxazolyl, thiazolyl, pyrazolyl, the furazan base, pyrryl, pyrazolyl, triazolyl, 1,2, the 4-thiadiazolyl group, pyrazinyl, pyridazinyl, quinoxalinyl, 2, the 3-phthalazinyl, the oxindole base, imidazo [1,2-a] pyridyl, imidazo [2,1-b] thiazolyl, benzo furazan base, indyl, the azaindole base, benzimidazolyl-, benzothienyl, quinolyl, imidazolyl, the thienopyridine base, quinazolyl, the Thienopyrimidine base, pyrrolopyridinyl, imidazopyridyl, isoquinolyl, benzo azaindole base, 1,2, the 4-triazinyl, benzothiazolyl etc.Term " heteroaryl " also refers to wherein to have the heteroaryl moieties of the fractional saturation of at least one aromatic ring, as tetrahydro isoquinolyl, tetrahydric quinoline group, indazolyl etc.

" aralkyl ", " arylalkyl " or " alkylidene group-aryl " are meant wherein aryl and the foregoing aryl-alkyl of alkyl-group.Preferred aralkyl comprises low alkyl group.The unrestricted example that is fit to aralkyl comprises benzyl, 2-styroyl and naphthyl methyl.Combination to parent fraction is to pass through alkyl.

" alkylaryl " is meant wherein alkyl and the foregoing alkyl-aryl of aryl-group.Preferred alkylaryl comprises low alkyl group.The unrestricted example that is fit to alkylaryl is a tolyl.Combination to parent fraction is to pass through aryl.

" cycloalkyl " be meant and comprise about 3 to about 10 carbon atoms, and preferred about 5 to the non-aromatic monocyclic of about 10 carbon atoms or encircle loop systems more.Preferred cycloalkyl ring comprises about 5 to about 7 annular atomses.Cycloalkyl can choose wantonly with one or more can be identical or different and as defined above " loop systems substituting group " replace.The unrestricted example that is fit to monocyclic cycloalkyl comprises cyclopropyl, cyclopentyl, cyclohexyl, suberyl etc.The unrestricted example that is fit to the polycyclic naphthene base comprises 1-naphthalane base, norcamphyl, adamantyl etc., also comprises the kind of fractional saturation, for example indanyl, tetralyl etc.

" cycloalkylalkyl " is meant the cycloalkyl moiety as defined above that is connected to parent nuclear by moieties (as above definition).The unrestricted example that is fit to cycloalkylalkyl comprises cyclohexyl methyl, adamantyl methyl etc.

" halogen " or " halogen " refers to fluorine, chlorine, bromine or iodine.Be preferably fluorine, chlorine and bromine.

" haloalkyl " is meant the alkyl of the above definition that the one or more hydrogen atoms on the alkyl are wherein replaced by the halo group of above definition.

" loop systems substituting group " is meant the substituting group that for example replaces the available hydrogen on the loop systems that is attached to aromatics or non-aromatics loop systems.The loop systems substituting group can be identical or different, and each substituting group independently is selected from alkyl; thiazolinyl; alkynyl; aryl; heteroaryl; aralkyl; alkylaryl; heteroaralkyl; the heteroaryl thiazolinyl; the heteroaryl alkynyl; miscellaneous alkyl aryl; hydroxyl; hydroxyalkyl; alkoxyl group; aryloxy; aralkoxy; acyl group; aroyl; halogen; nitro; cyano group; carboxyl; alkoxy carbonyl; the aryloxy carbonyl; aromatic alkoxy carbonyl; alkyl sulphonyl; aryl sulfonyl; heteroarylsulfonyl; alkylthio; arylthio; heteroarylthio; aromatic alkylthio; assorted aromatic alkylthio; cycloalkyl; heterocyclic radical;-C (=N-CN)-NH ₂,-C (=NH)-NH ₂,-C (=NH)-NH (alkyl), Y ₁Y ₂N-, Y ₁Y ₂The N-alkyl-, Y ₁Y ₂NC (O)-, Y ₁Y ₂NSO ₂-and-SO ₂NY ₁Y ₂, Y wherein ₁And Y ₂Can be identical or different, and independently be selected from hydrogen, alkyl, aryl, cycloalkyl and aralkyl." loop systems substituting group " also can refer to the contemporary single part of replacing two available hydrogen (hydrogen on each carbon) of two adjacent carbonss on the loop systems.The example of this type of part be methylene-dioxy, ethylenedioxy ,-C (CH ₃) ₂-etc., can form with the lower section, for example:

" heterocyclic radical " be meant and comprise about 3 to about 10 annular atomses, and preferred about 5 to the monocycle of about 10 annular atomses or encircle loop systems more, and wherein the one or more atoms in the loop systems are the element that is different from carbon, and for example nitrogen, oxygen or sulphur are separately or its combination.In loop systems, there are not adjacent oxygen and/or sulphur atom.Heterocyclic radical can for saturated fully, part is unsaturated or aromatics.Aromatic heterocyclic radical is called as " heteroaryl ", as defined above.Preferred heterocyclic radical comprises about 5 to about 6 annular atomses.Prefix azepine (a word used for translation), oxa-(Evil before the heterocyclic radical root name) or thia (thiophene) be meant that at least one nitrogen, oxygen or sulphur atom exist as an annular atoms respectively.Any-NH in the heterocyclic ring can be for example as shielded-N (Boc) ,-N (CBz) ,-existence such as N (Tos) group; Also can be with this protection as part of the present invention.Heterocyclic radical can choose wantonly with one or more can be identical or different and as defined herein " loop systems substituting group " replace.Nitrogen-atoms or the oxidized sulfur atom that can choose wantonly heterocyclic radical become corresponding N-oxide compound, S-oxide compound or S, the S-dioxide.The unrestricted example that is fit to the monocyclic heterocycles basic ring comprises saturated heterocyclic radical, for example piperidyl, pyrrolidyl, piperazinyl, morpholinyl, parathiazan base, thiazolidyl, 1,4-dioxane base, tetrahydrofuran base, tetrahydro-thienyl, lactan, lactones, isoxazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, 1,2,3-triazolyl etc.The unrestricted example of the undersaturated monocyclic heterocycles basic ring of part comprises for example thiazolinyl etc.

It should be noted that, comprise in the heteroatomic ring system on the carbon atom adjacent, do not have hydroxyl, and on the carbon adjacent, do not have N or S group with another heteroatoms with N, O or S of the present invention.Therefore, for example in following ring:

Be designated as 2 and 5 the not direct combination-OH of carbon.

Should also be noted that compound of the present invention comprises the tautomer of formula (I) compound.

" Heterocyclylalkyl " is meant and comprises about 3 to about 10 annular atomses, preferred about 5 to the non-aromatics saturated mono ring of about 10 annular atomses or encircle loop systems more, wherein the one or more atoms in the loop systems are the element that is different from carbon, and for example nitrogen, oxygen or sulphur are independent or its combination.In loop systems, there are not adjacent oxygen and/or sulphur atom.Preferred Heterocyclylalkyl comprises about 5 to about 6 annular atomses.Prefix azepine (a word used for translation), oxa-(Evil before the Heterocyclylalkyl root name) or thia (thiophene) be meant that at least one nitrogen, oxygen or sulphur atom exist as an annular atoms respectively.Heterocyclylalkyl can choose wantonly with one or more can be identical or different and as defined herein " loop systems substituting group " replace.Nitrogen-atoms or the oxidized sulfur atom that can choose wantonly Heterocyclylalkyl become corresponding N-oxide compound, S-oxide compound or S, the S-dioxide.The unrestricted example that is fit to monocyclic heterocycles alkyl ring comprises piperidyl, pyrrolidyl, piperazinyl, morpholinyl, 1,3-dioxolane base, tetrahydrofuran base, tetrahydro-thienyl etc.

" heteroaralkyl " is meant wherein heteroaryl and the foregoing heteroaryl-alkyl of alkyl-group.Preferred heteroaralkyl comprises low alkyl group.The unrestricted example that is fit to aralkyl comprises pyridylmethyl and quinoline-3-ylmethyl.Combination to parent fraction is to pass through alkyl.

" hydroxyalkyl " is meant the wherein foregoing HO-alkyl-group of alkyl.Preferred hydroxyalkyl comprises low alkyl group.The unrestricted example that is fit to hydroxyalkyl comprises hydroxymethyl and 2-hydroxyethyl.

" acyl group " be meant the foregoing H-C of wherein different groups (O)-, alkyl-C (O)-or cycloalkyl-C (O)-group.Combination to parent fraction is to pass through carbonyl.Preferred acyl group comprises low alkyl group.The unrestricted example that is fit to acyl group comprises formyl radical, ethanoyl and propionyl.

" aroyl " is meant the wherein foregoing aryl-C of aryl (O)-group.Combination to parent fraction is to pass through carbonyl.The unrestricted example that is fit to group comprises benzoyl and 1-naphthoyl.

" alkoxyl group " is meant the wherein foregoing alkyl of alkyl-O-group.The unrestricted example that is fit to alkoxyl group comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy and n-butoxy.Combination to parent fraction is by ether oxygen.

" aryloxy " is meant the wherein foregoing aryl of aryl-O-group.The unrestricted example that is fit to aryloxy comprises phenoxy group and naphthyloxy.Combination to parent fraction is by ether oxygen.

" alkylthio " is meant the wherein foregoing alkyl of alkyl-S-group.The unrestricted example that is fit to alkylthio comprises methylthio group and ethylmercapto group.Combination to parent fraction is to pass through sulphur.

" arylthio " is meant the wherein foregoing aryl of aryl-S-group.The unrestricted example that is fit to arylthio comprises thiophenyl and naphthalene sulfenyl.Combination to parent fraction is to pass through sulphur.

" aromatic alkylthio " is meant the wherein foregoing aralkyl of aralkyl-S-group.The unrestricted example that is fit to aromatic alkylthio is a benzylthio-.Combination to parent fraction is to pass through sulphur.

" alkoxy carbonyl " is meant alkyl-O-CO-group.The unrestricted example that is fit to alkoxy carbonyl comprises methoxycarbonyl and ethoxy carbonyl.Combination to parent fraction is to pass through carbonyl.

" aryloxycarbonyl " is meant aryl-O-C (O)-group.The unrestricted example that is fit to aryloxycarbonyl comprises phenyloxycarbonyl and naphthyloxy carbonyl.Combination to parent fraction is to pass through carbonyl.

" aromatic alkoxy carbonyl " is meant aralkyl-O-C (O)-group.The unrestricted example that is fit to aromatic alkoxy carbonyl is a benzyloxycarbonyl.Combination to parent fraction is to pass through carbonyl.

" alkyl sulphonyl " is meant alkyl-S (O ₂)-group.Preferred group is that wherein alkyl is those groups of low alkyl group.Combination to parent fraction is to pass through alkylsulfonyl.

" aryl sulfonyl " is meant aryl-S (O ₂)-group.Combination to parent fraction is to pass through alkylsulfonyl.

One or more hydrogen on term " replacement " the meaning specified atom are replaced by the indication group of selecting, and its condition is the normal valence state that is no more than specified atom under the existing environment, and replacement produces stable compound.The combination of substituting group and/or variable is only permitted when this combination results stable compound." stable compound " or " rock steady structure " is meant enough steadily and surely can standing and is separated into useful purity and is mixed with the compound of effective therapeutical agent from reaction mixture.

Term " the optional replacement " is meant optional with specifying group, base or part to replace.

Are meant " purifying " of compound, " purified form " or " separating and purified form " physical condition after described compound separates from synthetic method or natural origin or its combination.Therefore, are meant " purifying " of compound, " purified form " or " separating and purified form ", with the physical condition of the described compound that can obtain by the enough purity that standard analytical techniques described herein or that those skilled in the art are afamiliar with characterizes from purification process described herein or that those skilled in the art are afamiliar with.

Should also be noted that in text, scheme, embodiment and Biao supposition has unsaturated valent any carbon and heteroatoms all has the hydrogen atom of sufficient amount to satisfy this valence state.

When the functional group in the compound being called when being " protected ", this means that described group is a modification, at protected position unwanted side reaction takes place when preventing compound through reaction.The protecting group that is fit to should be those skilled in the art to be familiar with, but and the reference standard textbook, people such as T.W.Greene for example, Protective Groups in OrganicSynthesis (1991), Wiley, New York.

As any variable (for example, aryl, heterocycle, R ⁹Deng) when in any composition or formula I, occurring more than once, do not rely on the definition of each other appearance place in the definition of each appearance place.

Term used herein " composition " is intended to comprise that comprising specified amount specifies the product of composition and directly or indirectly result from the spawn that specified amount is specified the combination of composition.

The present invention also comprises the prodrug and the solvate of The compounds of this invention.Term used herein " prodrug " is meant a kind of compound, and this compound is as prodrug compound or its salt and/or solvate by metabolism or chemical process chemical conversion accepted way of doing sth I when giving the patient.The discussion of prodrug is provided in T.Higuchi and V.Stella, Pro-drugs as Novel DeliverySystems (1987), 14Of the A.C.S.Symposium Series, and BioreversibleCarriers in Drug Design, (1987) Edward B.Roche, ed., AmericanPharmaceutical Association and Pergamon Press, described document is attached to herein by reference.

" solvate " is meant that compound of the present invention and one or more solvent molecule physics associate.This physics associates and comprises that different ions and covalent linkage are right, comprises hydrogen bonding.In some cases, solvate can separate, for example, and when one or more solvent molecules are attached in the lattice of crystalline solid." solvate " comprises solution phase and separable solvate.The unrestricted example that is fit to solvate comprises ethylate, methylate etc." hydrate " is that solvent molecule is H ₂The solvate of O.

" significant quantity ' or " treatment significant quantity " is intended to describe compound of the present invention or composition effectively suppresses the amount that therefore following disease or illness also produce required treatment, improvement, inhibition or preventive effect.

The compound of formula (I) can form salt, and these salt also within the scope of the invention.Should be appreciated that except as otherwise noted, this paper comprises quoting its salt to quoting of formula (I) compound.Acid salt that term used herein " salt " expression and mineral acid and/or organic acid form and the subsalt that forms with mineral alkali and/or organic bases.In addition, formula (I) compound comprise simultaneously basic moiety (as but be not limited to pyridine or imidazoles) and acidic moiety (as but be not limited to carboxylic acid) time, can form zwitter-ion (" inner salt "), these salt are included in the term used herein " salt ".The preferred salt that uses pharmaceutically acceptable (that is, nontoxic, can accept on the physiology) is although also can use other salt.For example, but the reaction in medium (for example, wherein sedimentary medium of salt or water-bearing media) of through type (I) compound and a certain amount of acid or alkali (as equivalent), and freeze-drying subsequently forms the salt of formula (I) compound.

The acid salt of example comprises acetate, ascorbate salt, benzoate, benzene sulfonate, hydrosulfate, borate, butyrates, Citrate trianion, camphorate, camsilate, fumarate, hydrochloride, hydrobromate, hydriodate, lactic acid salt, maleate, mesylate, naphthalenesulfonate, nitrate, oxalate, phosphoric acid salt, propionic salt, salicylate, succinate, vitriol, tartrate, thiocyanate-, tosylate (being also referred to as tosylate) etc.In addition, generally be considered to be fit to by the alkaline drug compound formation pharmaceutically the acid of acceptable salts be discussed at, for example, people such as P.Stahl, Camille G. (eds.), Handbook ofPharmaceutical Salts, Properties, Selection and Use, (2002) Zurich:Wiley-VCH; People such as S.Berge, Journal of PharmaceuticalSciences (1977) 66 (1)1-19; P.Gould, International J.ofPharmaceutics (1986) 33201-217; People such as Anderson, The Practice ofMedicinal Chemistry (1996), Academic Press, New York; With The OrangeBook (Food ﹠amp; Drug Administration, Washington, D.C. sees on the website).These openly are attached to herein by reference.

The example subsalt comprise ammonium salt, an alkali metal salt (as sodium, lithium and sylvite), alkaline earth salt (as calcium and magnesium salts), with the salt of organic bases (for example, organic amine, for example dicyclohexylamine, TERTIARY BUTYL AMINE) and with the salt of amino acid (as arginine, Methionin etc.).The alkalescence nitrogen-containing group can be quaternized with some reagent, as low alkyl group halogen (for example, methyl, ethyl and Butyryl Chloride, bromine and iodine), the sulfuric acid dialkyl (for example, methyl-sulfate, diethyl ester and dibutylester), long-chain halogenide (for example, decyl, dodecyl and stearyl chloride, bromine and iodine), aralkyl halogen (for example, benzyl and phenethyl bromide) etc.

All these acid salt and subsalt are intended to be the pharmacy acceptable salt in the scope of the invention, and according to the invention is intended to, all these acid salt and subsalt all are considered to be equivalent to the free form of respective compound.

The pharmaceutically acceptable ester of The compounds of this invention comprises following kind: the carboxylicesters that (1) is obtained by hydroxy esterification; wherein the non-carbonyl moiety of the carboxylic moiety of ester group (for example is selected from the straight or branched alkyl; ethanoyl, n-propyl, the tertiary butyl or normal-butyl), alkoxyalkyl (for example; methoxymethyl), aralkyl (for example; benzyl), aryloxy alkyl (for example; phenoxymethyl), aryl (for example, for example halogen, (C of optional usefulness ₁-C ₄) alkyl or (C ₁-C ₄) alkoxyl group or the amino phenyl that replaces); (2) sulphonate is as alkyl-or aralkyl alkylsulfonyl (for example, methylsulfonyl); (3) amino acid ester (for example, L-valyl or L-isoleucyl-); (4) phosphonic acid ester and (5) single, two or triguaiacyl phosphate.Phosphoric acid ester can be further by for example C ₁-C ₂₀Alcohol or its reactive derivatives or 2,3-two (C ₆-C ₂₄) the acylglycerol esterification.

One or more compounds of the present invention also can be used as solvate existence or the optional solvate that changes into.The preparation of general known solvate.Therefore, people such as M.Caira for example, J.Pharmaceutical Sci., 93 (3), 601-611 (2004) is described in the ethyl acetate and water prepares the solvate of antifungal drug fluconazole.Similar preparation solvate, half solvate, hydrate etc. are described in people such as E.C.van Tonder, AAPS PharmSciTech., and 5 (1), article 12 (2004); With people such as A.L.Bingham, Chem.Commun., 603-604 (2001).General unrestricted method comprises, compound of the present invention is dissolved in the required solvent (organic solvent or water or its mixture) of aequum in the temperature that is higher than envrionment temperature, makes the solution cooling to be enough to forming crystalline speed, separated by standard method then.Analytical technology, for example I.R. spectrum shows that solvent (or water) is present in the crystallization as solvate (or hydrate).

Can its tautomeric forms there be (for example acid amides or imido ether) in the compound of formula (I) and salt, solvate, ester and prodrug.All these tautomeric forms all are included in the present invention as part of the present invention.

All steric isomers that comprise The compounds of this invention (comprising salt, solvate, ester and the prodrug of compound and salt, solvate and the ester of prodrug) within the scope of the present invention (for example, geometrical isomer, optical isomer etc.), for example, can be owing to the steric isomer of asymmetric carbon existence on the different substituents, comprise enantiomeric forms (even can lack under the asymmetric carbon exist), rotational isomer form, atropisomer and diastereomeric form, and positional isomers (for example 4-pyridyl and 3-pyridyl).The independent steric isomer of The compounds of this invention for example essence does not contain other isomer, perhaps can for example mix as racemic modification or with the steric isomer of every other or other selections.Chiral centre of the present invention can have S or R configuration, defines as IUPAC 1974 Recommendations.Used term " salt ", " solvate ", " ester ", " prodrug " etc. are intended to be applicable on an equal basis salt, solvate, ester and the prodrug of enantiomer, steric isomer, rotational isomer, tautomer, positional isomers, racemic modification or the prodrug of The compounds of this invention.

The polymorphic forms of salt, solvate, ester and the prodrug of the polymorphic forms of formula I compound and formula I compound is intended to be included in the present invention.

Formula of the present invention (I) compound or its pharmacy acceptable salt, solvate or ester have pharmacological property; Specifically, the compound of formula (I) can be selectivity CB ₁Antagonist.The compound of term " selectivity " meaning formula (I) is attached to CB ₁It is stronger that the acceptor ratio is attached to other Cannabined receptors.

The compound of formula of the present invention (I) or its pharmacy acceptable salt, solvate or ester are used for the treatment of and comprise obesity, metabolism disorder, addiction, central nervous system disease, cardiovascular disorder, respiratory disease, gastrointestinal dysfunction, lose weight, reduce waistline, the treatment hyperlipemia, insulin sensitivity, diabetes, hypertriglyceridemia, eating disorder, alcoholism, inflammation, mental disorder, migraine, nicotine dependence, Parkinson's disease (Parkinson ' s disease), psychosis, schizophrenia, somnopathy, attention deficit hyperactivity disorder (attention deficithyperactivity disorder), male sexual disorder, premature ejaculation, premenstrual tension syndrome, epileptic seizures, epileptics and convulsions, non-insulin-dependent diabetes mellitus (NIDDM), dull-witted, major depressive disorder, bulimia nervosa, pharmacological dependence, septic shock, cognitive disorder, endocrine disorder, eczema, vomiting, irritated, glaucoma, hemorrhagic shock, hypertension, stenocardia, thrombosis, arteriosclerosis, restenosis, hypertension, acute coronary syndrome, stenocardia, arrhythmia, in heart failure, cerebral ischemia, apoplexy, myocardial infarction, glomerulonephritis, thrombotic apoplexy and thromboembolic stroke, peripheral vascular disease, neurodegenerative disease, osteoporosis, tuberculosis, autoimmune disease, ypotension, joint disease, cancer, demyelinating disease, alzheimer's disease (Alzheimer ' s disease), the hyposexuality obstacle, the bipolarity obstacle, hyperlipidaemia, hypertension, narcotic dependence, Huntington chorea (Huntington ' s chorea), pain, multiple sclerosis, anxiety disorder, osteopathy, Paget's disease (Paget ' s disease), rheumatoid arthritis, ulcerative colitis, the disease of irritable bowel syndrome and inflammatory bowel or illness.

Term " pharmaceutical composition " also is intended to comprise body composition and independent dose unit, and dose unit comprises more than a kind of (for example two kinds) pharmaceutically active agents (compound for example of the present invention) and is selected from other medicaments of other medicament inventories described herein and the vehicle of any non-pharmaceutical activity.Body composition and each independent dose unit can comprise fixed amount aforementioned " more than a kind of pharmaceutically active agents ".Body composition is not for forming the material of individually dosed unit as yet.The example dose unit is an oral dosage units, as tablet, pill etc.Equally, also be intended to comprise by the methods described herein that give medicine composite for curing patient of the present invention and give aforementioned body composition and individually dosed unit.

The compound of formula (I) or its pharmacy acceptable salt, solvate or ester can any form administrations, and be for example individually dosed, or make up in pharmaceutical composition according to standard pharmacy standard and pharmaceutically acceptable carrier, vehicle or thinner.The compound of formula (I) or its pharmacy acceptable salt, solvate or ester Orally-administrable or parenteral admin comprise intravenously, intramuscular, intraperitoneal, subcutaneous, rectum or topical approach.

The pharmaceutical composition that comprises at least a formula I compound or its pharmacy acceptable salt, solvate or ester can be for being suitable for the form of oral administration, for example tablet, contain lozenge, capsule, dragee, water-based or oiliness suspensoid, can disperse powder or granule, emulsion, syrup or elixir.Oral compositions can prepare by any conventional pharmaceutical methods, and also can comprise sweeting agent, sweetener, tinting material and sanitas.

The doctor can according to patient's age, body weight and reaction and the decision of sanatory seriousness give patient's formula (I) compound or the amount of its pharmacy acceptable salt, solvate or ester.For example, give patient's the compound of formula I or its pharmacy acceptable salt, solvate or ester amount can for about 0.1mg/kg body weight/day to about 60mg/kg/d, preferably about 0.5mg/kg/d is about 40mg/kg/d extremely.

The compound of formula I or its pharmacy acceptable salt, solvate or ester also can with the combination with other therapeutic agents administration.For example, the compound of one or more formulas (I) or its pharmacy acceptable salt, solvate or ester can be with one or more other cholesterol-lowering agent administrations.

The unrestricted inventory that is used for cholesterol-lowering agent of the present invention comprises HMG CoA reductase inhibiter compounds, as lovastatin (for example,

Available from Merck ﹠amp; Co.), Simvastatin (for example,

Available from Merck ﹠amp; Co.), Pravastatin (for example Available from Bristol Meyers Squibb), atorvastatin, fluvastatin, Cerivastatin, CI-981, rivastatin (rivastatin) (7-(4-fluorophenyl)-2,6-di-isopropyl-5-methoxymethyl pyridin-3-yl)-3,5-dihydroxyl-6-enanthic acid sodium), ZD-4522 ( Available from AstraZeneca Pharmaceuticals), pitavastatin (as NK-104, available from Negma Kowa of Japan); HMG CoA synthase inhibitor, L-659 for example, 699 ((E, E)-11-[3 ' R-(hydroxymethyl)-4 '-oxo-2 ' R-oxetanyl]-3,5,7R-trimethylammonium-2,4-undecandienoic acid); The squalene synthetic inhibitor, for example squalestatin 1; The squalene epoxidase inhibitor, for example NB-598 ((E)-N-ethyl-N-(6,6-dimethyl-2-heptene-4-alkynyl)-3-[(3,3 '-di-thiophene-5-yl) methoxyl group] the benzene methanamine hydrochloride); Sterol (for example cholesterol) biosynthesis inhibitor is as DMP-565; Nicotinic acid derivates (for example, the compound that comprises pyridine-3-carboxylic acid structure or pyrazine-2-carboxylic acid structure, comprise acid type, salt, ester, zwitter-ion and tautomer), as pentaerythritol tetranicotinate, nicofurate sugar and Olbetam (5-methylpyrazine-2-carboxylic acid 4-oxide compound); Clofibrate; Gemfibrozil; Bile acid chelating agent, as QUESTRAN (styrene diethylene benzene copoly mer that comprises quaternary ammonium cation group that can conjugated bile acid, as

Or QUESTRAN

QUESTRAN is available from Bristol-Myers Squibb), colestipol (diethylenetriamine and 1-chloro-2, the multipolymer of 3-propylene oxide, as

Tablet is available from Pharmacia), the hydrochloric acid colesevelam (as

Tablet (with epoxy chloropropane crosslinked and with alkylating gather (the hydrochloric acid allyl amine) of 1-bromo-decane and bromination (6-bromine hexyl)-trimethyl ammonium), available from Sankyo), soluble derivative is as 3,3-ioene, N-(cycloalkyl) alkylamine and Poliglusam, insoluble quaternized polystyrene, saponin and composition thereof; Inorganic cholesterol sequestrant is as bismuth salicylate+polynite, aluminium hydroxide and lime carbonate antiacid; Ileal bile acid transfer (" IBAT ") inhibitor (or apical sodium is total to dependency bile acid transport (" ASBT ") inhibitor), as benzothiaheptylyin (benzothiepine), for example comprise 2,3,4,5-tetrahydrochysene-1-benzothiaheptylyin 1, the treatment compound of 1-dioxide structure, open as PCT patent application WO 00/38727, be attached to by reference herein; Acyl-CoA: cholesterol O-acyltransferase (" ACAT ") inhibitor, as avasimibe ([[2,4,6-three (1-methylethyl) phenyl] ethanoyl] thionamic acid 2, two (1-methylethyl) phenylesters of 6-, be called CI-1011 in the past), HL-004, (N-(2 for lecimibide (DuP-128) and CL-277082, the 4-difluorophenyl)-N-[[4-(2, the 2-dimethyl propyl) phenyl] methyl]-N-heptyl urea), and be described in people such as P.Chang, " Current, New and Future Treatments in Dyslipidaemia andAtherosclerosis ", Drugs 2000 Jul; 60 (1); The compound of 55-93 (described document is attached to herein by reference); Cholesteryl ester transfer protein (" CETP ") inhibitor, as PCT patent application WO 00/38721 and United States Patent (USP) 6,147,090 those disclosed inhibitor, described patent is attached to herein by reference; The probucol or derivatives thereof, as AGI-1067 and United States Patent (USP) 6,121,319 and 6,147,250 disclosed other derivatives, described patent is attached to herein by reference; Low-density lipoprotein (LDL) receptor activator, as HOE-402, active imidazolidyl-the pyrimidine derivatives of a kind of direct stimulation ldl receptor, be described in people such as M.Huettinger, " Hypolipidemic activity of HOE-402 is Mediated byStimulation of the LDL Receptor Pathway ", Arterioscler.Thromb.1993; 13:1005-12, described document is attached to herein by reference; The fish oil (3-PUFA) that contains omega-fatty acid; Water-soluble fiber is as Psyllium, guar gum, oat and pectin; The fatty acid ester of phytostanols and/or phytostanols, as

The sitostanol ester that uses in the oleomargarine; Nicotinic acid receptor agonists (the agonist of HM74 and HM74A acceptor for example, described acceptor is described in US 2004/0142377, US 2005/0004178, US2005/0154029, US 6902902, WO 2004/071378, WO 2004/071394, WO 01/77320, US 2003/0139343, WO 01/94385, WO 2004/083388, US 2004/254224, US 2004/0254224, US 2003/0109673 and WO98/56820), for example WO 2004/033431, WO 2005/011677, WO 2005/051937, US 2005/0187280, US 2005/0187263, WO 2005/077950, WO2005/016867 and WO 2005/016870 described receptor stimulant; The azetidinone of the replacement that goes through below reaching or the beta-lactam sterol absorption inhibitor of replacement.

As used herein, " sterol absorption inhibitor " is meant and giving Mammals or man-hour to treat effectively (sterol and/or 5 α-stanols absorbs and suppresses) amount, can suppress the compound that one or more sterols absorb, described sterol includes but not limited to cholesterol, plant sterol (as Sitosterol, campesterol, Stigmasterol and avenasterol), 5 α-stanols (as Dihydrocholesterol, 5 α-campestanol, 5 α-sitostanol) and/or its mixture.

The azetidinone of the replacement of formula (A)

In one embodiment, the azetidinone of the used replacement of composition of the present invention, therapeutic combination and method is by with following formula (A):

Or pharmacy acceptable salt, solvate or the ester of formula (A) compound represent, wherein in following formula (A):

Ar ¹And Ar ²Independently be selected from aryl and R ⁴The aryl of-replacement;

Ar ³Be aryl or R ⁵The aryl of-replacement;

X, Y and Z independently are selected from-CH ₂-,-CH (low alkyl group)-and-C (low alkyl group) ₂-;

R and R ²Independently be selected from-OR ⁶,-OC (O) R ⁶,-OC (O) OR ⁹With-OC (O) NR ⁶R ⁷

R ¹And R ³Independently be selected from hydrogen, low alkyl group and aryl;

Q is 0 or 1; R is 0 or 1; M, n and p independently are selected from 0,1,2,3 or 4; Its condition is that at least one of q and r is 1, and m, n, p, q and r sum are 1,2,3,4,5 or 6; And its condition for p be 0 and r be 1 o'clock, m, q and n sum are 1,2,3,4 or 5;

R ⁴For 1-5 independently be selected from low alkyl group ,-OR ⁶,-OC (O) R ⁶,-OC (O) OR ⁹,-O (CH ₂) _1-5OR ⁶,-OC (O) NR ⁶R ⁷,-NR ⁶R ⁷,-NR ⁶C (O) R ⁷,-NR ⁶C (O) OR ⁹,-NR ⁶C (O) NR ⁷R ⁸,-NR ⁶SO ₂R ⁹,-C (O) OR ⁶,-C (O) NR ⁶R ⁷,-C (O) R ⁶,-S (O) ₂NR ⁶R ⁷, S (O) _0-2R ⁹,-O (CH ₂) _1-10-C (O) OR ⁶,-O (CH ₂) _1-10CONR ⁶R ⁷,-(low-grade alkylidene) COOR ⁶,-CH=CH-C (O) OR ⁶,-CF ₃,-CN ,-NO ₂Substituting group with halogen;

R ⁵Independently be selected from-OR for 1-5 ⁶,-OC (O) R ⁶,-OC (O) OR ⁹,-O (CH ₂) _1-5OR ⁶,-OC (O) NR ⁶R ⁷,-NR ⁶R ⁷,-NR ⁶C (O) R ⁷,-NR ⁶C (O) OR ⁹,-NR ⁶C (O) NR ⁷R ⁸,-NR ⁶S (O) ₂R ⁹,-C (O) OR ⁶,-C (O) NR ⁶R ⁷,-C (O) R ⁶,-SO ₂NR ⁶R ⁷, S (O) _0-2R ⁹,-O (CH ₂) _1-10-C (O) OR ⁶,-O (CH ₂) _1-10C (O) NR ⁶R ⁷,-(low-grade alkylidene) C (O) OR ⁶With-CH=CH-C (O) OR ⁶Substituting group;

R ⁶, R ⁷And R ⁸Independently be selected from the low alkyl group that hydrogen, low alkyl group, aryl and aryl replace; And

R ⁹Low alkyl group for low alkyl group, aryl or aryl replacement.

Preferred R ⁴Be 1-3 the independent substituting group of selecting, and R ⁵Be preferably 1-3 the independent substituting group of selecting.

Therapeutic composition of the present invention or make up some used compound and can have at least one unsymmetrical carbon, so all isomer of formula A-M compound (if existence), comprise enantiomer, diastereomer, steric isomer, rotational isomer, tautomer and racemic modification, all be envisioned for part of the present invention.The present invention includes two kinds of pure state and blended d and l isomer, comprise racemic mixture.Isomer can prepare with routine techniques, can be by making the raw material reaction of optical purity or denseization of optics, the perhaps isomer of separate type A-M compound.Isomer also can comprise geometrical isomer, for example when having two key.

One skilled in the art will understand that some compounds for formula A-M, a kind of isomer may show bigger pharmacologically active than other isomer.

The preferred compound of formula (A) is these compounds, wherein Ar ¹Be phenyl or R ⁴The phenyl of-replacement, more preferably (4-R ⁴The phenyl of)-replace.Ar ²Be preferably phenyl or R ⁴The phenyl of-replacement, more preferably (4-R ⁴The phenyl of)-replace.Ar ³Be preferably R ⁵The phenyl of-replacement, more preferably (4-R ⁵The phenyl of)-replace.At Ar ¹Be (4-R ⁴During the phenyl of)-replace, R ⁴Be preferably halogen.At Ar ²And Ar ³Be respectively R ⁴-and R ⁵-replace phenyl the time, R ⁴Be preferably halogen or-OR ⁶, and R ⁵Be preferably-OR ⁶, R wherein ⁶Be low alkyl group or hydrogen.Especially preferably Ar wherein ¹And Ar ²Be respectively the 4-fluorophenyl, and Ar ³Compound for 4-hydroxy phenyl or 4-p-methoxy-phenyl.

X, Y and Z preferably are respectively-CH ₂-.R ¹And R ³Preferably be respectively hydrogen.R and R ²Be preferably-OR ⁶, R wherein ⁶For hydrogen or be metabolized to easily hydroxyl group (as defined above-OC (O) R ⁶,-OC (O) OR ⁹With-OC (O) NR ⁶R ⁷).

M, n, p, q and r sum are preferably 2,3 or 4, and more preferably 3.Wherein m, n and r are respectively 0, q be 1 and p be that the compound of 2 formula (A) is preferred.

Wherein p, q and n are respectively 0, r be 1 and m be that the compound of 2 or 3 formula (A) also is preferred.Be more preferably wherein that m, n and r are respectively 0, q is 1, and p is 2, and Z is-CH ₂-, and R is-OR ⁶(especially at R ⁶During for hydrogen) compound.

Wherein p, q and n are respectively 0, and r is 1, and m is 2, and X is-CH ₂-, and R ²For-OR ⁶(especially at R ⁶During for hydrogen) the compound of formula (A) also be preferred.

Another compound of organizing preferred formula (A) is Ar wherein ¹Be phenyl or R ⁴The phenyl of-replacement, Ar ²Be phenyl or R ⁴The phenyl of-replacement, and Ar ³Be R ⁵The compound of the phenyl of-replacement.Ar wherein ¹Be phenyl or R ⁴The phenyl of-replacement, Ar ²Be phenyl or R ⁴The phenyl of-replacement, Ar ³Be R ⁵The phenyl of-replacement, m, n, p, q and r sum are 2,3 or 4, more preferably 3 compound also is preferred.Ar wherein ¹Be phenyl or R ⁴The phenyl of-replacement, Ar ²Be phenyl or R ⁴The phenyl of-replacement, Ar ³Be R ⁵-the phenyl that replaces, and wherein m, n and r are respectively 0, q be 1 and p be 2, perhaps wherein p, q and n are respectively 0, r be 1 and m be that 2 or 3 compound is preferred.

The azetidinone of the replacement of formula (B)

In a preferred embodiment, the azetidinone of the replacement of the used formula (A) of composition of the present invention, therapeutic combination and method is by with following formula (B) (Yi Zemaibu):

Or pharmacy acceptable salt, solvate or the ester of formula (B) compound are represented.The compound of formula (B) can be anhydrous or hydrated form.Contain the product conduct of Yi Zemaibu compound

The Yi Zemaibu preparation is available from MSP Pharmaceuticals.

The compound of formula (A) can be prepared by the several different methods that those skilled in the art are familiar with, as United States Patent (USP) 5,631, and 365,5,767,115,5,846,966,6,207,822,6,627,757,6,093,812,5,306,817,5,561,227,5,688,785 and 5,688,787 is disclosed, and each patent is attached to herein by reference.

The azetidinone of the replacement of formula (C)

Composition of the present invention, therapeutic combination and method used for the azetidinone of the replacement of choosing by with following formula (C):

Or its pharmacy acceptable salt or solvate or ester represent, wherein in following formula (C):

Ar ¹Be R ³The aryl of-replacement;

Ar ²Be R ⁴The aryl of-replacement;

Ar ³Be R ⁵The aryl of-replacement;

Y and Z independently are selected from-CH ₂-,-CH (low alkyl group)-and-C (low alkyl group) ₂-;

A is selected from-O-,-S-,-S (O)-or-S (O) ₂-;

R ¹Be selected from-OR ⁶,-OC (O) R ⁶,-OC (O) OR ⁹With-OC (O) NR ⁶R ⁷

R ²Be selected from hydrogen, low alkyl group and aryl; Perhaps

R ¹And R ²Be jointly=O;

Q is 1,2 or 3;

P is 0,1,2,3 or 4;

R ⁵Independently be selected from-OR for 1-3 ⁶,-OC (O) R ⁶,-OC (O) OR ⁹,-O (CH ₂) _1-5OR ⁹,-OC (O) NR ⁶R ⁷,-NR ⁶R ⁷,-NR ⁶C (O) R ⁷,-NR ⁶C (O) OR ⁹,-NR ⁶C (O) NR ⁷R ⁸,-NR ⁶S (O) ₂-low alkyl group ,-NR ⁶S (O) ₂-aryl ,-C (O) NR ⁶R ⁷,-COR ⁶,-SO ₂NR ⁶R ⁷, S (O) _0-2-alkyl, S (O) _0-2-aryl ,-O (CH ₂) _1-10-C (O) OR ⁶,-O (CH ₂) _1-10C (O) NR ⁶R ⁷, o-halogen, m-halogen, o-low alkyl group, m-low alkyl group ,-(low-grade alkylidene)-C (O) OR ⁶With-CH=CH-C (O) OR ⁶Substituting group;

R ³And R ⁴Independently independently be selected from R for 1-3 ⁵, hydrogen, p-low alkyl group, aryl ,-NO ₂,-CF ₃Substituting group with the p-halogen;

R ⁶, R ⁷And R ⁸Independently be selected from the low alkyl group that hydrogen, low alkyl group, aryl and aryl replace; And R ⁹Low alkyl group for low alkyl group, aryl or aryl replacement.

The method of preparation formula (C) compound is familiar with by those skilled in the art.The unrestricted example of appropriate methodology is disclosed in United States Patent (USP) 5,688,990, and described patent is attached to herein by reference.

The azetidinone of the replacement of formula (D)

In another embodiment, the azetidinone of the used replacement of composition of the present invention, therapeutic combination and method is by with following formula (D):

Or its pharmacy acceptable salt or solvate or ester represent, wherein in following formula (D):

A is selected from R ²Heterocyclylalkyl, the R of-replacement ²Heteroaryl, the R of-replacement ²The benzo-fused Heterocyclylalkyl and the R of-replacement ²The benzo-fused heteroaryl of-replacement;

Ar ¹Be aryl or R ³The aryl of-replacement;

Ar ²Be aryl or R ⁴The aryl of-replacement;

Q is a key, and perhaps the 3-position ring carbon with azetidinone forms tap bolt

And

R ¹Be selected from:

-(CH ₂) _q-, wherein q is 2-6, its condition is that q also can be 0 or 1 when Q forms volution;

-(CH ₂) _e-G-(CH ₂) _r-, wherein G be-O-,-C (O)-, phenylene ,-NR ⁸-or-S (O) _0-2-, e is 0-5, and r is 0-5, its condition is that e and r sum are 1-6;

-(C ₂-C ₆Alkenylene)-; With

-(CH ₂) _f-V-(CH ₂) _g-, wherein V is C ₃-C ₆Cycloalkylidene, f are 1-5, and g is 0-5, and its condition is that f and g sum are 1-6;

R ⁵Be selected from:

R ⁶And R ⁷Independently be selected from-CH ₂-,-CH (C ₁-C ₆Alkyl)-,-C (two (C ₁-C ₆) alkyl) ,-CH=CH-and-C (C ₁-C ₆Alkyl)=CH-; Perhaps R ⁵With adjacent R ⁶Together, perhaps R ⁵With adjacent R ⁷Together formation-CH=CH-or-CH=C (C ₁-C ₆Alkyl)-group;

A and b independently are 0,1,2 or 3, and its condition is not 0 for the two simultaneously; Its condition is at R ⁶For-CH=CH-or-C (C ₁-C ₆Alkyl)=during CH-, a is 1; Its condition is at R ⁷For-CH=CH-or-C (C ₁-C ₆Alkyl)=during CH-, b is 1; Its condition is for being 2 or 3 o'clock at a, each R ⁶Can be identical or different; And its condition is for being 2 or 3 o'clock at b, each R ⁷Can be identical or different;

And when Q is key, R ¹Also can be selected from:

Wherein M be-O-,-S-,-S (O)-or-S (O) ₂-;

X, Y and Z independently are selected from-CH ₂-,-CH (C ₁-C ₆Alkyl)-and-C (two-(C ₁-C ₆) alkyl);

R ¹⁰And R ¹²Independently be selected from-OR ¹⁴,-OC (O) R ¹⁴,-OC (O) OR ¹⁶With-OC (O) NR ¹⁴R ¹⁵

R ¹¹And R ¹³Independently be selected from hydrogen, (C ₁-C ₆) alkyl and aryl; Perhaps R ¹⁰And R ¹¹Be jointly=O, perhaps R ¹²And R ¹³Be jointly=O;

D is 1,2 or 3;

H is 0,1,2,3 or 4;

S is 0 or 1; T is 0 or 1; M, n and p independently are 0-4; Its condition is that at least one of s and t is 1, and m, n, p, s and t sum are 1-6; Its condition for p be 0 and t be 1 o'clock, m, s and n sum are 1-5; And its condition for p be 0 and s be 1 o'clock, m, t and n sum are 1-5;

V is 0 or 1;

J and k independently are 1-5, and its condition is that j, k and v sum are 1-5;

R ²Be the substituting group of the 1-3 on the ring carbon atom, described substituting group is selected from hydrogen, (C ₁-C ₁₀) alkyl, (C ₂-C ₁₀) thiazolinyl, (C ₂-C ₁₀) alkynyl, (C ₃-C ₆) cycloalkyl, (C ₃-C ₆) cycloalkenyl group, R ¹⁷Aryl, the R of-replacement ¹⁷Benzyl, the R of-replacement ¹⁷Benzyloxy, the R of-replacement ¹⁷-replace aryloxy, halogen ,-NR ¹⁴R ¹⁵, NR ¹⁴R ¹⁵(C ₁-C ₆Alkylidene group)-, NR ¹⁴R ¹⁵C (O) (C ₁-C ₆Alkylidene group)-,-NHC (O) R ¹⁶, OH, C ₁-C ₆Alkoxyl group ,-OC (O) R ¹⁶,-C (O) R ¹⁴, hydroxyl (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl group (C ₁-C ₆) alkyl, NO ₂,-S (O) _0-2R ¹⁶,-S (O) ₂NR ¹⁴R ¹⁵With-(C ₁-C ₆Alkylidene group) C (O) OR ¹⁴At R ²During for the substituting group on the heterocycloalkyl ring, R ²As defined herein, perhaps R ²For=O or

And at R ²But during for the substituting group on the substituted ring nitrogen, R ²Be hydrogen, (C ₁-C ₆) alkyl, aryl, (C ₁-C ₆) alkoxyl group, aryloxy, (C ₁-C ₆) alkyl-carbonyl, aryl carbonyl, hydroxyl ,-(CH ₂) _1-6CONR ¹⁸R ¹⁸,

Wherein J be-O-,-NH-,-NR ¹⁸-or-CH ₂-;

R ³And R ⁴Independently be selected from 1-3 and independently be selected from (C ₁-C ₆) alkyl ,-OR ¹⁴,-OC (O) R ¹⁴,-OC (O) OR ¹⁶,-O (CH ₂) _1-5OR ¹⁴,-OC (O) NR ¹⁴R ¹⁵,-NR ¹⁴R ¹⁵,-NR ¹⁴C (O) R ¹⁵,-NR ¹⁴C (O) OR ¹⁶,-NR ¹⁴C (O) NR ¹⁵R ¹⁹,-NR ¹⁴S (O) ₂R ¹⁶,-C (O) OR ¹⁴,-C (O) NR ¹⁴R ¹⁵,-C (O) R ¹⁴,-S (O) ₂NR ¹⁴R ¹⁵, S (O) _0-2R ¹⁶,-O (CH ₂) _1-10-C (O) OR ¹⁴,-O (CH ₂) _1-10C (O) NR ¹⁴R ¹⁵,-(C ₁-C ₆Alkylidene group)-C (O) OR ¹⁴,-CH=CH-C (O) OR ¹⁴,-CF ₃,-CN ,-NO ₂Substituting group with halogen;

R ⁸Be hydrogen, (C ₁-C ₆) alkyl, aryl (C ₁-C ₆) alkyl ,-C (O) R ¹⁴Or-C (O) OR ¹⁴

R ⁹And R ¹⁷Independently independently be selected from hydrogen, (C for 1-3 ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl group ,-C (O) OH, NO ₂,-NR ¹⁴R ¹⁵, OH and halogen group;

R ¹⁴And R ¹⁵Independently be selected from hydrogen, (C ₁-C ₆) (the C that replaces of alkyl, aryl and aryl ₁-C ₆) alkyl;

R ¹⁶Be (C ₁-C ₆) alkyl, aryl or R ¹⁷The aryl of-replacement;

R ¹⁸Be hydrogen or (C ₁-C ₆) alkyl; And

R ¹⁹Be hydrogen, hydroxyl or (C ₁-C ₆) alkoxyl group.

The method of preparation formula (D) compound is familiar with by those skilled in the art.The unrestricted example of appropriate methodology is disclosed in United States Patent (USP) 5,656,624, and described patent is attached to herein by reference.

The azetidinone of the replacement of formula (E)

In another embodiment, the azetidinone of the used replacement of composition of the present invention, therapeutic combination and method is by with following formula (E):

Or its pharmacy acceptable salt or solvate or ester represent, wherein in following formula (E):

Ar ¹Be aryl, R ¹⁰The aryl or the heteroaryl of-replacement;

Ar ²Be aryl or R ⁴The aryl of-replacement;

Ar ³Be aryl or R ⁵The aryl of-replacement;

X and Y independently are selected from-CH ₂-,-CH (low alkyl group)-and-C (low alkyl group) ₂-;

R is-OR ⁶,-OC (O) R ⁶,-OC (O) OR ⁹Or-OC (O) NR ⁶R ⁷R ¹Be hydrogen, low alkyl group or aryl; Perhaps R and R ¹Be jointly=O;

Q is 0 or 1;

R is 0,1 or 2;

M and n independently are 0,1,2,3,4 or 5; Its condition is that m, n and q sum are 1,2,3,4 or 5;

R ⁴For 1-5 independently be selected from low alkyl group ,-OR ⁶,-OC (O) R ⁶,-OC (O) OR ⁹,-O (CH ₂) _1-5OR ⁶,-OC (O) NR ⁶R ⁷,-NR ⁶R ⁷,-NR ⁶C (O) R ⁷,-NR ⁶C (O) OR ⁹,-NR ⁶C (O) NR ⁷R ⁸,-NR ⁶S (O) ₂R ⁹,-C (O) OR ⁶,-C (O) NR ⁶R ⁷,-C (O) R ⁶,-S (O) ₂NR ⁶R ⁷, S (O) _0-2R ⁹,-O (CH ₂) _1-10-C (O) OR ⁶,-O (CH ₂) _1-10C (O) NR ⁶R ⁷,-(low-grade alkylidene) C (O) OR ⁶With-CH=CH-C (O) OR ⁶Substituting group;

R ⁵Independently be selected from-OR for 1-5 ⁶,-OC (O) R ⁶,-OC (O) OR ⁹,-O (CH ₂) _1-5OR ⁶,-OC (O) NR ⁶R ⁷,-NR ⁶R ⁷,-NR ⁶C (O) R ⁷,-NR ⁶C (O) OR ⁹,-NR ⁶C (O) NR ⁷R ⁸,-NR ⁶S (O) ₂R ⁹,-C (O) OR ⁶,-C (O) NR ⁶R ⁷,-C (O) R ⁶,-S (O) ₂NR ⁶R ⁷, S (O) _0-2R ⁹,-O (CH ₂) _1-10-C (O) OR ⁶,-O (CH ₂) _1-10C (O) NR ⁶R ⁷,-CF ₃,-CN ,-NO ₂, halogen ,-(low-grade alkylidene) C (O) OR ⁶With-CH=CH-C (O) OR ⁶Substituting group;

R ⁶, R ⁷And R ⁸Independently be selected from the low alkyl group that hydrogen, low alkyl group, aryl and aryl replace;

R ⁹Low alkyl group for low alkyl group, aryl or aryl replacement; And

R ¹⁰For 1-5 independently be selected from low alkyl group ,-OR ⁶,-OC (O) R ⁶,-OC (O) OR ⁹,-O (CH ₂) _1-5OR ⁶,-OC (O) NR ⁶R ⁷,-NR ⁶R ⁷,-NR ⁶C (O) R ⁷,-NR ⁶C (O) OR ⁹,-NR ⁶C (O) NR ⁷R ⁸,-NR ⁶S (O) ₂R ⁹,-C (O) OR ⁶,-C (O) NR ⁶R ⁷,-C (O) R ⁶,-S (O) ₂NR ⁶R ⁷, S (O) _0-2R ⁹,-O (CH ₂) _1-10-C (O) OR ⁶,-O (CH ₂) _1-10C (O) NR ⁶R ⁷,-CF ₃,-CN ,-NO ₂Substituting group with halogen;

The method of preparation formula (E) compound is familiar with by those skilled in the art.The unrestricted example of appropriate methodology is disclosed in United States Patent (USP) 5,624,920, and described patent is attached to herein by reference.

The azetidinone of the replacement of formula (F)

In another embodiment, the azetidinone of the used replacement of composition of the present invention, therapeutic combination and method is by with following formula (F):

Or its pharmacy acceptable salt or solvate or ester represent, wherein:

R ¹For:

R ²And R ³Independently be selected from-CH ₂-,-CH (low alkyl group)-,-C (low alkyl group) ₂-,-CH=CH-and-C (low alkyl group)=CH-; Perhaps

R ¹With adjacent R ²Together, perhaps R ¹With adjacent R ³Together formation-CH=CH-or-CH=C (low alkyl group)-group;

U and v independently are 0,1,2 or 3, and its condition is not 0 for the two simultaneously; Its condition is at R ²For-CH=CH-or-during C (low alkyl group)=CH-, v is 1; Its condition is at R ³For-CH=CH-or-during C (low alkyl group)=CH-, u is 1; Its condition is for being 2 or 3 o'clock at v, each R ²Can be identical or different; And its condition is for being 2 or 3 o'clock at u, each R ³Can be identical or different;

R ⁴Be selected from B-(CH ₂) _mC (O)-, wherein m is 0,1,2,3,4 or 5; B-(CH ₂) _q-, wherein q is 0,1,2,3,4,5 or 6; B-(CH ₂) _e-Z-(CH ₂) _r, wherein Z be-O-,-C (O)-, phenylene ,-N (R ⁸)-or-S (O) _0-2-, e is 0,1,2,3,4 or 5, and r is 0,1,2,3,4 or 5, and its condition is that e and r sum are 0,1,2,3,4,5 or 6; B-(C ₂-C ₆Alkenylene)-; B-(C ₄-C ₆Alkadienylene)-; B-(CH ₂) _t-Z-(C ₂-C ₆Alkenylene)-, wherein Z as above defines, and wherein t is 0,1,2 or 3, and its condition is that the carbonatoms sum is 2,3,4,5 or 6 in t and the alkenylene chain; B-(CH ₂) _f-V-(CH ₂) _g-, wherein V is C ₃-C ₆Cycloalkylidene, f are 1,2,3,4 or 5, and g is 0,1,2,3,4 or 5, and its condition is that f and g sum are 1,2,3,4,5 or 6; B-(CH ₂) _t-V-(C ₂-C ₆Alkenylene)-or B-(C ₂-C ₆Alkenylene)-V-(CH ₂) _t, wherein V and t as above define, and its condition is that the carbonatoms sum is 2,3,4,5 or 6 in t and the alkenylene chain; B-(CH ₂) _a-Z-(CH ₂) _b-V-(CH ₂) _d-, wherein Z and V as above define, and a, b and d independently are 0,1,2,3,4,5 or 6, and its condition is that a, b and d sum are 0,1,2,3,4,5 or 6; Perhaps T-(CH ₂) _s-, wherein T is C ₃-C ₆Cycloalkyl, s is 0,1,2,3,4,5 or 6; Perhaps

R ¹And R ⁴Form group together

B is selected from the heteroaryl that indanyl, indenyl, naphthyl, tetralyl, heteroaryl or W-replace, wherein heteroaryl is selected from pyrryl, pyridyl, pyrimidyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl, oxazolyl and furyl and N-oxide compound (for nitrogenous heteroaryl) thereof, perhaps

W be 1 to 3 independently be selected from low alkyl group, hydroxyl low-grade alkyl, lower alkoxy, alkoxyalkyl, alkoxyl group alkoxyl group, alkoxy carbonyl alkoxyl group, (lower alkoxy imino-)-low alkyl group, lower alkyl diacyl, low alkyl group lower alkyl diacyl, allyl group oxygen base ,-CF ₃,-OCF ₃, benzyl, R ⁷-benzyl, benzyl oxygen base, R ⁷-benzyl oxygen base, phenoxy group, R ⁷-phenoxy group, dioxolane base, NO ₂,-N (R ⁸) (R ⁹), N (R ⁸) (R ⁹)-low-grade alkylidene-, N (R ⁸) (R ⁹)-low-grade alkenyl (alkylenyl) oxygen base-, OH, halogen ,-CN ,-N ₃,-NHC (O) OR ¹⁰,-NHC (O) R ¹⁰, R ¹¹(O) ₂SNH-, (R ¹¹(O) ₂S) ₂N-,-S (O) ₂NH ₂,-S (O) _0-2R ⁸, the tertiary butyl dimethyl Si ylmethyl ,-C (O) R ¹²,-C (O) OR ¹⁹,-C (O) N (R ⁸) (R ⁹) ,-CH=CHC (O) R ¹²,-low-grade alkylidene-C (O) R ¹², R ¹⁰C (O) (low-grade alkenyl (alkylenyl) oxygen base)-, N (R ⁸) (R ⁹) C (O) (low-grade alkenyl (alkylenyl) oxygen base)-and

The substituting group of (for the replacement on the ring carbon atom), when existing, the substituting group on the heteroaryl ring nitrogen-atoms of replacement be selected from low alkyl group, lower alkoxy ,-C (O) OR ¹⁰,-C (O) R ¹⁰, OH, N (R ⁸) (R ⁹)-low-grade alkylidene-, N (R ⁸) (R ⁹)-low-grade alkenyl (alkylenyl) oxygen base ,-S (O) ₂NH ₂And 2-(trimethyl silyl)-ethoxyl methyl;

R ⁷For 1-3 independently be selected from low alkyl group, lower alkoxy ,-C (O) OH, NO ₂,-N (R ⁸) (R ⁹), the group of OH and halogen;

R ⁸And R ⁹Independently be selected from H or low alkyl group;

R ¹⁰Be selected from low alkyl group, phenyl, R ⁷-phenyl, benzyl or R ⁷-benzyl;

R ¹¹Be selected from OH, low alkyl group, phenyl, benzyl, R ⁷-phenyl or R ⁷-benzyl;

R ¹²Be selected from H, OH, alkoxyl group, phenoxy group, benzyloxy,

N (R ⁸) (R ⁹), low alkyl group, phenyl or R ⁷-phenyl;

R ¹³Be selected from-O-,-CH ₂-,-NH-,-N (low alkyl group)-or-NC (O) R ¹⁹

R ¹⁵, R ¹⁶And R ¹⁷The group that independently is selected from H and W is defined; Perhaps R ¹⁵Be hydrogen, and R ¹⁶And R ¹⁷Form the dioxolane basic ring with their bonded adjacent carbonss;

R ¹⁹Be H, low alkyl group, phenyl or phenyl lower alkyl; And

R ²⁰And R ²¹Independently be selected from naphthyl that phenyl, naphthyl, W-that phenyl, W-replace replace, indanyl, indenyl, tetralyl, benzodioxole base, heteroaryl, the heteroaryl that W-replaces, benzo-fused heteroaryl, benzo-fused heteroaryl and the cyclopropyl that W-replaces, wherein heteroaryl as above defines.

The method of preparation formula (F) compound is familiar with by those skilled in the art.The unrestricted example of appropriate methodology is disclosed in United States Patent (USP) 5,698,548, and described patent is attached to herein by reference.

The azetidinone of the replacement of formula (G)

In another embodiment, the azetidinone of the used replacement of composition of the present invention, therapeutic combination and method is by with following formula (GA) and (GB):

With

Or its pharmacy acceptable salt, solvate or ester represent, wherein:

A is-CH=CH-,-C ≡ C-or-(CH ₂) _p-, wherein p is 0,1 or 2;

B is

B ' is

D is-(CH ₂) _mC (O)-or-(CH ₂) _q-, wherein m is 1,2,3 or 4, q is 2,3 or 4;

E is C ₁₀To C ₂₀Alkyl or-C (O)-(C ₉To C ₁₉)-alkyl, wherein alkyl is straight chain or branching, saturated or comprise one or more pairs of keys;

R is hydrogen, C ₁-C ₁₅Alkyl, straight chain or branching, saturated or comprise one or more pairs of keys or B-(CH ₂) _r-, wherein r is 0,1,2 or 3;

R ¹, R ², R ³, R ¹', R ²' and R ³' independently be selected from hydrogen, low alkyl group, lower alkoxy, carboxyl, NO ₂, NH ₂, OH, halogen, low-grade alkyl amino, two elementary alkyl amido ,-NHC (O) OR ⁵, R ⁶(O) ₂SNH-and-S (O) ₂NH ₂

R ⁴For

Wherein n is 0,1,2 or 3;

R ⁵Be low alkyl group; And

R ⁶Be the phenyl of OH, low alkyl group, phenyl, benzyl or replacement, wherein substituting group is 1-3 and independently is selected from low alkyl group, lower alkoxy, carboxyl, NO ₂, NH ₂, OH, halogen, low-grade alkyl amino and two elementary alkyl amido group; Or its pharmacy acceptable salt, solvate or ester.

The sterol absorption inhibitor of formula (H)

In another embodiment, the used sterol absorption inhibitor of the compositions and methods of the invention is by with following formula (H):

Or its pharmacy acceptable salt, solvate or ester represent, wherein in following formula (H):

R ²⁶Be H or OG ¹

G and G ¹Independently be selected from

Its condition is at R ²⁶During for H or OH, G is not H;

R, R ^aAnd R ^bIndependently be selected from H ,-OH, halogen ,-NH ₂, azido-, (C ₁-C ₆) alkoxyl group (C ₁-C ₆)-alkoxyl group or-W-R ³⁰

W independently is selected from-NH-C (O)-,-O-C (O)-,-O-C (O)-N (R ³¹)-,-NH-C (O)-N (R ³¹)-and-O-C (S)-N (R ³¹)-;

R ²And R ⁶Independently be selected from H, (C ₁-C ₆) alkyl, aryl and aryl (C ₁-C ₆) alkyl;

R ³, R ⁴, R ⁵, R ⁷, R ^3aAnd R ^4aIndependently be selected from H, (C ₁-C ₆) alkyl, aryl (C ₁-C ₆) alkyl ,-C (O) (C ₁-C ₆) alkyl and-C (O) aryl;

R ³⁰Be selected from R ³²T, the R of-replacement ³²T-(the C of-replacement ₁-C ₆) alkyl, R ³²(the C of-replacement ₂-C ₄) thiazolinyl, R ³²(the C of-replacement ₁-C ₆) alkyl, R ³²(the C of-replacement ₃-C ₇) cycloalkyl and R ³²(the C of-replacement ₃-C ₇) cycloalkyl (C ₁-C ₆) alkyl;

R ³¹Be selected from H and (C ₁-C ₄) alkyl;

T is selected from phenyl, furyl, thienyl, pyrryl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl (iosthiazolyl), benzothiazolyl, thiadiazolyl group, pyrazolyl, imidazolyl and pyridyl;

R ³²Independently be selected from 1-3 and independently be selected from halogen, (C ₁-C ₄) alkyl, OH, phenoxy group ,-CF ₃,-NO ₂, (C ₁-C ₄) alkoxyl group, methylene-dioxy, oxo, (C ₁-C ₄) alkyl sulfenyl, (C ₁-C ₄) alkyl sulphinyl, (C ₁-C ₄) alkyl sulphonyl ,-N (CH ₃) ₂,-C (O)-NH (C ₁-C ₄) alkyl ,-C (O)-N ((C ₁-C ₄) alkyl) ₂,-C (O)-(C ₁-C ₄) alkyl ,-C (O)-(C ₁-C ₄) substituting group of alkoxyl group and pyrrolidyl carbonyl; Perhaps

R ³²Be covalent linkage, and R ³¹, its nitrogen and R of connecting ³²Form pyrrolidyl, piperidyl, N-methyl-piperazinyl, indolinyl or morpholinyl or (C ₁-C ₄) the alkoxy carbonyl pyrrolidyl, piperidyl, N-methyl-piperazinyl, indolinyl or the morpholinyl that replace;

Ar ¹Be aryl or R ¹⁰The aryl of-replacement;

Ar ²Be aryl or R ¹¹The aryl of-replacement;

And

R ¹Be selected from:

-(CH ₂) _e-E-(CH ₂) _r-, wherein E be-O-,-C (O)-, phenylene ,-NR ²²-or-S (O) _0-2-, e is 0-5, and r is 0-5, its condition is that e and r sum are 1-6;

-(C ₂-C ₆Alkenylene)-; With

R ¹²For:

R ¹³And R ¹⁴Independently be selected from-CH ₂-,-CH ((C ₁-C ₆) alkyl)-,-C ((C ₁-C ₆) alkyl) ₂-,-CH=CH-and-C ((C ₁-C ₆) alkyl)=CH-; Perhaps

R ¹²With adjacent R ¹³Together, perhaps R ¹²With adjacent R ¹⁴Together formation-CH=CH-or-CH=C (C ₁-C ₆Alkyl)-group;

A and b independently are 0,1,2 or 3, and its condition is not 0 for the two simultaneously;

Its condition is at R ¹³For-CH=CH-or-C (C ₁-C ₆Alkyl)=during CH-, a is 1;

Its condition is at R ¹⁴For-CH=CH-or-C (C ₁-C ₆Alkyl)=during CH-, b is 1;

Its condition is for being 2 or 3 o'clock at a, each R ¹³Can be identical or different; And

Its condition is for being 2 or 3 o'clock at b, each R ¹⁴Can be identical or different; And when Q is key, R ¹Also can for:

M is-O-,-S-,-S (O)-or-S (O) ₂-;

X, Y and Z independently are selected from-CH ₂-,-CH (C ₁-C ₆) alkyl-and-C ((C ₁-C ₆) alkyl) ₂

R ¹⁰And R ¹¹Independently be selected from 1-3 and independently be selected from (C ₁-C ₆) alkyl ,-OR ¹⁹,-OC (O) R ¹⁹,-OC (O) OR ²¹,-O (CH ₂) _1-5OR ¹⁹,-OC (O) NR ¹⁹R ²⁰,-NR ¹⁹R ²⁰,-NR ₁₉C (O) R ²⁰,-NR ¹⁹C (O) OR ²¹,-NR ¹⁹C (O) NR ²⁰R ²⁵,-NR ¹⁹S (O) ₂R ²¹,-C (O) OR ¹⁹,-C (O) NR ¹⁹R ²⁰,-C (O) R ¹⁹,-S (O) ₂NR ¹⁹R ²⁰, S (O) _0-2R ²¹,-O (CH ₂) _1-10-C (O) OR ¹⁹,-O (CH ₂) _1-10C (O) NR ¹⁹R ²⁰,-(C ₁-C ₆Alkylidene group)-C (O) OR ¹⁹,-CH=CH-C (O) OR ¹⁹,-CF ₃,-CN ,-NO ₂Substituting group with halogen;

R ¹⁵And R ¹⁷Independently be selected from-OR ¹⁹,-OC (O) R ¹⁹,-OC (O) OR ²¹With-OC (O) NR ¹⁹R ²⁰

R ¹⁶And R ¹⁸Independently be selected from H, (C ₁-C ₆) alkyl and aryl; Perhaps R ¹⁵And R ¹⁶Be jointly=O, perhaps R ¹⁷And R ¹⁸Be jointly=O;

D is 1,2 or 3;

H is 0,1,2,3 or 4;

S is 0 or 1; T is 0 or 1; M, n and p independently are 0-4;

Its condition is that at least one of s and t is 1, and m, n, p, s and t sum are 1-6;

Its condition for p be 0 and t be 1 o'clock, m, s and n sum are 1-5; And its condition for p be 0 and s be 1 o'clock, m, t and n sum are 1-5;

V is 0 or 1;

And at Q is key and R ¹For

The time, Ar ¹Also can be pyridyl, isoxazolyl, furyl, pyrryl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidyl or pyridazinyl;

R ¹⁹And R ²⁰Independently be selected from H, (C ₁-C ₆) (the C that replaces of alkyl, aryl and aryl ₁-C ₆) alkyl;

R ²¹Be (C ₁-C ₆) alkyl, aryl or R ²⁴The aryl of-replacement;

R ²²Be H, (C ₁-C ₆) alkyl, aryl (C ₁-C ₆) alkyl ,-C (O) R ¹⁹Or-C (O) OR ¹⁹

R ²³And R ²⁴Independently independently be selected from H, (C for 1-3 ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl group ,-C (O) OH, NO ₂,-NR ¹⁹R ²⁰The group of ,-OH and halogen; And

R ²⁵For H ,-OH or (C ₁-C ₆) alkoxyl group.

The method of preparation formula (H) compound is familiar with by those skilled in the art.The unrestricted example of appropriate methodology is disclosed in United States Patent (USP) 5,756,470, and described patent is attached to herein by reference.

The azetidinone of the replacement of formula (J)

In another embodiment, the azetidinone of the used replacement of the compositions and methods of the invention is by with following formula (J):

Or its pharmacy acceptable salt, solvate or ester represent, wherein in following formula (J):

R ¹Be selected from H, G, G ¹, G ²,-SO ₃H and-PO ₃H;

G be selected from H,

Wherein R, R ^aAnd R ^bIndependently be selected from respectively H ,-OH, halogen ,-NH ₂, azido-, (C ₁-C ₆) alkoxyl group (C ₁-C ₆) alkoxyl group or-W-R ³⁰

R ²And R ⁶Independently be selected from H, (C respectively ₁-C ₆) alkyl, ethanoyl, aryl and aryl (C ₁-C ₆) alkyl;

R ³, R ⁴, R ⁵, R ⁷, R ^3aAnd R ^4aIndependently be selected from H, (C respectively ₁-C ₆) alkyl, ethanoyl, aryl (C ₁-C ₆) alkyl ,-C (O) (C ₁-C ₆) alkyl and-C (O) aryl;

R ³⁰Independently be selected from R ³²T, the R of-replacement ³²T-(the C of-replacement ₁-C ₆) alkyl, R ³²(the C of-replacement ₂-C ₄) thiazolinyl, R ³²(the C of-replacement ₁-C ₆) alkyl, R ³²(the C of-replacement ₃-C ₇) cycloalkyl and R ³²(the C of-replacement ₃-C ₇) cycloalkyl (C ₁-C ₆) alkyl;

R ³¹Independently be selected from H and (C ₁-C ₄) alkyl;

T independently is selected from phenyl, furyl, thienyl, pyrryl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl group, pyrazolyl, imidazolyl and pyridyl;

R ³²Independently be selected from 1-3 and independently be selected from H, halogen, (C respectively ₁-C ₄) alkyl ,-OH, phenoxy group ,-CF ₃,-NO ₂, (C ₁-C ₄) alkoxyl group, methylene-dioxy, oxo, (C ₁-C ₄) alkyl sulfenyl, (C ₁-C ₄) alkyl sulphinyl, (C ₁-C ₄) alkyl sulphonyl ,-N (CH ₃) ₂,-C (O)-NH (C ₁-C ₄) alkyl ,-C (O)-N ((C ₁-C ₄) alkyl) ₂,-C (O)-(C ₁-C ₄) alkyl ,-C (O)-(C ₁-C ₄) substituting group of alkoxyl group and pyrrolidyl carbonyl; Perhaps

G ¹Represent by following structure:

R wherein ³³Independently be selected from unsubstituted alkyl, R ³⁴The alkyl, (R of-replacement ³⁵) (R ³⁶) alkyl-,

R ³⁴Be 1 to 3 substituting group, each R ³⁴Independently be selected from HO (O) C-, HO-, HS-, (CH ₃) S-, H ₂N-, (NH ₂) (NH) C (NH)-, (NH ₂) C (O)-and HO (O) CCH (NH ₃ ⁺) CH ₂SS-;

R ³⁵Independently be selected from H and NH ₂-;

R ³⁶Independently be selected from H, unsubstituted alkyl, R ³⁴Alkyl, unsubstituted cycloalkyl and the R of-replacement ³⁴The cycloalkyl of-replacement;

G ²Represent by following structure:

R wherein ³⁷And R ³⁸Independently be selected from (C respectively ₁-C ₆) alkyl and aryl;

R ²⁶Be 1 to 5 substituting group, each R ²⁶Independently be selected from:

a)H；

b)-OH；

c)-OCH ₃；

D) fluorine;

E) chlorine;

f)-O-G；

g)-O-G ¹；

h)-O-G ²；

I)-SO ₃H; With

j)-PO ₃H；

Its condition is at R ¹During for H, R ²⁶Be not H ,-OH ,-OCH ₃Or-O-G;

Ar ¹Be aryl, R ¹⁰Aryl, heteroaryl or the R of-replacement ¹⁰The heteroaryl of-replacement;

Ar ²Be aryl, R ¹¹Aryl, heteroaryl or the R of-replacement ¹¹The heteroaryl of-replacement;

L is selected from:

A) covalent linkage;

B)-(CH ₂) _q-, wherein q is 1-6;

C)-(CH ₂) _e-E-(CH ₂) _r-, wherein E be-O-,-C (O)-, phenylene ,-NR ²²-or-S (O) _0-2-, e is 0-5, and r is 0-5, its condition is that e and r sum are 1-6;

D)-(C ₂-C ₆) alkenylene-;

E)-(CH ₂) _f-V-(CH ₂) _g-, wherein V is C ₃-C ₆Cycloalkylidene, f are 1-5, and g is 0-5, and its condition is that f and g sum are 1-6; With

f)

Wherein M be-O-,-S-,-S (O)-or-S (O) ₂-;

X, Y and Z independently are selected from respectively-CH ₂-,-CH (C ₁-C ₆) alkyl-and-C ((C ₁-C ₆) alkyl) ₂-;

R ⁸Be selected from H and alkyl;

R ¹⁰And R ¹¹Independently be selected from 1-3 respectively and independently be selected from (C respectively ₁-C ₆) alkyl ,-OR ¹⁹,-OC (O) R ¹⁹,-OC (O) OR ²¹,-O (CH ₂) _1-5OR ¹⁹,-OC (O) NR ¹⁹R ²⁰,-NR ¹⁹R ²⁰,-NR ¹⁹C (O) R ²⁰,-NR ¹⁹C (O) OR ²¹,-NR ¹⁹C (O) NR ²⁰R ²⁵,-NR ¹⁹S (O) ₂R ²¹,-C (O) OR ¹⁹,-C (O) NR ¹⁹R ²⁰,-C (O) R ¹⁹,-S (O) ₂NR ¹⁹R ²⁰, S (O) _0-2R ²¹,-O (CH ₂) _1-10-C (O) OR ¹⁹,-O (CH ₂) _1-10C (O) NR ¹⁹R ²⁰,-(C ₁-C ₆Alkylidene group)-C (O) OR ¹⁹,-CH=CH-C (O) OR ¹⁹,-CF ₃,-CN ,-NO ₂Substituting group with halogen;

R ¹⁵And R ¹⁷Independently be selected from respectively-OR ¹⁹,-OC (O) R ¹⁹,-OC (O) OR ²¹,-OC (O) NR ¹⁹R ²⁰

R ¹⁶And R ¹⁸Independently be selected from H, (C respectively ₁-C ₆) alkyl and aryl; Perhaps

R ¹⁵And R ¹⁶Be jointly=O, perhaps R ¹⁷And R ¹⁸Be jointly=O;

D is 1,2 or 3;

H is 0,1,2,3 or 4;

S is 0 or 1;

T is 0 or 1;

M, n and p independently are selected from 0-4 respectively;

Its condition is that at least one of s and t is 1, and m, n, p, s and t sum are 1-6; Its condition for p be 0 and t be 1 o'clock, m, n and p sum are 1-5; And its condition for p be 0 and s be 1 o'clock, m, t and n sum are 1-5;

V is 0 or 1;

J and k are independent respectively to be 1-5, and its condition is that j, k and v sum are 1-5;

Q be key ,-(CH ₂) _q-, wherein q is 1-6, perhaps the 3-position ring carbon with azetidinone forms tap bolt

R wherein ¹²For

R ¹³And R ¹⁴Independently be selected from respectively-CH ₂-,-CH (C ₁-C ₆Alkyl)-,-C ((C ₁-C ₆) alkyl) ₂,-CH=CH-and-C (C ₁-C ₆Alkyl)=CH-; Perhaps R ¹²With adjacent R ¹³Together, perhaps R ¹²With adjacent R ¹⁴Together formation-CH=CH-or-CH=C (C ₁-C ₆Alkyl)-group;

A and b independently are respectively 0,1,2 or 3, and its condition is not 0 for the two simultaneously; Its condition is at R ¹³For-CH=CH-or-C (C ₁-C ₆Alkyl)=during CH-, a is 1; Its condition is at R ¹⁴For-CH=CH-or-C (C ₁-C ₆Alkyl)=during CH-, b is 1; Its condition is for being 2 or 3 o'clock at a, each R ¹³Can be identical or different; And its condition is for being 2 or 3 o'clock at b, each R ¹⁴Can be identical or different;

And at Q is that key and L are

R ¹⁹And R ²⁰Independently be selected from H, (C respectively ₁-C ₆) (the C that replaces of alkyl, aryl and aryl ₁-C ₆) alkyl;

R ²¹Be (C ₁-C ₆) alkyl, aryl or R ²⁴The aryl of-replacement;

R ²³And R ²⁴Independently be selected from 1-3 respectively and independently be selected from H, (C respectively ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl group ,-C (O) OH, NO ₂,-NR ¹⁹R ²⁰The substituting group of ,-OH and halogen; And

R ²⁵For H ,-OH or (C ₁-C ₆) alkoxyl group.

Be used for formula (J) examples for compounds of the inventive method and combination and prepare this compounds method therefor being disclosed in the u.s. patent application serial number of submitting on June 11st, 2,002 10/166,942, described application is attached to herein by reference.

The azetidinone of the replacement of formula (K)-(M)

The example of the azetidinone of used replacement is served as reasons with the compound of following formula (K) expression:

R wherein ¹As defined above.

Preferred compound is the compound by formula (L) expression:

Another kind of useful compound is represented by formula (M):

The azetidinone compounds of the replacement that other are useful comprises N-alkylsulfonyl-2-azetidinone, for example is disclosed in United States Patent (USP) 4,983,597; 4-(2-aza-oxo-cyclobutane-4-yl) phenoxy alkane acid ethyl ester for example is disclosed in people such as Ram, Indian J.Chem.Sect.B.29B, and 12 (1990), p.1134-7; Diphenylazetidinone and derivative, be disclosed in U.S. Patent Publication 2002/0039774,2002/0128252,2002/0128253 and 2002/0137689,2004/063929, WO 2002/066464, United States Patent (USP) 6,498,156 and 6,703,386, each patent is attached to herein by reference.

Other used sterol absorption inhibitors of the present composition, therapeutic combination and method are described in WO 2004/005247, WO 2004/000803, WO 2004/000804, WO2004/000805, WO 0250027, U.S. Patent Publication application 2002/0137689, and compound is described in L.

Deng the people, Angew.Chem.Int.Ed., 2004, vol.43, pp.4653-4656, all document is attached to herein by reference.

Example compound Deng the people is:

The compound of formula A-M can comprise that above discussion reaches for example WO 93/02048, U.S.5 by multiple currently known methods preparation, 306,817 and 5,561,227 methods of discussing, and described patent is attached to herein by reference, and it is described wherein-R ¹-Q-is the preparation of the compound of alkylidene group, alkenylene or the alkylidene group, phenylene or the cycloalkylidene that are interrupted by heteroatoms; WO 94/17038 and U.S.5,698,548 are attached to herein by reference, and describing wherein, Q is the preparation of the compound of volution base; WO 95/08532, U.S.5,631,365, U.S.5,767,115, U.S.5,846,966 and U.S.R.E.37,721 are attached to herein by reference, describe wherein-R ¹-Q-is the preparation of the compound of the alkylidene group that replaces of hydroxyl; PCT/US95/03196 is attached to herein by reference, describes wherein-R ¹-Q-is for passing through-O-or S (O) _0-2-group is connected to Ar ¹The compound of the alkylidene group that the hydroxyl of part replaces; The United States Patent (USP) sequence number 08/463,619 that submit to June 5 nineteen ninety-five is attached to herein by reference, describes wherein-R ¹-Q-is for passing through S (O) _0-2-group is connected to the preparation of the compound of the alkylidene group that the hydroxyl of azetidinone ring replaces.Each above patent and announcement are attached to herein in full by reference.

Give the experimenter sterol absorption inhibitor every day dosage can be for about 0.1 to about 1,000mg/ days, preferred about 0.25 to about 50mg/ day, more preferably from about 10mg/ days, single administration or 2-4 administration of branch.Yet exact dosage desired can determine by clinical attending doctor and according to effectiveness, patient's age, body weight, illness and the reaction of giving compound.

For the administration of the pharmacy acceptable salt of above compound, more than shown in weight be meant acid equivalent or alkali equivalent by salt deutero-treatment compound.

In another embodiment of the invention, above-mentioned composition or therapeutic combination comprise the selectivity CB of one or more formulas (I) ₁Receptor agonist compounds and one or more cholesteral biosynthesis inhibitors discussed below and/or lipopenicillinase combination of compounds.

Total per daily dose of general cholesteral biosynthesis inhibitor can be about 0.1 to about 160mg/ day, preferred about 0.2 to about 80mg/ day, and single administration or 2-3 administration of branch.

In another embodiment for choosing, composition of the present invention, therapeutic combination or method can comprise compound or its pharmacy acceptable salt, solvate or the ester of at least a formula (I), with with the compound of formula (I) or one or more bile acid chelating agents (insoluble anionite-exchange resin) of its pharmacy acceptable salt, solvate or ester co-administered or combination, and the azetidinone of replacement discussed above or the beta-lactam of replacement.

Bile acid chelating agent is in conjunction with the bile acide in the intestines, thus the enterohepatic circulation of interruption bile acide, and the drainage of increase steroid.Because the non-systemic fashion of its effect uses bile acid chelating agent to cater to the need.Bile acid chelating agent can reduce the liver inner cholesterol, and promotes the synthetic of apo B/E (LDL) acceptor, and this receptors bind is from the LDL of blood plasma, thereby further reduces the cholesterol level in the blood.

Total per daily dose of general bile acid chelating agent can be for about 1 to about 50 gram/skies, and preferably about 2 to about 16 gram/skies, single administration or 2-4 administration of branch.

In an embodiment for choosing, composition of the present invention or treatment can comprise compound or its pharmacy acceptable salt, solvate or ester and one or more ibat inhibitors of at least a formula (I).Ibat inhibitor can suppress bile acid transport, to reduce the LDL cholesterol amount.Total per daily dose of general ibat inhibitor can be about 0.01 to about 1000mg/ day, preferred about 0.1 to about 50mg/ day, and single administration or 2-4 administration of branch.

In another embodiment for choosing, composition of the present invention or treatment can comprise compound or its pharmacy acceptable salt, solvate or ester and nicotinic acid (nicotinic acid) and/or its derivative of at least a formula (I).Nicotinic acid and its derivative suppress liver and give birth to VLDL and metabolite LDL thereof, and increase HDL and apo A-1 amount.The example that is fit to the nicotinic acid product is (niacin slow-release tablet) is available from Kos.

Total per daily dose of general nicotinic acid or derivatives thereof can be for about 500 to about 10, and 000mg/ days, preferred about 1000 to about 8000mg/ days, more preferably from about 3000 to about 6000mg/ days, single administration or multiple dosing.

In another embodiment for choosing; composition of the present invention or treatment can comprise compound or its pharmacy acceptable salt, solvate or ester and one or more acyl-CoAs of at least a formula (I): cholesterol O-acyltransferase (" ACAT ") inhibitor, this inhibitor can reduce LDL and VLDL amount.ACAT is a kind of enzyme of being responsible for the esterification of excessive cell inner cholesterol, and it can be reduced to VLDL synthetic of cholesterol esterification product, and reduces the excessive generation of the lipoprotein that contains apo B-100.Total per daily dose of general AC AT inhibitor can be about 0.1 to about 1000mg/ day, single administration or 2-4 administration of branch.

In another embodiment for choosing, composition of the present invention or treatment can comprise compound or its pharmacy acceptable salt, solvate or ester and one or more cholesteryl ester transfer proteins (" CETP ") inhibitor of at least a formula (I).CETP is responsible for exchange or shifts cholesteryl ester, and cholesteryl ester carries HDL and the triglyceride level among the VLDL.Also can be with pancreas cholesterol ester hydrolase (pCEH) inhibitor common or combination medicine-feeding, as WAY-121898.

Total per daily dose of general CETP inhibitor can be about 0.01 to about 1000mg/ day, and preferred about 0.5 to about 20mg/kg body weight/day, single administration or multiple dosing.

In another embodiment for choosing, composition of the present invention or treatment can comprise compound or its pharmacy acceptable salt, solvate or the ester of at least a formula (I) and can reduce the probucol or derivatives thereof of LDL amount.

Total per daily dose of general probucol or derivatives thereof can be about 10 to about 2000mg/ days, preferred about 500 to about 1500mg/ days, and single administration or 2-4 administration of branch.

In another embodiment for choosing, composition of the present invention or treatment can comprise compound or its pharmacy acceptable salt, solvate or ester and low-density lipoprotein (LDL) receptor activator of at least a formula (I).

Total per daily dose of general ldl receptor activator can be about 1 to about 1000mg/ day, single administration or 2-4 administration of branch.

In another embodiment for choosing, composition of the present invention or treatment can comprise compound or its pharmacy acceptable salt, solvate or ester and the fish oil of at least a formula (I).Total per daily dose of general fish oil or omega-fatty acid can be for about 1 to about 30 gram/skies, single administration or 2-4 administration of branch.

In another embodiment for choosing, composition of the present invention or treatment can further comprise the compound of at least a formula (I) or its pharmacy acceptable salt, solvate or ester and water-soluble fiber that can the reducing cholesterol amount, as Psyllium, guar gum, oat and pectin.Total per daily dose of general water-soluble fiber can be for about 0.1 to about 10 gram/skies, single administration or divide 2-4 administration.

In another embodiment for choosing, composition of the present invention or treatment can comprise the fatty acid ester of the compound of at least a formula (I) or its pharmacy acceptable salt, solvate or ester and plant sterol, phytostanols and/or phytostanols that can the reducing cholesterol amount, as The sitostanol that uses in the oleomargarine.Total per daily dose of the fatty acid ester of general plant sterol, phytostanols and/or phytostanols can be for about 0.5 to about 20 gram/skies, single administration or 2-4 administration of branch.

In another embodiment for choosing, composition of the present invention or treatment can comprise compound or its pharmacy acceptable salt, solvate or ester and antioxidant such as probucol, tocopherol, xitix, β-Hu Luobusu and selenium or the VITAMIN such as the vitamins B of at least a formula (I) ₆Or vitamins B ₁₂Total per daily dose of general antioxidant or VITAMIN can be for about 0.05 to about 10 gram/skies, single administration or 2-4 administration of branch.

In another embodiment for choosing, composition of the present invention or treatment can comprise compound or its pharmacy acceptable salt, solvate or ester and monocyte and scavenger cell inhibitor (as polyunsaturated fatty acid (PUFA)), Triiodothyronine (comprising thyroxine analogues, as CGS-26214 (having the thyroxine compounds of fluoridizing ring)), the gene therapy of at least a formula (I) and use recombinant protein (as reorganization apoE).Total per daily dose of general these medicaments can be about 0.01 to about 1000mg/ day, single administration or 2-4 administration of branch.

The present invention also can utilize composition or the therapeutic combination that further comprises hormone replacement medicament and composition.Hormone agents that hormone replacement therapy of the present invention is used and composition comprise male sex hormone, oestrogenic hormon, Progesterone, its pharmacy acceptable salt and derivative.Also can use the combination of these medicaments and composition.

The dosage of male sex hormone and oestrogenic hormon combination cater to the need into about 1mg to about 4mg male sex hormone and about 1mg about 3mg oestrogenic hormon extremely.Example includes but not limited to male sex hormone and oestrogenic hormon combination, for example oestrogenic hormon of esterification (oestrone sodium sulfate and equilin sodium sulfate) and Synrotabs (17-hydroxyl-17-methyl-, (17B)-androstane-4-alkene-3-ketone) (with trade(brand)name Estratest available from SolvayPharmaceuticals, Inc., Marietta, combination GA).

The dosage of oestrogenic hormon and oestrogenic hormon combination can be about 0.01mg to 8mg, and about 0.3mg that caters to the need is to about 3.0mg.The example of used oestrogenic hormon and oestrogenic hormon combination comprises:

(a) mixture of nine kinds of synthetic estrogen substances, comprise oestrone sodium sulfate, equilin sodium sulfate, 17 α-dihydroequilin sodium sulfate, 17 alpha-estradiol sodium sulfate, 17 β-dihydroequilin sodium sulfate, 17 'alpha '-dihydroequilenin sodium sulfate, 17 β-dihydroequilenin sodium sulfate, equilenin sodium sulfate and 17 beta estradiol sodium sulfate, from Duramed Pharmaceuticals, Inc., Cincinnati, OH buys with trade(brand)name Cenestin;

(b) ethinylestradiol (19-removes first-17 α-pregnant-1,3,5 (10)-triolefins-20-alkynes-3, the 17-glycol, from Schering Plough Corporation, Kenilworth, NJ buys with trade(brand)name Estinyl;

(c) oestrogenic hormon of esterification combination, as oestrone sodium sulfate and equilin sodium sulfate, from Solvay with trade(brand)name Estratab with from Monarch Pharmaceuticals, Bristol, TN buys with trade(brand)name Menest;

(d) Piperazine Estrone Sulfate (Piperazine Sulfate female steroid-1,3,5 (10)-triolefins-17-ketone, 3-(sulphur oxygen base)-oestrone) is from Pharmacia ﹠amp; Upjohn, Peapack, NJ be with trade(brand)name Ogen with from WomenFirst Health Care, Inc., and San Diego, CA buys with trade(brand)name Ortho-Est; With

(e) conjugated estrogen hormone (17 α-dihydroequilin, 17 alpha-estradiols and 17 β-dihydroequilin), from Wyeth-Ayerst Pharmaceuticals, Philadelphia, PA buys with trade(brand)name Premarin.

Progesterone and oestrogenic hormon also can multiple dosed administrations, be generally about 0.05 to about 2.0mg Progesterone and about 0.001mg to about 2mg oestrogenic hormon, about 0.1mg that caters to the need is about 1mg Progesterone and about 0.01mg about 0.5mg oestrogenic hormon extremely extremely.Can change the Progesterone of dosage and scheme and the example of oestrogenic hormon combination comprises:

(a) combination of estradiol (female steroid-1,3,5 (10)-triolefins-3,17-isoallopregnane-3 semihydrate) and Norethisterone (17 β-acetoxyl group-19-removes first-17 α-pregnant steroid-4-alkene-20-alkynes-3-ketone) is from Pharmacia ﹠amp; Upjohn, Peapack, NJ, Activella buys with trade(brand)name;

(b) combination of Levonorgestrel (d (-)-13 β-ethyl-17 α-ethynyl-17 beta-hydroxies-18-methyl female steroid-4-alkene-3-ketone) and ethinylestradiol (ethinyl estradial), from Wyeth-Ayerst with trade(brand)name Alesse, from Watson Laboratories, Inc., Corona, CA is with trade(brand)name Levora and Trivora, buy with trade(brand)name Triphasil with trade(brand)name Nordette with from Wyeth-Ayerst from Monarch Pharmaceuticals;

(c) combination of ethynodiol diacetate (19-removes first-17 α-pregnant steroid-4-alkene-20-alkynes-3 β, 17-glycol diacetate) and ethinylestradiol is from G.D.Searle ﹠amp; Co., Chicago, IL buys with trade(brand)name Zovia with trade(brand)name Demulen with from Watson;

(d) desogestrel (13-ethyl-11-methylene radical-18,19-two removes first-17 α-pregnant steroid-4-alkene-20-alkynes-17-alcohol) and the combination of ethinylestradiol, from Organon with trade(brand)name Desogen and Mircette with from Ortho-McNeil Pharmaceutical, Raritan, NJ buys with trade(brand)name Ortho-Cept;

(e) combination of Norethisterone and ethinylestradiol, from Parke-Davis, Morris Plains, NJ with trade(brand)name Estrostep and FemHRT, from Watson with trade(brand)name Microgestin, Necon and Tri-Norinyl, from Ortho-McNeil with trade(brand)name Modicon and Ortho-Novum with from Warner Chilcott Laboratories, Rockaway, NJ buys with trade(brand)name Ovcon;

(f) promise ethisterone ((±)-13-ethyl-17-hydroxyl-18,19-two removes first-17 α-pregnant steroid-4-alkene-20-alkynes-3-ketone) and the combination of ethinylestradiol, buy with trade(brand)name Ogestrel and Low-Ogestrel with trade(brand)name Ovral and Lo/Ovral with from Watson from Wyeth-Ayerst;

(g) combination of Norethisterone, ethinylestradiol and mestranol (3-methoxyl group-19-removes first-17 α-pregnant steroid-1,3,5 (10)-triolefins-20-alkynes-17-alcohol) is buied with trade(brand)name Brevicon and Norinyl from Watson;

(h) 17 beta estradiols (female steroid-1,3,5 (10)-triolefins-3,17-isoallopregnane-3) and micronization norgestimate (17 α-17-(ethanoyl oxygen base)-13-ethyl-18,19-two norpregnas-4-alkene-20-alkynes-3-ketone 3-oxime) combination is buied with trade(brand)name Ortho-Prefest from Ortho-McNeil;

(i) norgestimate (18; 19-two removes the pregnant steroid of first-17--4-alkene-20-alkynes-3-ketone, 17-(ethanoyl oxygen base)-13-ethyl-oxime, the combination of (17 (α)-(+)-) and ethinylestradiol; from Ortho-McNeil buy with trade(brand)name Ortho Cyclen and Ortho Tri-Cyclen and

(j) conjugated estrogen hormone (oestrone sodium sulfate and equilin sodium sulfate) and medroxyprogesterone acetate (20-diketone; 17-(ethanoyl oxygen base)-6-methyl-; (6 (α))-pregnant steroid-4-alkene-3) combination is buied with trade(brand)name Premphase and Prempro from Wyeth-Ayerst.

Usually, if with the Progesterone administration of micron size, then the dosage of Progesterone is about .05mg about 10mg or up to about 200mg extremely.The example of Progesterone comprises Norethisterone, from ESI Lederle, and Inc., Philadelphia, PA buys with trade(brand)name Aygestin, buys with trade(brand)name Micronor from Ortho-McNeil, buys with trade(brand)name Nor-QD from Watson; The promise ethisterone is buied with trade(brand)name Ovrette from Wyeth-Ayerst; Micronization Progesterone (pregnant steroid-4-alkene-3,20-diketone) is buied with trade(brand)name Prometrium from Solvay; And medroxyprogesterone acetate, from Pharmacia ﹠amp; Upjohn buys with trade(brand)name Provera.

In another embodiment for choosing, composition of the present invention, therapeutic combination or method can comprise compound or its pharmacy acceptable salt, solvate or ester and one or more obesity control medicines of at least a formula (I).Used obesity control medicine includes but not limited to reduce that energy intake is gone into or the medicine of depress appetite, increase the medicine and the nutrient distribution agent of energy expenditure.The obesity control medicine that is fit to includes but not limited to norepinephrine energy medicament (as Diethylpropion, Mazindol, Phenylpropanolamine, phentermine, phendimetrazine, phendamine tartrate, methyl amphetamine, phendimetrazine and tartrate); Serotonin energy medicament (as sibutramine, Phenfluoramine, dexfenfluramine, fluoxetine, fluvoxamine and paroxetine); Thermogenic agent (as ephedrine, caffeine, theophylline and selectivity β 3-2-adrenergic agonist components); The alpha block agent; Kainite or ampa receptor antagonist; Leptin-steatolysis costimulatory receptor; Phosphodiesterase inhibitor; Compound with nucleotide sequence of mahogany gene; Fibroblast growth factor-10 polypeptide; Oxidase inhibitor (as befloxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol, Toloxatone, pirlindole, amiflamine, sercloremine, bazinaprine, lazabemide, milacemide and caroxazone); Improve the compound (for example evodiamine compound) of lipid metabolism; And lipase inhibitor (as orlistat).The total dose of general above-mentioned obesity control medicine can be 1 to 3, and 000mg/ days, it was about 1 to 1 to cater to the need, and 000mg/ days, more caters to the need single administration or divide 2-4 administration about 1 to 200mg/ day.

Composition of the present invention, therapeutic combination or method can comprise compound or its pharmacy acceptable salt, solvate or the ester of at least a formula (I), with with the azetidinone of replacement discussed above and the 'beta '-lactam compounds of replacement (as above Compound I I-XIII) and lipid conditioning agent at one or more chemically different Hemoregulatories, for example, they comprise the one or more atoms different with sterol absorption inhibitor discussed above or lipid conditioning agent, have different atomic arrangement or different one or more atomicities.Used Hemoregulatory includes but not limited to anti-coagulant (argatroban, Bivalirudin, dalteparin sodium, desirudin, temparin, lyapolate sodium, nafamostat mesilate, phenprocoumon, Tinzaparin sodium, Warnerin); Antithrombotic agent (anagrelide hydrochloride, Bivalirudin, Cilostazole, dalteparin sodium, Danaparoid sodium, dazoxiben hydrochloride, efegatran sulfate, Enoxaparin Sodium, fluretofen, Ifetroban, ifetroban sodium, Lamifiban, hydrochloric acid lotrafiban, Napsagatran, orbofiban acetate, acetic acid roxifiban, SIBRAFIBAN, Tinzaparin sodium, trifenagrel, ReoPro, zolimomab aritox); Fibrinogen deceptor antagonists (acetic acid roxifiban, Fradafiban, Orbofiban, hydrochloric acid lotrafiban, Tirofiban, Xemilofiban, monoclonal antibody 7E3, SIBRAFIBAN); Platelet suppressant drug (Cilostazole, SR-25990C, prostaglin X, U-53217A, ticlopidine hydrochloride, acetylsalicylic acid, ibuprofen, naprosine, sulindae, idomethacin, mefenamate, Droxicam, diclofenac, sulfinpyrazone, piroxicam, Dipyridamole); Anticoagulant (Acadesine, Beraprost, beraprost sodium, U 61431F, U 53059, lifarizine, hydrochloric acid lotrafiban, orbofiban acetate, oxagrelate, Fradafiban, Orbofiban, Tirofiban, Xemilofiban); Hemorheology agent (pentoxifylline); The blood clotting inhibitor that lipoprotein is relevant; Factor VIIa inhibitors (4H-31-benzoxazine-4-ketone, 4H-3,1-benzoxazine-4-thioketones, quinazoline-4-one, quinazoline-4-thioketones, benzothiazine-4-ketone, imidazolyl-boric acid deutero-peptide analogs TFPI-deutero-peptide, naphthalene-2-sulfonic acid 1-[3-(amino imino methyl)-benzyl]-2-oxo-tetramethyleneimine-3-(S)-yl } the acid amides trifluoroacetate, diphenylene-oxide-2-sulfonic acid 1-[3-(amino methyl)-benzyl]-5-oxo-tetramethyleneimine-3-yl } acid amides, toluene-4-sulfonic acid 1-[3-(amino imino methyl)-benzyl]-2-oxo-tetramethyleneimine-3-(S)-yl }-the acid amides trifluoroacetate, 3,4-dihydro-1H-isoquinoline 99.9-2-sulfonic acid 1-{3-(amino imino methyl)-benzyl]-2-oxo-pyrroline-3-(S)-yl }-the acid amides trifluoroacetate); Factor Xa inhibitor (disubstituted pyrazol quinoline, dibasic triazoline, the n-[(amino imino methyl that replaces) phenyl] propionic acid amide, the n-[(amino methyl that replaces) phenyl] propionic acid amide, tissue factor approach restrainer (TFPI), low molecular weight heparin, heparitin, benzimidazoline benzoxazolinone, benzo piperazine ketone, indone, divalence (dibasic) (amidino groups aryl) propanoic derivatives, the amidino groups Phenylpyrrolidine, amidino groups phenylpyrrole quinoline, amidino groups phenyl-isoxazole azoles alkane, the amidino groups indoles, the amidino groups azoles, two aryl sulphonyl amino yl-benzamide derivatives, peptide factor Xa inhibitor).

Composition of the present invention, therapeutic combination or method can comprise compound or its pharmacy acceptable salt, solvate or the ester of at least a formula (I), with with the azetidinone of replacement discussed above and the 'beta '-lactam compounds of replacement (as above Compound I I-XIII) and lipid conditioning agent at one or more chemically different cardiovascalar agents, for example, they comprise the one or more atoms different with sterol absorption inhibitor discussed above or PPAR receptor activator, have different atomic arrangement or different one or more atomicities.Used cardiovascalar agent includes but not limited to calcium channel blocker (toxilic acid clentiazem

Amlodipine besylate, Isrodipine, nimodipine, felodipine, nilvadipine, nifedipine, teludipine hydrochloride, diltiazem hydrochloride

, Belfosdil, verapamil hydrochloride, fostedil); Adrenergic blocking drug (fenspiride hydrochloride, labetalol hydrochloride, proroxan, alfuzosin hydrochloride, acebutolol, Acebutolol, alprenolol hydrochloride, atenolol USP 23, Bunolol Hydrochloride, carteolol hydrochloride, Celiprolol Hydrochorid, cetamolol hydrochloride, the hydrochloric acid cicloprolol, dexpropranolol hydrochloride, diacetolol hydrochloride, dilevalol hydrochloride, esmolol hydrochloride, exaprolol hydrochloride, flestolol sulfate, labetalol hydrochloride, hydrochloric acid left side Beta Luo Er, Levobunolol Hydrochorid, metalol hydrochloride, metoprolol, metoprolol tartrate, nadolol, pamatolol sulfate, penbutolol sulfate, practolol, propranolol hydrochloride, Sotalol hydrochloride, timolol, timolol maleate, tiprenolol hydrochloride, tolamolol, bisoprolol, the bisoprolol fumarate, nebivolol); Adrenergic agonists; Angiotensin-converting enzyme (ACE) inhibitor (benazepril hydrochloride, benazeprilat, captopril, delapril hydrochloride, fosinopril sodium, Libenzapril, SPM-925, pentopril, perindopril, quinapril hydrochloride, quinaprilat, Ramipril, spirapril hydrochloride, spiraprilic acid, teprotide, enalapril maleate, lisinopril, zofenopril calcium, perindopril tert-butylamine salt); Antihypertensive agents (Altizide, benzthiazide, captopril, CARVEDILOL, chlorothiazide sodium, Tenso-Timelets, cyclothiazide, delapril hydrochloride, dilevalol hydrochloride, doxazosin mesylate, fosinopril sodium, Guanfacine Hydrochloride, methyldopa, metroprolol succinate, SPM-925, monatepil maleate, pelanserin hydrochloride, phenoxybenzamine hydrochloride, PRAZOSINI HYDROCHLORIDE, primidolol, quinapril hydrochloride, quinaprilat, Ramipril, Vasocard, Candesartan, candesartan cilexetil, telmisartan, amlodipine besylate, amlodipine maleate, bevantolol hydrochloride); Angiotensin II receptor antagonists (Candesartan, irbesartan, the husky smooth potassium of fluorine, candesartan cilexetil, telmisartan); Antianginal agent (amlodipine besylate, amlodipine maleate, betaxolol hydrochloride, bevantolol hydrochloride, butoprozine hydrochloride, CARVEDILOL, cinepazic acid ethyl ester maleate, metroprolol succinate, molsidomine, monatepil maleate, primidolol, ranolazine hydrochloride, tosifen, verapamil hydrochloride); Coronary vasodilator (fostedil, azaclorzine hydrochloride, Cassella-Riedel), clonitrate, diltiazem hydrochloride

, Dipyridamole, Droprenilamine, erythrol tetranitrate, sorbide nitrate, isosorbide mononitrate, lidoflazine, mioflazine hydrochloride, mixidine, molsidomine, Nicoril, nifedipine, nisoldipine, pannonit, oxprenolol hydrochloride, pentrinitrol, perhexiline maleate, prenylamine, propatylnitrate, terodiline hydrochloride, tolamolol, verapamil); Diuretic(s) (combination product of the combination product of hydrochlorothiazide and spironolactone and hydrochlorothiazide and triamterene).

Composition of the present invention, therapeutic combination or method can comprise the compound of at least a formula (I) or the antidiabetic drug of its pharmacy acceptable salt, solvate or ester and one or more reduction blood glucose level in humans.Used antidiabetic drug includes but not limited to reduce that energy intake is gone into or the medicine of depress appetite, increase the medicine and the nutrient distribution agent of energy expenditure.The antidiabetic drug that is fit to includes but not limited to that sulfonylurea is (as acetohexamide, P-607, gliamilide, gliclazide, glimepiride, Glipizide, Glyburide (glyburide), Glyburide (glibenclamide), tolazamide and tolbutamide), meglitinide (as repaglinide and nateglinide), biguanides (as N1,N1-Dimethylbiguanide and buformin), alpha-glucosidase inhibitor is (as acarbose, miglitol, Camiglibose and voglibose), some peptide is (as amlinitide, tripro-amylin, the exciting peptide of exendin and GLP-1) and oral insulin or its intestines pass the analgesic composition of medicine.The total dose of general above-mentioned antidiabetic drug can be 0.1 to 1,000mg/ days, and single administration or 2-4 administration of branch.

Can in composition of the present invention and therapeutic combination, use the mixture of two kinds, three kinds, four kinds or more kinds of any above-mentioned pharmacological agent or therapeutical agent.

Since the present invention relates to by with activeconstituents combined therapy illness discussed above, therefore wherein activeconstituents can be individually dosed, the present invention also relates to kit form independent pharmaceutical composition.In other words, the present invention imagines a kind of test kit, wherein makes up two kinds of independent units: the selectivity CB that comprises at least a formula (I) ₁The pharmaceutical composition of receptor antagonist or its pharmacy acceptable salt, solvate or ester and comprise the drug alone composition of at least a above-mentioned decreasing cholesterol compound.Test kit preferably comprises the explanation of independent component administration.When independent component must be with different dosage form administration (for example, oral with parenteral) or with different medication interval administration, the kit form particularly advantageous.

In another embodiment, the invention provides a kind of treatment, alleviate or improve the metabolism syndrome that is selected from that needs the patient is arranged, obesity, waistline, fat distributes, insulin sensitivity, the neuritis sexual disorder, cognitive disorder, psychosis, the addiction behavior, gastrointestinal dysfunction, cardiovascular disorder, hyperlipidaemia, arteriosclerosis, hypercholesterolemia, sitosterolemia, vascular inflammation, apoplexy, the disease of diabetes and cardiovascular disorder or illness and/or reduction have the method for the sterol levels that needs the patient, and described method comprises compound or its pharmacy acceptable salt of at least a formula (I) that gives described patient's significant quantity, solvate or ester and one or more decreasing cholesterol compounds.

Comprise the compound of at least a formula (I) and the therapeutic composition and the therapeutic combination of at least a cholesterol-lowering agent and can suppress the absorption of cholesterol in mammal intestine, can be used for treating and/or preventing the illness of for example vascular disorder (for example arteriosclerosis, hypercholesterolemia and sitosterolemia), apoplexy, obesity and reduce the blood plasma cholesterol level of Mammals (especially Mammals).

In another embodiment of the invention, composition of the present invention and therapeutic combination can suppress sterol or 5 α-stanols and absorb or reduce at least a sterol plasma concentration that is selected from plant sterol (as Sitosterol, campesterol, Stigmasterol and avenasterol) and/or 5 α-stanols (as Dihydrocholesterol, 5 α-campestanol, 5 α-sitostanol), cholesterol and composition thereof.Mammals significant quantity by needing this treatment comprise at least a selectivity CB ₁(for example, above-mentioned sterol absorption inhibitor) at least a therapeutic composition or therapeutic combination can reduce its plasma concentration for receptor antagonist and at least a decreasing cholesterol compound.The plasma concentration of sterol or 5 α-stanols can reduce about 1 to about 70%, preferred about 10 to about 50%.The method of the total blood cholesterol of serum and total LDL cholesterol of measuring is familiar with by those skilled in the art, for example comprises PCT WO 99/38498 the 11st page of disclosed method, and described patent is attached to herein by reference.The method of measuring other sterol levels in the serum is disclosed in people such as H.Gylling, " Serum Sterols During Stanol Ester Feeding in a MildlyHypercholesterolemic Population ", J.Lipid Res.40:593-600 (1999), described document is attached to herein by reference.

Treatment of the present invention also can reduce the size of patch in the vasa vasorum or reduce its existence.The patch volume can be measured in the mode that those skilled in the art are afamiliar with (IVUS), and wherein ultrasonic probe that will be small inserts artery, with direct to the arteriosclerosis plaque imaging and measure the size of patch.

Abbreviation below in following scheme and test and specification sheets and claims, using:

The rt room temperature

The THF tetrahydrofuran (THF)

Et ₂The O ether

The Me methyl

The Et ethyl

The Bu butyl

The Bn benzyl

The Pr propyl group

The i-Pr sec.-propyl

The Ac ethanoyl

The EtOAc ethyl acetate

BnOCH ₂Cl benzyl chloride methyl ether

The BuLi butyllithium

The DBAD tert-butyl azodicarboxylate

DBU 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene

DCE 1, the 2-ethylene dichloride

The DCM methylene dichloride

DMF N, dinethylformamide

The DMSO methyl-sulphoxide

HOBT or HOBt hydroxybenzotriazole

Two (trimethyl silyl) potassium amides of KHMDS

LiHMDS or LHMDS: two (trimethyl silyl) Lithamide

NaB (O ₂CCH ₃) ₃The H sodium triacetoxy borohydride

OTf fluoroform sulphonate or triflate (CF ₃SO ₂-O-)

PhSeBr bromination phenyl selenium

The load of PS polymkeric substance

The hydrochloric acid dimethylaminopropyl ethyl carbodiimide of PS-EDC polymkeric substance load

The Py pyridine

The isocyanic ester of PS-NCO polymkeric substance load

PS-Tris-NH ₂The triamine of polymkeric substance load

The TFA trifluoroacetic acid

Ti (OiPr) ₄Titanium isopropoxide

The TLC thin-layer chromatography

TMSI trimethyl silyl iodine or iodo trimethyl silane

HATU phosphofluoric acid O-(7-azepine benzo triazol-1-yl)-N, N, N ' N '-tetramethyl-

Urea

DIPEA N, the N-diisopropyl ethyl amine

Dppp 1, two (diphenylphosphino) propane of 3-

Dppf 1,1 '-two (diphenylphosphino) ferrocene

2-tertbutylimido-2-diethylamino-1 on the polystyrene, 3-two

PS-BEMP

Methyl-perhydro-1,3,2-diaza phosphorus heterocycle hexene

DMAP N, the N-dimethyl aminopyridine

EDCl hydrochloric acid N (3-dimethylaminopropyl)-N '-ethyl carbodiimide

The HPLC high performance liquid chromatography

PhMe toluene

MeOH methyl alcohol

EtOH ethanol

Trisyl Azide 2,4,6-three-isopropyl benzene alkylsulfonyl nitrine

The DEAD diethyl azodiformate

The NMP N-Methyl pyrrolidone

DMPU 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone

Dess-Martin reagent 1,1,1-three (acetoxyl group)-1,1-dihydro-1,2-benzenesulfonyl-3 (1H)-ketone

The BOM benzyloxymethyl

The Cbz benzyloxycarbonyl

The MOM methoxymethyl

The Tf trifyl

TIPS triisopropyl silyl

TBS or TBDMS: t-butyldimethylsilyl

Embodiment

Preparation two (mixing) aryl-isoindole-1-ketone

General flow A:

Diaryl-the isoindole of formula (I)-1-ketone, two heteroaryls-isoindole-1-ketone and aryl-heteroaryl-isoindole-1-ketone can prepare by several different methods, for example, make the unsaturated amine condensation of diolefinic acid that aryl or heteroaryl replace or acyl chlorides and aryl or heteroaryl replacement, to form the triolefin acid amides, perhaps make diaryl, diolefinic acid or acyl chlorides and unsaturated amine condensation that two heteroaryls or aryl-heteroaryl replaces, make the triolefin acid amides cyclisation that obtains by intramolecularly Diels-Alder reaction then, to generate two (mixing) aryl-tetrahydrochysene-isoindole-1-ketone, further modification as required (for example, by reduction or alkylation etc.).

Can make aldehyde a and crot(on)yl phosphonate reaction,, after saponification,, obtain acyl chlorides c with the oxalyl chloride reaction so that ester b to be provided.Aryl or heteroaryl bromine or iodine or chlorine or O-triflate d and propargyl amine carry out Sonagashira coupling [people such as K.Sonogashira, Tet, Lett., 4467, (1975)] obtain alkynylamine e, become allyl amine f with hydrogen reduction with the Lindlar catalyzer again.Allyl amine f and acyl chlorides c coupling provide acid amides g.Make acid amides g through the Diels-Alder reaction conditions, use DBU (promptly 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene) processing then, so that cyclisation product h and i to be provided.Two key reduction obtain j and k.

Unless clearly indicate in addition, when compound below any by chromatography purification in the preparation or mixture, described chromatography is the conventional flash chromatography that utilizes the silica stationary phase.

Preparation compound 1-4

Step 1

Scheme 1:

The suspensoid of 60%NaH adds 4-phosphono Ba Dousuan triethyl (100g) in mineral oil (16g) in 1L THF.With gained solution stirring 2 hours, add the solution of 2,4 dichloro benzene formaldehyde (54g) in 200mL THF subsequently again.In stirring at room mixture 1 hour.By adding the moisture NH of 1L ₄Cl makes the reaction quencher, and makes the THF evaporation.Mixture 4x200ml ethyl acetate extraction, the organic layer water of merging, salt water washing are through MgSO ₄Drying, evaporation provides crude product then.Crude product utilizes 5% ethyl acetate-hexane by the silica gel column chromatography purifying, obtains 25.9g 5-(2,4 dichloro benzene base)-penta-2,4-diolefinic acid ethyl ester.MS：m/e 271.04(MH ⁺)

Step 2

Scheme 2:

To 5-(2,4 dichloro benzene base)-penta-2,4-diolefinic acid ethyl ester (25.5g) adds KOH (16g) at 100mL H at the solution of MeOH and THF difference 100mL ₂Solution among the O, with mixture stirring at room 2 hours.With mixture 300mL H ₂The O dilution with 1N HCl acidifying, and with sedimentary product separation, provides 23.3g acid.To the acid that is in room temperature (19.5g) at 400mLCH ₂Cl ₂In suspensoid add (COCl) ₂(20.7mL), add DMF (190 μ L) subsequently, with mixture stirring at room 3 hours.The settled solution that obtains is concentrated, so that 5-(2,4 dichloro benzene base)-penta-2,4-diene acyl chlorides to be provided.

NMR(300MHz，CDCl ₃)7.60(ddd，J＝15.0，11.2，0.8Hz，1H)，7.54(d，J＝8.4Hz，1H)，7.42-7.38(m，2H)，7.25-7.21(m，1H)，6.85(ddd，J＝15.4，11.2，0.8Hz)，6.20(d，J＝14.8Hz).

Step 3

Scheme 3:

In room temperature to 4-chlorine phenyl-iodide (25g) at 400mL CH ₂Cl ₂In solution add propargyl amine (13.5mL), diisopropylamine (37mL), CuI (4g) and Pd (PPh ₃) ₂Cl ₂(3.7g).In room temperature the mixture stirring is spent the night,, filter by the CELITE pad, to remove insoluble substance with 600mL EtOAc dilution.With solution with water, salt water washing, through MgSO ₄Drying concentrates, and by chromatography purification, provides 14.1g 3-(4-chloro-phenyl-)-Propargyl amine.

MS：m/e 166.1(MH ⁺)

Step 4

Scheme 4:

To 3-(4-chloro-phenyl-)-Propargyl amine (14.0g) at MeOH and CH ₂Cl ₂Add Et in the solution of 200mL respectively ₃N (1.2mL) and Lindlar catalyzer (1.4g), with the gained suspensoid at H ₂Balloon stirs down.Carry out TLC (being thin-layer chromatography) following response with 6% methyl alcohol-methylene dichloride as elutriant,, filter, concentrate, and, provide 10.5g 3-(4-chloro-phenyl-)-allyl amine by chromatography purification by the CELITE pad in case finish.MS：m/e 168.6(MH ⁺)

Step 5

Scheme 5:

To the 5-(2,4 dichloro benzene base)-penta-2 that is in 0 ℃, 4-diene acyl chlorides (62.5mmol) is at 300mL CH ₂Cl ₂In solution add Et ₃N (13.0mL) adds DMAP (being 4-diamino picoline) (760mg) subsequently.Add 3-(4-chloro-phenyl-)-allyl amine (10.5g) at 30mL CH to this ₂Cl ₂Solution.Stirred the mixture 1 hour at 0 ℃.Add 2mL MeOH then, and stirred solution 10 minutes.Then solution is used moisture NaHCO ₃Dilute, and extract with EtOAc.Cross filter solid and concentrate the EtOAc layer, provide to merge output 24.6g 5-(2,4 dichloro benzene base)-penta-2,4-diolefinic acid [3-(4-chloro-phenyl-)-allyl group] acid amides.MS：m/e 392.2(MH ⁺)

Step 6

Scheme 6:

With 5-(2,4 dichloro benzene base)-penta-2,4-diolefinic acid [3-(4-chloro-phenyl-)-allyl group] acid amides (13.6g) was at 1: 9 MeOH-CH ₂Cl ₂In solution filter by the aluminum oxide pad, and concentrate.This solid is absorbed in the 300mL toluene, and 185 ℃ of heating 10 hours.It is concentrated, and with DBU (promptly 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene) (1g) at 200mLCH ₂Cl ₂The middle stirring 1 hour.Mixture is concentrated,, provide the mixture of 8.5g cyclisation product 1 and 2 with 75: 25 ethyl acetate-hexane chromatographies.Also from these the reaction separated product 3 and 4.

Those skilled in the art also will be appreciated that, during compound among any preparation methods described herein from the racemize feedstock production, for example in the preparation of above-claimed cpd 1 and 2, products therefrom (for example compound 1 and 2) also is the racemic mixture of enantiomer.For example, should be appreciated that compound 1:

The racemic mixture of representing following enantiomer:

Those skilled in the art also it should be understood that and the racemic mixture from the product of racemize feedstock production can be separated into independent enantiomer, for example by the chiral layers analysis method.Perhaps, available chiral raw material prepares concrete enantiomer by the chirality synthetic method.

Structure described herein is intended to represent relative stereochemistry, promptly, both represented racemic mixture, also represent independent enantiomer, rather than absolute stereo chemistry, unless clearly indicate, described structure (is for example only represented racemic mixture, by described structure is marked as " racemic mixture ", " D/L " or "+/-"), perhaps described structure represent to have specify the absolute stereo chemistry single enantiomer (for example, with the described structure of " absolute stereo chemistry " clear and definite mark, perhaps with " R " or " S " name label chiral centre of knowing the Cahn-Ingold-Prelog system).

Preparation compound 5 and 6

Scheme 7:

Above 1 and 2 mixture is absorbed among the 200mL EtOAc, at H ₂Following and the 800mg PtO of balloon ₂H ₂O stirred 1.5 hours.Then mixture is filtered and concentrates by the CELITE pad.With solution absorption at minimum CH ₂Cl ₂In, use Et ₂Precipitated solid is filtered in the O dilution, obtains 1.93g 6.Filtrate is concentrated,, obtain 1.99g 5 by chromatography purification.

Chiral separation 5

Scheme 8:

With compound 5 (25-50mg) sonication 1 minute in about 1.5mL Virahol.Make solution left standstill after 30 minutes, adding about 2.5mL hexane, and mitigation stirs the mixture.After making mixture sedimentation minute, the decantation settled solution, and prepare on the HPLC post (5cmx50cm) being expelled to Chiralpac AD after the filtration, with 15% Virahol wash-out in the hexane, obtain the 5a and the 5b of equivalent substantially.Repeat this process, until each isomer that obtains aequum.Detect at 220nm, flow velocity is 100mL/min.

MS 5a：394.2(MH ⁺)

MS 5b：394.2(MH ⁺)

Preparation compound 7

Step 1

Scheme 9:

Add 1M LiAlH among the THF (30mL) to the solution of room temperature 3-(4-chloro-phenyl-)-Propargyl amine (2.5g) in 50mL THF ₄Solution, and mixture heating up refluxed 1 hour.Cool to room temperature adds 1.1mL H successively to it ₂O, 1.1mL 15% aqueous NaOH and 3.4mLH ₂O.With the precipitated solid elimination, filtrate is concentrated, and, obtain 1.45g3-(4-chloro-phenyl-)-allyl amine by chromatography purification.

NMR(400MHz，CDCl3)7.26-7.21(m，4H)，6.42(dt，J＝16.0，1.6Hz，1H)，6.29-6.22(m，1H)，3.44(dd，J＝5.6，1.6Hz，2H)

Step 2

Scheme 10:

To the 5-(2,4 dichloro benzene base)-penta-2 that is in 0 ℃, 4-diene acyl chlorides (7.6mmol) is at 30mLCH ₂Cl ₂In solution add Et ₃N (1.6mL), DMAP (47mg) adds 3-(4-chloro-phenyl-)-allyl amine (1.4g) subsequently at 10mL CH ₂Cl ₂In solution.Solution becomes thick slurry behind several minutes.Stirred 30 minutes at 0 ℃,, use H then stirring at room 30 minutes ₂The O dilution.Cross filter solid and use H ₂Et is used in the O washing subsequently ₂The O washing, dry in vacuum drying oven then, obtain 3.8g 5-(2,4 dichloro benzene base)-penta-2,4-diolefinic acid [3-(4-chloro-phenyl-)-allyl group] acid amides.MS：m/e 394.02(MH ⁺)

Step 3

Scheme 11:

With 5-(2,4 dichloro benzene base)-penta-2, the suspensoid of 4-diolefinic acid [3-(4-chloro-phenyl-)-allyl group] acid amides (3.8g) in 70mL toluene heated 6 hours in 185 ℃ of sealed tubes, and cool to room temperature also concentrates, and obtains 2.8g 7.MS：m/e 394.0(MH ⁺)

Preparation compound 8

Scheme 12:

To 7 (2.8g) at 1: 9 MeOH-CH of 70mL ₂Cl ₂Solution in add PtO ₂H ₂O (280mg) is at H ₂Under the balloon mixture was stirred 40 minutes.In suspensoid, add gac, then suspensoid is filtered by the CELITE pad, concentrate and from CH ₂Cl ₂/ hexane recrystallization obtains 1.4g 8.MS：m/e 394.03(MH ⁺)

Preparation compound 9-12

Scheme 13:

The available standards condition makes lactan 5 through the N-alkylation.For example, available NaH and allyl iodide make 5 through the N-alkylation, obtain 9.Make two key oxidisability fractures reduction or reductive amination subsequently, obtain respectively shown in scheme 12 11 and 12.

Preparation compound 13 and 14

Initial aldehyde a that compound 13 and 14 usefulness are fit to and iodide d are by the method preparation of option A.

Those of ordinary skill in the art it should be understood that the raw material that replaces by suitable selection heteroaryl, can independently replace the aryl moiety of the replacement of above isoindole-1-ketone with heteroaryl moieties.For example, available corresponding pyridine base aldehyde or pyridyl halo are for phenyl aldehyde and/or phenyl-iodide.

Preparation compound 15

Scheme 14

Add NaH (1.1 equivalents, 60% dispersion in mineral oil) to room temperature 5 (50mg) at the solution of 5mL DMF.Then with solution stirring 20 minutes.Add α-bromo-tolyl nitrile (75mg) and Bu to the solution that stirs ₄NI (5mg).Stir after 3 hours, add the part of other NaH (20mg), and with mixture in stirred overnight at room temperature.Then solution is diluted with EtOAc, water, 1N HCl, salt water washing are through MgSO ₄Drying is filtered, and concentrates.Crude product uses 10%MeOH at CH ₂Cl ₂In the mixture chromatography, obtain 40mg 15.MS：509.3(MH ⁺)

Preparation compound 16

Scheme 15

Add NaH (6mg, 60% dispersion in mineral oil) to room temperature 5 (50mg) at the solution of 5mL DMF.With solution stirring 20 minutes.Add 3 equivalent CH to the solution that stirs ₃I, and with mixture in stirred overnight at room temperature.The part that adds other NaH (20mg) then, and with mixture 50 ℃ the heating 1 day.Pour solution into EtOAc then, water, 1N HCl and salt water washing are through MgSO ₄Drying is filtered, and concentrates, and uses CH then ₂Cl ₂In 5%MeOH by chromatography purification, obtain 31mg 16.MS：406.2(MH ⁺)

-4 of preparation N-replacement, 5-phenylbenzene-isoindole

General flow B:

For example, by compound 17 respectively with methylsulfonyl chloride or the following compound 19 of cyclopropyl SULPHURYL CHLORIDE prepared in reaction and 20.

Preparation compound 21-36

Below for the EDCl that knows and HOBt coupling condition by the representation compound of isoindole 17 with the structure 18A of the carboxylic acid reaction preparation that is fit to.

Below be by the representation compound of isoindole 17 with the structure 18C of the isocyanate reaction preparation that is fit to.

Below be by the representation compound of isoindole 17 with the structure 18D of the chloro-formic ester prepared in reaction that is fit to.

Below for passing through isoindole 17 and the aldehydes or ketones that is fit to and sodium triacetoxy borohydride some representation compounds as the structure 18E of reductive agent prepared in reaction.

Those of ordinary skill in the art it should be understood that by the raw material that uses suitable heteroaryl to replace, and can independently replace the aryl moiety of the replacement of above isoindole with heteroaryl moieties.

Those of ordinary skill in the art it will also be appreciated that the isoindole that has different aryl and/or heteroaryl substitute mode on the six-ring by using suitable raw material, can being provided at.In addition, the replacement on the isoindole nitrogen-atoms can provide (for example alkylation, acidylate, arylation etc.) by methods known in the art.

Preparation two (mixing) aryl-isoindole-1-ylidene amines

Two (mixing) aryl-isoindole-1-ylidene amines can prepare by several different methods, for example makes isoindole-1-ketone change into corresponding amidine, revises amidine, for example acidylate subsequently again.

Preparation compound 37-39

Scheme 16:

Make lactan 5 change into amidine 37, amidine 37 can be used EDCl/HOBt and the carboxylic acid coupling that is fit to, thereby 37A is provided.

Step 1:

Add Tetrafluoroboric acid triethyl oxygen (2eq.) and yellow soda ash (2eq.) to 89mg 5 at the solution of about 3mL methylene dichloride, and under nitrogen, stirred the mixture 3 days.Reaction mixture is poured on pH 7 damping fluids, and with dichloromethane extraction three times.With the extraction liquid salt water washing that merges, use MgSO ₄Drying is filtered, and is evaporated to dried.To methyl alcohol (～resistates in 4mL) adds ammonium chloride (10eq.), and with mixture heating up to refluxing.After 24 hours, mixture is evaporated to dried, and at methylene dichloride and moisture K ₂CO ₃The middle distribution.Twice of dichloromethane extraction of water.With the organic phase salt water washing that merges, use MgSO ₄Drying is filtered, and is evaporated to dried.Obtain formate 37 by HPLC (C-18 post, water/acetonitrile w/0.1% formic acid wash-out) purifying.

MS：393.2(MH ⁺)

Preparation 38 and 39

20mg 37 (free alkali) in 0 ℃ of methylene dichloride (1.5mL) adds 4-cyanobenzoic acid (2eq.), HOBt (2eq.) and EDCl (2eq.), and stirs the mixture under nitrogen when slowly being warmed to room temperature.After 24 hours, mixture is poured on the aqueous carbonic acid hydrogen sodium, and with in the methylene dichloride～1% methanol extraction three times.With the extraction liquid MgSO that merges ₄Drying is filtered, and is evaporated to dried.By flash chromatography (0-50% ethyl acetate in the hexane) purifying, obtain 16mg 38.

Prepare compound 39 with conditions of similarity, difference is to replace the 4-cyanobenzoic acid with phenylformic acid.

MS 38：522.3(MH ⁺)

MS 39：497.3(MH ⁺)

Those of ordinary skill in the art will be appreciated that, isoindole-1-ketone raw material by suitable selection heteroaryl replacement, make isoindole-1-ketone change into isoindole-1-ylidene amines subsequently, as implied above, can independently replace the aryl moiety of the replacement of above isoindole-1-ylidene amines with heteroaryl moieties.In addition, by revising suitable isoindole-1-ketone raw material (for example, using 5,6-two (mixing) aryl-isoindole-1-ketone raw material, and do not use 4,5-two (mixing) aryl-isoindole-1-ketone), can obtain other substitute modes on the isoindole six-ring.

Preparation compound 40-43

Use EDCl and HOBt, under the condition that is similar to preparation compound 38 and 39, with cyclobutane formate or 4-methylvaleric acid coupling compound 37.Obtain above product (40-43).

Those of ordinary skill in the art will be appreciated that, replace raw material by suitable selection heteroaryl, make isoindole-1-ketone change into isoindole-1-ylidene amines subsequently, as implied above, can independently replace the aryl moiety of the replacement of above isoindole-1-ylidene amines with heteroaryl moieties.In addition, by revising suitable isoindole-1-ketone raw material (for example, using 5,6-two (mixing) aryl-isoindole-1-ketone raw material, and do not use 4,5-two (mixing) aryl-isoindole-1-ketone), can obtain other substitute modes on the isoindole six-ring.

For choosing preparation N-benzyl-4,5-two (mixing) aryl-isoindole-1-ketone

Scheme 17:

Perhaps, insertion is connected to requiredly 4 before Diels-Alder reaction, and the group of the N atom of 5-phenylbenzene-isoindole-1-ketone is shown in above scheme 17.Under the Sonagashira condition, make propargyl amine (3,4-two fluoro-benzyls)-third-2-alkynes-t-butyl carbamate and 4-chlorine phenyl-iodide or the coupling of 2-bromo-5-chloropyridine, obtain I-a/I-b.The alkynes that obtains is reduced into cis-alkene (m-a/m-b), and under acidic conditions, disconnects Boc group (n-a/n-b).Make amine and 5-(2,4 dichloro benzene base)-penta-2, the coupling of 4-diene acyl chlorides, and make Diels-Alder precursor o-a/o-b thermal cyclization, obtain 44a/44b and 45a/45b.Make trans lactan 44a/44b be isomerizated into cis lactan 46a/46b with DBU, and use H ₂/ PtO ₂Or use H ₂/ Rh (PPh ₃) ₃Cl reduces two keys.

For choosing preparation compound 49 and 50

Step 1

Scheme 18:

To 3, (5g, (4.85mL, 70.7mmol 2eq.), add Na (OAc) to the 4-difluorobenzaldehyde subsequently 35.2mmol) to add single propargyl amine at the solution of 200mL ethylene dichloride ₃BH (9g, 42.5mmol), and with mixture stirring at room 2 days.Solution with the dilution of 100mL methylene dichloride, is used the moisture NaHCO of 2x100mL ₃, the water washing of 100mL salt, through Na ₂SO ₄Drying is filtered, and concentrates.Crude product with 20: 80 ethyl acetate-hexane chromatographies, is obtained 3.8g (3, the 4-difluorobenzyl)-Propargyl amine oil.

MS：182.15(MH ⁺)

Step 2

Scheme 19:

With (3, the 4-difluorobenzyl)-Propargyl amine (3.7g, 20.4mmol), triethylamine (4.3mL, 30.9mmol, 1.5eq) and (Boc) ₂(1.5eq.) mixture in the 100mL methylene dichloride is in stirred overnight at room temperature for 6.7g, 30.7mmol for O.Solution with the dilution of 200mL ether, is used the moisture NaHCO of 2x100mL ₃, the water washing of 100mL salt, through MgSO ₄Drying is filtered, and concentrates, and with 1: 9 ethyl acetate-hexane chromatography, obtains 6.6g (3, the 4-difluorobenzyl)-Propargyl t-butyl carbamate.

MS：282.13(MH ⁺)

Step 3

Scheme 20:

With (3, the 4-difluorobenzyl)-Propargyl t-butyl carbamate (3.2g, 11.4mmol), 4-chlorine phenyl-iodide (4.1g, 17.2mmol, 1.5eq.), Pd (PPh ₃) ₂Cl ₂(0.4g, 0.57mmol, 5mol%), iPr ₂NH (4mL, 28.5mmol, 2.5eq.) and CuI (0.2eq.) mixture in the 100mL methylene dichloride is in stirred overnight at room temperature for 0.435g, 2.3mmol.Solution with the dilution of 300mL ether, is filtered by the CELITE pad, to remove insoluble composition.Filtrate is used 2x100mL 1N HCl, the water washing of 100mL salt, through MgSO ₄Drying is filtered, and concentrates, and with 6% ethyl acetate chromatography in the hexane, obtains 2.6g[3-(4-chloro-phenyl)-Propargyl]-(3, the 4-difluorobenzyl)-t-butyl carbamate.

MS：336.10([M- ^tBu] ⁺)

Step 4

Scheme 21:

To 3-(4-chloro-phenyl)-Propargyl]-(3, the 4-difluorobenzyl)-t-butyl carbamate (1.05g, 2.7mmol) solution in 1: 1 methyl alcohol-methylene dichloride of 20mL add triethylamine (40 μ L, 0.1eq) and Lindlar catalyzer (105mg).At H ₂Stirring suspension body under the balloon.After 1 hour, add other 500mg Lindlar catalyzer, and mixture was stirred other 1.5 hours.Mixture is filtered and concentrates by the CELITE pad, obtain crude product.

Use 1.5g[3-(4-chloro-phenyl)-Propargyl once more]-(3, the 4-difluorobenzyl)-t-butyl carbamate reacts.Crude product that obtains and the crude product for preparing in first are merged, as the solvent chromatography, obtain 2.04g[3-(4-chloro-phenyl)-allyl group with 6% ethyl acetate-hexane]-(3, the 4-difluorobenzyl)-t-butyl carbamate.

MS：338.11([M- ^tBu] ⁺)

Step 5

Scheme 22:

With 3-(4-chloro-phenyl)-allyl group]-solution of the 4N HCl of (3, the 4-difluorobenzyl)-t-butyl carbamate (2.04g) in the 20mL dioxane is stirring at room 1 hour.Pour solution into 150mL moisture K ₂CO ₃, and use the 3x50mL ethyl acetate extraction.With the organic layer that merges 50mL salt water washing, through Na ₂SO ₄Drying is filtered and is concentrated, and obtains 1.49g[3-(4-chloro-phenyl)-allyl group]-(3, the 4-difluorobenzyl) amine.

MS：294.12(MH ⁺)

Step 6

Scheme 23:

To [3-(4-chloro-phenyl)-allyl group]-(3 that is in 0 ℃, the 4-difluorobenzyl) amine (1.49g, 5.1mmol), triethylamine (1.06mL, 7.6mmol, 1.5eq.), DMAP (being dimethyl aminopyridine) (62mg, 0.51mmol, 0.1eq.) solution in the 15mL methylene dichloride adds 5-(2, the 4-dichlorophenyl)-penta-2, the solution of 4-diene acyl chlorides (6.3mmol) in the 15mL methylene dichloride, and stirred 1 hour.After water treatment, crude product by chromatography purification, obtains 2.05g 5-(2,4 dichloro benzene base)-penta-2,4-diolefinic acid [3-(4-chloro-phenyl-)-allyl group]-(3, the 4-difluorobenzyl) acid amides with 20% ethyl acetate-hexane.

MS：518.11(MH ⁺)

Step 7

Scheme 24:

In the pipe of sealing 150 ℃ with 5-(2,4 dichloro benzene base)-penta-2, the solution heating of 4-diolefinic acid [3-(4-chloro-phenyl-)-allyl group]-(3, the 4-difluorobenzyl) acid amides (2.04g) in 40mL toluene 2 hours.With solution concentration,, obtain 720mg 49 and 1.1g 50 with 15% to 30% ethyl acetate chromatography in hexane.

MS 49：518.3(MH ⁺)

MS 50：518.3(MH ⁺)

Preparation compound 51

Scheme 25:

Room temperature with 49 (215mg, 0.41mmol) and DBU (1eq.) solution stirring in the 6mL methylene dichloride is 2 hours for 63mg, 0.42mmol, concentrates and with 40% ethyl acetate-hexane chromatography, obtains 160mg 51.MS：519.07(MH ⁺)

Preparation compound 52

Scheme 26:

Add 10mg PtO to the solution of 51 (105mg) in the 5mL ethyl acetate ₂, at H ₂Under the balloon suspensoid was stirred 80 minutes.Then solution is filtered by the CELITE pad, concentrate,, obtain 67mg 52 with 40% to 70% ethyl acetate-hexane chromatography.

MS：521.03(MH+)

Preparation compound 53 and 54

Utilization is similar to above in the method described in the scheme 26, and compound 50 is reduced into compound 53.Between this reaction period, also obtain compound 54.

Preparation compound 55-59

Above with being similar at the preparation of the method described in the scheme 17 following compound (X=N).

Preparation compound 60-62

Scheme 27:

Preparation cis biaryl compound as implied above.To the 4-chlorocinnamaldehyde (1.45g, 8.70mmol) solution in the 100mL ethylene dichloride adds 3,4-difluorobenzyl amine, add subsequently sodium triacetoxy borohydride (3.7g, 17.5mmol, 2eq.).Mixture in stirred overnight at room temperature, is used moisture NaHCO ₃, the salt water washing, through MgSO ₄Drying is filtered, and concentrates, and with 40% ethyl acetate-hexane chromatography, obtains 0.84g[3-(4-chloro-phenyl)-allyl group]-(3, the 4-difluorobenzyl) amine.Make [3-(4-chloro-phenyl)-allyl group]-(3, the 4-difluorobenzyl) amine and 5-(2,4 dichloro benzene base)-penta-2, the coupling of 4-diene acyl chlorides obtains 5-(2,4 dichloro benzene base)-penta-2,4-diolefinic acid [3-(4-chloro-phenyl-)-allyl group]-(3, the 4-difluorobenzyl) acid amides.Make 5-(2,4 dichloro benzene base)-penta-2, during 4-diolefinic acid [3-(4-chloro-phenyl-)-allyl group]-(3, the 4-difluorobenzyl) acid amides process Diels-Alder reaction conditions, obtaining principal product 60.Trans lactan epimerization obtains 61, and two keys of reduction 61 obtain 62.

Compound	MS(MH ⁺)
Compound	MS(MH ⁺)	60	518.18
61	518.06	60	518.18
61	518.06	62	520.05

Preparation compound 63-65

By the N-benzyl-4 that the preparation of reduction corresponding lactam replaces, 5-phenylbenzene-isoindole 63-65.As representative example, below introduce 64 preparation.

Scheme 28

To 52 (160mg, 0.31mmol) adding of the solution in 3mL THF LiAlH ₄0.92mL 1M solution in THF, and with mixture heating up backflow 1 hour.With the solution cool to room temperature, and add 30 μ L water, the 30 μ L 15%NaOH aqueous solution and 90 μ L water successively.To precipitate elimination, and filtrate is concentrated and, obtain 108mg 64 with 30% ethyl acetate-hexane chromatography.

MS：506.3(MH ⁺)

Prepare compound 63 and 65 with similar approach by the initial lactan that is fit to.

63[MS：507.3(MH ⁺)]

65[MS：506.3(MH ⁺)].

Preparation compound 66-71

Use the intermediate of Boc protection; [5-(2-chloro-4-p-methoxy-phenyl)-penta-2 described in following scheme 29; 4-diene acyl]-[3-(4-chloro-phenyl-)-allyl group] t-butyl carbamate; (for example also can carry out the Diels-Alder reaction; scheme 45; step 3) obtains cyclisation product 66 and 67.Can make trans lactan 66 epimerizations become cis lactan 68,, obtain 69 two key reduction and disconnection Boc group.Perhaps, can at first disconnect the Boc group, carry out the two key preparations 69 of lactan epimerization and reduction subsequently.

Scheme 29:

Step 1

Scheme 30:

4-bromo-3-chloroneb in sealed tube (35g, 0.159mol), KCl (11.9g, 0.160mol, 1eq.), K ₂CO ₃(33g, 0.238mol, 1.5eq) mixture in 400mL DMF add the propenal diethyl acetal (73mL, 0.479mol, 3eq.) and Bu ₄NOAc (96g, 0.318mol, 2eq.).Make N ₂Bubbling is by mixture, and adding Pd (OAc) ₂(1.1g, 4.mmol, 3mol%).Reaction mixture was heated 6 hours in 100 ℃ of oil baths, in ice bath, cool off then.Add 300mL water then, add 500mL 1N HCl subsequently.Remove ice bath, and mixture was stirred 30 minutes.Solution with ethyl acetate extraction is once used extracted with diethyl ether three times then.With organic layer water, the salt water washing that merges, through MgSO ₄Drying is filtered and is concentrated, and crude product is provided, and crude product obtains 15.5g crystallinity 3-(2-chloro-4-p-methoxy-phenyl)-propenal with the ethyl acetate-hexane recrystallization of heat.Mother liquor is concentrated,, obtain other 5.6g 3-(2-chloro-4-p-methoxy-phenyl)-propenal with 10% ethyl acetate chromatography.

Step 2

Scheme 31:

(29mL 0.146mol), and stirred 30 minutes to add phosphine acyl acetic acid three ethyl to the suspensoid of room temperature NaH (6.3g, 0.157mol, 60% dispersion in mineral oil) in 400mLTHF.Solution is cooled off in ice bath, and add 3-(2-chloro-4-methoxyl group-phenyl)-propenal (22g, 0.112mol) solution in 200mL THF.Mixture was stirred 1 hour, and with adding moisture NH ₄Cl quencher reaction.Make the THF evaporation, the slurry extracted with diethyl ether.With organic layer water, the salt water washing that merges, through MgSO ₄Drying is filtered and is concentrated, and obtains thick 5-(2-chloro-4-p-methoxy-phenyl)-penta-2,4-diolefinic acid ethyl ester.

Thick ester products is absorbed among each 200mL methyl alcohol and the THF, is cooled to 0 ℃ then.(19g, 0.338mol is 3eq.) at 200mL H to add KOH to this mixture ₂The solution of O.In stirring at room mixture 1.5 hours, and make organic solvent evaporation.Water layer 300mL H ₂The O dilution is with the ether washing, to remove mineral oil.In ice bath, cool off then, and be acidified to～pH 2 with dense HCl.With thick sedimentation and filtration, water cleans, and is dry in 75 ℃ of vacuum drying ovens then, obtains 26.2g 5-(2-chloro-4-p-methoxy-phenyl)-penta-2, the 4-diolefinic acid.

MS：239.24(MH ⁺)

Step 3

Scheme 32:

To room temperature 5-(2-chloro-4-p-methoxy-phenyl)-penta-2, the 4-diolefinic acid (6g, 25.1mmol) suspensoid in the 100mL methylene dichloride add oxalyl chloride (4.4mL, 50.4mmol, 2eq.), add subsequently DMF (39 μ L, 0.51mmol, 2mol%).Mixture was stirred 1 hour, and the settled solution that obtains concentrates, and uses toluene evaporates, obtains acyl chlorides.

Acyl chlorides is dissolved in the 150mL methylene dichloride, is cooled to 0 ℃, add triethylamine (5.3mL, 38.0mmol then, 1.5eq.), DMAP (310mg, 2.54mmol, 0.1eq.), add 3-(4-chloro-phenyl-)-allyl amine (5.1g, 30.2mmol, 1.2eq.) solution in methylene dichloride subsequently.In stirring at room mixture 1 hour, then with the dilution of 700mL ethyl acetate, and with 1N HCl, moisture NaHCO ₃With the salt water washing.Through MgSO ₄Drying is filtered and is concentrated, and obtains 10.1g 5-(2-chloro-4-p-methoxy-phenyl)-penta-2,4-diolefinic acid [3-(4-chloro-phenyl-)-allyl group]-acid amides.

MS：388.19(MH ⁺)

Step 4

Scheme 33:

To 5-(2-chloro-4-p-methoxy-phenyl)-penta-2, and 4-diolefinic acid [3-(4-chloro-phenyl-)-allyl group]-acid amides (9.8g, 25mmol) and (Boc) ₂O (11g, 50.4mmol, 2eq.) suspensoid in the 150mL methylene dichloride add triethylamine (3.5mL, 25.1mmol, 1eq.), add subsequently DMAP (3.1g, 25.4mmol, 1eq.).In stirring at room mixture 1 hour, with the ether dilution, with 1N HCl, moisture NaHCO ₃, the salt water washing, through MgSO ₄Drying is filtered and is concentrated, and obtains 9.8g 5-(2-chloro-4-p-methoxy-phenyl)-penta-2,4-diene acyl]-[3-(4-chloro-phenyl-)-allyl group]-t-butyl carbamate.

Step 5

Scheme 34:

In the pipe of sealing at 150 ℃ with 5-(2-chloro-4-p-methoxy-phenyl)-penta-2,4-diene acyl]-the solution heating of [3-(4-chloro-phenyl-)-allyl group]-t-butyl carbamate (9.5g) in 200mL toluene 3 hours.With solution concentration,, obtain 4.8g 66 and 2.8g 67 with 15% to 30% ethyl acetate-hexane chromatography.

MS 66：488.3(MH ⁺)

MS 67：488.3(MH ⁺)

Step 6

Scheme 35:

(690mg, 1.41mmol) (215mg, 1.41mmol 1eq.) stirred 1 hour, concentrated and with 20% to 30% ethyl acetate-hexane chromatography, obtained a kind of product mixtures for solution in the 15mL methylene dichloride and DBU with 66 in room temperature.This mixture is absorbed in 1: 1 methyl alcohol-methylene dichloride of 15mL, and at H ₂Following and the 65mg PtO of balloon ₂Stirred 30 minutes, and filtered by the CELITE pad then, concentrate and, obtain 34mg 68 with 30% ethyl acetate-hexane chromatography.

MS：434.2([M- ^tBu] ⁺)

Step 7

Scheme 36:

In the flask that contains 32mg 68, add 1mL TFA (being trifluoroacetic acid).This mixture stirring at room 1 hour, is concentrated then and with 3% methyl alcohol-methylene dichloride chromatography, obtains 25mg69.

MS：390.2(MH ⁺)

Step 8

Scheme 37:

To 0 ℃ of 66 (2.3g, 4.71mmol) adding of the solution in 20mL methylene dichloride 20mLTFA.Mixture was stirred 50 minutes, concentrate then, de-protected product is provided.

De-protected product and 720mg DBU stirred in each 20mL methylene dichloride and acetonitrile spend the night.After stirring is spent the night, add other 25mL acetonitrile and 1.4g DBU, and mixture was stirred 2.5 hours.Mixture is diluted with ethyl acetate, with 1N HCl, salt water washing, through MgSO ₄Drying is filtered, and concentrates and with 50% to 60% ethyl acetate-hexane and use 5% methyl alcohol-methylene dichloride chromatography then, obtains 1.88g 71.

MS：388.2(MH ⁺)

For choosing preparation 69

Scheme 38:

Add 90mg PtO to the solution of 71 (1.8g) in 1: 9 methyl alcohol-methylene dichloride of 50mL ₂, at H ₂Under the balloon suspensoid was stirred 40 minutes.Then mixture is filtered by the CELITE pad, concentrate, crude product obtains 1.1g crystallization 69 with the methylene dichloride-hexanes mixtures recrystallization of heat.

MS：390.2(MH ⁺)

Preparation compound 72-78

Scheme 39:

Can make methoxy functional group be converted into multiple other groups at the 5-phenyl.For example, as implied above, can make 69 methoxyl group be hydrolyzed into hydroxyl 72, and then change into triflate 73.With Zn (CN) ₂Make triflate 73 change into CN derivative 74 with the Pd catalyzer, perhaps catalyst reduction becomes 75 with Pd with formic acid.Make triflate 73 and Zn reagent react, obtain compound 76 and 77, perhaps, obtain 78 with acid reaction.

Preparation compound 72

Scheme 40:

To 69 (600mg, 1.54mmol) adding of the solution in 15mL methylene dichloride BBr ₃(7.7mL 1M dichloromethane solution).At 0 ℃ mixture was stirred 1 hour, stirred 20 minutes with 100mL water then.Dichloromethane layer is separated the water ethyl acetate extraction.With organic layer water, the salt water washing that merges, through MgSO ₄Drying is filtered, and concentrates and with 3% to 10% methyl alcohol-methylene dichloride chromatography, obtains 535mg 72.

MS：376.2(MH ⁺)

Preparation compound 73

Scheme 41:

To 72 (400mg, 1.1mmol) suspensoid in the 10mL acetonitrile add triethylamine (300 μ L, 2.1mmol, 2eq.), add subsequently N-phenyl trifluoromethanesulfonate methylsulfonyl imines (870mg, 1.5eq.).Stirring at room 2.5 hours, clear soln was diluted with ethyl acetate, uses moisture NaHCO with mixture ₃, the salt solution washed twice, through MgSO ₄Drying is filtered, and concentrates, and with 3% methyl alcohol-methylene dichloride chromatography, obtains 490mg 73.

Preparation compound 74

Scheme 42:

With in the sealed tube 73 (62mg, 0.12mmol), Zn (CN) ₂(9mg, 0.08mmol, 0.6eq.) and Pd (PPh ₃) ₄(0.1eq.) mixture in 1mL DMF was 100 ℃ of heating 1 hour for 14mg, 0.012mmol.With the mixture dilute with water, water, salt solution washed twice are through MgSO ₄Drying is filtered, and concentrates, and crude product by preparation TLC purifying, obtains 50mg 74 with 80% ethyl acetate-hexane.

MS：385.21(MH ⁺)

Preparation compound 75

Scheme 43:

With in the sealed tube 73 (50mg, 0.10mmol), HCO ₂H (19 μ L, 0.50mmol, 5eq.), triethylamine (70 μ L, 0.5mmol, 5eq.) and Pd (PPh ₃) ₄(5mol%.) mixture in 1mL DMF was 100 ℃ of heating 4 hours for 6mg, 5.2 μ mol.Mixture is diluted with ethyl acetate, use moisture NaHCO ₃, the salt solution washed twice, through MgSO ₄Drying is filtered, and concentrates, and product by preparation TLC purifying, obtains 29mg 75 with 3% methyl alcohol-methylene dichloride.

MS：360.2(MH ⁺)

Preparation compound 76

Scheme 44:

With in the sealed tube 73 (50mg, 0.10mmol), MeZnCl (0.5mL 2M solution, 10eq.) and Pd (PPh ₃) ₄(5mol%.) mixture in 1mL THF was 80 ℃ of heating 4 hours for 6mg, 5.2 μ mol.With mixture methyl alcohol quencher, with the ethyl acetate dilution, with 1N HCl, salt solution washed twice, through MgSO ₄Drying is filtered and is concentrated, and crude product by preparation TLC purifying, obtains 26mg 76 with 60% ethyl acetate-hexane.

MS：385.21(MH ⁺)

Preparation compound 77

Scheme 45:

With in the sealed tube 73 (30mg, 0.059mmol), bromination 2-pyridyl zinc (0.59mL 0.5M solution, 5eq.) and Pd (PPh ₃) ₄(10mol%.) mixture in 0.5mL THF was 100 ℃ of heating 4 hours for 6.8mg, 5.8 μ mol.Mixture is diluted with ethyl acetate, use moisture NH ₄Cl, salt solution washed twice are through MgSO ₄Drying is filtered, and concentrates, and crude product by preparation TLC purifying, obtains 8mg 77 with 3% methyl alcohol-methylene dichloride.

MS：437.2(MH ⁺)

Preparation compound 78

Scheme 46:

With in the sealed tube 73 (30mg, 0.059mmol), phenyl-boron dihydroxide (15mg, 0.13mmol, 2eq.), K ₂CO ₃(33mg, 0.24mmol, 4eq.) and Pd (PPh ₃) ₄(6.8mg, 5.8 μ mol are 10mol%.) at 4: 2: 1 toluene-EtOH-H of 1mL ₂Mixture among the O was 100 ℃ of heating 4 hours.Mixture is diluted with ethyl acetate, use moisture K ₂CO ₃, the salt solution washed twice, through MgSO ₄Drying is filtered, and concentrates, and crude product by preparation TLC purifying, obtains 25mg 78 with 60% ethyl acetate-hexane.

MS：436.2(MH ⁺)

Preparation compound 79-86

Scheme 47:

By enolate and the electrophilic reagent reaction that is fit to, can shown in above scheme 47, make the 7a-position functional of isoindolone.For example, react with the oxa-aziridine subsequently, can in 66, introduce hydroxy functional group by generating enol potassium.Two keys reduce subsequently the Boc base and go protection, obtain 80.Perhaps, the two keys of reduction (for example, 66 reduction generate 81) before generating enolate.Make compound 81 and MeI and TFA reaction subsequently, obtain 82.Alkylation for example ethylizes with KHMDS/18-crown ether-6 and EtI, obtains 83.In a similar manner, by enolate and bromotoluene that is fit to optional replacement or allyl iodide reaction, make 81 to change into 84,85 and 86.

Preparation compound 79

Scheme 48:

To be in-78 ℃ 66 (44mg, 0.090mmol) solution in 1mL THF adds 0.5M KHMDS (that is two (trimethyl silyl) potassium amide) at toluene (0.27mL, 1.5eq.) solution in.Solution was stirred 10 minutes at-78 ℃, stirred 10 minutes at 0 ℃, cooling is got back to-78 ℃ then.Add (1S)-(+)-(camphor sulfonyl) oxa-aziridine (Davis reagent) (31mg, 0.135mmol, the 1.5eq.) solution in 0.5mL THF, and stirring 2 hours to refrigerative solution then.Then by adding moisture NH ₄Cl makes solution quencher reaction.Use 1% methyl alcohol-methylene dichloride chromatography purifying subsequently with ethyl acetate extraction, obtain 30mg 79.

MS：504.3(MH ⁺)

Preparation compound 80

Scheme 49:

With 79 (30mg) and PtO ₂(3mg) suspensoid in the 2mL ethyl acetate is at H ₂Balloon stirred 2 hours down.Mixture is filtered by the CELITE pad, concentrate, and stirred 1 hour with 0 ℃ of each 1mLTFA (being trifluoroacetic acid) and methylene dichloride.With solution concentration, utilize 3% methyl alcohol-methylene dichloride by preparation TLC purifying, obtain 24mg 80.

MS：406.2(MH ⁺)

Preparation compound 81

Scheme 50:

With 66 (230mg) and PtO ₂(23mg) suspensoid in the 5mL ethyl acetate is at H ₂Balloon stirred 30 minutes down, filtered and evaporation, obtained 230mg 81.

MS：490.3(MH ⁺)

Preparation compound 82

Scheme 51:

To-78 ℃ 81 (30mg, 0.061mmol) solution in 1mL THF adds 0.5MKHMS (0.15mL, 0.075mmol, the 1.2eq.) solution in toluene, and stirring the mixture 20 minutes.(19 μ L, 0.305mmol 5eq.), stir 10 minutes then, and use moisture NH to add MeI to mixture ₄Cl quencher reaction.After with the ethyl acetate extraction mixture, crude product by preparation TLC purifying, obtains the 11mg methylate with 30% ethyl acetate-hexane.The TFA of methylate and each 0.5mL and methylene dichloride were stirred 1 hour at 0 ℃, concentrate and use toluene evaporates, obtain 8mg 82.

MS：404.2(MH ⁺)

Preparation compound 83

Scheme 52:

50mg 81 in the anhydrous THF of 1.5mL adds hexaoxacyclooctadecane-6-6 (1.5eq.).Under argon gas, make the mixture degassing, and add two (trimethyl silyl) potassium amides (1.5eq., 306 μ L 0.5M toluene solutions) at-78 ℃.Stir and add iodic ether (1.5eq.) after 20 minutes.Mixture is with aqueous ammonium chloride quencher reaction, and with ethyl acetate extraction three times.With the organic extract liquid salt water washing that merges, use dried over mgso, filter, be evaporated to dried.By flash chromatography (0-25% ethyl acetate in the hexane) purifying, obtain 30mg ethylization product.

Add the 1mL trifluoroacetic acid to the solution of 0 ℃ of ethylization product that as above prepares in the 1.5mL methylene dichloride, and under nitrogen, stirred the mixture 1 hour.Mixture is evaporated to dried, resistates is dissolved in toluene, is evaporated to driedly, is dissolved in ether then, is evaporated to driedly once more, obtains 23mg83.

MS：418.2(MH ⁺)

Utilization is similar to and prepares 82 used methods, makes intermediate 81 change into 84,85 and 86, and difference is to use respectively 4-cyano-benzyl bromide, 3, and 4-difluoro benzyl bromide and allyl bromide 98 replace methyl-iodide.

Compound	MS(MH ⁺)
Compound	MS(MH ⁺)	84	505.3
85	516.3	84	505.3
85	516.3	86	430.2

Preparation compound 87-91

Scheme 53:

Utilization is similar to the method for preparing compound 72 and 73, makes 82 to change into 87 and triflate 88.The same utilization is similar to the method that 73 triflate functional group changes into compound 74,75 and 76, makes compound 88 change into compound 89,90 and 91.

Compound	MS(MH ⁺)
Compound	MS(MH ⁺)	87	390.2
88	522.3	87	390.2
88	522.3	89	399.2
90	374.2	89	399.2
90	374.2	91	388.2

Same with chirality HPLC condition fractionation compound 89.

Chiral separation 89

Enantiomer 1 enantiomer 2

With 89 (～550mg) solution in 1: 1 Virahol of 4ml and hexane injects ChiralpacAD and prepares HPLC post (5cmx50cm), and 15% Virahol wash-out with in the hexane obtains 149mg 89A and 230mg 89B.

MS 89A：399.2(MH ⁺)

MS 89B：399.2(MH ⁺)

Preparation compound 92-95

Scheme 54

Utilization is similar to and prepares the used methods of compound 66,82,89 and 91 and use suitable raw material shown in scheme 54, preparation compound 92,93,94 and 95.

Compound	MS(MH ⁺)
Compound	MS(MH ⁺)	93	404.2
94	399.2	93	404.2
94	399.2	95	388.2

Preparation compound 96-107

Scheme 55:

Step 1

Use is similar to the method shown in the scheme 25 makes compound 90 change into compound 96.

Step 2

Scheme 56:

Compound 96 under the room temperature argon gas atmosphere (30mg, 0.064mmol), LiCl (35mg, 0.826mmol, 6.5eq.) and 2; 4,6-tri isopropyl benzenesulfonyl base nitrine (45mg, 0.15mmoL; 2.3eq.) solution in 1mL DMF add DBU (19 μ L, 0.13mmol, 2eq.).Stirring at room solution 0.5 hour, and dilute with ethyl acetate.With solution NH ₄Cl (saturated) washing is through MgSO ₄Drying is filtered and is concentrated.Make resistates through preparation TLC purifying (SiO ₂, 3: 2 hexanes/EtOAc), obtain white solid 97 (25mg, 74%).LCMS：m/e 529.3(MH ⁺)

Step 3

Scheme 57:

(171mg is 0.323mmol) at 7mLEtOAc-H for compound 97 under the room temperature argon gas atmosphere ₂Solution among the O (10-1) adds PMe ₃(650 μ L, 1M, in THF, 0.65mmol, 2eq.).Stirring at room solution 4 hours.With solution concentration.Resistates obtains pale solid 98 (145mg, 89%) with 3% methyl alcohol-methylene dichloride chromatography.

Step 4

Use is similar to the method shown in the scheme 50 makes compound 98 change into compound 99.

Step 5

Scheme 58:

With compound 99 (50mg, 0.10mmol), hexaoxacyclooctadecane-6-6 (52mg, 2eq.), K ₂CO ₃(82mg, 6eq.) with 1, (29 μ L, 2eq.) mixture in 2mL MeCN was 90 ℃ of heating 19 hours for 5-two iodo pentanes.Mixture is filtered.Filtrate is dissolved in EtOAc, uses NH ₄Cl (saturated) washing is through MgSO ₄Drying is filtered and is concentrated.Make resistates through preparation TLC purifying (SiO ₂, 3: 2 hexanes/EtOAc), obtain 97f (10mg, 18%).Same separating compound 103 (18mg, 24%).

Step 6

Use is similar to the method shown in the scheme 36 makes compound 100 and 103 change into compound 101 and 105.

Scheme 59:

The similar compound 102 and 107 that shown in above scheme 60, prepares.

Also can be to change the amine functional group that order is introduced in the 7a-position slightly shown in following scheme.Intermediate 108 usefulness KHMDS with the method preparation that is similar to preparation 66 handle, and handle with trisyl azide subsequently, obtain azido-derivative 109.The reduction trinitride disconnects the BOC group subsequently, obtains amine 111, changes into acid amides 112 with 111.The similar normative document method of utilizing can make amine change into various analogues, as sulphonamide, carbamate, urea etc.

Preparation compound 109

Scheme 60:

1.0g 108 in 0 ℃ of anhydrous THF of 10mL adds 1.3eq. hexamethyl dimethyl silanyl potassium amide (0.5M toluene solution), and mixture was stirred 20 minutes, is cooled to-78 ℃ then.Add Tris-N subsequently ₃(1.5eq.) cooling in 2.5ml THF (78 ℃) solution adds acetate (3eq.) after 2 minutes.Make reaction be warmed to room temperature with warm water bath immediately, stirred then 1.5 hours.Mixture is evaporated to dried, is dissolved in the 10mL methylene dichloride, water, moisture NaHCO ₃With the salt water washing, use MgSO then ₄Drying filters and is evaporated to dried.Utilize 0% to 15% ethyl acetate-hexane by the flash chromatography purifying, obtain 864mg 109.

MS：479.3(MH ⁺).

Preparation compound 110

Scheme 61:

After the degassing, the 860mg 109 in 0 ℃ of 22mL ethyl acetate/water (10: 1) adds 2eq. trimethyl-phosphine (1.0M THF solution), and makes mixture slowly be warmed to room temperature under argon gas.After 16 hours, mixture is evaporated to dried, then toluene is joined resistates, and mixture is evaporated to dried.Utilize 0% to 2.5% methyl alcohol-methylene dichloride by the flash chromatography purifying, obtain 575mg 110.

MS：392.2(MH ⁺)

Preparation compound 111

Scheme 62:

565mg 110 in 0 ℃ of 5mL methylene dichloride adds the 2mL trifluoroacetic acid, and at N ₂Stir the mixture under the atmosphere.After 2 hours, reaction mixture is poured on moisture NaHCO ₃On, and with dichloromethane extraction three times.With the extraction liquid MgSO that merges ₄Drying is filtered, and is evaporated to driedly, obtains 465mg 111.

MS：409.2(MH ⁺)

Preparation compound 112

Scheme 63:

20mg 111 in 0 ℃ of 1.5mL pyridine adds the 3eq. Acetyl Chloride 98Min., mixture is warmed to room temperature, simultaneously at N ₂Stir under the atmosphere.Reaction mixture is poured on the aqueous ammonium chloride, and with ethyl acetate extraction three times.Wash the extraction liquid that merges with water twice, with the salt water washing once, use MgSO ₄Drying, filter and be evaporated to dried, with 0% to 2.5% methyl alcohol-methylene dichloride by behind the flash chromatography purifying, obtain 17mg 112.

MS：451.2(MH ⁺)

Preparation compound 113-117

Scheme 64:

Begin to be fit to functionalized propargyl amine, with the C of different group substituted lactams ₃The position.For example, described in above scheme 64, at C ₃Methyl is introduced in the position.

Step 1

Scheme 65:

To 4-chlorine phenyl-iodide (10g, 42mmol), the 3-butyne-2-alcohol (6.6mL, 84mmol, 2eq.) and iPr ₂(2.5eq.) (1.6g, 8.4mmol 0.2eq.), add Pd (PPh to the adding of the solution in 200mL methylene dichloride CuI to NH subsequently for 14.8mL, 105mmol ₃) ₂Cl ₂(1.5g, 2.1mmol, 5mol%).In stirring at room mixture 1.5 hours, concentrate, and dilute with ether.With the insoluble composition elimination of mixture, filtrate is with 1N HCl and salt water washing, through MgSO ₄Drying is filtered, and concentrates, and with 20% ethyl acetate-hexane chromatography, obtains 7.6g 4-(4-chloro-phenyl)-Ding-3-alkynes-2-alcohol.

Step 2

Scheme 66:

To be cooled to ice bath 0 ℃ 4-(4-chloro-phenyl)-Ding-3-alkynes-2-alcohol (3g, 16.6mmol), phthalic imidine (3.7g, 25.2mmol, 1.5eq.) and PPh ₃(4.8g, 18.3mmol, 1.1eq.) solution in 100mL THF drip DEAD (that is, the azoformic acid diethyl ester) (3.1mL, 19.9mmol, 1.2eq.).Remove ice bath, and with mixture in stirred overnight at room temperature.Make the THF evaporation, resistates and 1: 1 ether-hexanes mixtures of 200mL were stirred 1 hour.To precipitate elimination, and filtrate is concentrated and, obtain 4.1g 2-[3-(4-chloro-phenyl-)-1-methyl-Propargyl with 15% ethyl acetate-hexane chromatography]-isoindole-1, the 3-diketone.

MS：310.09(MH ⁺)

Step 3

Scheme 67:

To 2-[3-(4-chloro-phenyl-)-1-methyl-Propargyl]-isoindole-1, the 3-diketone (4.1g, 13.2mmol) solution in the 20mL methylene dichloride adds 30mL methyl alcohol, add subsequently hydrazine (4.2mL, 133mmol, 10eq.).Mixture was stirred 1 hour, filter, concentrate, and, obtain 1.5g 3-(4-chloro-phenyl-)-1-methyl-Propargyl amine with 3% methyl alcohol-methylene dichloride chromatography.

MS：163.21(MH ⁺)

Step 4

Scheme 68:

With 3-(4-chloro-phenyl-)-1-methyl-Propargyl amine (1.5g, 8.4mmol), triethylamine (0.12mL, 0.86mmol, 0.1eq.) and the mixture of Lindlar catalyzer (150mg) in 1: 1 methyl alcohol-methylene dichloride of 40mL stirred 1 hour, filter by the CELITE pad, concentrate, obtain 1.5g 3-(4-chloro-phenyl-)-1-methyl-allyl amine.

Utilization is similar to the method described in the above scheme 5, makes compound 3-(4-chloro-phenyl-)-1-methyl-allyl amine change into 5-(2,4 dichloro benzene base)-penta-2,4-diolefinic acid [3-(4-chloro-phenyl)-1-methyl-allyl group]-acid amides.Utilization is similar to the Diels-Alder condition described in the above scheme 6, makes compound 5-(2,4 dichloro benzene base)-penta-2, and 4-diolefinic acid [3-(4-chloro-phenyl)-1-methyl-allyl group]-acid amides changes into compound 113 and 114.Use is similar to the method described in the scheme 6, prepares compound 115 by compound 113 isomerization.Use is similar to the method described in the scheme 7, by reducing compound 115 preparation compounds 116.Use is similar to the method described in the scheme 7, by reducing compound 114 preparation compounds 117.

Compound	MS(MH ⁺)
Compound	MS(MH ⁺)	113	406.2
114	406.2	113	406.2
114	406.2	115	406.2
116	408.1	115	406.2
116	408.1	117	408.2

Preparation compound 118-121

Scheme 69

Enantiomer 1 enantiomer 2

As described in following scheme, further make from above synthetic intermediate 113 and change into 7a-methyl analogue 121.Further be split into single enantiomer 121a and 121b again.

Preparation compound 118 and 119

Scheme 70:

To 113 (500mg, 1.23mmol), (Boc) ₂O (2.8g, 12.8mmol, 10eq.), Et ₃N (345 μ L, 2.48mmol, 2eq.) solution in each 5ml methylene dichloride and acetonitrile add DMAP (300mg, 2.46mmol, 2eq.), and with mixture in stirred overnight at room temperature.Solution is diluted with ether, with 1N HCl, moisture NaHCO ₃With the salt water washing, through MgSO ₄Drying is filtered, evaporation, and, obtain 220mg 118 and 330mg 119 with 0% to 20% ethyl acetate-hexane chromatography.

MS 118：450.2(M ⁺- ^tBu)

MS 119：450.2(M ⁺- ^tBu)

Utilization is similar to 66 and changes into 81 method, makes compound 118 change into compound 120.Utilization is similar to 81 and changes into 82 method, makes 120 to change into 121.Split 121 with chirality HPLC condition as described below equally, obtain single enantiomer 121a and 121b.

Scheme 71:

Enantiomer 1 enantiomer 2

About 40mg 121 is dissolved in Virahol, and is expelled on the 5x50cm CHIR ALPAK AD post, use 220nm UV detector, utilize 10% Virahol in the hexane with the 100mL/min wash-out.Obtain each 15mg 121a (enantiomer 1) and 121b (enantiomer 2).Retention time was respectively 19.8 minutes and 25.4 minutes.

MS 120：510.3(MH ⁺)

MS 121：422.2(MH ⁺)

MS 121a：422.2(MH ⁺)

MS 121b：422.2(MH ⁺)

Scheme 72:

In above 121 preparation, utilize the racemize raw material, and use chirality HPLC condition to split independent enantiomer.Perhaps, shown in scheme 64 and 69, with 3-crotonylene (S)-alcohol beginning, with these chiralitys C ₃The analogue of-replacement synthesizes single enantiomer.

Scheme 72a

For example; utilize for example method of scheme 29; make 3-(4-chloro-phenyl)-1-methyl-allyl amine (for example the method by scheme 7 prepares) and 5-(2; the 4-dichlorophenyl)-penta-2; the reaction of 4-diolefinic acid; so that [3-(4-chloro-phenyl)-1-methyl-propyl group]-[5-(2,4 dichloro benzene base)-penta-2,4-two enoyl-s]-t-butyl carbamate to be provided.Make then that [3-(4-chloro-phenyl)-1-methyl-propyl group]-[5-(2; the 4-dichlorophenyl)-penta-2; 4-two enoyl-s]-the t-butyl carbamate cyclisation is (for example; utilize the method for scheme 47); so that 4-(4-chloro-phenyl)-5-(2 to be provided; the 4-dichlorophenyl)-3,7a-dimethyl-octahydro-isoindole-1-ketone.

Preparation compound 122-131

Scheme 73:

In above scheme 73,, another embodiment of the synthetic The compounds of this invention of chirality of preparation 130 and 131 is proposed in order to the optical activity form of optical activity 3-crotonylene (S)-alcohol beginning.

Preparation compound 122

Utilization is similar in order to prepare 113 the used method of acid amides and prepares acid amides 122, and difference is to replace racemize 3-butyne-2-alcohol with optically active 3-crotonylene (S)-alcohol.

Preparation compound 123

Scheme 74:

To room temperature 122 (10g, 24.8mmol), (Boc) ₂(10.9g, 2eq.) suspensoid in the 100mL methylene dichloride adds Et to O ₃N (3.5mL, 1eq), add subsequently DMAP (3.1g, 1eq), and at the stirring at room suspensoid.After 2 hours, add other 2 equivalents (Boc) ₂O, and mixture stirred spend the night.With solution concentration half, with the ethyl acetate dilution, with 1NHCl, moisture NaHCO to its volume ₃With the salt water washing, through MgSO ₄Drying is filtered, and concentrates and obtains crude product.Make crude product be suspended in MeOH-CH ₂Cl ₂Mixture, and dilute with ether.With the solid elimination, and wash with ether.Filtrate is concentrated,, obtain 9.5g 123 with 0% to 10% ethyl acetate-hexane chromatography.

MS：502.3(MH ⁺)

Preparation compound 124 and 125

Scheme 74

123 (9.5g) solution in 100mL toluene in the sealed tube was heated 2 hours at 130 ℃.With solution concentration,, obtain 4.3g 124 and 3.1g 125 with 0% to 20% ethyl acetate-hexane chromatography.

MS 124：502.3(MH ⁺)

MS 125：502.3(MH ⁺)

Preparation compound 126

Scheme 75

(215mg, 5wt%) suspensoid in the 100mL ethyl acetate stirred 30 minutes under hydrogen balloon, filtered and concentrated by the CELITE pad, obtained 4.15g 126 with 124 (4.3g) and aqua oxidation platinum.

MS：504.3(MH ⁺)

Preparation compound 127

Scheme 76:

(600mg, 1.19mmol) solution in 7mL THF adds 0.5M 1M LHMDS (being hexamethyl dimethyl silanyl Lithamide) (3.6mL, 1.8mmol, THF solution 1.5eq.), and stirring 20 minutes to-78 ℃ 126 that outgases under vacuum.(0.37mL, 5.94mmol 1.5eq.), stirred 10 minutes, used moisture NH to add methyl-iodide to this solution ₄Cl quencher reaction, and make the THF evaporation.With the mixture ethyl acetate extraction, the salt water washing of the organic layer of merging is through MgSO ₄Drying is filtered, and concentrates and with 0% to 15% ethyl acetate chromatography in hexane, obtains 470mg 127.MS：518.3(MH ⁺)

Preparation compound 128

Scheme 77:

(460mg, 0.89mmol) solution in the 5mL methylene dichloride adds 1MBBr to room temperature 127 ₃(4.5mmol, dichloromethane solution 5eq.), and with mixture stirring at room 2 hours.With solution with water dilution, stirred for several minute is separated organic layer, and water layer is with twice of dichloromethane extraction.With the organic layer salt water washing that merges, through MgSO ₄Drying is filtered and the concentrated 380mg 128 that obtains.

MS：404.2(MH ⁺)

Preparation compound 129

Scheme 78:

To 128 (330mg, 0.82mmol) solution in each 5mL methylene dichloride and acetonitrile add triethylamine (0.23mL, 1.65mmol, 2eq), add subsequently N-phenyl trifluoromethanesulfonate methylsulfonyl imines (440mg, 1.23mmol, 1.5eq.).Mixture was stirred 1.5 hours,, use moisture NaHCO with the ethyl acetate dilution ₃, the salt solution washed twice, through MgSO ₄Drying is filtered, and concentrates, and with 0% to 3% methyl alcohol-methylene dichloride chromatography, obtains 370mg 129.

MS：536.3(MH ⁺)

Preparation compound 130

Scheme 79:

In sealed tube 129 (150mg, 0.28mmol), Pd ₂(dba) ₃(13mg, 0.014mmol, 5mol%), dppf (being diphenylphosphine ferrocene complex compound) (19.5mg, 0.035mmol, 12.5mol%), Zn (OAc) ₂(14mg, 0.088mmol, 0.3eq.), the Zn powder (5.5mg, 0.084mmol, 0.3eq.), Zn (CN) ₂(23mg, 0.20mmol, the 0.7eq) drum of the mixture in 2mL DMF Argon Bubble, and in 100 ℃ of oil baths, heated 1 hour.Solution is diluted with ethyl acetate, with ferrous ammonium sulphate, salt water washing, through MgSO ₄Drying is filtered, and concentrates and with 0% to 3% methyl alcohol-methylene dichloride chromatography, obtains 120mg 130.

MS：413.2(MH ⁺)

Preparation compound 131

Scheme 80:

With 128 (40mg, 0.10mmol), K ₂CO ₃(69mg, 0.50mmol, 5eq.) and methyl iodide (0.04mL, 0.50mmol, 5eq.) heated overnight in 50 ℃ of sealed tubes of the mixture in 2mL acetone.With the mixture dilute with water, use ethyl acetate extraction three times, the salt water washing of the organic layer of merging is through MgSO ₄Drying is filtered, and evaporation obtains 47mg 131.

MS：432.2(MH ⁺)

General flow C:

Preparation compound 132 and 133

Step 1

Preparation 3-(2,4 dichloro benzene base)-methacrolein

(26.26g 0.15mol) is dissolved in toluene (200mL), and (8.4g 1eq), adds BnEt subsequently to add KOH in the entry (183mL) then with 2,4 dichloro benzene formaldehyde ₃NCl.Mixture is cooled to 0 ℃, and the positive propionic aldehyde in the dropping toluene (50mL) (26.15g, 0.45mol, 3eq).Mixture is warmed to room temperature, and stirs and spend the night.Organic layer is separated water, salt water washing successively, dry (MgSO ₄), and under reduced pressure concentrate.The gained resistates obtains 17.56g 3-(2,4 dichloro benzene base)-methacrolein by silica gel column chromatography (0-1-2-3%EtOAc in the hexane) purifying.

Step 2

Preparation 5-(2,4 dichloro benzene base)-4-methylpent-2,4-diolefinic acid ethyl ester

(dispersion of 4.88g 60% in mineral oil, 1.5eq 0.122mol) are suspended in THF (442mL) to make sodium hydride.Drip diethoxy phosphoryl ethyl acetate (27.5g, 0.122mol, 1.5eq) solution in THF (10mL) to this dispersion.After 10 minutes, drip 3-(2,4 dichloro benzene base)-methacrolein (17.56g, 0.082mol) solution in THF (50mL).Stir after 4 hours, mixture is joined NH ₄Cl (saturated), and extract with EtOAc.With the organic extract liquid drying (MgSO that merges ₄), under reduced pressure concentrate, obtain resistates, resistates obtains 20.9g 5-(2,4 dichloro benzene base)-4-methylpent-2,4-diolefinic acid ethyl ester by silica gel column chromatography (0-2.5-5%EtOAc in the hexane) purifying.

Step 3

Preparation 5-(2,4 dichloro benzene base)-4-methylpent-2, the 4-diolefinic acid

Make 5-(2,4 dichloro benzene base)-4-methylpent-2, (2.37g 0.083mol) is suspended in EtOH (50mL) to 4-diolefinic acid ethyl ester.Add 2N NaOH (13mL, 3eq), and with mixture 50 ℃ of heating 1 hour.With the mixture cool to room temperature, and be acidified to pH1.Collect the gained solid, obtain 2g 5-(2,4 dichloro benzene base)-4-methylpent-2, the 4-diolefinic acid.

Step 4

5-(2,4 dichloro benzene base)-4-methylpent-2,4-diolefinic acid [3-(4-chloro-phenyl-)-allyl group] acid amides

Make 5-(2,4 dichloro benzene base)-4-methylpent-2, (1g 0.0039mol) is suspended in CH to the 4-diolefinic acid ₂Cl ₂(10mL).(0.5mL 1.5eq), adds 1 DMF subsequently to add oxalyl chloride.After 2 hours, remove volatile matter, resistates is absorbed among the THF (10mL), and make mixture be cooled to 0 ℃.Drip 3-(4-chloro-phenyl-) allyl amine (0.0042mol is as scheme 4 preparations for 0.7g, 1.1eq) and Et ₃N (0.82mL, 0.0042mol, 1.5eq) mixture in THF (5mL).After 1 hour, TLC analyzes and shows that raw material transforms fully, uses EtOAc diluted mixture thing then.With organic layer NH ₄Cl (saturated) washing, dry (MgSO ₄), and under reduced pressure concentrate.The gained resistates obtains 1.25g 5-(2,4 dichloro benzene base)-4-methylpent-2,4-diolefinic acid [3-(4-chloro-phenyl-) allyl group] acid amides by silica gel column chromatography (0-10-20-30-40%EtOAc in the hexane) purifying.

Step 5

Preparation [3-(4-chloro-phenyl-) allyl group]-[5-(2,4 dichloro benzene base)-4-methylpent-2,4-two enoyl-s] t-butyl carbamate

Make 5-(2,4 dichloro benzene base)-4-methylpent-2, (1.25g 0.0032mol) is dissolved in CH to acid amides to 4-diolefinic acid [3-(4-chloro-phenyl-)-allyl group] ₂Cl ₂(20mL).Add Et to this mixture ₃N (0.443mL, 1eq), Boc ₂O (1.39g, 2eq) and DMAP (0.39g, 1eq).Stir after 16 hours, with mixture CH ₂Cl ₂NH is used in dilution ₄Cl (saturated) washing, dry (MgSO ₄).Silica gel column chromatography (5%EtOAc in the hexane) obtains 1.43g[3-(4-chloro-phenyl-) allyl group]-[5-(2,4 dichloro benzene base)-4-methylpent-2,4-two enoyl-s] t-butyl carbamate.

Step 6

(1.25g 0.00247mol) is dissolved in toluene (60mL), and heats 2.5 hours at 150 ℃ with [3-(4-chloro-phenyl-) allyl group]-[5-(2,4 dichloro benzene base)-4-methylpent-2,4-two enoyl-s] t-butyl carbamate.Mixture is concentrated, and resistates obtains 0.46g 132LCMS:452 (MH by silica gel column chromatography (5-15-20-40%EtOAc in the hexane) purifying by elution order ⁺-Bu ^t) and 0.46g 133 LCMS:452 (MH ⁺-Bu ^t).

General flow D:

Preparation compound 134

(120mg 0.000236mol) is dissolved in CH with compound 132 ₂Cl ₂(2mL), and be cooled to 0 ℃.Add TFA (being trifluoroacetic acid (2mL)), and mixture was stirred 30 minutes.Remove volatile matter and obtain 105mg compound 134.LCMS：406.2，408.2(MH ⁺)

Preparation compound 135

Utilization is similar to the method for preparation 134, begins to prepare compound 135 by compound 133.LCMS：406.2，408.2(MH ⁺)

Preparation compound 136

(100mg 0.000246mol) is suspended in MeCN/CH to make compound 134 ₂Cl ₂(2mL/2mL), adding DBU (0.111mL, 3eq), and with mixture stirring 4 hours.Mixture dilutes with EtOAc, uses NH ₄Cl (saturated) washing is with organic layer drying (MgSO ₄), and under reduced pressure concentrate, obtain 40mg 136.LCMS：406.2，408.2(MH ⁺)

Preparation compound 137

(30mg 0.000074mol) is dissolved in EtOAc with compound 136.Add PtO ₂(3mg), and with mixture at 1 normal atmosphere H ₂Under stirred 4 hours.Remove by filter catalyzer by the CELITE pad, filtrate is concentrated, obtain 29mg compound 137.LCMS：408.2，410.2(MH ⁺)

Preparation compound 138

With compound 132 (100mg, 0.000197mol) be dissolved in DMF (1mL), MeI (0.246mL, 20eq).Add then NaH (dispersion of 11.8mg 60% in mineral oil, 1.5eq).Stir after 2 hours reaction NH ₄Cl (saturated) quencher is with the EtOAc extraction, with the organic extract liquid drying (MgSO that merges ₄), and under reduced pressure concentrate.Gained resistates silica gel column chromatography purifying obtains 80mg compound 138.LCMS：466.3(MH ⁺-Bu ^t).

Preparation compound 139

(80mg 0.000154mol) is dissolved in CH with compound 138 ₂Cl ₂(5mL), and be cooled to 0 ℃.Add TFA (5mL), and mixture was stirred 30 minutes.Remove volatile matter, silica gel column chromatography (0-30-50-70%EtOAc in the hexane) obtains 35mg compound 139 subsequently.

LCMS：420.2(MH ⁺)

Preparation compound 140 and 141

With being similar to synthetic compound 132 and 133 used method synthetic compound 140 (LCMS:416.2 (MH ⁺-Bu ^t)) and 141 (LCMS:416.2 (MH ⁺-Bu ^t)).

Preparation compound 142

Utilization is similar to the used method of synthetic compound 134, by compound 140 preparation compounds 142.

Compound 142 LCMS:372.2 (MH ⁺).

Preparation compound 143

Utilization is similar to the used method of synthetic compound 134, by compound 141 preparation compounds 143.

Compound 143 LCMS:372.2 (MH ⁺).

Preparation compound 144

Utilization is similar to the used method of synthetic compound 136, by compound 142 preparation compounds 144.

Compound 144 LCMS:372.2 (MH ⁺).

Preparation compound 145

Utilization is similar to the used method of synthetic compound 137, by compound 144 preparation compounds 145.

Compound 145, LCMS:374.2 (MH ⁺).

Preparation compound 146

Utilization is similar to the used method of synthetic compound 138, by compound 140 preparation compounds 146.

Compound 146 LCMS:430.2 (MH ⁺-Bu ^t).

Preparation compound 147

Utilization is similar to the used method of synthetic compound 139, by compound 146 preparation compounds 147.

Compound 147 LCMS:386.2 (MH ⁺).

General flow E

Preparation compound 148 and 149

Step 1

Preparation 5-(2,4 dichloro benzene base)-3-methylpent-2,4-diolefinic acid ethyl ester

(34.24g, 0.129mol 1.3eq) are dissolved in THF/DMPU (100mL/200mL), and mixture is cooled to-78 ℃ with 3-methyl-4-phosphono Ba Dousuan triethyl.Dropping BuLi (51.8mL 2.5M hexane solution, 1.3eq).Mixture was stirred 20 minutes, drip the solution in the 2,4 dichloro benzene formaldehyde (17.6g is 0.1mol) at THF/DMPU (20mL/40mL)) then.The gained mixture was stirred 1 hour, be warmed to room temperature then.Add NH ₄Cl (saturated), mixture extracts with EtOAc.With organic layer water, salt water washing, dry (MgSO ₄).Under reduced pressure remove and desolvate, silica gel column chromatography (0-1-2-3%EtOAc in the hexane) obtains 23.3g5-(2,4 dichloro benzene base)-3-methylpent-2,4-diolefinic acid ethyl ester subsequently.

Step 2

Preparation 5-(2,4 dichloro benzene base)-3-methylpent-2, the 4-diolefinic acid

Make 5-(2,4 dichloro benzene base)-3-methylpent-2, (5g 0.0184mol) is dissolved in THF (125mL) to 4-diolefinic acid ethyl ester.Add then entry (50mL), MeOH (50mL) and NaOH (the 18.44mL 2M aqueous solution, 2eq).After 6 hours, TLC analyzes and shows that raw material transforms fully, by adding 6NHCl mixture is acidified to pH1.Collect the gained solid, obtain 4.24g 5-(2,4 dichloro benzene base)-3-methylpent-2, the 4-diolefinic acid.

Step 3

Preparation [3-(4-chloro-phenyl-) allyl group]-[5-(2,4 dichloro benzene base)-3-methylpent-2,4-two enoyl-s] t-butyl carbamate

Make 5-(2,4 dichloro benzene base)-3-methylpent-2, (4.24g 0.0165mol) is suspended in CH to the 4-diolefinic acid ₂Cl ₂(40mL), (2.12mL 1.5eq), adds 1 DMF subsequently to add oxalyl chloride.After 2 hours, remove volatile matter, resistates is absorbed among the THF (34mL), and make mixture be cooled to 0 ℃.Drip 3-(4-chloro-phenyl-) allyl amine (3.2g, 1.1eq, scheme 4) and Et ₃N ((3.6mL, 1.5eq) mixture in THF (20mL).After 1 hour, TLC analyzes and shows that raw material transforms fully, uses EtOAc diluted mixture thing then.With organic layer NH ₄Cl (saturated) washing, dry (MgSO ₄), under reduced pressure concentrate, and make the gained resistates be absorbed in CH ₂Cl ₂(100mL).Add Et to this mixture ₃N (2.3mL, 1eq), Boc ₂O (7.17g, 2eq) and DMAP (2g, 1eq).Stir after 16 hours, with mixture CH ₂Cl ₂NH is used in dilution ₄Cl (saturated) washing, dry (MgSO ₄).Silica gel column chromatography (0-2-4%EtOAc in the hexane) obtains 5.8g[3-(4-chloro-phenyl-) allyl group]-[5-(2,4 dichloro benzene base)-3-methylpent-2,4-two enoyl-s] t-butyl carbamate.

Step 4

(5.8g 0.011mol) is dissolved in toluene (350mL), and heats 3 hours at 110 ℃ with [3-(4-chloro-phenyl-) allyl group]-[5-(2,4 dichloro benzene base)-3-methylpent-2,4-two enoyl-s] t-butyl carbamate.Mixture is concentrated, and resistates obtains 2.4g compound 148LCMS:452 (MH by silica gel column chromatography (0-2.5-5-10-40%EtOAc in the hexane) purifying by elution order ⁺-Bu ^t) and 2.2g compound 149 LCMS:452 (MH ⁺-Bu ^t).

General flow F

Preparation compound 150

Utilization is similar to the used method of synthetic compound 134, by compound 148 preparation compounds 150.

Compound 150, LCMS:406.2,408.2 (MH ⁺).

Preparation compound 151

Utilization is similar to the used method of synthetic compound 134, by compound 149 preparation compounds 151.

Compound 151, LCMS:406.2,408.2 (MH ⁺).

Preparation compound 152

Utilization is similar to the used method of synthetic compound 136, by compound 150 preparation compounds 152.

Compound 152, LCMS:406.2,408.2 (MH ⁺).

Preparation compound 153 and 154

Utilization is similar to the used method of synthetic compound 137, by hydrogenated compound 152 preparation compounds 153 and 154.

Compound 153, LCMS:408.2,410.2 (MH ⁺).

Compound 154, LCMS:408.2,410.2 (MH ⁺).

Preparation compound 155

Utilization is similar to the used method of synthetic compound 138, by compound 148 preparation compounds 155.

Compound 155, LCMS:466.3 (MH ⁺-Bu ^t).

Preparation compound 156

Utilization is similar to the used method of synthetic compound 139, by compound 155 preparation compounds 156.

Compound 156, LCMS:420.2 (MH ⁺).

Preparation 5,6-two (mixing) aryl-isoindole-1-ketone

General flow G:

Can be by 5 of the preparation of the method shown in above general flow G replacement, 6-two (mixing) aryl-isoindole-1-ketone.By the Sonogashira reaction, can make aryl or heteroaryl acetylenic p be coupled to aryl or heteroaryl iodine or bromine q, obtain alkynes r.Iodinate is used in palladium catalysis addition by tributyltin hydride subsequently, obtains vinyl iodide t.Carry out the Heck coupled reaction with posthydrolysis with methyl acrylate, obtain diolefinic acid u, by acyl chlorides or EDCI (being 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide) coupling, diolefinic acid u changes into allyl acid amides v.Intramolecularly Diels-Alder reaction obtains product w, and product w can change into product x by hydrogenation, perhaps changes into product y by alkylation.

Preparation compound 157 and 158

Step 1

Scheme 81:

With 1-chloro-4-ethynyl-benzene (2.71g, 0.020mol), 2,4-two chloro-1-iodo-benzene (3.23mL, 0.024mol), PdCl ₂(PPh ₃) ₂(0.10g, 1.4mmol), CuI (1.44g, 7.6mmol) and diisopropylamine (7mL) at the mixture of DCM (being methylene dichloride) in (100mL) stirring at room 16 hours.Mixture is filtered by CELITE.Filtrate is concentrated in a vacuum.Resistates chromatography (SiO ₂, hexane), obtain white solid 2,4-two chloro-1-(4-chloro-phenylacetylene base)-benzene (3.23g, 87%).

Step 2

Scheme 82:

With tributyltin hydride (2.7mL 10mmol) joins room temperature 2,4-two chloro-1-(4-chloro-phenylacetylene base)-benzene (2.01g, 7.13mmol) and PdCl ₂(PPh ₃) ₂(0.45g, 0.64mmol) mixture in THF (70mL) and stirring 1 hour.(2.7g 11mmol) joins the mixed at room temperature thing, and stirs 30 minutes with iodine crystal.Then with mixture and sodium thiosulfate solution and the stirring of the KF aqueous solution.Mixture is filtered by CELITE.Separate the organic layer of filtrate also concentrated in a vacuum.With resistates chromatography (SiO ₂, hexane), obtain light yellow solid 2,4-two chloro-1-[2-(4-chloro-phenyl)-1-iodo-vinyl]-benzene (2.43g, 83%).

Step 3

Scheme 83:

To 2,4-two chloro-1-[2-(4-chloro-phenyl)-1-iodo-vinyl]-benzene (270mg, 0.66mmol) solution in DMF (6mL) add methyl acrylate (0.30mL, 3.3mmol), Et ₃N (0.30mL, 2.2mmol) and Pd (PPh ₃) ₂Cl ₂(46mg, 0.07mmol).Stirred the mixture 16 hours at 100 ℃.Mixture is filtered by CELITE.Filtrate is concentrated in a vacuum.Mixture dilutes with EtOAc, and uses NH ₄Cl (saturated) washing.With organic layer drying (MgSO ₄), and concentrate in a vacuum.Resistates as elutriant flash chromatography on silicagel column, obtains methyl esters clarified oil (98mg, 40%) with EtOAc-hexane (5-95).

(98mg, 0.27mmol) (3mL, 1-1) solution in adds NaOH (1.5mL, 10%) at THF-MeOH to methyl esters.In stirring at room mixture 1 hour.The mixture dilute with water, and make the organism evaporation.The dilute with water aqueous mixture is used the 10%HCl acidifying, and uses CH ₂Cl ₂Extraction.With organic layer salt water washing, dry (MgSO ₄), under vacuum, concentrate, obtain pale solid 5-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-penta-2,4-diolefinic acid (82mg, 87%).

Step 4

Scheme 84:

With the used similar fashion of preparation acid amides g among the general flow A, make 5-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-penta-2, the 4-diolefinic acid changes into 5-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-penta-2,4-diolefinic acid allyl acid amides.

Step 5

Scheme 85:

Make 5-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-penta-2,4-diolefinic acid allyl acid amides (55mg) and quinol (dihydroquinone) (4mg) are dissolved in o-Xylol, and heating 16 hours in 220 ℃ of penstocks that seal under nitrogen.Behind cool to room temperature, solution with EtOAc and hexane dilution, is used 10%NaOH and salt water washing, dry (MgSO ₄), concentrate.With resistates chromatography (SiO ₂, 9: 1-2: 1 CH ₂Cl ₂/ EtOAc), obtain 157 white solids (12mg, 22%), LCMS:m/e 392 (MH ⁺) and 158 white solids (2mg, 4%), LCMS:m/e392 (MH ⁺).

Preparation compound 159 and 160

Step 1

Scheme 86:

With the used similar fashion of preparation acid amides g among the general flow A, make 5-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-penta-2 equally, the 4-diolefinic acid changes into 5-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-penta-2,4-diolefinic acid diene propionic acid amide.

Step 2:

Scheme 87:

Make 5-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-penta-2,4-diolefinic acid diallyl acid amides (39mg) and quinol (dihydroquinone) (2mg) are dissolved in toluene, and heating 16 hours in 175 ℃ of penstocks that seal under nitrogen.Behind cool to room temperature, solution with EtOAc and hexane dilution, is used 10%NaOH and salt water washing, dry (MgSO ₄), concentrate.With resistates chromatography (SiO ₂, 4: 1-3: 2 hexanes/EtOAc), obtain 159 pale solids (15mg, 38%), LCMS:m/e 432 (MH ⁺) and 160 pale solids (12mg, 30%), LCMS:m/e432 (MH ⁺).

Preparation compound 161

Scheme 88:

Compound 159 (12mg) and 1 DBU (that is, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene) are dissolved in CH ₂Cl ₂(2mL), and stirring at room 1 hour.With solution concentration.With resistates chromatography (SiO ₂, 4: 1-3: 2 hexanes/EtOAc), obtain canescence resin 161 (7mg, 58%), LCMS:m/e 432 (MB ⁺).

Preparation compound 162

Scheme 89:

To be similar in the scheme 7 preparation compound 5 and 6 used modes, make compound 157 change into 162.LCMS：m/e 394(MH ⁺).

Preparation compound 163

Scheme 90:

Room temperature to 157 (31mg, 0.079mmol) and to cyano-benzyl bromide (46mg, 0.24mmol) solution in DMF (6mL) adds NaH (31mg, 0.79mmol is 60%, in mineral oil), and with mixture stirring at room 16 hours.Mixture is concentrated in a vacuum.Resistates dilutes with EtOAc, and uses NH ₄Cl (saturated) washing.With organic layer drying (MgSO ₄), and concentrate in a vacuum.Resistates as elutriant chromatography on the preparation silica-gel plate, obtains white solid 163 (10mg, 25%) with EtOAc-hexane (40-60).LCMS：m/e 507(MH ⁺).

For choosing preparation 5,6-phenylbenzene-isoindole-1-ketone

General flow H:

5 of preparation replacement, the choosing method that supplies of 6-phenylbenzene-isoindole-1-ketone is shown among the above general flow H.By being similar to Acta Chem Scand, 1993,47,1112 (described document is attached to herein in full by reference) disclosed method, can prepare the ester z that two aryl or two heteroaryl replace, and can change into diolefinic acid ab by the well-known process shown in the general flow H.Use is similar to the used method of general flow G makes diolefinic acid ab change into target compound.

Preparation compound 164-170

Scheme 91:

By method for reporting (Acta Chem Scand, 1993,47,1112; Be attached to herein by reference in full) prepare 2-(4-chloro-phenyl)-3-(2,4 dichloro benzene base)-methyl acrylate, and change into 4-(4-chloro-phenyl)-5-(2,4 dichloro benzene base)-penta-2,4-diolefinic acid by the well-known process shown in scheme 92.Utilization is similar to and prepares the used method of compound 157,158 and 162, and by 4-(4-chloro-phenyl)-5-(2,4 dichloro benzene base)-penta-2, the 4-diolefinic acid prepares compound 164 and 166.

General flow I:

Shown in general flow I, make acid amides ai alkylation equally, to obtain aj, make aj change into compound 168-171 again.

Preparation 5,6-two (mixing) aryl-isoindole-1,3-diketone or 3,4-two (mixing) aryl-hexamethylene-3-alkene methane amide

General flow J:

Can pass through prepared in various methods two (mixing) aryl-isoindole-1,3-diketone or 3,4-two (mixing) aryl-hexamethylene-3-alkene methane amide, for example pass through diene and the pyrroles-2 that diaryl, two heteroaryls or aryl-heteroaryl replaces, the intermolecular Diels-Alder reaction of 5-diketone or acrylamide derivative is shown in for example above general flow J.

Preparation compound 172-175

Scheme 92:

By make commercially available 1-(4-chloro-phenyl)-third-2-ketone change into 3-(4-chloro-phenyl)-Ding-3-alkene-2-ketone with Eschenmoser salt, prepare compound 172-175.Use trifluoromethanesulfanhydride anhydride and steric hindrance pyridine base then, make 3-(4-chloro-phenyl)-Ding-3-alkene-2-ketone change into trifluoromethanesulfonic acid 2-(4-chloro-phenyl)-1-methylene radical-allyl ester.The Suzuki coupling obtains 2,4-two chloro-1-[2-(4-chloro-phenyl-)-1-methylene radical-allyl group]-benzene.As shown in above scheme 93,2,4-two chloro-1-[2-(4-chloro-phenyl-)-1-methylene radical-allyl group]-benzene obtains compound 172-175 with the Diels-Alder reaction of different dienophiles.

Step 1:

(8.6g, 51mmol) (12.3g 66.3mmol) is dissolved in glacial acetic acid, and heats 1 hour in 125 ℃ of penstocks that seal under nitrogen with Eschenmoser salt to make 1-(4-chloro-phenyl-)-third-2-ketone.Behind cool to room temperature, with solution concentration.Resistates is dissolved in EtOAc, uses saturated NaHCO ₃Solution washing, dry (MgSO ₄), concentrate and chromatography (SiO ₂, 39: 1-19: 1 hexane/EtOAc), obtain yellow oil 3-(4-chloro-phenyl)-Ding-3-alkene-2-ketone (3.92g, 43%).

Step 2:

(0.23mL, (189mg, 1.04mmol) with 2, (0.32g is 1.6mmol) at CH for 6-two-tertiary butyl-4-picoline 1.4mmol) to join 3-(4-chloro-phenyl)-Ding-3-alkene-2-ketone with trifluoromethanesulfanhydride anhydride ₂Cl ₂Mixture (10mL), and refluxed 16 hours.Behind cool to room temperature, with solution 10%HCl solution and saturated NH ₄The Cl solution washing, dry (MgSO ₄), concentrate and chromatography (SiO ₂, hexane), obtain clarified oil trifluoromethanesulfonic acid 2-(4-chloro-phenyl)-1-methylene radical-allyl ester (136mg, 41%).

Step 3

Scheme 93:

By above Suzuki method, make trifluoromethanesulfonic acid 2-(4-chloro-phenyl)-1-methylene radical-allyl ester change into 2,4-two chloro-1-[2-(4-chloro-phenyl)-1-methylene radical-allyl group]-benzene.

Step 4

Scheme 94:

By with Diels-Alder method identical shown in the scheme 88, make 2,4-two chloro-1-[2-(4-chloro-phenyl)-1-methylene radical-allyl group]-benzene changes into the corresponding product shown in the above scheme 95.

Preparation compound 176

Utilization be similar to prepare that the used methods preparation of compound 172 replaces 5,6-phenylbenzene-isoindole-1-diketone 176, difference is with diene 4-chloro-1-[2-(4-chloro-phenyl)-1-methylene radical-allyl group]-benzene replacement 2,4-two chloro-1-[2-(4-chloro-phenyl)-1-methylene radical-allyl group]-benzene.

Preparation compound 177

Utilization is similar to and prepares compound 172 used methods and prepare compound 171, and difference is with 4-chloro-1-[2-(4-chloro-phenyl)-1-methylene radical-allyl group]-benzene replaces 2,4-two chloro-1-[2-(4-chloro-phenyl)-1-methylene radical-allyl group]-benzene.(utilization is similar to preparation 2,4-two chloro-1-[2-(4-chloro-phenyl)-1-methylene radical-allyl group]-the used method of benzene prepares 4-chloro-1-[2-(4-chloro-phenyl)-1-methylene radical-allyl group]-benzene, shown in above scheme 93).

Preparation compound 178-185

General flow K:

Can pass through the intermolecular Diels-Alder reaction of the diene and the unsaturated amides of diaryl, two heteroaryls or aryl-heteroaryl replacement, perhaps be subsequently converted to acid amides by the diene of diaryl, two heteroaryls or aryl-heteroaryl replacement and the intermolecular Diels-Alder reaction of insatiable hunger ester, preparation two (mixing) aryl-hexamethylene-3-alkene methane amide is shown in above general flow K.By the compound exhibits of method shown in general flow K preparation in following table:

Preparation two (mixing) aryl-isobenzofuran-1-ketone

General flow L:

Can prepare two (mixing) aryl-isobenzofuran-1-ketone by several different methods.For example, by the method shown in the above general flow L, unsaturated alcohol or sour diolefinic acid or the acyl chlorides c condensation that replaces with aryl or heteroaryl that aryl or heteroaryl are replaced are to provide triolefin ester ay.Triolefin ester ay can be cyclized into two (mixing) aryl-tetrahydrochysene-isobenzofuran-1-ketone az by intramolecularly Diels-Alder reaction, can further az be revised (for example passing through reduction etc.) and become saturated two (mixing) aryl-isobenzofuran-1-ketone ba.

Preparation compound 186-191

Step 1

Scheme 95:

With fourth-3-alkynes-2-alcohol (7.0g, 0.10mol), 2, the 5-dibromo pyridine (15.89g, 0.067mol), PdCl ₂(PPh ₃) ₂(2.35g, 3.4mmol), CuI (2.55g, 0.013mol) and the mixture of diisopropylamine (300mL) stirring at room 1 hour.Mixture is filtered by CELITE.Filtrate is concentrated in a vacuum.Resistates is dissolved in CH ₂Cl ₂, use saturated NH ₄The Cl solution washing, dry (MgSO ₄) and concentrate.With resistates chromatography (SiO ₂, 7: 3 hexanes/EtOAc), obtain alkynol product 4-(5-bromo-pyridine-2-yl)-Ding-3-alkynes-2-alcohol are a kind of brown solid (13.24g, 87%).

Scheme 96:

Shown in scheme 95, prepare 4-(4-chloro-phenyl)-Ding-3-alkynes-2-alcohol.

Step 2

Scheme 97:

(2.26g 0.010mol) is dissolved in EtOAc (50mL) to 4-(the 5-bromo-pyridine-2-yl)-Ding-3-alkynes-2-alcohol that will prepare in step 1.Add Lindlar catalyzer (1.13g), and mixture was being shaken under 55psi hydrogen 16 hours on the Parr wobbler.Mixture is filtered and concentrates.With resistates chromatography (SiO ₂, 9/1 to 4/1 hexane/EtOAc), obtain 4-(5-bromo-pyridine-2-yl)-Ding-3-alkene-2-alcohol is a kind of clarified oil (1.12g, 49%).

Scheme 98:

Utilize 1 normal atmosphere hydrogen and 10-20% weight Lindlar catalyzer, shown in scheme 97, prepare 5-(2,4 dichloro benzene base)-penta-2,4-diolefinic acid 3-(4-chloro-phenyl)-1-methyl-allyl ester.

Step 3

Scheme 99:

To be similar to above scheme 5 preparation 5-(2, the 4-dichlorophenyl)-penta-2,4-diolefinic acid [3-(4-chloro-phenyl)-the allyl group]-used method of acid amides, make 4-(the 5-bromo-pyridine-2-yl)-Ding-3-alkene-2-alcohol of preparation in step 2 change into 5-(2, the 4-dichlorophenyl)-penta-2,4-diolefinic acid 3-(5-bromo-pyridine-2-yl)-1-methyl allyl ester.

Scheme 100:

Similar preparation 5-(2,4 dichloro benzene base)-penta-2 shown in scheme 101,4-diolefinic acid 3-(4-chloro-phenyl)-1-methyl-third-2-alkynes ester.

Step 4:

Scheme 101:

With the 5-(2,4 dichloro benzene base)-penta-2 of above preparation in step 3,4-diolefinic acid 3-(5-bromo-pyridine-2-yl)-1-methyl allyl ester (248mg) is dissolved in o-Xylol, and presses down in the solenoid heating 1 hour at 175 ℃ at nitrogen.Behind cool to room temperature, with solution concentration.With resistates chromatography (SiO ₂, 19: 1-5: 1 hexane/EtOAc), obtain pale solid ring adducts 186 (141mg, 49%), LCMS:m/e 452.1 (MH ⁺). isolate a small amount of ring adducts 187 (12mg, 5%) equally, LCMS:m/e 452.1 (MH ⁺) and 188 (35mg, 14%), LCMS:m/e452.1 (MH ⁺).

Scheme 102:

Prepare compound 189-191 in mode shown in the scheme 101.

Preparation compound 192 and 193

Scheme 103:

With lactones 186 (140mg) and NiCl ₂Hexahydrate (110mg) is dissolved in THF (5mL) and MeOH (1mL).Add NaBH4 (18mg) at 0 ℃.Stirred the mixture 10 minutes at 0 ℃.Mixture is diluted with EtOAc, use saturated NH ₄The Cl solution washing, dry (MgSO ₄) and concentrate.Resistates separates (SiO by preparation TLC ₂, 3: 1 hexanes/EtOAc), obtain reduzate 192 are a kind of white solid (35mg, 25%), LCMS:m/e 454.1 (MH ⁺).Isolate a small amount of reduzate 193 (10mg, 7%) equally, LCMS:m/e 454.1 (MH ⁺).

Preparation compound 194

Scheme 104:

Prepare compound 192 by the method for reducing described in the scheme 12.

Preparation compound 195

Scheme 105:

Prepare compound 193 by being similar to the method shown in scheme 55 steps 2, difference is to replace Trisyl Azide with methyl-iodide.

Preparation compound 195

Scheme 106:

With pyridine bromide 192 (6.5mg), Pd (PPh ₃) ₄(2mg), 2,5-dichlorophenyl boric acid (7mg), K ₂CO ₃(22mg), ethanol (0.2mL), water (0.1mL) and toluene (0.4mL) were 90 ℃ of heating 1 hour.Reaction mixture is diluted with EtOAc, use saturated NH ₄The Cl solution washing, dry (MgSO ₄) and concentrate.Make resistates through preparation TLC purifying (SiO ₂, 3: 2 hexanes/EtOAc), obtain white solid 196 (6mg, 81%).LCMS：m/e 520.1(MH ⁺)

Preparation compound 197 and 198

The suitable diene acyl chlorides c of use shown in general flow L prepares 4-pyridyl-5-phenyl-isobenzofuran-1-ketone 197 and 198 that compound 196 used method preparations replace with being similar to.

Preparation compound 199-201

Preparation compound 199-201 shown in following scheme 107:

Scheme 107:

Scheme 108:

With methylate 126 to provide 127 (square cases 73) similar, introduce other alkyl at the alpha-position of lactan carbonyl.For example, introducing ethyl as described below:

Preparation compound 210

Scheme 108:

With 126 (1.16g, 2.30mmol) and hexaoxacyclooctadecane-6-6 (2eq.) de-gassed solution in 20ml THF is cooled to-78 ℃ for 1.2g, 4.54mmol, is added in toluene (9.1ml, 4.55mmol, 2eq.) the 0.5M KHMDS solution in, and stirring 1 hour.(2.8ml, 34.68mmol 15eq.), and-78 ℃ of stirrings 2 hours, use moisture NH then to add iodoethane to this ₄Cl quencher reaction.Make the THF evaporation, aqueous slurry 3x ethyl acetate extraction.The organic layer salt water washing that merges is through MgSO ₄Drying is filtered, and concentrates and is used in 0% in the hexane to 20% ethyl acetate and pass through chromatography purification, obtains 1.04g 210, is white solid.

MS：476.3(M- ^tBu ⁺)

Preparation compound 211,212,213 and 214

Prepare these analogues with scheme 73 and 80 times described similar approach of scheme.

MS 211：418.2(MH ⁺)

MS 212：550.3(MH ⁺)

MS 213：427.2(MH ⁺)

MS 214：446.2(MH ⁺)

Scheme 109:

Available 128 phenol functional group (square case 73) is introduced various other groups as general handle.For example, described phenol can be with the alkylogen alkylation that is fit to, so that ether shown below to be provided.

Preparation compound 215,216 and 217

Prepare these analogues with being similar to the used method of preparation 131 (square cases 80).

MS 215：446.2(MH ⁺)

MS 216：458.3(MH ⁺)

MS 217：462.3(MH ⁺)

Preparation compound 218

Scheme 110:

With in the sealed tube 128 (50mg, 0.12mmol), the trifluoro iodoethane (25 μ L, 1.27mmol, 10eq.) and K ₂CO ₃(3eq.) mixture in 1ml DMF is～85 ℃ of heated overnight for 50mg, 0.36mmol.Mixture is diluted with ethyl acetate, with 1N HCl, salt water washing 3x, through MgSO ₄Drying is filtered, and concentrates and passes through chromatography purification with 0% to 3% methyl alcohol in the methylene dichloride, obtains 55mg 218.

MS：486.3(MH ⁺)

Preparation compound 219

Scheme 111:

With in the sealed tube 128 (30mg, 0.072mmol), iodo-acid amide (67mg, 0.36mmol, 5eq.) and K ₂CO ₃(4eq.) mixture in 1ml DMF was～60 ℃ of heating 2.5 hours for 40mg, 0.29mmol.Mixture is diluted with ethyl acetate, with 1N HCl, salt water washing 3x, through MgSO ₄Drying is filtered, and concentrates and passes through chromatography purification with 0% to 4% methyl alcohol in the methylene dichloride, obtains 32mg 219.MS：475.3(MH ⁺)

Preparation compound 220 and 221

Scheme 112:

With in the sealed tube 128 (25mg, 0.044mmol), (2-bromine oxethyl)-tert-butyl dimethylsilane (106 μ L, 10eq.) and K ₂CO ₃(28mg, 4eq.) mixture in 0.5ml DMF was～65 ℃ of heating 2 hours.Mixture is diluted with ethyl acetate, with 1N HCl, salt water washing 3x, through MgSO ₄Drying is filtered, and concentrates and passes through chromatography purification with 0% to 4% methyl alcohol in the methylene dichloride, obtains 25mg 220.

This is dissolved in 0.5ml THF, and (0.14mmol, 3eq) stir about is 3 hours, with the ethyl acetate dilution, with 1N HCl, salt water washing 3x, through MgSO with 0.14ml 1M tetrabutylammonium fluoride solution in THF ₄Drying is filtered, and concentrates and passes through chromatography purification with 0% to 4% methyl alcohol in the methylene dichloride, obtains 20mg 221.

MS 220：562.3(MH ⁺)

MS 221：448.2(MH ⁺)

Preparation compound 222

Scheme 113:

Contain 128 (50mg, 0.124mmol) and K ₂CO ₃(68mg, 0.49mmol) two neck round-bottomed flasks of the solution in 2mlDMF are equipped with cold finger.Cold finger is introduced difluorochloromethane gas by the cooling of dry ice-propanone mixture from steel cylinder, and condensation under cold finger.Round-bottomed flask is immersed in～oil bath of 40 ℃ of maintenances in, and stirred 5 hours.Mixture is diluted with ethyl acetate, with 3x 1N HCl, salt water washing, through MgSO ₄Drying is filtered, and evaporation.Crude product by chromatography purification, obtains 22mg 222 with 0% to 3% methyl alcohol in the methylene dichloride.MS：454.2(MH ⁺)

Preparation compound 224

Scheme 114:

In sealed tube 128 (50mg, 0.124mmol), Na ₂CO ₃(8mg, 0.076mmol, 0.6eq.), [Ir (COD) Cl] ₂(8mg, 0.012mmol, 0.1eq.) and vinyl-acetic ester (57 μ l, 0.616mmol, the 5eq.) mixture in 1ml toluene drum Argon Bubble, and～105 ℃ of heating 8 hours.Mixture is diluted with ethyl acetate, and water, salt water washing 2x are through MgSO ₄Drying is filtered and with 0% to 3% methyl alcohol chromatography in the methylene dichloride, is obtained 45mg 223.(reference method Organic Synthesis, volume 82, page55-58).

(45mg, 0.105mmol) solution in the 2mL methylene dichloride is added in 1M zinc ethyl solution in the hexane (5eq.), (39 μ l, 0.52mmol 5eq.), and stirred 10 minutes to add trifluoroacetic acid subsequently for 0.52mmol, 0.52mmol to 0 ℃ 223.To this add methylene iodide (42 μ l, 0.52mmol, 5eq.), and with mixture in stirred overnight at room temperature.It is used moisture NH ₄The 3x ethyl acetate extraction is used in Cl quencher reaction, with the organic layer salt water washing that merges, through MgSO ₄Drying is filtered and with 0% to 3% methyl alcohol chromatography in the methylene dichloride, is obtained the 38mg product, and product contains some unreacted raw materials.This product is handled with each 10eq. zinc ethyl, trifluoroacetic acid and methylene iodide in the above conditions again, and as above purifying provides 34mg 224 after processing.MS：444.2(MH ⁺)

Preparation compound 225-229

Use to the described method of preparation compound, begins prepare these compounds with 211 scheme 109 times.

MS 225：520.3 MS(MH ⁺)

MS 226：576.3 MS(MH ⁺)

MS 227：462.3 MS(MH ⁺)

MS 228：475.3 MS(MH ⁺)

MS 229：474.3 MS(MH ⁺)

Scheme 115

Can be by carboxylic acid 231 preparation amide analogues, as 232.Can be easy to again obtain carboxylic acid 231 from phenol 128.

Preparation compound 230

Scheme 116:

With 128 (300mg, 0.742mmol), methyl bromoacetate (350 μ l, 3.7mmol, 5eq.) and K ₂CO ₃(4eq.) mixture in 5ml DMF was～60 ℃ of heating 4 hours for 410mg, 2.97mmol.Mixture is diluted with ethyl acetate, with 1N HCl, salt water washing 3x, through MgSO ₄Drying is filtered, concentrate and with 0% to 4% methyl alcohol in the methylene dichloride by chromatography purification, by the filtration of alkali alumina pad, obtain 305mg 230 then.

MS：476.3(MH ⁺)

Preparation compound 231

Scheme 117:

To 230 (300mg, 0.63mmol) solution in each 2mL methyl alcohol and THF adds the 2ml1M NaOH aqueous solution, and with mixture stirring at room 2 hours.With its dilute with water,, and use the 3x ethyl acetate extraction with 1N HCl acidifying.With the organic layer salt water washing that merges, through MgSO ₄Drying is filtered and the concentrated 250mg 231 that obtains.

MS：462.3(MH ⁺)

Preparation compound 232

Scheme 118:

To 231 (50mg, 0.108mmol), N-Mono Methyl Ethanol Amine (41mg, 0.546mmol, 5eq.), (2eq.) solution in 1ml DMF and 0.5ml methylene dichloride adds EDCI (42mg to HOBt for 30mg, 0.22mmol, 0.219mmol, 2eq.), and with mixture in stirred overnight at room temperature.Solution is diluted with ethyl acetate, with 1N HCl, salt water washing 3x, through MgSO ₄Drying is filtered, and concentrates and passes through chromatography purification with 0% to 5% methyl alcohol in the methylene dichloride, obtains 52mg 232.

MS：519.3(MH ⁺)

Preparation compound 234

Scheme 119:

To 231 (110mg, 0.238mmol), aminoacetaldehyde dimethylacetal (125mg, 1.19mmol, 5eq.), HOBt (65mg, 0.48mmol 2eq.) solution in 1.5ml DMF and 0.5ml methylene dichloride adds EDCI (92mg, 0.48mmol, 2eq.), and with mixture in stirred overnight at room temperature.Solution is diluted with ethyl acetate, with 1N HCl, salt water washing 3x, through MgSO ₄Drying is filtered, and concentrates and passes through chromatography purification with 0% to 5% methyl alcohol in the methylene dichloride, obtains 51mg 233.

In room temperature 1: 1 trifluoroacetic acid of this and 3ml and methylene dichloride and number are dripped and to stir 3 hours.It is diluted with ethyl acetate, and water, salt water washing 2x are through MgSO ₄Drying is filtered and the concentrated 41mg aldehyde that obtains.This is dissolved in 1: 1 methyl alcohol of 1ml and methylene dichloride, is cooled to 0 ℃, and (4mg, 0.10mmol 1eq) handled 2 minutes with sodium borohydride.It with aqueous ammonium chloride quencher reaction, is used ethyl acetate extraction 3x, and the salt water washing of the organic layer of merging is through MgSO ₄Drying is filtered, evaporation and with 5% methyl alcohol in the methylene dichloride by preparing the TLC purifying, obtain 38mg 234.

MS：505.3(MH ⁺)

Preparation compound 235-237

Scheme 120:

Prepare these compounds with 115 times described similar approach of scheme.

MS 235：504.3(MH ⁺)

MS 236：476.3(MH ⁺)

MS 237：489.3(MH ⁺)

Scheme 121:

Preparation 250:

(400mg, 0.786mmol) de-gassed solution in 5mL THF is added in 0.5M KHMDS solution in the toluene (2.4ml, 1.2mmol 1.5eq.), and stirred 30 minutes to-78 ℃ 120.(125 μ l, 1.58mmol 2eq.), and stirred 30 minutes to add cyano methyl formate to this.The ferrous ammonium sulphate quencher is used in reaction, and uses the 3x ethyl acetate extraction.The organic layer salt water washing that merges is through MgSO ₄Drying is filtered, and concentrates and is used in 0% in the hexane to 20% ethyl acetate chromatography, obtains 394mg 250.

MS：566.3(MH ⁺)

Preparation 251:

Be added in methylene dichloride (2.3ml, 2.3mmol, 5eq.) the 1M BBr in to the solution of room temperature 250 (0.459mmol) in the 3mL methylene dichloride ₃Solution, and stirred 2 hours.Make the reaction quencher by adding water, and use dichloromethane extraction 3x.With the organic layer salt water washing that merges, through MgSO ₄Drying is filtered and is concentrated, and obtains 177mg 251, is a kind of solid.

MS：452.2(MH ⁺)

Preparation 252-254:

To room temperature 251 (20mg, 0.044mmol), tetramethyleneimine (11 μ l, 0.134mmol, 3eq), HOBt (9mg, 0.067mmol, 1.5eq) solution in the 0.75ml methylene dichloride add EDCI (13mg, 0.068mmol, 1.5eq), and in stirred overnight at room temperature.It is diluted with ethyl acetate, with 2x 1N HCl, salt water washing, through MgSO ₄Drying is filtered, and concentrates and with 0% to 3% methyl alcohol chromatography in the methylene dichloride, obtains 10mg 252.

Prepare compound 253 and 254 with similar approach.

MS 252：505.3(MH ⁺)

MS 253：491.3(MH ⁺)

MS 254：495.3(MH ⁺)

Preparation 255:

(390mg, 0.688mol) solution in 1: 1 methylene dichloride-trifluoroacetic acid stirred 1 hour and concentrated at 0 ℃, obtained 320mg255 with 250.

MS：466.3(MH ⁺)

Preparation 256:

(300mg, 0.643mmol) solution in 3mL THF is added in THF (1ml, 2mmol, 3eq.) the 2M LiBH in to room temperature 255 ₄Solution, and stirred 1.5 hours.It is used moisture NH ₄Cl quencher reaction, and use ethyl acetate extraction 3x.With the organic layer salt water washing that merges, through MgSO ₄Drying is filtered, and concentrates and with 0% to 3% methyl alcohol chromatography in the methylene dichloride, obtains 256mg 256.

MS：438.2(MH ⁺)

Preparation 257 and 258

To 0 ℃ 256 (50mg, 0.114mmol) solution in 1mL DMF be added in 60%NaH in the mineral oil (4.6mg, 0.115mmol, 1eq.), add subsequently methyl iodide (35 μ l, 0.562mol, 5eq).

Mixture was stirred 2 hours at 0 ℃, stirring at room 1 hour.It is diluted with ethyl acetate, and water, salt water washing 3x are through MgSO ₄Drying is filtered, and concentrates and is used in 0% to 4% methyl alcohol chromatography in the methylene dichloride, carries out subsequently that the overlapping fraction in 3% methyl alcohol prepares the TCL purifying in methylene dichloride, obtains 14mg 257 and 16mg 258.

MS 257：452.2(MH ⁺)

MS 258：466.3(MH ⁺)

Scheme 122:

Utilization is similar to 81 and changes into 84 method (square case 47), makes compound 120 change into compound 259,260 and 261 with suitable benzyl (benzylic) bromine.

Scheme 123:

Utilization is similar to 81 and is alkylated into 86 method, with intermediate 120 allyl bromide 98 alkylation, changes into 80 condition (square case 47) two keys are reduced with being similar to 79 then.

Scheme 124:

Preparation 263 and 264

0 ℃ with the solution stirring of 127 (30mg) in each 0.5mL methylene dichloride and trifluoroacetic acid 40 minutes, concentrate and, obtain 21mg 263 with 0% to 3% methyl alcohol chromatography in the methylene dichloride.

Utilization is similar to scheme 108 used conditions ethylizes intermediate 120, disconnects the Boc group in order to the protective condition that gets on then, obtains 264.

MS 263：418.2(MH ⁺)

MS 264：432.2(MH ⁺)

Scheme 125:

Preparation 265:

With 211 (70mg, 0.167mmol), tosic acid (R)-2,2-dimethyl-1,3-dioxolane-4-base methyl esters (145mg, 0.506mmol, 3eq.), K ₂CO ₃(93mg, 0.67mmol, 4eq), NaI (25mg, 0.166mmol, 1eq) mixture in 2ml DMF in sealed tube 80 ℃ the heating 2 days.It is diluted with ethyl acetate, with 1N HCl, salt water washing, through MgSO ₄Drying is filtered, and concentrates and with 0% to 4% methyl alcohol chromatography in the methylene dichloride, obtains the mixture of 82mg alkylate and unreacting material.With this mixture and the dense HCl of 1.5ml 1: 3v/v and dioxane stirring at room 4 hours.Mixture is diluted water, moisture NaHCO with ethyl acetate ₃With the salt water washing, through MgSO ₄Drying is filtered, and concentrates and with 0% to 5% methyl alcohol chromatography in the methylene dichloride, obtains 31mg 265.

MS：492.3(MH ⁺)

With the following compound of similar approach preparation.

Scheme 126:

With in the sealed tube 129 (30mg, 0.056mmol) and tetramethyleneimine (10eq.) mixture in 1ml NMP heated 60 minutes in 200 ℃ of microwave reactors for 46 μ l, 0.56mmol.It is diluted with ethyl acetate, and water, salt water washing are through MgSO ₄Drying is filtered, concentrate and with 4% methyl alcohol in the methylene dichloride by preparing the TLC purifying, obtain 17mg 269.

With similar approach preparation 270.

MS 269：457.3(MH ⁺)

MS 270：473.3(MH ⁺)

Scheme 127:

Preparation 271:

Add excessive NaBH to the solution of room temperature 229 (5mg) in 1: 1 v/v methylene chloride-methanol of 1mL mixture ₄, and stirring at room 10 minutes.With its water quencher reaction, use ethyl acetate extraction, use the salt water washing, through MgSO ₄Drying is filtered, concentrate and with 4% methyl alcohol in the methylene dichloride by preparing the TLC purifying, obtain 4mg 271.

MS：476.3(MH ⁺)

Preparation 272:

(60mg, 0.126mmol) solution in 2mL THF is added in the 1.4M MeMgBr solution in toluene/THF mixture to-78 ℃ 229.Reaction mixture was stirred 30 minutes at-78 ℃, then stirring at room 1.5 hours.It is used moisture NH ₄Ethyl acetate extraction 3x is used in Cl quencher reaction.With the organic layer salt water washing that merges, through MgSO ₄Drying is filtered, concentrate and with 4% methyl alcohol in the methylene dichloride by preparing the TLC purifying, obtain 20mg 272.

MS：490.3(MH ⁺)

Scheme 128:

Preparation 273 and 274

To-78 ℃ of 235 (65mg, 0.129mmol) adding of the solution in 2mL THF Ti (O ⁱPr) ₄(115 μ l, 0.388mmol, 3eq.), be added in subsequently 3M EtMgCl solution in the ether (0.39ml, 1.17mmol, 9eq.).Mixture was stirred 1 hour at-78 ℃, and stirring at room 2 hours.By adding moisture NH ₄The dilution of aqueous tartaric acid sodium potassium was stirred 20 minutes and was used in Cl quencher reaction.Slurry ethyl acetate extraction 3x, the organic layer of merging is used the salt water washing subsequently with the washing of aqueous tartaric acid sodium potassium.With its process MgSO ₄Drying is filtered, concentrate and with 4% methyl alcohol in the methylene dichloride by preparing the TLC purifying, obtain 33mg 273.

Similarly make 230 to change into 274.

MS 273：518.3(MH ⁺)

MS 274：504.3(MH ⁺)

Scheme 129:

Preparation 275:

With in the sealed tube 213 (25mg, 0.059mmol), NaN ₃(39mg, 0.60mmol) and NH ₄(32mg, 0.59mmol) mixture in 0.5ml DMF is 120 ℃ of heated overnight for Cl.Mixture is used ethyl acetate extraction 3x with 1N HCl dilution.With the organic layer salt water washing that merges, through MgSO ₄Drying is filtered and concentrated obtaining～30mg 275.

MS：470.3(MH ⁺)

Scheme 130:

Preparation 276:

To 130 (55mg, 0.133mmol) adding of the solution in 2mL ether Ti (O ⁱPr) ₄(120 μ l, 0.401mmol 3eq.), are cooled to-78 ℃, and (0.27ml, 0.81mmol 6eq.), stirred 10 minutes at-78 ℃, and stirring at room 1 hour to be added in 3M EtMgBr solution in the ether.Add BF to this ₃OEt ₂(101 μ l, 0.80mmol, 6eq), and stirring at room 1 hour.Pour mixture into aqueous tartaric acid sodium potassium, and use ethyl acetate extraction 3x.With the organic layer salt water washing that merges, through MgSO ₄Drying is filtered, and concentrates and with 0% to 4% methyl alcohol chromatography in the methylene dichloride, obtains 26mg 276.

MS：444.2(MH ⁺)

Scheme 131:

Utilization is similar to the chemical reaction of scheme 73 and 109 times alkylation conditions of giving of scheme, makes intermediate 126 and 120 change into compound 277-281.

Similar:

Scheme 132:

Utilization is similar to the condition of 109 times described conversions of scheme, makes intermediate 211 and 128 change into compound 282-287.

Scheme 133:

Utilization is similar to intermediate 124 and changes into 221 condition (square case 73 and scheme 109), makes intermediate 124 change into compound 288-292.

Similar:

Scheme 134:

Preparation compound 295:

Add hexaoxacyclooctadecane-6-6 to 250mg compound 120, mixture is dissolved in toluene and is evaporated to and do twice.Resistates in-78 ℃ of anhydrous THF of 3mL adds 2 equivalent hexamethyl dimethyl silanyl potassium amides (as the 0.5M toluene solution), mixture was stirred 1.5 hours under argon gas, subsequently with reaction mixture at O ₂Balloon stirred 2 hours down.Make mixture quencher reaction with moisture S-WAT then, and be warmed to room temperature.With mixture ethyl acetate extraction three times, MgSO is used in the salt water washing of the organic phase of merging then ₄Drying is filtered, and is evaporated to dried.By flash chromatography (0-40% acetone in the hexane) purifying, obtain 96mg compound 293.

Add hexaoxacyclooctadecane-6-6 to 45mg compound 293, mixture is dissolved in toluene and is evaporated to and do twice.Resistates in-78 ℃ of anhydrous THF of 3mL adds 2 equivalent hexamethyl dimethyl silanyl potassium amides (as the 0.5M toluene solution), with mixture stir about 1 hour under argon gas, add 10 equivalent iodoethane subsequently, after 2 hours, mixture is put into refrigerator spend the night.With reaction mixture with aqueous ammonium chloride quencher reaction, and with ethyl acetate extraction three times.With the organic phase salt water washing that merges, use MgSO ₄Drying is filtered, and is evaporated to dried.By flash chromatography (0-50% ethyl acetate in the hexane) purifying, obtain 12mg compound 294.

12mg compound 294 in 0 ℃ of 2mL anhydrous methylene chloride adds the 0.5mL trifluoroacetic acid, and stirs the mixture under nitrogen.After 1 hour, mixture is evaporated to dried, and is dissolved in toluene and is evaporated to and do twice, obtain 10mg 295.

MS 295：452.2(MH ⁺)

Preparation 296:

30mg 293 in 0 ℃ of 2mL dry DMF adds 2 equivalent sodium hydrides (5mg 60% NaH in mineral oil), and stirs the mixture under nitrogen.After 15 minutes, add 5 equivalent methyl iodide, and make mixture slowly be warmed to room temperature.After two hours, mixture is with aqueous ammonium chloride quencher reaction, and with ethyl acetate extraction three times.With the organic extract liquid salt water washing that merges, use dried over mgso, filter, be evaporated to dried.By flash chromatography (0-30%EtOAc in the hexane) purifying, obtain 15mg 296.

MS：538.3(MH ⁺)

Preparation 297:

13mg 296 in 0 ℃ of 1.5mL methylene dichloride adds the 1mL trifluoroacetic acid, and stirs the mixture under nitrogen 2 hours.Then reaction mixture is evaporated to driedly, and is dissolved in toluene and is evaporated to and do twice.Crude product obtains 5mg 297 by the reversed-phase HPLC purifying.

MS：438.2(MH ⁺)

Preparation 298:

30mg 293 in 0 ℃ of 2mL methylene dichloride adds the 1mL trifluoroacetic acid, and stirs the mixture under nitrogen 2 hours.Then reaction mixture is evaporated to driedly, and is dissolved in toluene and is evaporated to and do twice, obtain 24mg 298.

MS：424.2(MH ⁺)

Scheme 135:

100mg 120 in-78 ℃ of anhydrous THF of 3mL adds 2 equivalent hexaoxacyclooctadecane-6-6 and 2 equivalent hexamethyl dimethyl silanyl potassium amides (as the 0.5M toluene solution), and mixture was stirred 15 minutes under argon gas, adds 10 equivalent allyl iodides subsequently.1.5 after hour, mixture is poured on the aqueous ammonium chloride, and with ethyl acetate extraction three times.With the extraction liquid salt water washing that merges, use MgSO ₄Drying is filtered, and is evaporated to dried.Crude mixture obtains the mixture of 61mg compound 299 and 300 by flash chromatography purifying (0 to 20%EtOAc in the hexane).

This mixture in 0 ℃ of 2mL methylene dichloride adds the 1mL trifluoroacetic acid, and stirs the mixture under nitrogen 1 hour.Then reaction mixture is evaporated to driedly, and is dissolved in toluene and is evaporated to and do twice, obtain the mixture of 60mg compound 301 and 302.

Add 2 equivalents 2 to 301 and 302 mixtures in 3mL dioxane and 1mL water, 6-lutidine, 4 equivalent sodium periodates and 2% mole of perosmic anhydride (as 2.5% t-butanol solution), and under nitrogen, stir the mixture.After 5 hours, mixture was put into refrigerator 16 hours, subsequently mixture is poured on waterborne, and with dichloromethane extraction three times.With the extraction liquid salt water washing that merges, use MgSO ₄Drying is filtered, and is evaporated to driedly, obtains the mixture of 60mg compound 303 and 304.

To 303 and 304 mixture adding～10mg sodium borohydrides in 5mL methyl alcohol, mixture was stirred 10 minutes under nitrogen, then with aqueous ammonium chloride quencher reaction, and with dichloromethane extraction three times.With the extraction liquid salt water washing that merges, use MgSO ₄Drying is filtered, and is evaporated to dried.Crude product obtains 15mg 305 and 12mg 306 by the reversed-phase HPLC purifying.

MS 305：452.2(MH ⁺)

MS 306：468.3(MH ⁺)

Flow process 136:

Preparation 308:

98mg 256 in the 5mL anhydrous methylene chloride adds 2 equivalent sodium bicarbonates and 1.2 equivalent Dess-Martin reagent, and stirs the mixture under nitrogen.After 1 hour, aqueous carbonic acid hydrogen sodium and ether are joined reaction mixture, and stirred 10 minutes.Make to be separated the water extracted with diethyl ether.MgSO is used in the organic phase salt water washing that merges ₄Drying is filtered, and is evaporated to driedly, obtains 90mg aldehyde 307.

90mg 307 in 0 ℃ of anhydrous THF of 5mL adds 3 equivalent methylmagnesium-bromides (as the 1.4M toluene solution), and stirs the mixture under nitrogen.After 1 hour, add other 1 equivalent methylmagnesium-bromide (as the 1.4M toluene solution), after other 20 minutes, reaction mixture is with aqueous ammonium chloride quencher reaction, and with ethyl acetate extraction three times.MgSO is used in the organic phase salt water washing that merges ₄Drying is filtered, and is evaporated to driedly, obtains the 100mg crude product.By flash chromatography (0-2%MeOH among the DCM) purifying, obtain 6mg 308.

MS：452.2(MH ⁺)

Preparation 310:

22mg 308 in anhydrous methylene chloride adds 2 equivalent sodium bicarbonates and 1.2 equivalent Dess Martin reagent, and stirs the mixture under nitrogen.After 2 hours, reaction mixture is poured on the aqueous carbonic acid hydrogen sodium, and with ethyl acetate extraction three times.MgSO is used in the organic phase salt water washing that merges ₄Drying is filtered, and is evaporated to driedly, obtains the thick ketone 309 of 26mg.

The thick ketone 309 of 26mg in 0 ℃ of anhydrous THF of 5mL adds 5 equivalent methylmagnesium-bromides (as the 1.4M toluene solution), and stirs the mixture under nitrogen.After 3 hours, reaction mixture is with aqueous ammonium chloride quencher reaction, and with ethyl acetate extraction three times.With the organic phase salt water washing that merges, use MgSO ₄Drying is filtered, and is evaporated to dried.By flash chromatography (0-2%MeOH among the DCM) purifying, obtain 1.2mg 310.

MS：466.3(MH ⁺)

Scheme 137:

Similar with 112 preparations of acid amides in scheme 59 and the scheme 63, prepare multiple acid amides, sulphonamide, urea and carbamate with the acyl chlorides, SULPHURYL CHLORIDE, isocyanic ester and the chloro-formic ester that are fit to, obtain 311A to 311BB.

Scheme 138:

Preparation 312:

111 adding 5 equivalent propionic aldehyde and 5 equivalent sodium triacetoxy borohydrides in the anhydrous ethylene dichloride of 2mL, and under nitrogen, stir the mixture.After about 16 hours, reaction mixture is poured on the aqueous carbonic acid potassium, and with ethyl acetate extraction three times.With the organic phase salt water washing that merges, use MgSO ₄Drying is filtered, and is evaporated to dried.By flash chromatography (0-35% ethyl acetate in the hexane) purifying, obtain 25mg 312.

MS：493.3(MH ⁺)

Preparation 313:

40mg 111 in the anhydrous ethylene dichloride of 2mL adds 5 equivalent acetaldehyde and 5 equivalent sodium triacetoxy borohydrides, and stirs the mixture under nitrogen.After 16 hours, reaction mixture is poured on the aqueous carbonic acid potassium, and with ethyl acetate extraction three times.With the organic phase salt water washing that merges, use MgSO ₄Drying is filtered, and is evaporated to dried.Crude product obtains 5mg 313 by the reversed-phase HPLC purifying.

MS：465.3(MH ⁺)

Scheme 139:

Utilization is similar to 108 and changes into 112 method (square case 59), makes intermediate 120 change into amine 314, changes into multiple aminoderivative 315A-315Q then.

Scheme 140:

60mg 128 in the 1mL dry DMF adds 4 equivalent salt of wormwood and 5 equivalent 2-(chloromethyl)-3,5-two oxa-s oneself-1-alkene.After 1 minute, mixture had been heated to 65 ℃ of experience 3 hours with the argon gas bubbling in penstock.Reaction mixture is diluted with ethyl acetate, wash with water three times, with the salt water washing once, use MgSO ₄Drying is filtered, and is evaporated to dried.By flash chromatography (hexane-95: 5 DCM/MeOH) purifying, obtain 61mg 316.

MS：504.3(MH ⁺)

Scheme 141:

Preparation 318:

750mg 128 in the 10mL dry DMF adds 10 equivalent salt of wormwood and 10 equivalent N (2-bromotrifluoromethane) phthalic imidine.After 1 minute, mixture had been heated to 75 ℃ of experience 8 hours with the argon gas bubbling in penstock.Add other 5 equivalent salt of wormwood and 5 equivalent N (2-bromotrifluoromethane) phthalic imidine, and with mixture heated overnight in 75 ℃ of penstocks.Reaction mixture is diluted with ethyl acetate, wash with water three times, with the salt water washing once, use MgSO ₄Drying is filtered, and is evaporated to dried.By flash chromatography (hexane-95: 5 DCM/MeOH) purifying, obtain 1.08g compound 317.

30mg compound 317 in the 2mL methylene dichloride adds 300 μ L hydrazines, and stirs the mixture under nitrogen and spend the night.Reaction mixture is washed with water three times then, then with the moisture HCl extraction of 1N.Acid water washed with dichloromethane three times.Making acid water with aqueous carbonic acid potassium is alkalescence, uses dichloromethane extraction then three times.The alkaline extraction thing is merged, use MgSO ₄Drying is filtered, and is evaporated to driedly, obtains 5mg 318.

MS：447.2(MH ⁺)

Preparation 319:

40mg 318 in 2mL methylene dichloride and 2mL aqueous carbonic acid potassium adds 5 equivalent Acetyl Chloride 98Min.s, and stirs the mixture under nitrogen.After 3 hours, make to be separated twice of dichloromethane extraction of water.With the organic phase salt water washing that merges, use MgSO ₄Drying is filtered, and is evaporated to dried.Crude product obtains 12mg 319 by the reversed-phase HPLC purifying.

MS：489.3(MH ⁺)

Similar preparation compound 320-326.

Scheme 142:

Utilization is similar to scheme 73 and 109 times described methods of scheme, makes compound 124 change into compound 327-334.

Scheme 143:

Prepare compound 335 to 344 with being similar to 109 times described conversions of scheme 73 and scheme.

Scheme 144:

Prepare compound 345 to 353 with being similar to scheme 39, scheme 73 and 109 times described conversions of scheme.

The following compound of similar preparation:

Scheme 145:

30mg 357 in 1mL toluene adds 50 μ L water, 1.3 equivalent cyclopropane boric acid, 10% mole of tricyclohexyl phosphine and 5% mole of acetic acid palladium.After 2 minutes, mixture is being heated to 100 ℃ with the argon gas bubbling in penstock.After the heated overnight, add other 10% mole of tricyclohexyl phosphine and 5% mole of acetic acid palladium, and make temperature rise to 120 ℃.After other 16 hours, reaction mixture is poured on waterborne, and with ethyl acetate extraction three times.MgSO is used in the organic phase salt water washing that merges ₄Drying is filtered, and is evaporated to dried.By flash chromatography (0-45% ethyl acetate in the hexane) purifying, obtain 22mg 360.

MS：425.2(MH ⁺)

Scheme 146:

Prepare compound 361 to 370 with being similar to general flow A, scheme 29, scheme 39, scheme 73 and 109 times described conversions of scheme.

Scheme 147:

With ozone right-78 ℃ in 1: 1 v/v methylene chloride-methanol of 50mL solution 114 (2.6g, 6.39mmol) solution bubbling continue up to blueness.With nitrogen the excessive ozone bubbling is blown out, add the 3ml dimethyl thioether, stirred 20 minutes, stirred 30 minutes at 0 ℃ at-78 ℃.Add 3.5g K to this mixture ₂CO ₃, and stirring at room 1.5 hours.The mixture dilute with water is used ethyl acetate extraction 3x, and the salt water washing of the organic layer of merging is through MgSO ₄Drying is filtered, and evaporation obtains thick aldehyde.It is dissolved in 2: 1 v/v methyl alcohol-methylene dichloride of 30ml, is cooled to 0 ℃, add 240mg NaBH ₄Mixture was stirred 10 minutes, use moisture NH then ₄Cl quencher reaction.Slurry ethyl acetate extraction 3x, the salt water washing of the organic layer of merging is through MgSO ₄Drying is filtered, and evaporation obtains crude product.Crude product is left in the refrigerator as diethyl ether solution,, obtain 1.07g 371 the precipitated solid elimination.Filtrate is concentrated,, obtain 0.65g 372 with 0% to 5% methyl alcohol chromatography in the methylene dichloride.

MS 371：440.2(MH ⁺)

MS 372：440.2(MH ⁺)

Scheme 148:

Preparation 380

With compound 212 (860mg, 0.000156mol) be dissolved in DMF/MeOH (17mL, 1.58mL), add dppp (65mg, 10mol%), Pd (OAc) ₂(35mg, 10mol%) and Et ₃N (0.463mL, 2eq).Mixture is placed under the CO atmosphere, and 70 ℃ of heating 16 hours.Mixture is cooled to room temperature, adds NH ₄Cl (saturated), the gained mixture washes the extraction liquid that merges with water with EtOAc (x3) extraction, dry (MgSO ₄), concentrate.Resistates obtains the 675mg title compound by silica gel column chromatography (1: 3-3: 1 EtOAc/ hexane) purifying.LCMS：460.3(MH ⁺)

Scheme 149:

Preparation 381

Utilization is similar to and prepares 380 used methods, by compound 129 preparation compounds 381.LCMS：446.2(MH ⁺)

Scheme 150:

Preparation 382

With compound 380,675mg (0.00147mol) is dissolved in MeOH/THF (5.6mL/5.6mL), adds NaOH (3.37mL 1M solution), mixture is stirred spend the night.Organic solvent is under reduced pressure removed, and the solution with water dilution that stays after mixture is acidified to pH2, is filtered and collected the gained solid, obtains the 573mg title compound.LCMS：446.2(MH ⁺).

Scheme 151:

Preparation 383

Utilization is similar to and prepares 382 used methods, by compound 381 preparation compounds 383.LCMS：446.2(MH ⁺)

Scheme 152:

Preparation 384

With compound 382 (50mg 0.112mmol) is dissolved in DMF (2mL), add DIPEA (94 μ L, 5eq) and HATU (110mg, 2.5eq).Mixture was stirred 5 hours,, and use NH with the EtOAc dilution ₄Cl (saturated) washing.Organic layer is through MgSO ₄Drying under reduced pressure concentrated, by reversed-phase HPLC C18 (10: 90: 0.5 to 90: 10: 0.5MeCN/H ₂O/HCO ₂H) purifying obtains the 36mg title compound, LCMS:445.2 (MH ⁺).

Scheme 153:

Preparation 385A-385AAA

Utilization is similar to and prepares 384 used methods, by compound 383 and the suitable synthetic following compound of amine/amine hydrochlorate.

Scheme 154:

Compound 386A-386I

Utilization is similar to and prepares 384 used methods, by compound 382 and the suitable synthetic following compound of amine/amine hydrochlorate.

Scheme 155:

Preparation 387

With compound 382 (25mg 0.056mmol) is dissolved in DMF (1mL), add then DIPEA (23 μ L, 2.5eq), the methoxyl group acethydrazide (14.5mg, 2.5eq) and HATU (53mg, 2.5eq).Mixture was stirred 3 hours, dilute with EtOAc then.With mixture NH ₄Cl (saturated) washing, drying concentrates and is dissolved in THF (3mL).Be added in the 2-tertbutylimido-2-diethylamino-1 on the polystyrene, 3-dimethyl-perhydro-1,3,2-diaza phosphorus heterocycle hexene (PS-BEMP) (140mg, 5eq, 2.2mmol alkali/g) and TsCl (13.5mg, 1.2eq), heated the gained mixtures 15 minutes by microwave at 120 ℃.In case the mixture cool to room temperature filters mixture, concentrate, by reversed-phase HPLC C18 (10: 90: 0.5 to 90: 10: 0.5MeCN/H ₂O/HCO ₂H) purifying obtains the 17mg title compound, LCMS:514.3 (MH ⁺).

Scheme 156:

Preparation 388A-388D

Utilization is similar to and prepares 387 used methods, replaces with the carboxylic acid hydrazides that is fit to, by compound 382 synthetic following compounds.

Scheme 157:

Preparation 389A-389B

Utilization is similar to and prepares 387 used methods, synthesizes following compounds with the carboxylic acid hydrazides that is fit to by compound 383.

Scheme 158:

Preparation 390

(55mg 0.107mmol) is dissolved in CH with compound 387 ₂Cl ₂, and in ice-water bath, cool off.Add BBr ₃(45 μ L, 4.5eq), and with mixture stirring 4 hours.Slowly add water, the gained mixture was stirred 15 minutes.Mixture is extracted with EtOAc, use the salt water washing, concentrate, by reversed-phase HPLC C18 (10: 90: 0.5 to 90: 10: 0.5 MeCN/H ₂O/HCO ₂H) purifying obtains the 25mg title compound, LCMS:500.3 (MH ⁺).

Scheme 159:

Preparation 391

Utilization is similar to and prepares 390 used methods, by compound 389B synthetic compound 391.LCMS：486.3(MH ⁺).

Scheme 160:

Preparation 392

Step 1

With compound 382 (50mg 0.112mmol) is dissolved in DMF (1mL), add DIPEA (55 μ L, 3eq), the aminoacetaldehyde dimethylacetal (37 μ g, 3eq) and HATU (128mg, 3eq).Mixture was stirred 4 hours, dilute with EtOAc then.With mixture NH ₄Cl (saturated) washing, dry (MgSO ₄), concentrate and be dissolved in THF/1M HCl (3mL/3mL).Mixture was stirred 4 hours, dilute with EtOAc then.With mixture NaHCO ₃(saturated) washing, dry (MgSO ₄) and concentrate, obtain the 50mg product.

Step 2

With the product of step 1 (50mg 0.0113mmol) is dissolved in THF (3mL), add Burgess reagent (54mg, 2eq), with mixture in microwave 120 ℃ of heating 15 minutes.Mixture is concentrated, by reversed-phase HPLC C18 (10: 90: 0.5 to 90: 10: 0.5 MeCN/H ₂O/HCO ₂H) purifying obtains the 5mg title compound, LCMS:469.3 (MH ⁺).

Utilization is similar to and prepares 392 used methods, by compound 383 synthetic compounds 393.LCMS：455.3(MH ⁺).

Scheme 161:

Preparation 394

Step 1

(80mg 0.165mmol) is dissolved in CH with compound 386H ₂Cl ₂, add Dess-MartinPeriodinate (88mg), and mixture stirred 1 hour.Add EtOAc, add NaHCO subsequently ₃(saturated) and Sulfothiorine (saturated) stir mixture 1 hour, collected organic layer, dry (MgSO ₄) and concentrate, obtain the 74mg product.

Step 2

With the product of step 1 (74mg 0.0147mmol) is dissolved in THF (3mL), add Burgess reagent (65mg, 2eq), with mixture in microwave 120 ℃ of heating 15 minutes.Mixture is concentrated, by reversed-phase HPLC C18 (10: 90: 0.5 to 90: 10: 0.5 MeCN/H ₂O/HCO ₂H) purifying obtains the 7mg title compound, LCMS:484.3 (MH ⁺).

Scheme 162:

Preparation 395

With compound 383 (55mg 0.127mmol) is dissolved in DMF (2.5mL), add DIPEA (55 μ L, 2.5eq), the acetyl amidoxime (24mg, 2.5eq) and HATU (121mg, 2.5eq).With mixture stirring at room 3 hours, then by microwave 191 ℃ of heating 4 minutes.Behind cool to room temperature, mixture is diluted with EtOAc, use NH ₄Cl (saturated) washing, dry (MgSO ₄) and concentrate.Resistates passed through reversed-phase HPLC C18 (10: 90: 0.5 to 90: 10: 0.5MeCN/H ₂O/HCO ₂H) purifying obtains the 17mg title compound, LCMS:470.3 (MH ⁺).

Scheme 163:

Preparation 396

Utilization is similar to and prepares 395 used methods, by compound 382 synthetic compounds 396.LCMS：484.3(MH ⁺).

Scheme 164:

Preparation 397

Utilization is similar to and prepares 395 used methods, replaces the acetyl amidoxime with N-hydroxyl-2-methoxyl group ethanamidine, by compound 382 synthetic compounds 397.LCMS：514.3(MH ⁺).

Scheme 165:

Preparation 398

Utilization is similar to and prepares 390 used methods, by compound 397 synthetic compounds 398.LCMS：500.3(MH ⁺).

Scheme 166:

Preparation 399

With compound 384 (55mg 0.123mmol) is dissolved in N, dinethylformamide dimethylacetal (2mL), and 120 ℃ the heating 1.5 hours.Under reduced pressure remove excess reagent, (7 μ L 1.1eq) handled 1.5 hours at 90 ℃ resistates with the hydrazine hydrate in the acetate (1mL).Under reduced pressure remove volatile matter, resistates NaHCO ₃(saturated) handled, and mixture extracts with EtOAc, dry (MgSO ₄), concentrate, and passed through reversed-phase HPLC C18 (10: 90: 0.5 to 90: 10: 0.5MeCN/H ₂O/HCO ₂H) purifying obtains the 17mg title compound.LCMS：469.3(MH ⁺).

Scheme 167:

Preparation 400

Utilization is similar to and prepares 399 used methods, replaces hydrazine hydrate with methyl hydrazine, by compound 384 synthetic compounds 400.LCMS：483.3(MH ⁺).

Scheme 168:

Preparation 401

To be similar to the mode of compound 153, replace 3-(4-chloro-phenyl-) allyl amine synthetic compound 401 with 3-(4-chloro-phenyl-)-1 (R)-methacrylic amine.LCMS：422.2(MH ⁺).

Scheme 169:

Preparation 402 and 403

Step 1

(10g 0.045mol) is dissolved in THF (200mL), and makes mixture be cooled to-78 ℃ with 3-chloro-4-bromoanisole.Added through 5 minutes n-BuLi (18mL 2.5M hexane solution, 1eq).With the gained mixture-78 ℃ stir 30 minutes after, add DMF (5.24mL, 1.5eq).Mixture was stirred other 30 minutes, be warmed to room temperature then.Add NH ₄Cl (saturated), the mixture extracted with diethyl ether.The extract that merges washes with water, dry (MgSO ₄) and concentrate, obtain the product of step 1.

Step 2

Utilization is similar to synthetic compound 153 and 154 used methods, replaces 3-(4-chloro-phenyl-) allyl amine with 3-(4-chloro-phenyl-)-1 (R)-methacrylic amine, makes the product of step 1 change into compound 402 and 403.LCMS：87a，418.2(MH ⁺)，88a，418.2(MH ⁺).

Scheme 170:

Preparation 404

Utilization is similar to and prepares 72 used methods, by compound 402 preparation compounds 404.LCMS：404.2(MH ⁺)

Scheme 171:

Preparation 405

Utilization is similar to and prepares 72 used methods, by compound 403 preparation compounds 405.LCMS：404.2(MH ⁺)

Scheme 172:

Preparation 406

Utilization prepares compounds 406 with two steps by compound 404 to compound 129 and compound 380 described methods.LCMS：446.2(MH ⁺)

Scheme 173:

Preparation 407

Utilization is similar to and prepares 382 used methods, by compound 406 preparation compounds 407.LCMS：432.2(MH ⁺)

Scheme 174:

Preparation 408

Utilization is similar to and prepares 230 used methods, by compound 404 preparation compounds 408.LCMS：476.3(MH ⁺)

Scheme 175:

Preparation 409

Utilization is similar to and prepares 231 used methods, by compound 408 preparation compounds 409.LCMS：462.3(MH ⁺)

Scheme 176:

Preparation 410

Utilization is similar to and prepares 221 used methods, by compound 404 preparation compounds 410.LCMS：448.2(MH ⁺)

Scheme 177:

Preparation 411

Utilization is similar to and prepares 131 used methods, by compound 404 preparation compounds 411.LCMS：461.3(MH ⁺)

Scheme 178:

Preparation 412

To be similar to 137 mode, usefulness 3-(4-chloro-phenyl-)-1 (R)-methacrylic amine replaces 3-(4-chloro-phenyl-) allyl amine synthetic compound 412.LCMS：424.2(MH ⁺).

Scheme 179:

Step 1:

With (S)-2-methyl-2-propyl group sulfinyl amine (19.4g, 0.16mol), benzyloxy acetaldehyde (20g, 0.133mol) and anhydrous CuSO ₄(12.8g, 80mmol) in DCM (170mL) mixture at N ₂Down stirring at room 6 hours.Add the anhydrous CuSO of other 30g ₄(12.8g, 80mmol), and with mixture stirring at room 16 hours.Mixture is filtered by CELITE.Filtrate concentrates in a vacuum.Resistates obtains 420 (27.5g, 82%) with EtOAc (0 to the 50%) chromatography on silicagel column in the hexane.

Similar to racemize 2-methyl-2-sulfonyl propyl amine acquisition racemize 420.By racemize 420 preparation racemize final products, as racemize 428.

Step 2:

(in ether, 0.102mol) solution joins the following 50 ℃ of 4-chloro-phenyl-acetylene of argon gas (15g, the 0.11mol) solution in anhydrous diethyl ether (370mL), and refluxing 1 hour for 31.5mL, 3.0M with EtMgBr.Under argon gas, gained Grignard solution joined 420 (13g, 0.051mol) solution in DCM (150mL) at-78 ℃.Stirred the mixture 5 hours at-78 ℃, and stirring at room 16 hours.Reaction NH ₄Cl (saturated) quencher, and extract with EtOAc.With organic layer drying (MgSO ₄), and concentrate in a vacuum.(24g) is used for next step reaction with crude product.

(93mL, 4.0M 0.372mol) join the solution of above reacting coarse product (24g) in MeOH, and stirred 1.5 hours with the solution of HCl in dioxane at 0 ℃.Mixture is concentrated in a vacuum.Resistates dissolves with EtOAc, and uses NaHCO ₃(saturated) washing.With organic layer drying (MgSO ₄), and concentrate in a vacuum.Resistates obtains the mixture (7.3g, 50%) of 422a and 422b with EtOAc (0 to the 70%) chromatography on silicagel column in the hexane.According to final product (for example 434) ratio, the ratio of 422a and 422b is about 4: 1.

Similar to racemize 420 acquisition racemizes 422.By racemize 422 preparation racemize final products, as racemize 428.

Step 3:

With with shown in the scheme 4 similarly mode reduce alkynes 422, obtain cis-form olefin 423.

Step 4 and 5

With with similar mode shown in the scheme 73, make cis-form olefin 423 change into Diels-Alder precursor 424, change into Diels-Alder product 425 then.

Step 6:

Diels-Alder product 425 is ethylized, obtain 426 with similar mode shown in the scheme 52.

Step 7:

To be similar to the mode shown in the scheme 77, make intermediate 426 change into compound 427.Use pure BBr ₃Replace 1M solution.LCMS 427：450.2(MH ⁺)

With with similar mode separating compound 427 shown in the scheme 71, to obtain single enantiomer 427a and 427b.Chiralpac OD post is used for chirality HPLC to be separated.

LCMS 427a：450.2(MH ⁺)

LCMS 427b：450.2(MH ⁺)

Step 8:

With with similar mode shown in scheme 75 and 71, make compound 427 change into single enantiomer 428a and 428b.Chiralpac OD post is used for chirality HPLC to be separated.

LCMS 428a：452.2(MH ⁺)

LCMS 428b：452.2(MH ⁺)

Step 9:

(30mg, 0.066mmol) solution in anhydrous THF (1.3mL) joins NaH (15mg 0.33mmol), and stirred 0.5 hour with 427 in room temperature.(0.20mL 0.22mmol), and stirred 16 hours to add the bromoethyl methyl ether.React the water quencher, and extract with DCM.With organic layer drying (MgSO ₄), and concentrate in a vacuum.Resistates obtains racemize 431 (26mg, 76%) with EtOAc (0 to the 60%) chromatography on silicagel column among the DCM.LCMS：508.3(MH ⁺)

Utilize the alkylating agent that is fit to, similar to the following compound of 427 preparations:

Compound number	R	LCMS
Compound number	R	LCMS	429A	Me	464.3
429B	Et	478.3	429A	Me	464.3
429B	Et	478.3	429C	n-Pr	492.3

To be similar to mode shown in the scheme 75, by the following compound of precursor preparation (for example, preparing 430A) that is fit to by 429A.

Compound number	R	LCMS
Compound number	R	LCMS	430A	Me	466.3
430B	Et	480.3	430A	Me	466.3
430B	Et	480.3	430C	-CH ₂CH ₂OMe	510.3

Diels-Alder product 425 is transformed, obtain 432 with similar mode shown in the scheme 52:

LCMS 432：512.3(MH ⁺)

Scheme 180:

Synthetic 433 and 434

To be similar to the mode shown in above synthetic 428, make cis-form olefin 16 change into racemize 433.Be similar to scheme 109 the mode shown in the Synthetic 2 of being given 21, make racemize 433 change into single enantiomer 434, separate as carrying out chirality HPLC as described in the scheme 71 subsequently.Chiralpac OD post is used for chirality HPLC to be separated.

LCMS 433：434.2(MH ⁺)

LCMS 434：478.3(MH ⁺)

Scheme 181:

Synthetic 436-438:

To be similar to the mode shown in the scheme 39, make compound 433 change into 436,437 and 438.

LCMS 436：485.3(MH ⁺)

LCMS 437：484.3(MH ⁺)

LCMS 438：525.3(MH ⁺)

Scheme 182:

Synthetic 440:

To make commercially available 2-chloro-4-fluoro-phenyl aldehyde change into 440 with similar mode shown in scheme 1,2 and 64.LCMS：420.2(MH ⁺)

Scheme 183:

Synthetic 443-446

Step 1:

With with shown in scheme 1,2 and 179 similarly mode make commercially availablely 2,4-dimethoxy-phenyl aldehyde changes into intermediate 443.

Step 2:

With intermediate 443 (241mg, 0.624mmol), trifluoromethanesulfonic acid triisopropyl estersil (0.42mL, 1.6mmol) and pyridine (0.25mL, 3.1mmol) mixture in DCM (6mL) was stirring at room 1.5 hours.With solution NH ₄Cl (saturated) washing.With organic layer drying (MgSO ₄), and concentrate in a vacuum.Resistates obtains intermediate 444 (294mg, 87%) with MeOH (0 to the 15%) chromatography on silicagel column among the DCM.

Step 3:

To be similar to the mode shown in the scheme 39, make intermediate 444 change into 445.During triflate changed into nitrile group, the triisopropyl fracture obtained phenol.

445，LCMS：409.2(MH ⁺)

Step 4:

To be similar to the mode shown in the Synthetic 2 21 (square case 109), make compound 445 change into 446.

LCMS：453.2(MH ⁺)

Scheme 184:

Preparation compound 450-452:

Utilization is similar to 73 and changes into 78 method (square case 46), by intermediate 212 and 341 and suitable boric acid or boric acid ester prepare compound 450-452.

Preparation 453:

With 211 (160mg, 0.382mmol), O-(tolysulfonyl)-L-(-)-ethyl lactate (520mg, 1.91mmol, 5eq) (reference: Tetrahedron, 1985, vol.41, page541-546) and K ₂CO ₃(160mg, 1.16mmol, 3eq.) heated overnight in 100 ℃ of sealed tubes of the mixture in 3ml DMF.Mixture is diluted with ethyl acetate, with 1N HCl, salt water washing 3x, through MgSO ₄Drying is filtered, and concentrates and with 0% to 5% methyl alcohol chromatography in the methylene dichloride, obtains 204mg 453.

MS：518.3(MH ⁺)

Preparation 454:

(100mg, 0.21mmol) solution in 2mL THF is added in THF (0.5ml, 1mmol) the 2M LiBH in to room temperature 453 ₄Solution, and in stirring at room mixture 1 hour.Be poured into moisture NH ₄Cl uses ethyl acetate extraction 3x, and the salt water washing of the organic layer of merging is through MgSO ₄Drying is filtered, concentrate and with 0% in the methylene dichloride to 5% methyl alcohol chromatography, obtain 84mg 454.

MS：476.3(MH ⁺)

Preparation 455:

With 211 (40mg, 0.095mmol) and the mixture of～7 equivalent methylsulfonyl chlorides in the 1ml pyridine stir and spend the night.It is diluted with ethyl acetate, with 1N HCl, salt water washing 3x, through MgSO ₄Drying is filtered, concentrate and with 4% methyl alcohol in the methylene dichloride as elutriant by preparing the TLC purifying, obtain 16mg 455.

MS：496.3(MH ⁺)

Preparation 461

Utilize the used method of compound 390, prepare compound 461 by 388H.LCMS：514.3(MH ⁺).

Preparation 462

Utilization is similar to the used mode of compound 399, replaces the dimethyl formamide dimethylacetal with the N,N-DIMETHYLACETAMIDE dimethylacetal, by compound 384 preparation compounds 462.LCMS：483.3(MH ⁺).

Scheme 186:

Preparation 463

(110mg 0.2mmol) is dissolved in PhMe/EtOH/H with compound 212 ₂O (1.1mL/1.1mL/0.45mL).Add Pd (dppf) Cl ₂.CH ₂Cl ₂(15mg, 10mol%), Na ₂CO ₃(64mg, 3eq) and 1-methylpyrazole-4-boric acid pinacol ester (62mg, 1.5eq).Mixture was heated 20 minutes at 120 ℃ in microwave.Add NH ₄Cl (saturated), mixture extracts with EtOAc.With the extract drying, concentrate, then purifying (SiO ₂, hexane/EtOAc 2: 1-1: 2), obtain the 28mg title compound, LCMS:482.3 (MH ⁺).

Scheme 187:

Preparation 464

(94mg, 0.171mmol) (317mg 5eq) is dissolved in THF with 1-methyl-2-(tributyl stannyl) imidazoles with compound 212.Add Pd (Ph ₃P) ₄(60mg, 0.3eq), and with mixture 85 ℃ of heated overnight.Mixture is diluted with EtOAc, use NH ₄Cl (saturated), salt water washing, dry and concentrated.Purifying (SiO ₂, hexane/EtOAc 2: 1-1: 2) obtain the 20mg title compound, LCMS:482.3 (MH ⁺).

To be similar to 463 mode, the following compound of boric acid pinacol ester preparation that usefulness is fit to.

To be similar to 464 mode, the following compound of tributyl stannane preparation that usefulness is fit to.

Preparation 471

With the similar fashion of compound 211, by 5-(4-p-methoxy-phenyl)-2 (E), 4 (E)-pentadienoic acids prepare compound 471.LCMS 384.2(MH ⁺)。To be similar to the mode shown in the scheme 39, prepare following compound by 435 with organic boron that is fit to or organotin reagent:

LCMS 480：524.3(MH ⁺)

LCMS 481：537.3(MH ⁺)

LCMS 482：519.3(MH ⁺)

LCMS 483：539.3(MH ⁺)

LCMS 484：525.3(MH ⁺)

LCMS 485：526.3(MH ⁺)

LCMS 486：512.3(MH ⁺)

LCMS 487：498.3(MH ⁺)

LCMS 488：484.3(MH ⁺)

Preparation 4,5-two (mixing) aryl-octahydro-benzo [1,2,5] thiadiazoles 2,2-dioxide and 4,5-two (mixing) aryl-octahydro-benzimidazolyl-2 radicals-ketone

General flow M:

Can shown in above general flow M, prepare 4,5-two (mixing) aryl-octahydro-benzo [1,2,5] thiadiazoles 2,2-dioxide and 4,5-two (mixing) aryl-octahydro-benzimidazolyl-2 radicals-ketone (representing) by bg and bh.By handling and handle with trifluoromethanesulfanhydride anhydride subsequently with LDA (being lithium diisopropylamine), can produce triflate bc by ketone bb, gained triflate bc can carry out the Stille coupling with the hydrogenated vinyl tributyl tin, obtains diene bd.Diene bd and maleic anhydride carry out the Diels-Alder reaction, obtain acid anhydride be.Compound b e can reset (for example use people such as R.Seito, Bull.Chem.Soc.Jpn.59,1689 (1986) method, described document is attached to herein in full by reference) through Curtius, to generate diamines bf.By handling with SULPHURYL CHLORIDE and carbonyl dimidazoles respectively, can be easy to make diamines bf to change into compound b g and bh.

Synthetic different lactone and different lactan bl and bp

General flow N:

Can prepare different lactone bl and different lactan bp according to above general flow N.Styryl carbinol bi can with the propynoic acid coupling that replaces, obtain ester bj, ester bj can select to produce bk under the hydrogenation conditions.Bk carries out standard Diels-Alder cyclisation and reduces internal double bonds subsequently, and compound b l can be provided.The similar bi of making changes into amine bm.By reacting selective reduction subsequently, can make amine bm change into Diels-Alder precursor bo with propynoic acid.Bo carries out hot Diels-Alder reaction, can obtain lactan bp behind the two keys of reduction.

General flow:

Use the Diels-Alder reaction synthetic the comprising of formula I embodiment.By diolefinic acid I ^aWith allyl amine II ^aCoupling can be easy to prepare Diels-Alder precursor II I ^aAcid amides can be used the protective group (R that is fit to ^aBe protecting group), perhaps can anyly protect (R ^aBe hydrogen).At III ^aDuring through the Diels-Alder reaction, obtain cyclisation product IV ^aThe responsible multiple reaction conditions of the yield of the product in this step and selectivity is as the additive that uses in solvent for use, the used temperature of cyclisation, the reaction medium such as Lewis acid etc.After the Diels-Alder reaction, can introduce R ¹⁵The two keys of group and reduction are to provide V ^a, V ^aCan to disconnect protecting group, obtain VI through the past protective condition ^aCan make Ar ¹Or Ar ²Substituting group further functionalized or transform.R ^aThe unrestricted example of protecting group comprise the protecting group of all known protection nitrogen, the example can be found in people such as Green, (Protective Groups in Organic Synthesis by T.W.Greene and P.G.Wuts; 1999, Third edition, John Wiley ﹠amp; Sons, Inc.).Preferred acid amides protecting group includes but not limited to tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), to methoxy-benzyl, 3,4-dimethoxy-benzyl, allyl group, trimethyl silyl ethyl (TMSE), methoxymethyl (MOM), benzyloxymethyl (BOM), methoxyl group, t-butyldimethylsilyl (TBDMS), triisopropyl silyl (TIPS), methoxycarbonyl and ethoxy carbonyl etc.Preferred electrophilic reagent comprises for example optional alkylogen that replaces (for example methyl-iodide, iodoethane, propyl iodide, Br-CH ₂CH ₂-OTBS), the optional benzyl halide that replaces (for example, bromotoluene, to cyano-benzyl bromide, o-cyanobenzyl bromine and a cyano-benzyl bromide).Electrophilic reagent is can be by accepting the electron deficiency reagent that electron pair and another molecular reaction generate new key.Electrophilic reagent (also being Lewis acid) but positively charged, atom with band portion positive charge, perhaps have do not have electronics eight corners atom [referring to Mechanism and Theory in Organic Chemistry, T.H.Lowry and K.S.Richardson, Third edition, Harper Collins Publishers, Page 541].

Another embodiment of the invention is a kind of preparation formula V ^aThe method of compound,

R wherein ^aBe H or protecting group, R ³, R ¹⁵, Ar ¹And Ar ²As above definition, described method comprises

A) make formula I ^aCompound

With formula II ^aCompound:

Coupling is to obtain formula III ^aCompound

B) make formula III ^aThe compound cyclisation, to obtain formula IV ^aCompound

C) produce enolate, and with the electrophilic reagent reaction, with R ¹⁵Group is introduced formula III ^aCompound and

D) with IV ^aTwo key reduction of compound are to obtain formula V ^aCompound

One embodiment of the invention are a kind of acquisition formula V ^aThe method of compound, wherein R ^aFor H, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), to methoxy-benzyl, 3,4-dimethoxy-benzyl, allyl group or trimethyl silyl ethyl (TMSE), methoxymethyl (MOM), benzyloxymethyl (BOM), methoxyl group, t-butyldimethylsilyl (TBDMS), triisopropyl silyl (TIPS), methoxycarbonyl or ethoxy carbonyl, wherein said electrophilic reagent is an alkyl iodide.

Measure

Assessment cannaboid CB ₁And CB ₂The method of avidity

Carry out cannaboid CB by the film of cultivating by the cell preparation of expressing each receptor subtype (8 μ g pro) that is purchased ₁And CB ₂The competition of avidity is cultivated and is utilized buffer reagent A (5mMMgCl in conjunction with mensuration ₂, 2.5mM EDTA and 0.13%BSA) and middle 0.5nM ³H-CP55, the medicine of 940 (a kind of non-selective cannabinoid agonists) and 0.0001-3 μ M concentration.Non-specific binding is at 10 μ MCP55, and 940 existence are determined down.For saturated research, at 10 μ M CP55,940 exist and do not exist down with film and cultivate 0.1-5nM concentration ³H-CP55,940.After cultivating 1.5 hours, by termination test on the GF/C filter plate of filtering the processing of 0.3% polyvinylamine with the BRANDEL cell harvestor fast.With the plate drying, add the MICROSCINT scintillation mixed solution, use the quantitative assay of TOPCOUNT scintillometer in conjunction with radioactivity subsequently.

By in each radioligand concentration specific combination being mapped and, measuring by nonlinear regression analysis ³H-CP55,940 at CB ₁And CB ₂Dissociation constant (the K of acceptor _d).For competition research, suppress 50% ³H-CP55,940 in conjunction with (IC ₅₀) each drug level determine by the nonlinear regression analysis of radioligand displacement curve.The formula that utilization is derived by Cheng and Prusoff (1973) calculates avidity constant (K _i), it is defined as IC ₅₀/ 1+[ligand concentration/K _d].

GTP γ S is in conjunction with rules

Second messenger's effect uses GTP γ S in conjunction with test determination in the compound activating cells.Guanylic acid by agonist in conjunction with and activate after, phosphorylation in the plasma membrane of cell.Utilize the radio-labeling derivative of guanine triguaiacyl phosphate (GTP) in this test because it can not dephosphorylation, therefore at agonist in conjunction with the back accumulation.Antagonist enters this system simultaneously will make the agonist concentration curve move to right, and antagonist concentration increases thereupon, makes the bigger displacement of agonist dose response curve to the right.

Be purchased film with 10mM GDP cultivation, to allow enough substrate phosphorylations in the presence of agonist.Cultivated described film in advance 30 minutes with the test compound that increases concentration then, whether can stimulate phosphorylation separately to determine them.Add the non-selective cannabinoid agonists WIN55 that increases concentration, 122 in each concentration test compound existence or not then.Then room temperature culture experiment 1 hour.For finishing test, add ³⁵S-GTP γ S, and other 30 minutes of culture experiment.By termination test on the GF/C filter plate of filtering the processing of 10mM sodium phosphate with the BRANDEL cell harvestor fast.With the plate drying, add the Microscint scintillation mixed solution, use the quantitative assay of TOPCOUNT scintillometer in conjunction with radioactivity subsequently.

Test compound do not exist and in the presence of, right ³⁵S-GTP γ S bonded stimulates as agonist WIN55, the function construction of 122 concentration, and determine EC by nonlinear regression analysis with GraphPad Prism software ₅₀By test compound concentration with respect to dosage than [1-(EC ₅₀The EC of agonist+test compound/independent agonist ₅₀)] the mapping of negative logarithm, determine in the presence of test compound WIN55, the Schild analytical results of the right shift of 122 dose response curves.Linear regression analysis obtains Kb, and it is defined as the X-intercept of linear formula.

The preferred compound of formula I of the present invention and salt thereof, solvate or ester have about 200nM or littler K _iValue.In another embodiment, the compound of formula of the present invention (I) and salt, solvate or ester have about 100nM or littler K _iValue.In another embodiment, the compound of formula of the present invention (I) and salt, solvate or ester have about 50nM or littler K _iValue.In another embodiment, the compound of formula of the present invention (I) and salt, solvate or ester have about 20nM or littler K _iValue.In another embodiment, the compound of formula of the present invention (I) and salt, solvate or ester have about 10nM or littler K _iValue.In another embodiment, the compound of formula of the present invention (I) and salt, solvate or ester have about 5nM or littler K _iValue.In another embodiment, the compound of formula of the present invention (I) and salt, solvate or ester have about K of 10 to about 1nM _iValue.In another embodiment, the compound of formula of the present invention (I) and salt, solvate or ester have about K of 10 to about 0.1nM _iValue.In another embodiment, the compound of formula of the present invention (I) and salt, solvate or ester have about K of 10 to about 0.01nM _iValue.Embodiment 40,42,169,170,174,178,180,181,183,182,185,213,221,227,228,260,282,387,397,438,451,454,463 and 483 has about K of 10 to about 1nM _iValue.

Claims

1. the compound of a formula (I):

Or its pharmacy acceptable salt, solvate or ester, wherein:

M is 0 or 1, and n is 1 or 2, and m+n is 1 or 2;

Dotted line in the formula (I)

The expression valency requires singly-bound or two key of permission;

R ¹Be selected from-C (O)-N (R ¹⁰) ₂,-C (O)-O-alkyl and-C (O)-R ¹⁴

Wherein Q is selected from:

Y ¹For-O-or-N (R ⁷)-;

Y ²For-O-or-N (R ⁸)-;

R ⁹Be selected from H, TBS, TIPS, Tf and R ¹¹

R ¹⁶Be selected from R ⁹With-C (O)-R ¹²

R ¹⁹Be selected from H, TBS, TIPS, Tf and R ²¹

Two W ³Group forms carbonyl with their bonded ring carbon atoms;

Each W ⁴Independent is halogen or alkyl;

Ar ¹And Ar ²Independently be selected from R ¹²And R ¹³

Two X ³Group forms carbonyl with their bonded ring carbon atoms;

Each X ⁴Independent is halogen or alkyl;

Two Z groups form carbonyl with their bonded ring carbon atoms.

2. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester,

Wherein:

M is 0 or 1, and n is 1 or 2, and m+n is 1 or 2;

Dotted line in the formula (I)

The expression valency requires singly-bound or two key of permission;

Wherein Q is selected from:

Y ¹For-O-or-N (R ⁷)-;

Y ²For-O-or-N (R ⁸)-;

R ⁹Be selected from H, TBS, TIPS, Tf and R ¹¹

R ¹⁶Be selected from R ⁹With-C (O)-R ¹²

R ¹⁹Be selected from H, TBS, TIPS, Tf and R ²¹

Two W ³Group forms carbonyl with their bonded ring carbon atoms;

Each W ⁴Independent is halogen or (C ₁-C ₆) alkyl;

Ar ¹And Ar ²Independently be selected from R ¹²And R ¹³

Each X ¹Independently be selected from halogen ,-CN ,-O-R ¹⁹,-OH ,-O-S (O) ₂-(C ₁-C ₆) haloalkyl, unsubstituted (C ₆-C ₁₂) the aryl, (C that replaces with one or more Z groups ₆-C ₁₂) aryl, unsubstituted (C ₂-C ₁₀) the heteroaryl, (C that replaces with one or more Z groups ₂-C ₁₀) heteroaryl ,-O-(C ₃-C ₇) cycloalkyl ,-O-(C ₃-C ₇) cycloalkyl (C ₁-C ₆) alkyl ,-O-(C ₁-C ₆) alkylidene group-OR ¹⁹,-O-(C ₁-C ₆) alkylidene group-C (O) N (R ²⁰) ₂,-O-(C ₁-C ₆) alkylidene group-O-R ¹⁹, unsubstituted (C ₁-C ₆) the alkyl, (C that replaces with one or more U groups ₁-C ₆) alkyl, unsubstituted-O-(C ₁-C ₆) alkyl, with one or more U groups replace-O-(C ₁-C ₆) alkyl ,-O-(C ₂-C ₇) thiazolinyl ,-O-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkylidene group-OR ¹⁹,-O-(C ₁-C ₆) alkylidene group-C (O) R ²⁴,-O-(C ₁-C ₆) alkylidene group-C (O) OR ¹⁹,-O (C ₁-C ₆) alkyl ,-N (R ²⁵) ₂,-C (O) (C ₁-C ₆) alkyl ,-C (O) OH ,-C (O) O-(C ₁-C ₆) alkyl ,-C (O) O-(C ₃-C ₇) cycloalkyl ,-C (O) N (R ²⁵) ₂,-O-(C ₁-C ₆) alkylidene group-(C ₃-C ₅) Heterocyclylalkyl, use one or more W ³Group replaces-O-(C ₁-C ₆) alkylidene group-(C ₃-C ₅) Heterocyclylalkyl, unsubstituted (C ₃-C ₅) Heterocyclylalkyl, use one or more W ³Group replaces-(C ₃-C ₅) Heterocyclylalkyl ,-O-(C ₂-C ₇) alkenylene-O-(C ₁-C ₆) alkylidene group-O-R ²⁴,-O-(C ₁-C ₆) alkylidene group-N (R ²⁵) ₂,-O-(C ₁-C ₆) alkylidene group-C (O) N (R ²⁵) ₂, unsubstituted (C ₃-C ₇) cycloalkyl, use one or more W ⁴(the C that group replaces ₃-C ₇) cycloalkyl ,-S (O)-R ²⁴,-S (O) ₂-R ²⁴(C ₂-C ₇) thiazolinyl;

Two X ³Group forms carbonyl with their bonded ring carbon atoms;

Each X ⁴Independent is halogen or (C ₁-C ₆) alkyl;

Each Z independently is selected from-OH ,-O-(C ₁-C ₆) alkyl, halogen, (C ₁-C ₆) alkyl ,-CN ,-CF ₃, (C ₃-C ₇) cycloalkyl ,-(C ₁-C ₆) alkylidene group-OH ,-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkyl, with one or more being selected from-OH ,-O-(C ₁-C ₆) alkyl, halogen ,-CN, (C ₃-C ₇) cycloalkyl, (C ₃-C ₅) Heterocyclylalkyl, (C ₆-C ₁₂) aryl, (C ₂-C ₁₀) group of heteroaryl replaces-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkylidene group-O-(C ₆-C ₁₂) aryl ,-(C ₁-C ₆) alkylidene group-O-(C ₆-C ₁₂) aryl and with one or more be selected from halogen ,-CN ,-OH ,-O-S (O) ₂-(C ₁-C ₆) haloalkyl, (C ₆-C ₁₂) aryl, (C ₂-C ₁₀) heteroaryl and-O-(C ₁-C ₆) group of alkyl replaces-(C ₁-C ₆) alkylidene group-O-(C ₆-C ₁₂) aryl; Perhaps two Z groups form carbonyl with their bonded ring carbon atoms.

3. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, it has with following formula (II):

4. the compound of claim 3 or its pharmacy acceptable salt, solvate or ester, it has with following formula (IIA):

5. the compound of claim 4 or its pharmacy acceptable salt, solvate or ester, it has with following formula (IIB):

6. the compound of claim 4 or its pharmacy acceptable salt, solvate or ester, wherein:

Ar ¹And Ar ²Independently be selected from R ¹²And R ¹³

R ⁷Be selected from H, alkyl, thiazolinyl ,-alkylidene group-N (R ⁹) ₂,-alkylidene group-O-R ⁹,-alkylidene group-R ¹²,-C (O)-R ¹⁴,-alkylidene group-C (O) H and-C (O)-O-R ¹¹

R ⁹Be selected from H and alkyl;

Each R ¹⁵Independently be selected from H, alkyl, thiazolinyl ,-alkylidene group-R ¹²With-the O-thiazolinyl.

7. the compound of claim 6 or its pharmacy acceptable salt, solvate or ester, wherein:

Ar ¹For using one or more X ¹The phenyl that group replaces;

R ⁷Be H; And

R ¹⁵Be alkyl.

8. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, it has with following formula (III):

9. the compound of claim 8 or its pharmacy acceptable salt, solvate or ester, it has with following formula (IIIA):

Wherein:

Ar ¹And Ar ²Independently be selected from R ¹²And R ¹³

R ³And R ⁴Independent respectively is H or alkyl;

10. the compound of claim 9 or its pharmacy acceptable salt, solvate or ester, wherein:

R ³And R ⁴Respectively independent be H or-CH ₃

11. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, it has with following formula (IV):

12. the compound of claim 11 or its pharmacy acceptable salt, solvate or ester, it has with following formula (IVA):

Wherein:

Ar ¹And Ar ²Independently be selected from R ¹²And R ¹³

R ⁹Be selected from H and alkyl;

R ¹⁴Be selected from alkyl, unsubstituted cycloalkyl or use one or more X ⁴The cycloalkyl that group replaces;

Each R ¹⁸Independently be selected from H, R ¹²And R ¹⁴

13. the compound of claim 12 or its pharmacy acceptable salt, solvate or ester, wherein:

R ⁹Be selected from H and alkyl;

14. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, it has following formula V:

15. the compound of claim 14 or its pharmacy acceptable salt, solvate or ester, it has with following formula (VA):

Wherein:

R ⁷For H or-alkylidene group-R ¹²And

16. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, it has with following formula (VI):

17. the compound of claim 16 or its pharmacy acceptable salt, solvate or ester, it has with following formula (VIA):

Wherein:

R ⁹Be H or alkyl;

Ar ²Be selected from R ¹²And R ¹³

18. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, it has with following formula (VII):

19. the compound of claim 18 or its pharmacy acceptable salt, solvate or ester, it has with following formula (VIIA):

Wherein:

R ¹⁶For-C (O)-R ¹²And

20. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, it has with following formula (VIII):

21. the compound of claim 20 or its pharmacy acceptable salt, solvate or ester, it has with following formula (VIIIA):

Wherein:

R ³, R ⁴And R ⁵Respectively independent be H or-N (R ¹⁶) ₂

R ⁹Be selected from H and R ¹¹

R ¹⁶Be selected from R ⁹With-C (O)-R ¹²

22. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, wherein:

R ¹Be selected from-C (O)-N (R ¹⁰) ₂,-C (O)-O-alkyl and-C (O)-R ¹⁴And

23. the compound of claim 22 or its pharmacy acceptable salt, solvate or ester, it has with following formula (IB):

Wherein:

R ⁹Be selected from H and alkyl;

24. the compound of claim 22 or its pharmacy acceptable salt, solvate or ester, it has with following formula (IC):

Wherein:

R ¹For-C (O)-N (R ¹⁰) ₂Or-C (O)-O-alkyl;

R ¹⁵For H or-OH.

25. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, it has with following formula (ID):

26. the compound of claim 25 or its pharmacy acceptable salt, solvate or ester, it has with following formula (IE):

27. the compound of claim 25 or its pharmacy acceptable salt, solvate or ester, wherein:

Y ¹Be NH or N-Boc;

R ³Be H or alkyl;

R ⁴Be H or alkyl;

R ¹⁵Be alkyl; And

28. the compound of claim 27 or its pharmacy acceptable salt, solvate or ester, wherein:

Each X ¹Independently be selected from halogen ,-CN ,-OH ,-the O-cycloalkyl ,-the O-cycloalkylalkyl ,-O-alkylidene group-OR ¹⁹,-O-alkylidene group-C (O) N (R ²⁰) ₂,-O-alkylidene group-O-R ¹⁹, unsubstituted alkyl, the alkyl that replaces with one or more U groups, unsubstituted-the O-alkyl, with one or more U groups replacements-the O-alkyl ,-the O-thiazolinyl ,-O-alkylidene group-O-alkylidene group-OR ¹⁹,-O-alkylidene group-C (O) R ²⁴,-O-alkylidene group-C (O) OR ¹⁹With-the O-alkyl.

29. the compound of claim 27 or its pharmacy acceptable salt, solvate or ester, wherein:

30. the compound of a formula (ID),

Or its pharmacy acceptable salt, solvate or ester, wherein:

Y ¹Be NH or N-Boc;

R ³Be H or alkyl;

R ⁴Be H or alkyl;

R ¹⁵Be alkyl;

31. the compound of a formula (IE),

Or its pharmacy acceptable salt, solvate or ester, wherein:

Y ¹Be NH or N-Boc;

R ³Be H or alkyl;

R ⁴Be H or alkyl;

R ¹⁵Be alkyl; And

32. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, wherein:

Each R ¹⁵Independently be selected from H ,-N ₃, halogen, thiazolinyl ,-alkylidene group-R ¹²,-alkylidene group-O-R ⁹,-alkylidene group-N (R ¹⁸) ₂,-alkylidene group-C (O) H ,-OH ,-CN ,-the O-alkyl ,-C (O) N (R ¹⁸) ₂,-N (R ¹⁸) ₂,-NHC (O) R ¹⁸,-NHC (O) ₂R ¹⁸,-NR ¹⁸C (O) N (R ¹⁸) ₂,-NHS (O) ₂R ¹⁸,-O-thiazolinyl ,-C (O) ₂R ¹⁸, unsubstituted alkyl, the alkyl that replaces with one or more U groups ,-O-alkylidene group-C (O) R ¹⁸Or-C (O) R ¹⁸

Its condition is wherein said group-N (R ¹⁸) ₂Two R ¹⁸Group forms unsubstituted Heterocyclylalkyl, uses one or more X with their bonded N atoms ³The Heterocyclylalkyl that group replaces, perhaps described replacement or unsubstituted Heterocyclylalkyl and aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl condense.

33. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, wherein:

Each R ¹⁵Independently be selected from H ,-OH ,-OCH ₃,-OCH ₂CH ₃,-CH ₃,-CH ₂CH ₃,-CH ₂CH ₂CH ₃,-N ₃,-NH ₂,-CO ₂H ,-CO ₂CH ₃,-CH ₂OH ,-CH ₂CH ₂OH ,-CH ₂CH ₂OTBS ,-CH ₂OCH ₃,-OCH ₂CH ₂OH,

34. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, wherein:

R ³And R ⁴Independently be selected from respectively H ,-O-R ⁹, R ¹¹With-N (R ¹⁶) ₂

35. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, wherein:

Each R ³And R ⁴Independently be selected from H ,-CH ₃,-CH ₂OH ,-CH ₂OCH ₂CH ₂OCH ₃,-CH ₂OCH ₃,-CH ₂OCH ₂CH ₃,-CH ₂OCH ₂CH ₂CH ₃,-CH ₂CH ₂OH,

36. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, wherein

R ⁷Be selected from H, alkyl, arylalkyl, thiazolinyl ,-alkylidene group-N (R ⁹) ₂,-alkylidene group-O-R ⁹,-alkylidene group-R ¹²,-C (O)-R ¹⁴,-alkylidene group-C (O) H ,-C (O)-O-R ¹¹And Boc.

37. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, wherein

R ⁷For H ,-CH ₃, Boc,

38. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, wherein

Ar ¹For using one or more X ¹The phenyl that group replaces; And

Its condition is wherein said group-N (R ²⁰) ₂Or-N (R ²⁵) ₂Two R ²⁰Or R ²⁵Group forms unsubstituted Heterocyclylalkyl, uses one or more X with their bonded N atoms ³The Heterocyclylalkyl that group replaces, perhaps described replacement or unsubstituted Heterocyclylalkyl and aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl condense.

39. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, wherein:

Each X ¹Independently be selected from Cl, F ,-CH ₃,-OCH ₃,-OCH ₂CH ₃,-OH ,-OTf ,-CN ,-OCH ₂CH ₃,-OCH (CH ₃) ₂,

40. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, wherein

X ¹Be selected from-OH ,-CN, halogen ,-OTIPS ,-OTf, alkyl ,-the O-alkyl ,-O-alkyl-OH and heteroaryl; And

X ²Be selected from halogen and cycloalkyl.

41. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, wherein

Ar ²For using one or more X ¹The phenyl that group replaces or use one or more X ²The pyridyl that group replaces,

X ¹Be selected from-OH ,-CN, Cl ,-OTIPS ,-CH ₃,-OCH ₃,-OCH ₂CH ₃,-OTf and

And

X ²Be selected from Cl, Br and

42. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, it has with following formula (IF) or (IFa):

43. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, it has with following formula (IG):

44. the compound of claim 1 or its pharmacy acceptable salt, solvate or ester, it has with following formula (IH):

45. a compound or its pharmacy acceptable salt, solvate, ester or steric isomer, it is selected from:

46. the purifying compounds of claim 1.

47. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

48. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

49. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

50. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

51. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

52. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

53. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

54. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

55. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

56. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

57. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

58. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

59. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

60. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

61. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

62. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

63. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

64. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

65. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

66. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

67. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

68. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

69. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

70. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

71. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

72. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

73. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

74. compound with following structural formula:

Or its pharmacy acceptable salt, solvate or ester.

75. a composition, described composition comprises:

The compound of the formula of at least a claim 1 (I) or its pharmacy acceptable salt, solvate or ester; With

At least a decreasing cholesterol compound.

76. the composition of claim 75, wherein said at least a decreasing cholesterol compound are at least a sterol absorption inhibitor or at least a 5 α-stanols absorption inhibitor.

77. the composition of claim 75, the azetidinone compounds that wherein said at least a decreasing cholesterol compound is at least a replacement or 'beta '-lactam compounds or its pharmacy acceptable salt, solvate or the ester of replacement.

78. the composition of claim 75, wherein said at least a decreasing cholesterol compound is Yi Zemaibu.

79. a method for the treatment of disease, disorder or illness, described method comprise compound or its pharmacy acceptable salt, solvate or the ester of at least a claim 1 that the patient treatment of needs significant quantity is arranged; Wherein said disease, disorder or illness are selected from obesity, metabolism disorder, addiction, central nervous system disease, cardiovascular disorder, respiratory disease, gastrointestinal dysfunction, lose weight, reduce waistline, the treatment hyperlipemia, insulin sensitivity, diabetes, hypertriglyceridemia, eating disorder, alcoholism, inflammation, mental disorder, migraine, nicotine dependence, Parkinson's disease, psychosis, schizophrenia, somnopathy, attention deficit hyperactivity disorder, male sexual disorder, premature ejaculation, premenstrual tension syndrome, epileptic seizures, epileptics and convulsions, non-insulin-dependent diabetes mellitus (NIDDM), dull-witted, major depressive disorder, bulimia nervosa, pharmacological dependence, septic shock, cognitive disorder, endocrine disorder, eczema, vomiting, irritated, glaucoma, hemorrhagic shock, hypertension, stenocardia, thrombosis, arteriosclerosis, restenosis, hypertension, acute coronary syndrome, stenocardia, arrhythmia, in heart failure, cerebral ischemia, apoplexy, myocardial infarction, glomerulonephritis, thrombotic apoplexy and thromboembolic stroke, peripheral vascular disease, neurodegenerative disease, osteoporosis, tuberculosis, autoimmune disease, ypotension, joint disease, cancer, demyelinating disease, alzheimer's disease, the hyposexuality obstacle, the bipolarity obstacle, hyperlipidaemia, hypertension, narcotic dependence, Huntington chorea, pain, multiple sclerosis, anxiety disorder, osteopathy, Paget's disease, rheumatoid arthritis, ulcerative colitis, irritable bowel syndrome and inflammatory bowel.

80. the method for claim 79, wherein said disease, disorder or illness are metabolism syndrome.

81. further comprising, the method for claim 79, described method give at least a other activeconstituentss.

82. the method for claim 81, wherein said at least a other activeconstituentss are the decreasing cholesterol compound.

83. the method for claim 81, wherein said at least a other activeconstituentss are at least a sterol absorption inhibitor or at least a 5 α-stanols absorption inhibitor.

84. the method for claim 81, the azetidinone compounds that the wherein said at least a decreasing cholesterol compound of wherein said at least a other activeconstituentss is at least a replacement or 'beta '-lactam compounds or its pharmacy acceptable salt, solvate or the ester of replacement.

85. the method for claim 81, wherein said other activeconstituentss are Yi Zemaibu.

86. preparation formula V ^aThe method of compound,

R wherein ^aBe H or protecting group;

R ⁹Be selected from H, TBS, TIPS, Tf and R ¹¹

R ¹⁶Be selected from R ⁹With-C (O)-R ¹²

R ¹⁹Be selected from H, TBS, TIPS, Tf and R ²¹

Two W ³Group forms carbonyl with their bonded ring carbon atoms;

Each W ⁴Independent is halogen or alkyl;

Ar ¹And Ar ²Independently be selected from R ¹²And R ¹³

Two X ³Group forms carbonyl with their bonded ring carbon atoms;

Each X ⁴Independent is halogen or alkyl;

Two Z groups form carbonyl with their bonded ring carbon atoms;

Described method comprises

A) make formula I ^aCompound

With formula II ^aCompound:

Coupling is to obtain formula III ^aCompound

B) make formula III ^aThe compound cyclisation, to obtain formula IV ^aCompound

D) with IV ^aTwo key reduction of compound are to obtain formula V ^aCompound

87. the method for claim 86, wherein Ra be H, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), to methoxy-benzyl, 3,4-dimethoxy-benzyl, allyl group or trimethyl silyl ethyl (TMSE), methoxymethyl (MOM), benzyloxymethyl (BOM), methoxyl group, t-butyldimethylsilyl (TBDMS), triisopropyl silyl (TIPS), methoxycarbonyl or ethoxy carbonyl.

88. the method for claim 86, wherein said electrophilic reagent are alkyl iodide.