CN101282963A

CN101282963A - Pyrazole derivatives as therapeutic agents

Info

Publication number: CN101282963A
Application number: CNA2006800374501A
Authority: CN
Inventors: M·阿尔奎斯特; 程磊峰; R·伦德奎斯特; H·索伦森
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2005-08-13
Filing date: 2006-08-09
Publication date: 2008-10-08
Also published as: AR055368A1; NO20080372L; CA2619228A1; GB0516661D0; AU2006281300A1; TW200728300A; ZA200800698B; ECSP088250A; WO2007020388A1; JP2009504717A; BRPI0614626A2; EP1915364A1; RU2008108179A; KR20080039939A; MX2008002065A; IL188759A0; UY29741A1

Abstract

Salts of 1,5-diarylpyrazole-3-carboxamides and processes for preparing such compounds, their use in the treatment of obesity, psychiatric and neurological disorders, to methods for their therapeutic use and to pharmaceutical compositions containing them.

Description

Pyrazole derivatives as curative

Invention field

The present invention relates to some 1, the salt of 5-diaryl pyrazole-3-methane amide, the method for preparing these compounds, their purposes in treatment of obesity, mental disorder and sacred disease, the pharmaceutical composition that is used for the treatment of the method for purposes and contains them.

Background of invention

Clear, some CB ₁Conditioning agent (being called antagonist or inverse agonists) is used for the treatment of obesity, mental disorder and sacred disease (WO 01/70700, EP 658,546 and EP656,354).Yet, still need to have the CB of improved physico-chemical property and/or DMPK character and/or pharmacodynamic property ₁Conditioning agent.WO 95/15316, WO 96/38418, WO97/11704, WO 99/64415, EP 418845 and WO2004050632 disclose the pyrazole compound with anti-inflammatory activity.WO2004050632 discloses [2-[4-[3-[(ethyl methylamino-) carbonyl]-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group] ethyl] carboxylamine 1,1-dimethyl ethyl ester, 5-[4-(2-amino ethoxy) phenyl]-N-ethyl-1-(4-p-methoxy-phenyl)-N-methyl isophthalic acid H-pyrazole-3-formamide, 1-[[5-[4-(2-amino ethoxy) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl] carbonyl] piperidines and [2-[4-[1-(4-p-methoxy-phenyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] phenoxy group] ethyl] carboxylamine 1,1-dimethyl ethyl ester.All compounds and salt thereof that WO2004050632 exemplified are not included in the scope of The compounds of this invention claim.

US 5,624, and 941, WO 01/29007, WO 2004/052864, WO03/020217, US 2004/0119972, Journal of Medicinal Chemistry, 46 (4), 642-645,2003, Bioorganic ﹠amp; Medicinal Chemistry Letters, 14 (10), 2393-2396,2004, Biochemical Pharmacology, 60 (9), 1315-1323,2000, Journal of Medicinal Chemistry, 42 (4), 769-776,1999 and U.S. Patent Application Publication No. US 2003199536 disclose and had CB ₁Regulate active 1,5-diaryl pyrazole-3-carboxamides derivatives.

The PCT application number PCT/GB2005/000534 of pending trial discloses compound and the pharmacy acceptable salt thereof of following formula A simultaneously:

Wherein

R ¹The C that expression a) is replaced by one or more following groups _1-3Alkoxyl group: i) fluorine, ii) group NR ^cR ^d, R wherein ^cAnd R ^dIndependent expression H, C _1-6Alkyl or C _1-6Alkoxy carbonyl, precondition are R ^cAnd R ^dOne of be not H, perhaps iii) 1,3-dioxolane-2-base; B) R ¹The optional C that is replaced by one or more following groups of expression _4-6Alkoxyl group: i) fluorine, ii) group NR ^cR ^d, R wherein ^cAnd R ^dIndependent expression H, C _1-6Alkyl or C _1-6Carbalkoxy, precondition are R ^cAnd R ^dOne of be not H, perhaps iii) 1,3-dioxolane-2-base; C) formula phenyl (CH ₂) _pThe group of O-, wherein p is 1,2 or 3, and benzyl ring is chosen wantonly by 1,2 or 3 by the represented group replacement of Z, d) radicals R ⁵S (O) ₂O or R ⁵S (O) ₂NH, wherein R ⁵The optional C that is replaced by one or more fluorine of expression _1-6Alkyl, perhaps R ⁵Expression phenyl or heteroaryl, wherein any group is optional is replaced by the represented group of Z by 1,2 or 3; E) formula (R ⁶) ₃The group of Si, wherein R ⁶Expression can be identical or different C _1-6Alkyl; Perhaps f) formula R ^bThe group of O (CO) O, wherein R ^bThe optional C that is replaced by one or more fluorine of expression _1-6Alkyl;

R ^aExpression halogen, C _1-3Alkyl or C _1-3Alkoxyl group;

M is 0,1,2 or 3;

R ²Expression C _1-3Alkyl, C _1-3Alkoxyl group, hydroxyl, nitro, cyano group or halogen;

N is 0,1,2 or 3;

R ³Expression

A) radicals X-Y-NR ⁷R ⁸

Wherein X is CO or SO ₂,

Y does not exist, and perhaps expression is optional by C _1-3The NH that alkyl replaces;

R ⁷And R ⁸Independent expression:

Optional by 1,2 or 3 C that replaces by the represented group of W _1-6Alkyl;

Optional by 1,2 or 3 C that replaces by the represented group of W _3-15Cycloalkyl;

Optional by 1,2 or 3 (C that replaces by the represented group of W _3-15Cycloalkyl) C _1-3Alkylidene group;

Group-(CH ₂) _r(phenyl) _s, wherein r is 0,1,2,3 or 4, s is 1 when r is 0, otherwise s is 1 or 2, phenyl is optional to be replaced by the represented group of Z by 1,2 or 3 independently;

The 5-8 unit saturated heterocyclyl that contains 1 nitrogen and optional 1 following atom: oxygen, sulphur or another nitrogen, wherein heterocyclic radical is optional by one or more C _1-3Alkyl, hydroxyl or benzyl replace;

Group-(CH ₂) _tHet, wherein t is 0,1,2,3 or 4, alkylidene chain is optional by one or more C _1-3Alkyl replaces, and Het represents aromatic heterocycle, chooses wantonly and is selected from C by 1,2 or 3 _1-5Alkyl, C _1-5The group of alkoxy or halogen replaces, and wherein alkyl and alkoxyl group are optional is replaced by one or more fluorine independently;

Perhaps R ⁷Expression H, R ⁸As above definition;

Perhaps R ⁷And R ⁸Represent the first saturated or undersaturated heterocyclic radical of part of the 5-8 that contains 1 nitrogen-atoms and choose 1 following atom wantonly with the nitrogen-atoms that they connected: oxygen, sulphur or another nitrogen; Wherein heterocyclic radical is optional by one or more C _1-3Alkyl, hydroxyl, fluorine or benzyl replace;

Perhaps b) oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazyl, thienyl, furyl Huo oxazolinyl,

Described each group is optional to be replaced by 1,2 or 3 group Z;

R ⁴Expression H, halogen, hydroxyl, cyano group, C _1-6Alkyl, C _1-6Alkoxyl group or contain the C of maximum 6 carbon atoms _1-6Alkoxy C _1-6Alkylidene group, described each group is optional to be replaced by one or more fluorine or cyano group;

Z represents C _1-3Alkyl, C _1-3Alkoxyl group, hydroxyl, halogen, trifluoromethyl, trifluoromethylthio, difluoro-methoxy, trifluoromethoxy, trifyl, nitro, amino, a C _1-3Alkylamino, two C _1-3Alkylamino, C _1-3Alkyl sulphonyl, C _1-3Carbalkoxy, carboxyl, cyano group, formamyl, a C _1-3Alkyl-carbamoyl, two C _1-3Alkyl-carbamoyl and ethanoyl;

W represents hydroxyl, fluorine, C _1-3Alkyl, C _1-3Alkoxyl group, amino, a C _1-3Alkylamino, two C _1-3Alkylamino, C _1-6Carbalkoxy, perhaps for being selected from the heterocycle amido of morpholinyl, pyrrolidyl, piperidyl or piperazinyl, wherein the heterocycle amido is optional by C _1-3Alkyl or hydroxyl replace;

But do not comprise [2-[4-[3-[(ethyl methylamino-) carbonyl]-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group] ethyl] carboxylamine 1,1-dimethyl ethyl ester and [2-[4-[1-(4-p-methoxy-phenyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] phenoxy group] ethyl] carboxylamine 1,1-dimethyl ethyl ester.

The generic term of salt is explained in the following manner in PCT/GB2005/000534: " pharmacy acceptable salt " is possible comprising this class salt of pharmaceutically-acceptable acid addition and base addition salt.The suitable pharmacy acceptable salt of formula A compound is for for example having the acid salt of the formula A compound of enough alkalescence, for example with the acid salt of mineral acid or organic acid (for example hydrochloric acid, Hydrogen bromide, sulfuric acid, trifluoroacetic acid, citric acid or toxilic acid); The salt that perhaps for example has enough tart formula A compounds, for example salt of an alkali metal salt or alkaline earth salt (for example sodium salt, calcium salt or magnesium salts) or ammonium salt or the organic bases salt of (for example with methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three-(2-hydroxyethyl) amine).

Two kinds of concrete salt of formula A compound are only disclosed among the PCT/GB2005/000534.They are: pyridine-3-sulphonic acid 4-{1-(2; the 4-dichlorophenyl)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenyl ester hydrochloride and 1-(2; the 4-dichlorophenyl)-and 5-{4-[2-(ethylamino) oxyethyl group] phenyl }-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide dihydrochloride, two all are not included in the present invention's scope required for protection.

Have now found that and have other salt that suitable character is used for pharmaceutical preparation.

When pharmaceutical compositions, the medicament forms of being convenient to handle and process is crucial.Not only from the viewpoint of the manufacturing process that obtains viable commercial, but also comprise the viewpoint of the pharmaceutical preparation of active compound from preparation subsequently, this all is important.

In addition, when pharmaceutical compositions, importantly after giving the patient, can provide reliable, can reproduce and the medicine of constant plasma levels feature.

The chemical stability of activeconstituents, solid-state stability and " storage life " equally also are important factors.The medicine and the composition that contain activeconstituents should preferably can be preserved in one considerable period effectively, and obvious variation does not take place the physico-chemical property of active ingredient (for example its chemical constitution, density, water absorbability and solubleness).

In addition, it is also important that medicine provides with chemically pure as far as possible form.

The technician generally it should be understood that if easily obtain medicine with stable form (for example stable crystal formation), then can provide various advantages with regard to being easy to handle, be easy to prepare suitable pharmaceutical preparation and more reliable solvability feature.

Detailed Description Of The Invention

The invention provides the mesylate, half-1 that is selected from following compound, 5-napadisilate, 1,2-ethanedisulphonate, hydrochloride or hydrosulfate form:

(1) butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester;

(2) 1-(2,4 dichloro benzene base)-4-methyl-5-[4-(4,4,4-trifluoro butoxy) phenyl]-N-piperidines-1-base-1H-pyrazole-3-formamide;

(3) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester;

(4) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(morpholine-4-base formamyl)-2H-pyrazole-3-yl] phenyl ester;

(5) 3,3,3-trifluoro propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester;

(6) 4,4,4-trifluoro butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester;

(7) propane-1-sulfonic acid [2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl]-2,6-difluoro phenyl ester;

(8) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester;

(9) propane-1-sulfonic acid 4-[4-bromo-2-(2,4 dichloro benzene base)-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester;

(10) oxygen base 1-{[(1-(2,4 dichloro benzene base)-4-methyl-5-{4-[(third alkylsulfonyl)] phenyl }-the 1H-pyrazole-3-yl) carbonyl] amino } the cyclopentane-carboxylic acid methyl esters;

(11) carbonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl]-the phenyl ester propyl ester;

(12) thiophene-2-sulfonic acid 4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenyl ester;

(13) pyridine-3-sulphonic acid 4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenyl ester;

(14) [2-(4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenoxy group) ethyl] the ethyl carbamic acid tert-butyl ester;

(15) 3-methylbutane-1-sulfonic acid 4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenyl ester;

(16) 3,3-dimethylbutane-1-sulfonic acid 4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenyl ester;

(17) 1-(2,4 dichloro benzene base)-5-{4-[2-(1,3-dioxolane-2-yl) oxyethyl group] phenyl }-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide;

(18) propane-1-sulfonic acid 4-[2-(2,4-two chloro-3-fluorophenyls)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester; With

(19) 5-chlorothiophene-2-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester;

But do not comprise that pyridine-3-sulphonic acid 4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } the phenyl ester hydrochloride.

Concrete aspect of the present invention provides one or more following compounds:

(1) butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] the phenyl ester hydrochloride;

(2) butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester half-1, the 5-napadisilate;

(3) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(morpholine-4-base formamyl)-2H-pyrazole-3-yl] the phenyl ester hydrochloride;

(4) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(morpholine-4-base formamyl)-2H-pyrazole-3-yl] phenyl ester half-1, the 5-napadisilate;

(5) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(morpholine-4-base formamyl)-2H-pyrazole-3-yl] the phenyl ester mesylate;

(6) 4,4,4-trifluoro butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] the phenyl ester hydrochloride;

(7) 4,4,4-trifluoro butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] the phenyl ester mesylate;

(8) 4,4,4-trifluoro butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester half-1, the 5-napadisilate;

(9) 4,4,4-trifluoro butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] the phenyl ester hydrosulfate;

(10) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl]-2,6-difluoro phenyl ester hydrochloride;

(11) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl]-2,6-difluoro phenyl ester mesylate;

(12) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl]-2,6-difluoro phenyl ester half-1,5-napadisilate;

(13) 3,3,3-trifluoro propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] the phenyl ester hydrochloride;

(14) 3,3,3-trifluoro propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] the phenyl ester mesylate;

(15) 3,3,3-trifluoro propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester half-1, the 5-napadisilate;

(16) 3,3,3-trifluoro propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] the phenyl ester hydrosulfate;

(17) 3-methylbutane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] the phenyl ester hydrochloride;

(18) 3-methylbutane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] the phenyl ester mesylate;

(19) 3-methylbutane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester half-1, the 5-napadisilate;

(20) 3,3-dimethylbutane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] the phenyl ester hydrochloride;

(21) 3,3-dimethylbutane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] the phenyl ester mesylate;

(22) 3,3-dimethylbutane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester half-1, the 5-napadisilate;

(23) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] the phenyl ester hydrochloride;

(24) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] the phenyl ester mesylate;

(25) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester half-1, the 5-napadisilate;

(26) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] the phenyl ester hydrosulfate;

(27) carbonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester propyl ester hydrochloride;

(28) carbonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester propyl ester mesylate;

(29) carbonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester propyl ester half-1, the 5-napadisilate;

(30) pyridine-3-sulphonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] the phenyl ester mesylate;

(31) pyridine-3-sulphonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester half-1, the 5-napadisilate.

It should be understood that a kind of combination or any combination that the present invention includes above more than a kind of salt.

We find that some compound of the present invention has the advantage that can be prepared into crystal formation.

It is the The compounds of this invention of crystal formation basically that another aspect of the invention provides.

Yet, we find to produce crystal formation and surpass 80% The compounds of this invention, and so-called " basic crystallization " comprises and surpass 20%, preferably surpass 30%, more preferably surpass 40% that (for example surpass in 50%, 60%, 70%, 80% or 90% each) is crystalline.

Another aspect of the invention also provides the The compounds of this invention of part crystal formation.So-called " partial crystallization " comprises that 5% crystallization or crystallization are between 5% and 20%.

Can adopt X-ray powder diffraction (XRPD) to measure degree of crystallinity (%) by the technician.Also can adopt other technology, for example solid state NMR, FT-IR, Raman spectroscopy (Ramanspectroscopy), differential scanning calorimetry (DSC) and microcalorimetry.

Compound of the present invention, crystalline compounds particularly of the present invention when comparing with the disclosed compound of PCT/GB2005/000534, may have improved stability.

Term described herein " stability " comprises chemical stability and solid-state stability.

So-called " chemical stability ", be included under the normal preservation condition, when preserving The compounds of this invention with independent form or with dosage form, inessential chemical degradation or decomposition degree may only be arranged, the compound that provides in the preparation mixes (for example with the form of oral dosage form, for example tablet, capsule etc.) mutually with pharmaceutically acceptable carrier, thinner or auxiliary.

So-called " solid-state stability ", be included under the normal preservation condition, when preserving The compounds of this invention with independent solid form or with the solid preparation form, inessential solid state transformation (for example crystallization, recrystallize, solid-state phase changes, aquation, dehydration, solvation or desolvation) degree may only be arranged, the compound that provides in the solid preparation mixes (for example with the form of oral dosage form, for example tablet, capsule etc.) mutually with pharmaceutically acceptable carrier, thinner or auxiliary.

The example of " normal preservation condition " comprises that temperature between-80 ℃ to+50 ℃ is (preferably between 0-40 ℃, more preferably room temperature, for example 15-30 ℃), 0.1 crust is to the relative humidity (preferably 10-60%) between the pressure (preferred atmosphere pressures), 5% to 95% between 2 crust and/or be exposed under the UV/ visible light of 460 luxs, long preservative period (promptly 〉=6 month).Under these conditions, the chemical degradation/decomposition or the solid state transformation that can be observed The compounds of this invention are lower than 15%, more preferably less than 10%, especially are lower than 5%, conform with stability requirement.The technician it should be understood that the upper and lower bound of said temperature, pressure and relative humidity represents the extremum of normal preservation condition, in normal preservation process, can not run into certain combination (for example 50 ℃ temperature and 0.1 bar pressure) of these extremums.

When solvent systems exists or do not exist, may make the salt crystallization (for example crystallization can be obtained by melt, perhaps obtains by distillation) of The compounds of this invention under super critical condition.Yet, preferably produce crystallization by suitable solvent systems.

Another aspect of the invention provides the preparation method of crystalline compounds of the present invention, and this method comprises crystallizes out The compounds of this invention from suitable solvent systems.

Tc and crystallization time depend on the concentration and the employed solvent systems of salt to be crystallized, salts solution.

Can also cause and/or the realization crystallization by standard technique, for example add or do not add the crystal seed of the suitable crystalline compounds of the present invention.

The different crystal forms of The compounds of this invention for example can easily adopt, and the following X-ray powder diffraction of this paper (XRPD) method characterizes.

Do not prepare when other crystal formation does not exist in order to ensure concrete crystal formation, preferably when the nucleus of other crystal formation and/or crystal seed did not exist basically fully, nucleus and/or the crystal seed of putting into required crystal formation carried out crystallization.Can be for example by from the solution of part acceptable acid addition salts evaporating solvent slowly, the crystal seed of preparation suitable combination thing.

Can use technology well known to those skilled in the art, for example decantation, filtration or centrifugal, the compound of the present invention of emanating out.

Can the application standard technology with the compound drying.

In addition, use technology well known to those skilled in the art, can be further purified The compounds of this invention.For example can remove impurity by recrystallize from suitable solvent systems.For recrystallize, suitable temperature and time depends on the concentration and the employed solvent systems of salts solution.

If The compounds of this invention is as mentioned above by crystallization or recrystallize, then gained salt should be the form that aforesaid chemical stability and/or solid-state stability are improved.

The advantage that The compounds of this invention has is, The compounds of this invention is compared with compound known in the art, effect is higher, toxicity is lower, action period is long, field of activity is wide, render a service side effect strong, that produce less, more easily absorb and/or pharmacokinetics feature (for example oral administration biaavailability is higher and/or clearance rate lower) arranged preferably and/or have other useful pharmacological properties, physical properties or chemical property.The advantage that The compounds of this invention also has other is that their administration frequency is lower than compound known in the art.

The advantage that The compounds of this invention also can have is that they provide with the improved form of being convenient to handle.In addition, the advantage that The compounds of this invention has is that they are with the form preparation of improved chemical stability and/or solid-state stability (comprising for example owing to lower water absorbability).Therefore, such The compounds of this invention can be stable when prolonged preservation.

The advantage that The compounds of this invention also may have is, the yield that they can be good, high purity, fast, convenient and carry out crystallization at low cost.

It is to be further understood that The compounds of this invention can solvation form (for example hydrated form) exist and exist with the non-solvent form.It should be understood that all these solvation forms that the present invention includes.

The preparation method

Can prepare The compounds of this invention as follows.Yet the present invention is not limited to these methods.

Can be in 0-100 ℃ temperature range, in inert solvent (for example butanone), will be by the compound of the described method preparation of PCT/GB2005/000534 and the embodiment of the present application part and suitable acid (for example methylsulfonic acid, naphthalene-1,5-disulfonic acid, 1,2-ethionic acid, sulfuric acid or hydrochloric acid) solid salt of emanating out after the reaction, prepare described all kinds of salt.By making reaction soln cooling, optionally in solution, put into crystal seed and/or concentrated solution is emanated salt with required product.Choose wantonly and can make the product segregation by in inert solvent intermediate product solution, adding anti-solvent.Can pass through those skilled in the art's currently known methods (for example filtration or centrifugal) and collect solid.

For methylsulfonic acid and hydrochloric acid, with regard to free alkali, specifically use the acid of 1 molar equivalent, and for sulfuric acid, 1,5-naphthalene disulfonic acid and 1, the 2-ethionic acid then uses 0.5 molar equivalent for free alkali.Should be understood that, can use excessive slightly basic cpd or acid.For example can use the ratio of 1 molar equivalent sulfuric acid and 0.5 molar equivalent alkali.

Term " inert solvent " is meant dissolving or is partly dissolved free alkali and/or acid and/or product salt, but the liquid that can not react with mode and raw material, reagent, intermediate or the product of the required product yield of negative impact.

The present invention provides compound on the other hand, and described compound can pass through following a kind of compound:

(1) butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl]-phenyl ester;

(2) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(morpholine-4-base formamyl)-2H-pyrazole-3-yl] phenyl ester;

(3) 4,4,4-trifluoro butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester;

(4) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl]-2,6-difluoro phenyl ester;

(5) 3,3,3-three fluoro-propane-1-sulfonic acid 4-[2-(2,4-two chloro-phenyl)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl]-phenyl ester;

(6) 3-methyl-butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester;

(7) 3,3-dimethylbutane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester;

(8) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester;

(9) carbonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] the phenyl ester propyl ester; With

(10) pyridine-3-sulphonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester;

Obtain with following any sour butanone solution reaction:

A) 1 molar equivalent hydrochloric acid, perhaps

B) 1 molar equivalent methylsulfonic acid, perhaps

C) 0.5 molar equivalent sulfuric acid, perhaps

D) 0.5 molar equivalent 1, the 5-naphthalene disulfonic acid, perhaps

E) 0.5 molar equivalent 1, the 2-ethionic acid.

One skilled in the art will appreciate that used molar equivalent in the scope of experimental error, can comprise a kind of excessive reactant slightly, for example theoretical equivalent value ± 10%.

The present invention provides the mesylate, half-1 of following formula I compound on the other hand, 5-napadisilate or 1, and 2-ethionic acid salt form:

Wherein

R ¹The C that expression a) is replaced by one or more following groups _1-3Alkoxyl group: i) fluorine, ii) group NR ^cR ^d, R wherein ^cAnd R ^dIndependent expression H, C _1-6Alkyl or C _1-6Carbalkoxy, precondition are R ^cAnd R ^dOne of be not H, perhaps iii) 1,3-dioxolane-2-base; B) R ¹The optional C that is replaced by one or more following groups of expression _4-6Alkoxyl group: i) fluorine, ii) group NR ^cR ^d, R wherein ^cAnd R ^dIndependent expression H, C _1-6Alkyl or C _1-6Carbalkoxy, precondition are R ^cAnd R ^dOne of be not H, perhaps iii) 1,3-dioxolane-2-base; C) formula phenyl (CH ₂) _pThe group of O-, wherein p is 1,2 or 3, and benzyl ring is chosen wantonly by 1,2 or 3 by the represented group replacement of Z, d) radicals R ⁵S (O) ₂O or R ⁵S (O) ₂NH, wherein R ⁵The optional C that is replaced by one or more fluorine of expression _1-6Alkyl, perhaps R ⁵Expression phenyl or heteroaryl, wherein any group is optional is replaced by the represented group of Z by 1,2 or 3; E) formula (R ⁶) ₃The group of Si, wherein R ⁶Expression can be identical or different C _1-6Alkyl; Perhaps f) formula R ^bThe group of O (CO) O, wherein R ^bThe optional C that is replaced by one or more fluorine of expression _1-6Alkyl;

R ^aExpression halogen, C _1-3Alkyl or C _1-3Alkoxyl group;

M is 0,1,2 or 3;

N is 0,1,2 or 3;

R ³Expression:

A) radicals X-Y-NR ⁷R ⁸

Wherein X is CO or SO ₂,

R ⁷And R ⁸Independent expression:

Optional by 1,2 or 3 C that replaces by the represented group of W _1-6Alkyl;

Group-(CH ₂) _r(phenyl) _s, wherein r is 0,1,2,3 or 4, when r was 0, s was 1, otherwise s is 1 or 2, phenyl is optional to be replaced by the represented group of Z by 1,2 or 3 independently;

Perhaps R ⁷Expression H, R ⁸As above definition;

Described each group is optional to be replaced by 1,2 or 3 group Z;

Pharmaceutical preparation

The common following medication of compound of the present invention: to comprise the pharmaceutical dosage forms of activeconstituents or pharmaceutically acceptable addition salt, with pharmaceutically acceptable formulation, by oral, parenteral, intravenously, intramuscular, subcutaneous or other injection system, oral cavity, rectum, vagina, through skin and/or nasal passage and/or pass through inhalation.According to disease to be treated, patient and route of administration to be treated, give composition by different dosage.

In the human therapeutic treatment, the per daily dose that The compounds of this invention is suitable is about the 0.001-10mg/kg body weight, is preferably the 0.01-1mg/kg body weight.

Preferred oral preparation, particularly tablet or capsule can be 0.5mg～500mg so that dosage range to be provided by the preparation of those skilled in the art's currently known methods, for example the active compound of 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg and 250mg.

Another aspect of the invention also provides pharmaceutical preparation, and said preparation comprises any compound of the present invention or its pharmaceutically acceptable derivates and pharmaceutically acceptable auxiliary, thinner and/or carrier.

Pharmacological properties

Formula (I) compound is used for the treatment of obesity or overweight (for example promoting to lose weight and keep to lose weight), prevent weight increase (weight increase after for example drug-induced weight increase or the smoking cessation), modulation of appetite and/or full sense, eating disorder (disease of eating too much at one meal (binge eating) for example, apositia, exessive appetite and obsession (compulsive)), habituation is (to medicine, tobacco, alcohol, any appetitive macronutrient or nonessential food class habituation), be used for the treatment of mental disorder for example psychosis and/or mood disorder, schizophrenia and Schizoaffective mental disorder (schizo-affective disorder), bipolar disorder, anxiety disorder, anxiety-depression disease (anxio-depressive disorder), dysthymia disorders, mania, compulsive disorder, impulse control disorder (for example tourette's syndrome (Gilles de la Tourette ' s syndrome)), attention deficit disorder such as ADD/ADHD, stress disorders, for example dull-witted and cognition dysfunction of sacred disease and/or memory dysfunction (lethe for example, alzheimer's disease (Alzheimer ' s disease), pik dementia (Pick ' s dementia), senile dementia, vascular dementia, mild cognitive goes down, age related cognitive decline and slight senile dementia), sacred disease and/or neurodegenerative disease (multiple sclerosis for example, Raynaud syndrome (Raynaud ' s syndrome), Parkinson's disease (Parkinson ' s disease), Huntington Chorea (Huntington ' s chorea) and alzheimer's disease), the demyelination relative disease, neural inflammatory diseases (for example acute febrile polyneuritis (Guillain-Barr é syndrome)).

Described compound also may be used for prevention or treatment dependent conditions and behavior and habituation venereal disease disease and behavior (for example alcohol abuse and/or drug abuse, pathosis gambling (pathologicalgambling), kleptomania), drug withdrawal illness (for example to be had or the alcohol of unaware obstacle is given up; Alcohol withdrawal delirium; Amphetamine is given up; Cocaine is given up; Nicotine withdrawal; OPIOIDS is given up; Have or tranquilizer, soporific or the anxiolytic of unaware obstacle are given up; Tranquilizer, soporific or anxiolytic give up delirium and by the Withrawal symptom due to other material), give up during the alcohol of outbreak and/or drug-induced mood disorder, anxiety disorder and/or somnopathy, and alcohol is drunk again and/or medicine is reverted to take drugs.

Described compound also may be used for prevention or for example dystonia, the dyskinesia of treatment neurological dysfunction, cathisophobia, trembles and spasticity, is used for the treatment of Spinal injury, neuropathy, migraine, alertness obstacle, somnopathy (for example Sleep architecture disorder, sleep apnea, obstructive sleep apneas, sleep apnea syndrome), painful diseases, craniocerebral injury.

Described compound also may be used for the treatment of Immunological diseases, cardiovascular disorder (atherosclerosis for example, arteriosclerosis, stenocardia, abnormal heart rhythm and irregular pulse, congestive heart failure, coronary artery disease, heart trouble, hypertension, prevention and treatment left ventricular hypertrophy, myocardial infarction, transient ischemic attack, peripheral vascular disease, the systemic inflammation of vascular system, septic shock, apoplexy, cerebral crisis, cerebral infarction, cerebral ischemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhage), metabolism disorder (is for example showed the illness (per-cent that accounts for total fat-free mass with rest energy consumption is represented) that metabolic activity reduces or increases, diabetes, hyperlipemia (dyslipidemia), fatty liver, gout, hypercholesterolemia, hyperlipidaemia, hypertriglyceridemia, hyperuricemia, impaired glucose tolerance, fasting plasma glucose lowers (impaired fasting glucose), insulin resistant, insulin resistance syndrome, metabolism syndrome, X syndrome, obesity-underventilation syndrome (pickwickian syndrome (Pickwickian syndrome)), type i diabetes, type ii diabetes, low HDL cholesterol levels and/or high LDL cholesterol levels, low fat connects protein level), dysgenesia and endocrine disturbance (are for example treated male gonad hypofunction, are treated sterile or as contraceptive bian, menoxenia/menopathy, polycystic ovarian disease, Female sexual dysfunction and reproductive function obstacle, male sexual disorder and reproductive function obstacle (erective dysfunction), growth hormone deficiency patient, female hirsutism, the spy sends out property short stature (normal variant short stature)) and respiratory system relative disease (for example asthma and chronic obstructive pulmonary disease), gastro-intestinal system relative disease (gastrointestinal dysfunction for example, small intestine pusher dysfunction, diarrhoea, vomiting, feel sick, gallbladder disease, chololithiasis, the obesity-related gastroesophageal reflux, ulcer).

Described compound also may be used as following treatment of diseases medicine: dermatosis, cancer (colorectal carcinoma for example, the rectum cancer, prostate cancer, mammary cancer, ovarian cancer, carcinoma of endometrium, cervical cancer, carcinoma of gallbladder, cholangiocarcinoma), craniopharyngioma, Pu-Wei syndrome (Prader-Willisyndrome), Turner syndrome (Turner syndrome), Fei Helixi syndrome (Frohlich ' s syndrome), glaucoma, transmissible disease, urethral disease and inflammatory diseases (arthritis deformans for example, inflammation, the inflammatory sequela of viral encephalitis, osteoarthritis) and orthopedic obstacle (orthopedic disorders).Described compound also may do (oesophagus) relax can not curative.

On the other hand, the invention provides The compounds of this invention as defined above as medicine.

Another aspect, the invention provides The compounds of this invention preparation be used for the treatment of or prophylactic medicine in purposes, described medicine is used for the treatment of or obesity prevention or overweight (for example promoting to lose weight and keep to lose weight), prevent weight increase (weight increase after for example drug-induced weight increase or the smoking cessation), modulation of appetite and/or full sense, eating disorder (disease of eating too much at one meal for example, apositia, exessive appetite and obsession), habituation is (to medicine, tobacco, alcohol, any appetitive macronutrient or nonessential food class habituation), be used for the treatment of mental disorder for example psychosis and/or mood disorder, schizophrenia and Schizoaffective mental disorder, bipolar disorder, anxiety disorder, anxiety-depression disease, dysthymia disorders, mania, compulsive disorder, impulse control disorder (for example tourette's syndrome), attention deficit disorder such as ADD/ADHD, stress disorders, for example dull-witted and cognition dysfunction of sacred disease and/or memory dysfunction (lethe for example, alzheimer's disease, the pik dementia, senile dementia, vascular dementia, mild cognitive goes down, age related cognitive decline and slight senile dementia), sacred disease and/or neurodegenerative disease (multiple sclerosis for example, Raynaud syndrome, Parkinson's disease, Huntington Chorea and alzheimer's disease), the demyelination relative disease, neural inflammatory diseases (for example acute febrile polyneuritis).

Another aspect the invention provides compound of the present invention and is used for the treatment of or prevents purposes in the medicine of following disease in preparation: dependent conditions and behavior and habituation venereal disease disease and behavior (for example alcohol abuse and/or drug abuse, pathosis gambling, kleptomania), drug withdrawal illness (for example have or the alcohol of unaware obstacle is given up; Alcohol withdrawal delirium; Amphetamine is given up; Cocaine is given up; Nicotine withdrawal; OPIOIDS is given up; Have or tranquilizer, soporific or the anxiolytic of unaware obstacle are given up; Tranquilizer, soporific or anxiolytic are given up delirium; With by the Withrawal symptom due to other material), give up during the alcohol of outbreak and/or drug-induced mood disorder, anxiety disorder and/or somnopathy, and alcohol is drunk again and/or medicine is reverted to take drugs.

Another aspect, the invention provides compound of the present invention is used for the treatment of or prevents purposes in the medicine of following disease in preparation: for example dystonia, dyskinesia of neurological dysfunction, cathisophobia, tremble and spasticity, treatment Spinal injury, neuropathy, migraine, alertness obstacle, somnopathy (for example Sleep architecture disorder, sleep apnea, obstructive sleep apneas, sleep apnea syndrome), painful diseases, craniocerebral injury.

Another aspect, the invention provides compound of the present invention is used for the treatment of or prevents purposes in the medicine of following disease in preparation: Immunological diseases, cardiovascular disorder (atherosclerosis for example, arteriosclerosis, stenocardia, abnormal heart rhythm and irregular pulse, congestive heart failure, coronary artery disease, heart trouble, hypertension, prevention and treatment left ventricular hypertrophy, myocardial infarction, transient ischemic attack, peripheral vascular disease, the systemic inflammation of vascular system, septic shock, apoplexy, cerebral crisis, cerebral infarction, cerebral ischemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhage), metabolism disorder (is for example showed the illness (per-cent that accounts for total fat-free mass with rest energy consumption is represented) that metabolic activity reduces or increases, diabetes, hyperlipemia, fatty liver, gout, hypercholesterolemia, hyperlipidaemia, hypertriglyceridemia, hyperuricemia, impaired glucose tolerance, fasting plasma glucose lowers, insulin resistant, insulin resistance syndrome, metabolism syndrome, X syndrome, obesity-underventilation syndrome (pickwickian syndrome), type i diabetes, type ii diabetes, low HDL cholesterol levels and/or high LDL cholesterol levels, low fat connects protein level), dysgenesia and endocrine disturbance (are for example treated male gonad hypofunction, are treated sterile or as contraceptive bian, menoxenia/menopathy, polycystic ovarian disease, Female sexual dysfunction and reproductive function obstacle, male sexual disorder and reproductive function obstacle (erective dysfunction), growth hormone deficiency patient, female hirsutism, the special property sent out short stature), respiratory system relative disease (for example asthma and chronic obstructive pulmonary disease), gastro-intestinal system relative disease (gastrointestinal dysfunction for example, small intestine pusher dysfunction, diarrhoea, vomiting, feel sick, gallbladder disease, chololithiasis, the obesity-related gastroesophageal reflux, ulcer).

Another aspect the invention provides compound of the present invention and is used for the treatment of or prevents purposes in the medicine of following disease in preparation: dermatosis, cancer (for example colorectal carcinoma, the rectum cancer, prostate cancer, mammary cancer, ovarian cancer, carcinoma of endometrium, cervical cancer, carcinoma of gallbladder, cholangiocarcinoma), craniopharyngioma, Pu-Wei syndrome, Turner syndrome, Fei Helixi syndrome, glaucoma, transmissible disease, urethral disease and inflammatory diseases (for example inflammatory sequela, the osteoarthritis of arthritis deformans, inflammation, viral encephalitis) and orthopedic obstacle.

Again on the one hand, the invention provides the method that is used to prevent or treat disease, this method comprises the The compounds of this invention that the patient of needs pharmacologically effective dose is arranged, be used for prevention or treatment of obesity or overweight (for example promoting to lose weight and keep to lose weight), prevent weight increase (weight increase after for example drug-induced weight increase or the smoking cessation), modulation of appetite and/or full sense, eating disorder (disease of eating too much at one meal for example, apositia, exessive appetite and obsession), habituation is (to medicine, tobacco, alcohol, any appetitive macronutrient or nonessential food class habituation), be used for the treatment of mental disorder for example psychosis and/or mood disorder, schizophrenia and Schizoaffective mental disorder, bipolar disorder, anxiety disorder, anxiety-depression disease, dysthymia disorders, mania, compulsive disorder, impulse control disorder (for example tourette's syndrome), attention deficit disorder such as ADD/ADHD, stress disorders, for example dull-witted and cognition dysfunction of sacred disease and/or memory dysfunction (lethe for example, alzheimer's disease, the pik dementia, senile dementia, vascular dementia, mild cognitive goes down, age related cognitive decline and slight senile dementia), sacred disease and/or neurodegenerative disease (multiple sclerosis for example, Raynaud syndrome, Parkinson's disease, Huntington Chorea and alzheimer's disease), the demyelination relative disease, neural inflammatory diseases (for example acute febrile polyneuritis).

Again on the one hand, the invention provides the method that is used to prevent or treat disease, this method comprises the The compounds of this invention that the patient of needs pharmacologically effective dose is arranged, and being used for prevention or treatment dependent conditions and behavior and habituation venereal disease disease and behavior (for example alcohol abuse and/or drug abuse, pathosis gambling, kleptomania), drug withdrawal illness (for example has or the alcohol of unaware obstacle is given up; Alcohol withdrawal delirium; Amphetamine is given up; Cocaine is given up; Nicotine withdrawal; OPIOIDS is given up; Have or tranquilizer, soporific or the anxiolytic of unaware obstacle are given up; Tranquilizer, soporific or anxiolytic are given up delirium; With by the Withrawal symptom due to other material), give up during outbreak alcohol and/or drug-induced mood disorder, anxiety disorder and/or somnopathy and alcohol is drunk again and/or medicine is reverted to take drugs.

Again on the one hand, the invention provides the method that is used to prevent or treat disease, this method comprises the The compounds of this invention that the patient of needs pharmacologically effective dose is arranged, be used for prevention or for example dystonia, the dyskinesia of treatment neurological dysfunction, cathisophobia, tremble and spasticity, treatment Spinal injury, neuropathy, migraine, alertness obstacle, somnopathy (for example Sleep architecture disorder, sleep apnea, obstructive sleep apneas, sleep apnea syndrome), painful diseases, craniocerebral injury.

Again on the one hand, the invention provides the method that is used to prevent or treat disease, this method comprises the The compounds of this invention that the patient of needs pharmacologically effective dose is arranged, be used for prevention or treatment Immunological diseases, cardiovascular disorder (atherosclerosis for example, arteriosclerosis, stenocardia, abnormal heart rhythm and irregular pulse, congestive heart failure, coronary artery disease, heart trouble, hypertension, prevention and treatment left ventricular hypertrophy, myocardial infarction, transient ischemic attack, peripheral vascular disease, the systemic inflammation of vascular system, septic shock, apoplexy, cerebral crisis, cerebral infarction, cerebral ischemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhage), metabolism disorder (is for example showed the illness (per-cent that accounts for total fat-free mass with rest energy consumption is represented) that metabolic activity reduces or increases, diabetes, hyperlipemia, fatty liver, gout, hypercholesterolemia, hyperlipidaemia, hypertriglyceridemia, hyperuricemia, impaired glucose tolerance, fasting plasma glucose lowers, insulin resistant, insulin resistance syndrome, metabolism syndrome, X syndrome, obesity-underventilation syndrome (pickwickian syndrome), type i diabetes, type ii diabetes, low HDL cholesterol levels and/or high LDL cholesterol levels, low fat connects protein level), dysgenesia and endocrine disturbance (are for example treated male gonad hypofunction, are treated sterile or as contraceptive bian, menoxenia/menopathy, polycystic ovarian disease, Female sexual dysfunction and reproductive function obstacle, male sexual disorder and reproductive function obstacle (erective dysfunction), growth hormone deficiency patient, female hirsutism, the special property sent out short stature), respiratory system relative disease (for example asthma and chronic obstructive pulmonary disease), gastro-intestinal system relative disease (gastrointestinal dysfunction for example, small intestine pusher dysfunction, diarrhoea, vomiting, feel sick, gallbladder disease, chololithiasis, the obesity-related gastroesophageal reflux, ulcer).

Again on the one hand, the invention provides the method that is used to prevent or treat disease, this method comprises the The compounds of this invention that the patient of needs pharmacologically effective dose is arranged, and is used for prevention or treatment dermatosis, cancer (colorectal carcinoma for example, the rectum cancer, prostate cancer, mammary cancer, ovarian cancer, carcinoma of endometrium, cervical cancer, carcinoma of gallbladder, cholangiocarcinoma), craniopharyngioma, Pu-Wei syndrome, Turner syndrome, Fei Helixi syndrome, glaucoma, transmissible disease, urethral disease and inflammatory diseases (arthritis deformans for example, inflammation, the inflammatory sequela of viral encephalitis, osteoarthritis) and orthopedic obstacle.

The compounds of this invention is specially adapted to treatment of obesity or overweight (for example promoting to lose weight and keep to lose weight), prevention or reverse weight increase (weight increase after for example bounce-back, drug-induced weight increase or the smoking cessation) are used for modulation of appetite and/or full sense, eating disorder (for example disease of eating too much at one meal, apositia, exessive appetite and obsession), habituation (to medicine, tobacco, alcohol, any appetitive macronutrient or nonessential food class habituation).Formula (I) compound is used for the treatment of obesity, mental disorder for example psychosis, schizophrenia, bipolar disorder, anxiety disorder, anxiety-depression disease, dysthymia disorders, cognitive disorder, dysmnesia, compulsive disorder, apositia, exessive appetite, attention deficit disorder such as ADHD, epilepsy and relative disease, and sacred disease for example dementia, sacred disease (for example multiple sclerosis), Raynaud syndrome, Parkinson's disease, Huntington Chorea and alzheimer's disease.The compounds of this invention also can be used for treating Immunological diseases, cardiovascular disorder, dysgenesia, endocrine disturbance, septic shock, respiratory system relative disease, gastro-intestinal system relative disease (for example diarrhoea).The compounds of this invention also may be as the curative of the substance abuse of treatment persistence, habituation and/or recurrence indication, and for example medicine (Nicotine, alcohol, Cocaine, opium etc.) relies on symptom and/or medicine (Nicotine, alcohol, Cocaine, opium etc.) Withrawal symptom.The compounds of this invention also can eliminate smoking cessation usually with weight increase.

Another aspect, the invention provides compound of the present invention is used for the treatment of or prevents purposes in the medicine of following disease in preparation: obesity, mental disorder is psychosis for example, schizophrenia, bipolar disorder, anxiety disorder, anxiety-depression disease, dysthymia disorders, cognitive disorder, dysmnesia, compulsive disorder, apositia, exessive appetite, attention deficit disorder such as ADHD, epilepsy and relative disease, sacred disease is for example dull-witted, sacred disease (for example multiple sclerosis), Parkinson's disease, Huntington Chorea and alzheimer's disease, Immunological diseases, cardiovascular disorder, dysgenesia, endocrine disturbance, septic shock, the respiratory system relative disease, gastro-intestinal system relative disease (for example diarrhoea), the persistence substance abuse, habituation and/or recurrence indication, for example medicine (Nicotine, alcohol, Cocaine, opium etc.) rely on symptom and/or medicine (Nicotine, alcohol, Cocaine, opium etc.) Withrawal symptom.

Again on the one hand, the invention provides the method that is used for the treatment of disease, this method comprises the The compounds of this invention that the patient of needs pharmacologically effective dose is arranged, be used for prevention or treatment of obesity, mental disorder is mental case such as schizophrenia and bipolar disorder for example, anxiety disorder, anxiety-depression disease, dysthymia disorders, cognitive disorder, dysmnesia, compulsive disorder, apositia, exessive appetite, attention deficit disorder such as ADHD, epilepsy and relative disease, sacred disease is for example dull-witted, sacred disease (for example multiple sclerosis), Parkinson's disease, Huntington Chorea and alzheimer's disease, Immunological diseases, cardiovascular disorder, dysgenesia, endocrine disturbance, septic shock, the respiratory system relative disease, gastro-intestinal system relative disease (for example diarrhoea), the persistence substance abuse, habituation and/or recurrence indication, for example medicine (Nicotine, alcohol, Cocaine, opium etc.) rely on symptom and/or medicine (Nicotine, alcohol, Cocaine, opium etc.) Withrawal symptom.

The compounds of this invention for example is specially adapted to by reducing appetite and body weight, keeping and lose weight and prevent that bounce-back from coming treatment of obesity.

The weight increase that The compounds of this invention also can be used to prevent or reversing drug causes is for example treated caused weight increase by antipsychotic drug (neural Depressant).The compounds of this invention also can be used to prevent or reverse smoking cessation with weight increase.

The compounds of this invention is applicable to the above-mentioned indication of treatment adolescent patient colony.

The compounds of this invention also applicable to regulating the loss of bone mass and bone, therefore, can be used for treating osteoporosis and other osteopathy.

Conjoint therapy

The compounds of this invention can be used for the treatment of the curative coupling of obesity (for example other anti-obesity medicine) with other, and these drug influence energy expenditures, glycolysis-, glyconeogenesis, glycolysis (glucogenolysis), steatolysis, steatogenesis, fat absorbing, depot fat, fat are drained, hungry and/or satisfy sense and/or habituation mechanism, appetite/motivation, ingestion of food or stomach and intestine maneuvering ability.

The compounds of this invention also can be used for the treatment of the curative coupling of obesity relative disease with other, and described obesity relative disease is hypertension, hyperlipidaemia, hyperlipemia, diabetes, sleep apnea, asthma, heart change, atherosclerosis, macroangiopathy, microangiopathies, fatty degeneration of liver, cancer, joint disease and gallbladder disease for example.For example The compounds of this invention can bring high blood pressure down with other or reduce LDL: the curative of the ratio of HDL or cause the drug combination that LDL cholesterol cyclical level increases.In the diabetic subject, The compounds of this invention also can with the medicine coupling that is used for treating the microangiopathy related complication.

The compounds of this invention can together use with the other therapies that is used for the treatment of obesity and related complication metabolism syndrome and type ii diabetes, and these medicines comprise biguanides, Regular Insulin (synthetic insulin analogue) and oral antihyperglycemic (being divided into meals blood sugar regulator and alpha-glucosidase inhibitor).

The present invention on the other hand, compound of the present invention or its pharmacy acceptable salt can with PPAR modulator Combined Preparation.The PPAR modulator includes but not limited to the solvate or the prodrug of PPAR alfa agonists and/or PPAR gamma agonist or its pharmacy acceptable salt, solvate, these salt.The solvate or the prodrug of suitable PPPAR alfa agonists and/or PPAR gamma agonist, its pharmacy acceptable salt, solvate, these salt are well-known in the art.

In addition, the present invention can unite use with sulfonylurea.The present invention also comprises compound of the present invention and pravastatin coupling.The mentioned pravastatin of the application includes but not limited to HMG CoA-reductase (3-hydroxy-3-methylglutaryl-coenzyme A reductase enzyme) inhibitor.Appropriate H MG CoA-reductase inhibitors is a statin.

Among the application, term " pravastatin " is active or the chemically modified of the HMG CoA-reductase inhibitors of non-activity, for example ester, prodrug and metabolite no matter also comprise.

The present invention also comprises The compounds of this invention and ileal bile acid transfer system inhibitor (ibat inhibitor) coupling.The present invention also comprises The compounds of this invention and the coupling of bile acide binding resin.

The present invention also comprises The compounds of this invention and bile acid chelating agent (for example colestipol or Colestyramine or Cholestagel) coupling.

The present invention provides combination therapy in addition more on the one hand, this treatment comprises The compounds of this invention or its pharmacy acceptable salt of warm-blooded animal (for example people) significant quantity that needs this therapeutic treatment, optional pharmaceutically acceptable diluent or carrier, and simultaneously, sequential or give solvate or the prodrug that one or more are selected from following medicine or its pharmacy acceptable salt, solvate, these salt, optional pharmaceutically acceptable diluent or carrier separately:

CETP (cholesteryl ester transfer protein) inhibitor;

The cholesterol absorption antagonist;

MTP (microsome transfer protein) inhibitor;

Nicotinic acid derivates comprises slowly-releasing and combined prod;

The plant sterol compound;

Probucol;

The anti-freezing medicine;

Omega-fatty acid;

Other anti-obesity compound, for example sibutramine, phentermine, orlistat, Bupropion, ephedrine, thyroxine;

Anti-hypertension compound, for example angiotensin-converting enzyme (ACE) inhibitor, angiotensin II receptor antagonists, adrenergic blocking drug, alpha-1 adrenergic blocker, Beta-3 adrenergic blocker, blend alpha/Beta-3 adrenergic blocker, adrenergic stimulant, calcium channel blocker, AT-1 blocker, saluretic, hydragog(ue) or vasodilator;

Melanin-concentrating hormone (melanin concentrating hormone, MCH) conditioning agent;

The npy receptor conditioning agent;

The orexin receptor conditioning agent;

Phosphoinositide deopendent protein kinase (PDK) conditioning agent; Perhaps

Nuclear receptor modulators, for example LXR, FXR, RXR, GR, ERR α, ERR β, PPAR α, PPAR β, PPAR γ and ROR α;

Monoamine transmits modulator (monoamine transmission-modulating agent), for example selectivity serotonin reuptake inhibitor (SSRI), norepinephrine reuptake inhibitor (NARI), norepinephrine-serotonin reuptake inhibitor (SNRI), oxidase inhibitor (MAOI), tricyclic antidepressant (TCA), norepinephrine energy and specificity serotonin energy thymoleptic (NaSSA);

Antipsychotic drug is olanzapine and leoponex for example;

The 5-hydroxytryptamine receptor conditioning agent;

Leptin/Leptin receptor modulators;

Ghrelin/ghrelin receptor modulators;

The DPP-IV inhibitor.

The present invention provides combination therapy in addition more on the one hand, this treatment comprises The compounds of this invention or its pharmacy acceptable salt that gives significant quantity, optional pharmaceutically acceptable diluent or carrier, and simultaneously, sequential or give very low calorie diet (very low caloriediet separately, VLCD) or low-calorie diet (low-calorie diet, LCD).

Therefore, the another feature of the present invention is, be provided for treating the obesity of the warm-blooded animal (for example people) that needs this treatment and the method for related complication thereof, this method comprises The compounds of this invention or its pharmacy acceptable salt that gives described animal effective dose, and simultaneously, sequential or give the compound from other type of significant quantity separately, the compound of described other type is the solvate or the prodrug of the described compound of this paper combination therapy part or its pharmacy acceptable salt, solvate, these salt.

Therefore, the another feature of the present invention is, the method of the hyperlipidaemia of the warm-blooded animal (for example people) that treatment needs this treatment is provided, this method comprises The compounds of this invention or its pharmacy acceptable salt that gives described animal effective dose, and simultaneously, sequential or give the compound from other type of significant quantity separately, the compound of described other type is the solvate or the prodrug of the described compound of this paper combination therapy part or its pharmacy acceptable salt, solvate, these salt.

Another aspect of the invention provides pharmaceutical composition, described composition comprises The compounds of this invention or its pharmacy acceptable salt and from the solvate or the prodrug of the compound of described other type of this paper combination therapy part or its pharmacy acceptable salt, solvate, these salt, and pharmaceutically acceptable diluent or carrier.

Another aspect of the invention provides medicine box, and described medicine box comprises The compounds of this invention or its pharmacy acceptable salt and from the solvate or the prodrug of the compound of described other type of this paper combination therapy part or its pharmacy acceptable salt, solvate, these salt.

Another aspect of the invention provides medicine box, and described medicine box comprises:

A) The compounds of this invention of first unit dosage or pharmacy acceptable salt;

B) the solvate or the prodrug from the compound of described other type of this paper combination therapy part or its pharmacy acceptable salt, solvate, these salt of second unit dosage; With

C) packing of described first formulation and second formulation is housed.

A) The compounds of this invention of first unit dosage or pharmacy acceptable salt, and pharmaceutically acceptable diluent or carrier;

C) packing of described first formulation and second formulation is housed.

Another feature provides the solvate of compound of the present invention or its pharmacy acceptable salt and described other compound of a kind of this paper combination therapy part or its pharmacy acceptable salt, solvate, these salt or prodrug to be used for the treatment of purposes in the medicine of the obesity of warm-blooded animal (for example people) and related complication thereof in preparation according to the present invention.

Another feature provides the solvate of compound of the present invention or its pharmacy acceptable salt and described other compound of a kind of this paper combination therapy part or its pharmacy acceptable salt, solvate, these salt or prodrug to be used for the treatment of purposes in the medicine of hyperlipidaemia of warm-blooded animal (for example people) in preparation according to the present invention.

Another aspect of the invention provides combination therapy, this treatment comprises The compounds of this invention or its pharmacy acceptable salt and the optional pharmaceutically acceptable diluent or carrier of warm-blooded animal (for example people) significant quantity that needs this therapeutic treatment, and simultaneously, sequential or give solvate or the prodrug and the optional pharmaceutically acceptable diluent or carrier of described other compound of a kind of this paper combination therapy part of significant quantity or its pharmacy acceptable salt, solvate, these salt separately.

In addition, The compounds of this invention also can with the medicine coupling that is used for the treatment of obesity associated conditions (for example type ii diabetes, metabolism syndrome, hyperlipemia, impaired glucose tolerance, hypertension, coronary heart disease, non-alcoholic fatty liver disease inflammation, osteoarthritis and some cancer) and mental disorder and sacred disease.

It should be understood that obesity and overweight have medically acceptable definition.The patient can come determine by for example measuring constitutional index (BMI), constitutional index be with body weight (kilogram) divided by height (rice) square, result and definition can be compared.

Pharmacologically active

The compounds of this invention has activity to CB1 genetic recipient product.Devane etc., Molecular Pharmacology, 1988,34,605 or WO 01/70700 or EP 656354 introduced the method for mensuration The compounds of this invention to the avidity of central authorities' (central) Cannabined receptor.

Perhaps, can followingly measure.

10 μ g are suspended in 200 μ l100mM NaCl, 5mM MgCl with the film that CB1 stable gene cells transfected prepares ₂, among 1mM EDTA, 50mM HEPES (pH 7.4), 1mM DTT, 0.1%BSA and the 100 μ M GDP.Test compound and 0.1 μ Ci[to the agonist that wherein adds EC80 concentration (CP55940), desired concn ³⁵S]-GTP γ S.Under 30 ℃, reacted 45 minutes.Then with cell harvestor with sample transfer to the GF/B filter plate, with lavation buffer solution (50mM Tris (pH 7.4), 5mM MgCl ₂, 50mM NaCl) washing.Filter plate covers with scintillator then, to be retained on the filter plate [ ³⁵S]-GTP γ S counts.

When not having all parts (minimum active), perhaps in the presence of the CP55940 of EC80 concentration (maximum activity), measure active.Respectively these activity are set at 0% and 100% activity.Under the different concns of new part, calculate activity, represent with the per-cent that accounts for maximum activity, and draw.The utilization equation

The substitution data are obtained the IC50 value, promptly under used condition, reach GTP γ S and suppress the needed concentration of half in conjunction with maximum.

The compounds of this invention has activity when CB1 acceptor (IC50＜1 micromole).The IC50 of most preferred compound＜200 nmoles.

We think that The compounds of this invention is selectivity CB1 antagonist or inverse agonists.Effect, selectional feature and side effect tendency may limit and it is said the clinical validity of known compound with CB1 antagonist properties/inverse agonists character up to now.In this, clinical preceding evaluation of The compounds of this invention shows in gastrointestinal function and/or the cardiovascular function model, compares with representativeness contrast CB1 antagonists/inverse agonists, and The compounds of this invention provides remarkable advantages.

Effect, selectional feature, bioavailability, blood plasma half life, blood brain permeability, plasma proteins in conjunction with aspect (for example free fraction of higher drug) or the solubleness, compare with representativeness contrast CB1 antagonists/inverse agonists, The compounds of this invention can provide additional benefit.

The effect of The compounds of this invention in treatment of obesity and relative disease, the weight increase of the obesity mice by self-service diet induced is confirmed.Make female C57B1/6J mouse arbitrarily obtain high calorie " self-service " diet (soft chocolate/cocoa profile group, chocolate, greasiness cheese and nougat) and standard laboratory mouse feed 8-10 week.Systematicness gives (intravenously, intraperitoneal, subcutaneous or per os) compound to be tested then, once a day, minimum 5 days, the body weight of monitoring mouse on the every day basis.By the DEXA imaging when research begins and study end, carry out obesity evaluation simultaneously.Also blood sample is carried out the variation mensuration of the relevant blood plasma marker of obesity.

Embodiments of the invention

Abbreviation

AcOH acetate

The DCM methylene dichloride

The DMF dimethyl formamide

The DEA diethylamine

DIEA N, the N-diisopropylethylamine

DMAP 4-Dimethylamino pyridine

The EtOAc ethyl acetate

Et ₃The N triethylamine

Ex or EX embodiment

LiHMDS hexamethyl dimethyl silanyl Lithamide

Two (trimethyl silyl) Lithamides of LiHMDSA

The MEK methyl ethyl ketone

MeOH methyl alcohol

The MeCN acetonitrile

NMM 4-methylmorpholine

The NMP N-Methyl pyrrolidone

Rt or RT room temperature

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

The TEA triethylamine

The TFA trifluoroacetic acid

The THF tetrahydrofuran (THF)

The t triplet

S is unimodal

D is bimodal

The q quartet

The qvint quintet

The m multiplet

The br broad peak

Bs is wide unimodal

The two multiplets of dm

The wide triplet of bt

The two doublets of dd

General experimental technique

With single quadrupole mass spectrometer of Micromass ZQ that has been equipped with pneumatic auxiliary electrical spraying interface or the single quadrupole mass spectrometer record of Micromass LCZ mass spectrum (LC-MS).With Varian Mercury300 or Varian Inova 500, exist respectively ¹H frequency 300MHz and 500MHz be operation down, carries out ¹H NMR measures.Use CDCl ₃For the interior ppm of being marked with provides chemical shift.CDCl ₃As the solvent of NMR, except as otherwise noted.The fraction collector that triggers with half preparation HPLC (high performance liquid chromatography) and quality---be equipped with 19x100mm C8 post Shimadzu QP 8000 single quadrupole mass spectrometers carry out purifying.Used moving phase be acetonitrile and buffer reagent (the 0.1M ammonium acetate: acetonitrile 95: 5), except as otherwise noted.

For isomer separation, adopt Kromasil CN E9344 (250x20mm i.d.) post.Heptane: ethyl acetate: DEA is used as moving phase (1ml/ minute) at 95: 5: 0.1.Adopt UV detector (330nm) guiding flow point to collect.

The typical HPLC parameter of purity check:

HPLC system: Agilent 1100

Post: Zorbax Eclipse XDB-C8 150x4.6mm

Analysis time: 15 minutes

Flow velocity: 1.5ml/ minute

Moving phase: A: water, 5%MeOH

B：MeOH

Temperature: 40 ℃

Detector: Uv 240nm

Embodiment

The universal method of salt preparation

Free alkali (15-30mg usually) is dissolved in butanone (for example 0.08-0.2ml, 0.8-2ml usually), contains methyl alcohol (usually less than 1ml) in case of necessity.Choose wantonly solution is put into ultra sonic bath (Decon FS200b).Add the acid (1 molar equivalent (equivalent) hydrochloric acid or 1 equivalent methylsulfonic acid or 0.5 equivalent naphthalene-1,5-disulfonic acid) or 1 equivalent or the 0.5 equivalent sulfuric acid that are dissolved in methyl alcohol (0.1-0.2ml usually).Drip heptane (0.5-2ml usually), the gained mixture is placed ultra sonic bath.Collect formed solid, high vacuum dry by filtering.

With Reichert fusing point measurement microscope fusing point, measured value is not proofreaied and correct.Those skilled in the art should be understood that, heating rate can influence the fusing point that is obtained, some salt (for example hydrochloride) when slow heating feasible solution from, so the fusing point that the last fusing point that obtains may be a free alkali, or the fusing point of free alkali and hydrochloride mixture.Under these circumstances, can adopt combustion analysis to confirm the structure of salt.Those skilled in the art it will also be appreciated that drying temperature should not too high (for example above 45 ℃), decompose otherwise salt may take place.Preferred vacuum-drying.

Prepare following salt with suitable acid by method described in the universal method.

Embodiment 1: butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester

Hydrochloride: fusing point 106-112 ℃.

Half-1,5-napadisilate: fusing point 160-163 ℃.

Embodiment 2: propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(morpholine-4-base formamyl)-2H-pyrazole-3-yl] phenyl ester

Hydrochloride: fusing point 220-223 ℃.

Half-1,5-napadisilate: fusing point 270-274 ℃.

Mesylate: fusing point 218-223 ℃.

Embodiment 3:4,4,4-trifluoro butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester

Hydrochloride: fusing point 100-105 ℃.

Mesylate: fusing point 169-174 ℃.

Half-1,5-napadisilate: fusing point 260-265 ℃.

Hydrosulfate: fusing point 203-207 ℃.

Embodiment 4: propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl]-2,6-difluoro phenyl ester

Hydrochloride: fusing point 104-108 ℃.

Mesylate: fusing point 141-145 ℃.

Half-1,5-napadisilate: fusing point 271-274 ℃.

Embodiment 5:3,3,3-three fluoro-propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester

Hydrochloride: fusing point 101-107 ℃.

Mesylate: fusing point 168-173 ℃.

Half-1,5-napadisilate: fusing point 159-164 ℃.

Hydrosulfate: fusing point 205-209 ℃.

Embodiment 6:3-methyl-butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester

Hydrochloride: fusing point 110-115 ℃.

Mesylate: fusing point 122-127 ℃.

Half-1,5-napadisilate: fusing point 161-164 ℃.

Embodiment 7:3,3-dimethyl-butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester

Hydrochloride: fusing point 112-119 ℃.

Mesylate: fusing point 160-167 ℃.

Half-1,5-napadisilate: fusing point 276-279 ℃.

Embodiment 8: propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester

Hydrochloride: fusing point 185-189 ℃.

Mesylate: fusing point 111-114 ℃.

Half-1,5-napadisilate: fusing point 156-161 ℃.

Hydrosulfate: fusing point 203-209 ℃.

Embodiment 9: carbonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] the phenyl ester propyl ester

Hydrochloride: fusing point 99-108 ℃.

Mesylate: fusing point 110-115 ℃.

Half-1,5-napadisilate: fusing point 175-180 ℃.

Embodiment 10: pyridine-3-sulphonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenyl ester

Mesylate: fusing point 225-227 ℃.

Half-1,5-napadisilate: fusing point 168-172 ℃.

The preparation of free alkali

1) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base carbamyl Base)-the 2H-pyrazole-3-yl]-phenyl ester

Steps A 1-(4-benzyloxy phenyl) third-1-ketone

With 4-hydroxy phenyl ethyl ketone (15.0g, 0.10mol) be dissolved in acetone (200ml) and salt of wormwood (13.8g, 0.10mol) in.(17.1g 0.10mol), spends the night the reaction mixture reflux to add bromotoluene.After mixture is cooled to room temperature, filters also and on rotatory evaporator, concentrate, obtain 24.0g (100%) title compound, be white solid.

Step B 1-(4-benzyloxy phenyl)-2-bromine third-1-ketone

(4.80g 20.0mmol) is suspended in acetate (25ml) postcooling to 0 ℃ with 1-(4-benzyloxy phenyl) third-1-ketone.(3.20g 20.0mmol), at room temperature stirred reaction mixture 2 hours dripping bromine, and reaction mixture becomes yellow transparent solution when the time comes, after the cooling, added entry (100ml), and product extracts with ether (2x100ml).The organic extract water, sodium bicarbonate and the salt water washing that merge.Organic phase drying (Na ₂SO ₄), filter the back evaporation, obtain title compound (6.17g, 97%, light yellow solid).

Step C 2-[2-(4-benzyloxy-phenyl)-2-oxo-ethyl]-3-oxo-ethyl butyrate

(0.53g, 30ml ethanol solution 23.0mmol) makes alcohol sodium solution by the sodium metal.Under 0 ℃, in this solution, add methyl aceto acetate (3.00g, 23.0mmol).After 30 minutes.This solution is added to 1-(4-benzyloxy phenyl)-2-bromo-third-1-ketone, and (6.17g, 19.0mmol) and ethanol: (30: in solution 15ml), stirred reaction mixture spends the night toluene.Carry out acid treatment with 1M HCl,, use the salt water washing, dry (Na with ethyl acetate extraction (3 times) ₂SO ₄), filter the back evaporation, the institute's crude product that arrives purified by flash chromatography (hexane: EtOAc95: 5～70: 30), obtain the 5.18g title compound, be light yellow oil.

Step D 5-(4-benzyloxy phenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-formic acid

(0.19g, 20ml ethanol solution 8.26mmol) makes alcohol sodium solution by the sodium metal.In this solution, add 2-[2-(4-benzyloxy phenyl)-2-oxo-ethyl]-(2.13g 6.00mmol), at room temperature stirred reaction mixture 30 minutes 3-oxo-ethyl butyrate.When keeping 5 ℃ of following temperature, divide the prefabricated solution that adds 2,4 dichloro benzene base diazonium chloride for 5 times (by 2,4 dichloro aniline (1.19g, 7.30mmol) 3ml 24%HCl solution and Sodium Nitrite (0.52g, 3ml aqueous solution 7.50mmol) 0 ℃ down preparation and get).At room temperature stir after 2.5 hours and add entry, product is with EtOAc extraction (3 times).With the organic extract drying (Na that merges ₂SO ₄), filter the back evaporation.Resistates is dissolved in ethanol (40ml), adds sodium hydroxide (0.80g, 10ml aqueous solution 20.0mmol).Reflux boiling after 2 hours, make the reaction mixture cooling, use the HCl acidifying, product extracts (3 times) with EtOAc.After the washing, dry (Na ₂SO ₄), filter the back and concentrate, resistates purified by flash chromatography (hexane: EtOAc70: 30～50: 50), obtain 1.84g (68%) title compound, be light yellow solid.

Step e 5-(4-benzyloxy phenyl)-1-(2,4 dichloro benzene base)-4-methyl-N-piperidines-1-base-1H- Pyrazole-3-formamide

With 5-(4-benzyloxy phenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-formic acid (1.84g 4.07mmol) is suspended in methylene dichloride, drip several DMF after, add oxalyl chloride (1.03g, 8.14mmol).With reaction mixture refluxed 2 hours, be cooled to room temperature after, remove and desolvate, rough acyl chlorides is dissolved in methylene dichloride again and is cooled to 0 ℃.Add successively triethylamine (1.15ml, 8.20mmol) and the 1-amino piperidine (0.5ml, 4.50mmol).Remove ice bath, reaction mixture was at room temperature stirred 2 hours.Add entry, product dichloromethane extraction (3 times).Extract drying (the Na that merges ₂SO ₄), filter the back evaporation.With purified by flash chromatography (hexane: EtOAc 80: 20～70: 30), obtain 1.13g (52%) title compound, be solid.

Step F 1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrrole Azoles-3-methane amide

(1.00g 1.87mmol) is dissolved in 25ml dehydrated alcohol and the 100mg palladium charcoal (10%Pd) with 5-(4-benzyloxy phenyl)-1-(2,4 dichloro benzene base)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide.Reactant spends the night with hydrogen gas tank hydrogenation.Filter, concentrate, (hexane: EtOAc 50: 50～EtOAc), obtain 0.83g (100%) title compound is solid with purified by flash chromatography.

Step G Propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene the base)-4-methyl-5-(piperidines-amino first of 1-base Acyl group)-the 2H-pyrazole-3-yl]-phenyl ester

With 1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide (222mg 0.50mmol) is dissolved in methylene dichloride (10ml), add triethylamine (0.07ml, 0.50mmol).(71mg 0.50mmol), removes ice bath, and reactant was at room temperature stirred 2 hours to add third SULPHURYL CHLORIDE down at 0 ℃.Add entry, product dichloromethane extraction, dry (Na ₂SO ₄), filter the back and concentrate.With purified by flash chromatography (hexane: EtOAc70: 30～50: 50), products therefrom is from hexane: recrystallize the EtOAc, obtain 135mg (49%) title compound, be white solid, 190 ℃ of fusing points.

¹H NMR (CDCl ₃): δ 7.66 (1H, wide unimodal), 7.44-7.17 (7H, m), 3.25 (2H, t), 2.90 (4H, m), 2.39 (3H, s), 2.09-1.97 (2H, m), 1.78 (4H, m), 1.45 (2H, m), 1.17 (3H, t)

MS?m/z?573(M+Na)。

2) 1-(2,4 dichloro benzene base)-4-methyl-5-[4-(4,4,4-trifluoro butoxy)-phenyl]-N-piperidines-1- Base-1H-pyrazole-3-formamide

Will be by the 1-(2 of step F preparation in 1, the 4-dichlorophenyl)-5-(4-hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide (250mg, 0.56mmol) be dissolved in acetone (10ml), add salt of wormwood (77mg successively, 0.56mmol) and 1-iodo-4,4, and 4-trifluoro butane (140mg, 0.56mmol).Reaction mixture refluxed is boiled the back of spending the night concentrate, with purified by flash chromatography (hexane: EtOAc 70: 30～60: 40), obtain 130mg (42%) white solid, use hexane: EtOAc grinds and filters at 95: 5.

¹H NMR (CDCl ₃) δ 7.63 (1H, wide unimodal), 7.43 (1H, m), 7.30 (2H, m), 7.10-7.00 (2H, m), 6.85-6.78 (2H, m), 4.05 (2H, t), 2.90 (4H, m), 2.40-2.19 (5H, s and m), 2.15-1.97 (2H, m), 1.78 (4H, m), 1.45 (2H, m).MSm/z?577(M+Na)。HPLC：98.4％。

3) butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base carbamyl Base)-the 2H-pyrazole-3-yl]-phenyl ester

Will by 1-(2,4 dichloro benzene base)-5-(4-hydroxyl-phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide of step F preparation in 1 (350mg 0.78mmol) is dissolved in methylene dichloride (10ml), add triethylamine (0.11ml, 0.78mmol).(0.12g 0.78mmol), removes ice bath, and at room temperature reaction stirred is spent the night to add the fourth SULPHURYL CHLORIDE down at 0 ℃.Add entry, product dichloromethane extraction, dry (Na ₂SO ₄), filter the back and concentrate, with purified by flash chromatography (hexane: EtOAc 70: 30～50: 50), products therefrom is from hexane: recrystallize the EtOAc, obtain 200mg (45%) title compound, be solid.

¹H?NMR(CDCl ₃)：δ7.48-7.19(8H，m)，3.29(2H，m)，2.96(4H，m)，2.41(3H，s)，2.09-1.97(2H，m)，1.81(4H，m)，1.64-1.50(4H，m)，1.02(3H，t)。

4) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(morpholine-4-base carbamyl Base)-and the 2H-pyrazole-3-yl] phenyl ester

Steps A 5-(4-benzyloxy phenyl)-1-(2,4 dichloro benzene base)-4-methyl-N-morpholine-4-base-1H-pyrrole Azoles-3-methane amide

5-(4-benzyloxy phenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-formic acid (1.18g, 25ml CH 2.6mmol) of step D preparation in by 1 ₂Cl ₂In the solution, add successively 2 DMF and oxalyl chloride (0.44ml, 5.2mmol).Mixture refluxed boiled 2 hours, be cooled to be evaporated to after the room temperature dried.Resistates is dissolved in 25ml CH ₂Cl ₂Postcooling to 0 ℃.(0.73ml, 5.2mmol) (0.28ml 2.9mmol), at room temperature stirred mixture 3 hours with the 1-amino piperidine to add triethylamine successively.Add entry (100ml), mixture CH ₂Cl ₂(3x50ml) extraction, dry (Na ₂SO ₄), filter the back and concentrate.(silica gel, hexane: EtOAc 1: 2 EtOAc), obtain 215mg (15%) title compound, are white solid with purified by flash chromatography.

Step B 1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-4-methyl-N-morpholine-4-base-1H-pyrazoles- The 3-methane amide

(215mg 0.40mmol) is dissolved in 20ml CH with 5-(4-benzyloxy phenyl)-1-(2,4 dichloro benzene base)-4-methyl-N-morpholine-4-base-1H-pyrazole-3-formamide ₂Cl ₂Postcooling to 0 ℃.(78 μ l 0.80mmol), at room temperature stirred reaction mixture 2.5 hours to drip boron tribromide.Add entry (50ml), solution extracts with EtOAc (3x50ml).With the organic phase drying (Na that merges ₂SO ₄), filter the back and concentrate.With purified by flash chromatography (silica gel, hexane: EtOAc1: 2, EtOAc), obtain 180mg (99%) title compound, be white solid.

Step C Propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene the base)-4-methyl-5-(morpholine-amino first of 4-base Acyl group)-the 2H-pyrazole-3-yl]-phenyl ester

With 1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-4-methyl-N-morpholine-4-base-1H-pyrazole-3-formamide (180mg, 10ml CH 0.40mmol) ₂Cl ₂Solution is cooled to 0 ℃.(56 μ l, 0.40mmol) (45 μ l 0.40mmol), at room temperature stirred reaction mixture 5 hours with 1-propane SULPHURYL CHLORIDE to add triethylamine successively.Add entry, mixture CH ₂Cl ₂(3x20ml) extraction, dry (Na ₂SO ₄), filter the back and concentrate.With purified by flash chromatography (silica gel, hexane: EtOAc 1: 2), obtain 82mg (46%) title compound, be white solid.

¹H?NMR(CDCl ₃)：δ7.7(1H，s)，7.5-7.4(1H，m)，7.4-7.1(6H，m)，3.9-3.8(4H，m)，3.3-3.2(2H，m)，3.0-2.9(4H，m)，2.4(3H，s)，2.1-1.9(2H，m)，1.2(3H，t)。

MS?m/z?576(M+Na)。HPLC：98.0％。

5) 3,3,3-trifluoro propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base ammonia The base formyl radical)-and the 2H-pyrazole-3-yl] phenyl ester

Steps A 1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrrole Azoles-3-methane amide

Will by step e preparation in 5 5-(4-benzyloxy phenyl)-(330mg 0.62mmol) is dissolved in 20mlCH to 1-(2,4 dichloro benzene base)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide ₂Cl ₂Postcooling to 0 ℃.(120 μ l 1.24mmol), at room temperature stirred reaction mixture 1 hour to drip boron tribromide.Add entry (50ml), solution extracts with EtOAc (3x20ml).With the organic phase drying (Na that merges ₂SO ₄), filter the back and concentrate.(silica gel, hexane: EtOAc 1: 3 EtOAc), obtain 130mg (47%) title compound, are white solid with purified by flash chromatography.

Step B 3,3,3-trifluoro propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1- The base formamyl)-and the 2H-pyrazole-3-yl] phenyl ester

With 1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide (130mg, 10ml CH 0.30mmol) ₂Cl ₂Solution is cooled to 0 ℃.Add triethylamine (42 μ l successively, 0.30mmol) and 3,3,3-trifluoro propane-1-SULPHURYL CHLORIDE (59mg, 0.30mmol) (available from Manchester Organics, but also available WO 200010968 described 4,4, the similar approach preparation of 4-trifluoro butane-1-SULPHURYL CHLORIDE), reaction mixture was at room temperature stirred 2 hours.Add entry, mixture CH ₂Cl ₂(3x20ml) extraction, dry (Na ₂SO ₄), filter the back and concentrate.With purified by flash chromatography (silica gel, hexane: EtOAc 7: 3,6: 4), obtain 150mg (82%) title compound, be white solid, 160 ℃ of fusing points.

¹H NMR (CDCl ₃): δ 7.7 (1H, wide unimodal), 7.5-7.2 (7H, m), 3.6-3.5 (2H, m), 3.0-2.7 (6H, m), 2.4 (3H, s), 1.9-1.7 (4H, m), 1.6-1.4 (2H, m).MSm/z?628(M+Na)。HPLC：92.5％。

6) 4,4,4-trifluoro butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base ammonia The base formyl radical)-and the 2H-pyrazole-3-yl] phenyl ester

Will be by the 1-(2 of steps A preparation in 5, the 4-dichlorophenyl)-5-(4-hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide (0.49g, 1.20mmol) be dissolved in methylene dichloride (20ml) postcooling to 0 ℃, add triethylamine (0.67ml successively, 4.8mmol) and press 4 of the described method preparation of WO200010968,4, and 4-trifluoro butane-1-SULPHURYL CHLORIDE (0.38g, 1.80mmol).Reaction mixture at room temperature stirred spend the night.Add entry, product dichloromethane extraction, dry (Na ₂SO ₄), filter the back and concentrate.With the purified by flash chromatography (back recrystallize (hexane: EtOAc), obtain 0.32g (43%) title compound, be colorless solid of hexane: EtOAc 1: 1～EtOAc).

¹H NMR (CDCl ₃): δ 7.80 (1H, wide unimodal), 7.50-7.19 (7H, m), 3.40 (2H, m), 3.05-2.90 (4H, m), 2.50-2.20 (7H, s and m), 1.92-1.70 (4H, m), 1.57-1.40 (2H, m).MS?m/z?641(M+Na)。HPLC：96.5％。

7) propane-1-sulfonic acid [2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)- The 2H-pyrazole-3-yl]-2,6-difluoro phenyl ester

Steps A 1-(4-benzyloxy-3,5-difluorophenyl)-third-1-ketone

With 1-(3,5-two fluoro-4-hydroxy phenyls) third-1-ketone (5.00g, 26.9mmol) be dissolved in acetone (100ml) and salt of wormwood (3.90g, 28.2mmol).(4.82g 28.2mmol), spends the night the reaction mixture boiling reflux to add bromotoluene.After being cooled to room temperature, mixture being filtered the back on rotatory evaporator, concentrate, obtain 7.43g (100%) title compound, be white solid.

Step B 1-(4-benzyloxy-3,5-difluorophenyl)-2-bromine third-1-ketone

(7.43g 26.9mmol) is suspended in acetate (35ml) with 1-(4-benzyloxy-3,5-difluorophenyl) third-1-ketone.(4.28g 26.8mmol), at room temperature stirred reaction mixture 2 hours, when the time comes reaction mixture yellowing clear solution dripping bromine.After the cooling, add frozen water (100ml), product extracts with ether (2x100ml).The organic extract water, sodium hydrogen carbonate solution and the salt water washing that merge.With organic phase drying (Na ₂SO ₄), filter the back evaporation, obtain 9.30g (98%) title compound, be light yellow oil.

Step C 2-ethanoyl-4-(4-benzyloxy-3,5-difluorophenyl)-3-methyl-4-ketobutyric acid ethyl ester

Under 0 ℃, (0.74g, 40ml dehydrated alcohol 32.0mmol) makes alcohol sodium solution by the sodium metal.In this solution, add methyl aceto acetate (4.16g, 32.0mmol).After 30 minutes, this solution is added to 1-(4-benzyloxy-3,5-difluorophenyl)-2-bromine third-1-ketone, and (9.30g, ethanol 26.2mmol): (40: 20ml) in the solution, stirred reaction mixture spends the night toluene.Carry out acid treatment with 1M HCl,, use the salt water washing, dry (Na with ethyl acetate extraction (3 times) ₂SO ₄), filter the back evaporation, the institute's crude product that arrives purified by flash chromatography (hexane: EtOAc95: 5～70: 30), obtain 6.95g (66%) title compound, be oily matter.

Step D 5-(4-benzyloxy-3,5-difluorophenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrrole Azoles-3-formic acid

(0.53g, 60ml dehydrated alcohol 22.0mmol) makes alcohol sodium solution by the sodium metal.(6.95g 17.2mmol), at room temperature stirred reaction mixture 30 minutes to add 2-ethanoyl-4-(4-benzyloxy-3,5-difluorophenyl)-3-methyl-4-ketobutyric acid ethyl ester in this solution.When keeping 5 ℃ of following temperature, divide to add the prefabricated solution of 2,4 dichloro benzene base diazonium chloride for 5 times (by 2,4 dichloro aniline (3.39g, 9ml 24%HCl 21.0mmol) and Sodium Nitrite (48g, 3ml aqueous solution 21.0mmol) is 0 ℃ of preparation down).0 ℃ down stir 2 hours after, reaction mixture is reached stirs after the room temperature and spend the night.Add entry, product extracts (3 times) with EtOAc.With the organic extract drying (Na that merges ₂SO ₄), filter the back evaporation, obtain the rough ethyl ester of 9.20g, be oily matter.Resistates (9.20g) is dissolved in ethanol (120ml) and sodium hydroxide, and (2.30g 57.5mmol), adds 15ml water.After backflow is boiled 2 hours, make the reaction mixture cooling, use the HCl acidifying, product extracts (3 times) with EtOAc.After the washing, dry (Na ₂SO ₄), filter the back and concentrate, resistates purified by flash chromatography (80: 20: 2～hexane of hexane: EtOAc: AcOH: EtOAc: AcOH 50: 50: 2), obtain 5.46g (65%, two step back) title compound, be solid.

Step e 5-(4-benzyloxy-3,5-difluorophenyl)-1-(2,4 dichloro benzene base)-4-methyl-N-piperidines- 1-base-1H-pyrazole-3-formamide

With 5-(4-benzyloxy-3,5-difluorophenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-formic acid (5.46g 11.2mmol) is suspended in methylene dichloride (60ml), drip several DMF after, add oxalyl chloride (4.70ml, 55.8mmol).With reaction mixture boiling reflux 1.5 hours.Be cooled to remove after the room temperature and desolvate, rough acyl chlorides is dissolved in methylene dichloride again, be cooled to 0 ℃, add Et successively ₃N (3.10ml, 22.2mmol) and the 1-amino piperidine (1.2ml, 11.2mmol).Remove ice bath, reaction mixture is at room temperature stirred spend the night.Add entry, product is with dichloromethane extraction (3 times), with the extract drying (Na that merges ₂SO ₄), filter the back evaporation.With purified by flash chromatography (hexane: EtOAc 80: 20～70: 30), obtain 1.86g (30%) title compound, be yellow solid.

Step F 5-(4-hydroxyl-3,5-difluorophenyl)-1-(2,4 dichloro benzene base)-4-methyl-N-piperidines-1- Base-1H-pyrazole-3-formamide

(1.86g 3.25mmol) is dissolved in 50ml methylene dichloride postcooling to-78 ℃ with 5-(4-benzyloxy-3,5-difluorophenyl)-1-(2,4 dichloro benzene base)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide.Slowly add BBr ₃(0.60ml 6.50mmol), stirs reaction mixture 30 minutes down at 0 ℃.Add entry, product CH ₂Cl ₂Extraction (3 times).With the organic extract drying (Na that merges ₂SO ₄), filter the back and concentrate.With purified by flash chromatography (hexane: EtOAc50: 50), obtain 0.64g (41%) title compound, be light yellow solid.

Step G Propane-1-sulfonic acid [2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base carbamyl Base)-and the 2H-pyrazole-3-yl]-2,6-difluoro phenyl ester

With 5-(4-hydroxyl-3, the 5-difluorophenyl)-1-(2, the 4-dichlorophenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide (0.64g, 1.32mmol) be dissolved in methylene dichloride (20ml) postcooling to 0 ℃, add triethylamine (0.18ml successively, 1.32mmol) and the propane SULPHURYL CHLORIDE (0.19g, 1.31mmol).Reaction mixture at room temperature stirred spend the night.Add entry, product dichloromethane extraction, dry (Na ₂SO ₄), filter the back and concentrate.With purified by flash chromatography (hexane: EtOAc 70: 30～50: 50), obtain 410mg (53%) title compound, be light yellow solid.

¹H NMR (CDCl ₃): δ 7.66 (1H, wide unimodal), 7.60-7.24 (4H, m), 6.97-6.78 (1H, m), 3.50-3.37 (2H, m), 3.02-2.80 (4H, m), 2.40 (3H, s), 2.20-2.00 (2H, m), 1.92-2.72 (4H, m), 1.60-1.40 (2H, m), 1.08 (3H, t).MS?m/z609(M+Na)。HPLC：97.5％。

8) propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-5-(piperidines-1-base formamyl)-2H-pyrrole Azoles-3-yl] phenyl ester

Steps A 4-(4-benzyloxy phenyl)-2,4-dioxo ethyl butyrate

Under nitrogen atmosphere ,-78 ℃, in 1 hour, in LiHMDS (88ml, the THF solution of 1M) and ether (50ml) solution, add 1-(4-benzyloxy phenyl) ethyl ketone (20g, suspension 88.4mmol) that is dissolved in ether (150ml) and THF (50ml).With the gained mixture in-78 ℃ stir 1 hour after, add oxalic acid diethyl ester (14.2g, 97.2mmol).After making the gained mixture slowly be warming up to room temperature, standing over night.Reaction mixture dilutes with pentane (90ml), and crude product is separated out, and is its lithium salts.With gained solid (27.2g) vacuum-drying, be directly used in next step.

Step B 5-(4-benzyloxy phenyl)-1-(2,4 dichloro benzene base)-1H-pyrazoles-3-ethyl formate

With 4-(4-benzyloxy phenyl)-2,4-dioxo ethyl butyrate (27.2g is from the lithium salts of previous step) is suspended in the ethanol (350ml), and adding 2,4 dichloro benzene hydrazine (17.8g, 83.3mmol).Reaction mixture at room temperature stirred spend the night.Removal of solvent under reduced pressure is dissolved in acetate with resistates then, and the gained mixture was refluxed 24 hours.Reaction mixture is used saturated NaHCO then with ethyl acetate (1L) dilution ₃(6x250ml) and salt solution (100ml) washing.Organic layer drying (MgSO ₄), filter the back concentrating under reduced pressure, obtain oily matter.Oily matter purified by flash chromatography (SiO ₂, the n-heptane solution of 20%EtOAc).The product part is behind concentrating under reduced pressure, and resistates obtains white solid (after 19.6,57%, two steps) by recrystallize (ethyl acetate/heptane) repurity.

¹H-NMR(CDCl ₃)：δ1.42(t，3H)，4.45(q，2H)，5.03(s，2H)，6.88(d，2H)，7.01(s，1H)，7.11(d，2H)，7.3-7.45(m，8H)。MS：467(M+1)。

Step C 1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-1H-pyrazoles-3-ethyl formate

Under nitrogen atmosphere, (735mg is 1.57mmol) with (CH to 5-(4-benzyloxy phenyl)-1-(2,4 dichloro benzene base)-1H-pyrazoles-3-ethyl formate ₃) ₂(0.58ml 7.86mmol) and in the solution of methylene dichloride (30ml) drips BF to S ₃-diethyl ether solution (diethyl etherate) (1.0ml, 7.86mmol).The gained mixture at room temperature stirred spend the night.And then adding (CH ₃) ₂S (0.58ml, 7.86mmol) and BF ₃-diethyl ether solution (1.0ml, 7.86mmol), with gained mixture restir 3 days.Reaction mixture is diluted to 80ml with methylene dichloride, water (3x30ml) and salt solution (40ml) washing.Organic layer drying (MgSO ₄), filter the back concentrating under reduced pressure, obtain white solid (573mg, 96%).Crude product can directly use.

¹H-NMR(CDCl ₃)：δ1.41(t，3H)，4.44(q，2H)，6.74(d，2H)，7.00(s，1H)，7.06(d，2H)，7.3-7.45(m，3H)。MS：375(M-1)。

Step D 1-(2,4 dichloro benzene base)-5-[4-(propane-1-alkylsulfonyl oxygen base)-phenyl]-1H-pyrazoles-3- Ethyl formate

Under nitrogen atmosphere, with 1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-1H-pyrazoles-3-ethyl formate (510mg 1.35mmol) is suspended in methylene dichloride (20ml), add triethylamine (0.75ml, 5.4mmol).Make gained make mixture be cooled to 0 ℃, and dropping 1-propane SULPHURYL CHLORIDE (0.30ml, 2.7mmol).Mixture was stirred 1 hour down at 0 ℃.Reaction mixture is diluted to 40ml with methylene dichloride then, uses saturated NaHCO again ₃(3x20ml) and salt solution (20ml) washing.Organic layer drying (MgSO ₄), filter the back concentrating under reduced pressure, obtain oily matter (0.64g, 98%).Crude product need not to be further purified just and can use.

¹H-NMR(CDCl ₃)：δ1.12(t，3H)，1.43(t，3H)，2.01(m，2H)，3.23(m，2H)，4.46(q，2H)，7.07(s，1H)，7.19-7.46(m，7H)。

MS：483(M+1)。

Step e Propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-5-(piperidines-1-base formamyl)- The 2H-pyrazole-3-yl] phenyl ester

Under nitrogen atmosphere, (36mg 0.26mmol) is dissolved in toluene (1.0ml) with the 1-amido piperidine hydrochlorate.At room temperature drip trimethyl aluminium (toluene solution of 2M, 0.17ml).Then the gained mixture was at room temperature stirred 40 minutes.Again this mixture is added to 1-(2,4-two chloro-phenyl)-5-[4-(propane-1-alkylsulfonyl oxygen base) phenyl]-1H-pyrazoles-3-ethyl formate (42mg, 0.087mmol) with the stirred suspension of DCM (1.0ml) in, with the gained mixture in 60 ℃ of heated overnight.Reactant distributes between water (20ml) and DCM (20ml) then by adding the entry quencher.Organic layer washes (3x10ml), concentrating under reduced pressure then with water.Resistates reversed-phase HPLC purifying (C8 post, 5-100% acetonitrile solution (buffer reagent: the 0.1M ammonium acetate)).The product part washes several times with water with the ethyl acetate dilution.Behind the organic layer concentrating under reduced pressure,, obtain white solid (26mg, 55%) with the resistates lyophilize.

¹H-NMR(CDCl ₃)：1.11(t，3H)，1.43(m，2H)，1.76(m，4H)，2.00(m，2H)，2.85(m，4H)，3.22(m，2H)，7.11(m，1H)，7.20(m，4H)，7.37(m，2H)，7.49(m，1H)。MS：537(M+1)。

9) propane-1-sulfonic acid 4-[4-bromo-2-(2,4 dichloro benzene base)-5-(piperidines-1-base formamyl)- The 2H-pyrazole-3-yl] phenyl ester

Steps A 4-bromo-1-(2,4 dichloro benzene base)-5-[4-(propane-1-alkylsulfonyl oxygen base) phenyl]-the 1H-pyrrole Azoles-3-ethyl formate

Will be by the 1-(2 of step D preparation in 8; the 4-dichlorophenyl)-5-[4-(propane-1-alkylsulfonyl oxygen base) phenyl]-1H-pyrazoles-3-ethyl formate (597mg; 1.23mmol) be dissolved in methylene dichloride (15ml); add bromine (0.06ml; 1.23mmol) methylene dichloride (1ml) solution, the gained mixture at room temperature stirred spends the night.Add again bromine (0.06ml, 1.23mmol), with mixture restir 20 hours.Reaction mixture is diluted to 80ml with methylene dichloride, uses saturated NaHCO then ₃(40ml), 20%Na ₂S ₂O ₅(40ml), saturated NaHCO ₃(2x40ml) and salt solution (40ml) washing.Organic layer drying (MgSO ₄), filter the back concentrating under reduced pressure, obtain orange (0.598,73%).Crude product need not to be further purified just and can use.

¹H-NMR(CDCl ₃)：δ1.12(t，3H)，1.44(t，3H)，2.01(m，2H)，3.24(m，2H)，4.48(q，2H)，7.2-7.46(m，7H)。MS：561。

Step B Propane-1-sulfonic acid 4-[4-bromo-2-(2,4 dichloro benzene base)-5-(piperidines-1-base carbamyl Base)-and the 2H-pyrazole-3-yl] phenyl ester

Title compound is pressed the described similar approach preparation of step e in 8; make 4-bromo-1-(2; the 4-dichlorophenyl)-5-[4-(propane-1-alkylsulfonyl oxygen base) phenyl]-1H-pyrazoles-3-ethyl formate and the reaction of 1-amido piperidine hydrochlorate, obtain the 26mg title compound, be white solid.Yield: 25%.

¹H-NMR(CDCl ₃)：1.12(t，3H)，1.43(m，2H)，1.74(m，4H)，2.01(m，2H)，2.90(m，4H)，3.24(m，2H)，7.21-7.45(m，7H)。

MS：615。

10) oxygen base 1-{[(1-(2,4 dichloro benzene base)-4-methyl-5-{4-[(third alkylsulfonyl)] phenyl }-the 1H-pyrrole Azoles-3-yl) carbonyl] amino } the cyclopentane-carboxylic acid methyl esters

Steps A 1-Aminocyclopentane methyl-formiate hydrochloride

With thionyl chloride (1.5ml) be dissolved in pour into behind the methyl alcohol (15ml) 1-Aminocyclopentane formic acid (100mg, 0.774mmol) in.Mixture was refluxed 1 hour.Evaporating solvent obtains product (107mg, 77%).

¹H?NMR(399.964MHz)δ9.00-8.60(br，3H)，3.79(s，3H)，2.23(s，4H)，2.14-2.00(m，2H)，1.90-1.76(m，2H)。

Step B 1-({ [5-[4-(benzyloxy) phenyl]-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3- Base] carbonyl } amino) the cyclopentane-carboxylic acid methyl esters

Will be by the 5-[(4-benzyloxy of step D preparation in 1) phenyl]-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-formic acid (59mg, DCM (20ml) the solution mixing of (2ml) solution of DCM 0.130mmol) and oxalyl chloride (2ml).Add a DMF, be reflected under the room temperature lucifuge and continue 1 hour.Evaporating solvent adds DCM (2ml), and the acyl chlorides mixture is added to 1-Aminocyclopentane methyl-formiate hydrochloride, and (23mg is 0.130mmol) with DCM (2ml) and K ₂CO ₃(aqueous solution, 10% (weight) is in mixture 2ml).Reaction at room temperature continues 3 hours.Separate each phase, organic phase washes with water, through MgSO ₄Drying obtains product (71mg, 94%).

¹H?NMR(399.964MHz)δ7.43-7.23(m，9H)，7.06-7.00(m，2H)，6.93-6.87(m，2H)，5.02(s，2H)，3.75(s，3H)，2.40-2.30(m，2H)，2.34(s，3H)，2.14-2.04(m，2H)，1.87-1.77(m，4H)。

MS?m/z?578，580，582(M+H) ⁺。

Step C 1-({ [1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-4-methyl isophthalic acid H-pyrazole-3-yl] Carbonyl } amino) the cyclopentane-carboxylic acid methyl esters

With boron trifluoride-diethyl ether solution (156 μ l, 1.23mmol) be added to 1-({ [5-[4-(benzyloxy) phenyl]-1-(2, the 4-dichlorophenyl)-and 4-methyl isophthalic acid H-pyrazole-3-yl] carbonyl } amino) cyclopentane-carboxylic acid methyl esters (51mg, 0.088mmol) and methyl-sulfide (90 μ l, 1.23mmol) with the mixture of DCM (2ml) in.Be reflected under the room temperature lucifuge and continue 46 hours.Add entry and DCM, separate each phase, organic phase washes with water, through MgSO ₄Dry (39mg, 90%).

¹H?NMR(399.964MHz)δ7.60-6.60(m，8H)，3.72(s，3H)，2.43-2.23(m，2H)，2.26(s，3H)，2.15-2.00(m，2H)，1.85-1.75(m，4H)。

MS?m/z?488，490，492(M+H) ⁺。

Step D 1-{[(1-(2,4 dichloro benzene base)-4-methyl-5-{4-[(third alkylsulfonyl) oxygen base] phenyl }- The 1H-pyrazole-3-yl) carbonyl] amino } the cyclopentane-carboxylic acid methyl esters

Under-78 ℃, successively with TEA (100 μ l) and 1-propane SULPHURYL CHLORIDE (30 μ l, 0.268mmol) ({ [1-(2 to be added to 1-, the 4-dichlorophenyl)-5-(4-hydroxy phenyl)-4-methyl isophthalic acid H-pyrazole-3-yl] carbonyl amino) the cyclopentane-carboxylic acid methyl esters (39mg, 0.080mmol) with the mixture of anhydrous DCM (1.5ml) in.At-78 ℃, N ₂(g) under, will react lasting 1.5 hours.Add entry and DCM, make temperature rise to room temperature.Separate each phase, organic phase washes with water, through MgSO ₄Dry.(kromasil C8 post, ammonium acetate (aqueous solution, 0.1M): acetonitrile, product occurs when about 88% acetonitrile) obtains product (17mg, 35%, the Powdered thing of near-white) to product with the preparation HPLC purifying.

¹H?NMR(399.964MHz)δ7.45-7.39(br，1H)，7.32-7.28(m，2H)，7.27-7.19(m，3H)，7.18-7.12(m，2H)，3.76(s，3H)，3.26-3.20(m，2H)，2.40-2.30(m，2H)，2.35(s，3H)，2.15-2.05(m，2H)，2.05-1.95(m，2H)，1.88-1.78(m，4H)，1.12(t，3H)。

For [C ₂₇H ₂₉Cl ₂N ₃O ₆S+H] ⁺, the HRMS calculated value: 594.123, measured value: 594.121.

11) carbonic acid 4-[2-(2,4-two chloro-phenyl)-4-methyl-5-(piperidines-1-base formamyl)-2H- Pyrazole-3-yl]-the phenyl ester propyl ester

Will by 1-(2,4-two chloro-phenyl)-5-(4-the hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide of step F preparation in 1 (0.44g 1.00mmol) is dissolved in methylene dichloride (10ml), add triethylamine (0.28ml, 2.24mmol).Adding propyl chloroformate under 0 ℃ (0.14ml, 1.24mmol), reaction stirred concentrated after 40 minutes, and product obtains 345mg (65%) title compound with purified by flash chromatography (hexane: EtOAc 70: 30～50: 50).Use the preparation HPLC purifying again, obtain the 239mg title compound.

¹H?NMR(CDCl ₃)：δ7.71-7.18(8H，m)，4.24(2H，t)，2.93(4H，m)，2.40(3H，s)，1.78(6H，m)，1.46(2H，m)，1.03(3H，t)。

MS?m/z?553(M+Na)。

HPLC：94.15％。

12) thiophene-2-sulfonic acid 4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl Base]-1H-pyrazoles-5-yl } phenyl ester

At-78 ℃, N ₂(g) under, with thiophene-2-SULPHURYL CHLORIDE (433mg, 2.37mmol) DCM (2.5ml) solution be added to 1-(2 by step F preparation in 1, the 4-dichlorophenyl)-5-(4-hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide (200mg, 0.45mmol) and TEA (0.5ml, 3.59mmol) with the mixture of DCM (2.5ml) in.Being reflected at-78 ℃ continues down to continue 19 hours in room temperature after 2 hours.Add entry, separate each phase.Organic phase washes with water, through MgSO ₄Dry.Product is used the preparation HPLC purifying again, and (kromasil C8 post, ammonium acetate (aqueous solution, 0.1M): acetonitrile, product appearance when 100% acetonitrile) obtains the Powdered thing of near-white (158mg, 60%).

¹H?NMR(399.964MHz)δ7.71-7.67(m，1H)，7.67-7.57(br，1H)，7.50-7.46(m，1H)，7.35(s，1H)，7.25(s，2H)，7.07-7.00(m，3H)，6.98-6.92(m，2H)，2.86-2.76(m，4H)，2.29(s，3H)，1.73-1.65(m，4H)，1.42-1.33(m，2H)。

For [C ₂₆H ₂₄Cl ₂N ₄O ₄S ₂+ H] ⁺, HRMS calculated value: 591.069.Measured value: 591.067.

13) pyridine-3-sulphonic acid 4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl Base]-1H-pyrazoles-5-yl } phenyl ester

Steps A: Pyridine-3-sulphonic acid 4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) Carbonyl]-1H-pyrazoles-5-yl } phenyl ester

At-78 ℃, N ₂(g) under, with pyridine-3-SULPHURYL CHLORIDE (144mg, 0.67mmol) be added to 1-(2 with the suspension of DCM (10ml) by step F preparation among the embodiment 1, the 4-dichlorophenyl)-5-(4-hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide (200mg, 0.45mmol) and TEA (0.5ml, 3.59mmol) with the mixture of DCM (2.5ml) in.Being reflected at-78 ℃ continues down at room temperature to continue 30 minutes after 1.5 hours.Add entry, separate each phase.Organic phase washes with water, through MgSO ₄Dry.Product is used purified by flash chromatography (SiO again ₂, toluene: ethyl acetate, product occurs when 42% ethyl acetate), obtain title compound (216mg, 82%, Powdered thing).

¹H?NMR(399.964MHz)δ8.95-8.85(m，2H)，8.10-8.04(m，1H)，7.64(s，1H)，7.50-7.45(m，1H)，7.44-7.40(m，1H)，7.34-7.24(m，2H)，7.09-7.04(m，2H)，7.00-6.95(m，2H)，2.88-2.78(m，4H)，2.33(s，3H)，1.78-1.68(m，4H)，1.46-1.36(m，2H)。

For [C ₂₇H ₂₅Cl ₂N ₅O ₄S+H] ⁺, HRMS calculated value: 586.108.Measured value: 586.111.

14) [2-(4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrrole Azoles-5-yl } phenoxy group) ethyl] the ethyl carbamic acid tert-butyl ester

Steps A: Ethyl (2-hydroxyethyl) t-butyl carbamate

With tert-Butyl dicarbonate (3.19g, THF 14.6mmol) (10ml) solution be added to 2-(ethylamino) ethanol (1.00g, 11.2mmol) in, at room temperature reacted 3 hours.Solvent evaporated under reduced pressure obtains crude product (2.28g).

¹H?NMR(499.961MHz)δ3.71-3.65(br，2H)，3.55-3.35(br，1H)，3.35-3.30(br，2H)，3.30-3.20(br，2H)，1.43(s，9H)，1.07(t，3H)。

Step B: [2-(4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H- Pyrazoles-5-yl } phenoxy group) ethyl] the ethyl carbamic acid tert-butyl ester

Will be by the 1-(2 of step F preparation in 1, the 4-dichlorophenyl)-5-(4-hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide (151.6mg, 0.34mmol) and ethyl (2-hydroxyethyl) t-butyl carbamate (408.6mg, 1.73mmol) mixing in toluene (1ml), in single-unit (single node) microwave oven in 180 ℃ of reaction repeated.Reaction times is 2 hours altogether.Methylene tri-(total amount is 925mg to N-butyl phosphorane, 3.83mmol) to add cyano group before each heating.Evaporating solvent then, (kromasil C8 post, ammonium acetate (aqueous solution, 0.1M): acetonitrile, product occurs when 100% acetonitrile) is with purified by flash chromatography (SiO with the preparation HPLC purifying for product ₂, toluene: ethyl acetate, product occurs when 30% ethyl acetate), obtain the Powdered thing of near-white (125mg, 60%).

¹H?NMR(399.964MHz)δ7.62(s，1H)，7.37(s，1H)，7.23(s，2H)，7.01-6.95(m，2H)，6.81-6.75(m，2H)，4.05-3.95(br，2H)，3.55-3.45(br，2H)，3.35-3.25(br，2H)，2.86-2.78(br，4H)，2.32(s，3H)，1.75-1.65(m，4H)，1.41(s，9H)，1.45-1.35(m，2H)，1.08(t，3H)。

MS?m/z?616，618，620(M+H) ⁺。

15) 3-methylbutane-1-sulfonic acid 4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base ammonia Base) carbonyl]-1H-pyrazoles-5-yl } phenyl ester

At-78 ℃, N ₂(g) under, with 3-methylbutane-1-SULPHURYL CHLORIDE (84mg, 0.49mmol) DCM (2ml) solution be added to 1-(2 by step F preparation in 1, the 4-dichlorophenyl)-5-(4-hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide (100mg, 0.23mmol) and TEA (0.5ml, 3.59mmol) with the mixture of DCM (2ml) in.Be reflected at-78 ℃ and continue 1 hour down.Add entry, separate each phase.Organic phase washes with water, through MgSO ₄Dry.Product is used the preparation HPLC purifying again, and (kromasil C8 post, ammonium acetate (aqueous solution, 0.1M): acetonitrile, product appearance when 100% acetonitrile) obtains the Powdered thing of near-white (94mg, 72%).

¹H?NMR(399.964MHz)δ7.85-7.45(br，1H)，7.38(s，1H)，7.29-7.25(m，2H)，7.23-7.18(m，2H)，7.16-7.11(m，2H)，3.25-3.18(m，2H)，2.88-2.80(m，4H)，2.33(s，3H)，1.86-1.77(m，2H)，1.76-1.65(m，5H)，1.45-1.34(m，2H)，0.92(d，6H)。

For [C ₂₇H ₃₂Cl ₂N ₄O ₄S+H] ⁺, HRMS calculated value: 579.160.Measured value: 579.159.

16) 3,3-dimethylbutane-1-sulfonic acid 4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base Amino) carbonyl]-1H-pyrazoles-5-yl } phenyl ester

At 78 ℃, N ₂(g) under, with 3,3-dimethylbutane-1-SULPHURYL CHLORIDE (59mg, 0.32mmol) DCM (2ml) solution be added to 1-(2 by step F preparation in 1, the 4-dichlorophenyl)-5-(4-hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide (103mg, 0.23mmol) and TEA (0.5ml, 3.59mmol) with the mixture of DCM (2ml) in.Be reflected at-78 ℃ and continue 1 hour down.Add entry, separate each phase.Organic phase washes with water, through MgSO ₄Dry.Product is used the preparation HPLC purifying again, and (kromasil C8 post, ammonium acetate (aqueous solution, 0.1M): acetonitrile, product appearance when 100% acetonitrile) obtains the Powdered thing of near-white (94mg, 68%).

¹H?NMR(399.964MHz)δ8.20-7.40(br，1H)，7.36(s，1H)，7.28-7.22(m，2H)，7.21-7.16(m，2H)，7.15-7.09(m，2H)，3.20-3.13(m，2H)，2.87-2.80(m，4H)，2.31(s，3H)，1.83-1.76(m，2H)，1.73-1.65(m，4H)，1.43-1.32(m，2H)，0.89(s，9H)。

For [C ₂₈H ₃₄Cl ₂N ₄O ₄S+H] ⁺, HRMS calculated value: 593.176.Measured value: 593.176.

17) 1-(2,4 dichloro benzene base)-5-{4-[2-(1,3-dioxolane-2-yl) oxyethyl group] phenyl }- 4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide

2-(2-bromotrifluoromethane)-1,3-dioxolane (60mg, 0.33mmol), by the 1-(2 of step F preparation in 1, the 4-dichlorophenyl)-5-(4-hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide (100mg, 0.22mmol) and salt of wormwood (150mg 1.09mmol) refluxed in acetonitrile (25ml) 15 hours.Evaporating solvent adds entry and DCM, separates each phase, and organic phase washes after drying (MgSO with water ₄).Product is used the preparation HPLC purifying again, and (kromasil C8 post, ammonium acetate (aqueous solution, 0.1M): acetonitrile, product appearance when 100% acetonitrile) obtains the Powdered thing of near-white (60mg, 49%).

¹H?NMR(399.964MHz)δ7.80-7.50(br，1H)，7.36(s，1H)，7.21(s，2H)，7.00-6.94(m，2H)，6.80-6.74(m，2H)，5.02(t，1H)，4.04(t，2H)，3.96-3.78(m，4H)，2.86-2.78(m，4H)，2.30(s，3H)，2.09(q，2H)，1.74-1.65(m，4H)，1.42-1.32(m，2H)。

For [C ₂₇H ₃₀Cl ₂N ₄O ₄+ H] ⁺, HRMS calculated value: 545.172.Measured value: 545.172.

18) (piperidines-1-base is amino for propane-1-sulfonic acid 4-[2-(2,4-two chloro-3-fluorophenyls)-4-methyl-5- Formyl radical)-and the 2H-pyrazole-3-yl] phenyl ester

Steps A: 1-(2,4-two chloro-3-fluorophenyls)-5-(4-p-methoxy-phenyl)-4-methyl isophthalic acid H-pyrazoles-3- Formic acid

(0.18g, 20ml dehydrated alcohol 7.89mmol) makes alcohol sodium solution by the sodium metal.(1.73g 5.92mmol), at room temperature stirred reaction mixture 30 minutes to add 2-ethanoyl-4-(4-methoxyl group-phenyl)-3-methyl-4-oxo-ethyl butyrate in this solution.When keeping 5 ℃ of following temperature, divide 5 times and add 2, and the prefabricated solution of 4-two chloro-3-fluorine diazonium chloride (by 2,4-two chloro-3-fluoroaniline (1.30g, 7.22mmol) 3ml 24%HCl solution and Sodium Nitrite (0.51g, 3.5ml aqueous solution 7.39mmol) is 0 ℃ of down preparation).At room temperature stir after 2.5 hours and add entry, product is with EtOAc extraction (3 times).With the organic extract drying (Na that merges ₂SO ₄), filter the back evaporation.Resistates is dissolved in ethanol (40ml), adds sodium hydroxide (1.00g, water 25.0mmol) (5ml) solution.Reflux boiling after 2 hours, make the reaction mixture cooling, use the HCl acidifying, product extracts (3 times) with EtOAc.Washing, dry (Na ₂SO ₄), filter the back and concentrate, resistates purified by flash chromatography (hexane: EtOAc70: 30～50: 50), obtain 1.37g (31%) title compound, be light brown solid.

Step B: 1-(2,4-two chloro-3-fluoro-phenyl)-5-(4-methoxyl group-phenyl)-4-methyl-N-piperidines-1- Base-1H-pyrazole-3-formamide

With 1-(2,4-two chloro-3-fluoro-phenyl)-5-(4-methoxyl group-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-formic acid (1.37g 3.43mmol) is suspended in the methylene dichloride (20ml), drip several DMF after, add oxalyl chloride (0.87g, 6.86mmol).With reaction mixture refluxed 2 hours.Be cooled to remove after the room temperature and desolvate, rough acyl chlorides is dissolved in methylene dichloride (20ml) again, be cooled to 0 ℃, add Et successively ₃N (0.96ml, 6.94mmol) and the 1-amino piperidine (0.37ml, 3.62mmol).Remove ice bath, reaction mixture is at room temperature stirred spend the night.Add entry, product is with dichloromethane extraction (3 times), with the extract drying (Na that merges ₂SO ₄), filter the back evaporation.With purified by flash chromatography (hexane: EtOAc 50: 50), obtain 0.79g (48%) title compound, be light brown solid.

Step C: 1-(2,4-two chloro-3-fluoro-phenyl)-5-(4-hydroxyl-phenyl)-4-methyl-N-piperidines-1-base- The 1H-pyrazole-3-formamide

Under 0 ℃, (2,4-two chloro-3-fluoro-phenyl)-(0.79g 1.66mmol) is dissolved in the 40ml methylene dichloride to 5-(4-methoxyl group-phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide with 1-.(0.32ml 3.31mmol), removes ice bath, at room temperature continues to stir after 2 hours, is poured in the frozen water, with DCM extraction (3 times) to add boron tribromide.With the extract drying (Na that merges ₂SO ₄), filter the back and concentrate.With purified by flash chromatography (EtOAc), obtain 0.36g (47%) title compound, be colorless solid.

Step D: Propane-1-sulfonic acid 4-[2-(2,4-two chloro-3-fluoro-phenyl)-4-methyl-5-(piperidines-1-base Formamyl)-the 2H-pyrazole-3-yl]-phenyl ester

To 1-(2,4-two chloro-3-fluoro-phenyl)-5-(4-hydroxyl-phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide (0.36g, 0.78mmol) methylene dichloride (10ml) solution in add triethylamine (0.22ml 1.56mmol), make reaction mixture be cooled to 0 ℃.(0.22g 1.56mmol), removes ice bath, and reaction mixture was at room temperature stirred 2 hours to add 1-propane SULPHURYL CHLORIDE.Add entry, product extracts (2 times) with DCM, and the organic extract of merging washes with water, dry (Na ₂SO ₄), filter the back and concentrate.With purified by flash chromatography (hexane: the EtOAc gradient), obtain 100mg (23%) title compound, be colorless solid.HPLC purity 80%.Use the preparation HPLC purifying, obtain the 40mg title compound.

¹H?NMR(CDCl ₃)：δ7.50-7.20(7H，m)，3.57-3.23(6H，m)，2.37(3H，s)，2.10-1.80(6H，m)，1.70-1.50(2H，m)，1.10(3H，t)。

MS：591(M+Na)。HPLC：97.1％。

19) 5-chlorothiophene-2-sulfonic acid 4-[2-(2,4 dichloro benzene the base)-4-methyl-5-(piperidines-amino first of 1-base Acyl group)-and the 2H-pyrazole-3-yl] phenyl ester

Under nitrogen atmosphere, will be by the 1-(2 of step F preparation in 1,4-two chloro-phenyl)-(100mg 0.22mmol) is dissolved in anhydrous methylene chloride (3ml) to 5-(4-hydroxyl-phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-formamide, adds triethylamine (0.09ml).Add then the 5-chlorothiophene-2-SULPHURYL CHLORIDE be dissolved in the anhydrous methylene chloride (2ml) (0.54mg, 0.24mmol).Reaction mixture was at room temperature stirred weekend.After reaction mixture is diluted to 20ml with methylene dichloride, water (2x5ml) and salt solution (5ml) washing.Organic layer obtains oily matter through concentrating under reduced pressure.Crude product reversed-phase HPLC purifying (Kromasil C8, the water of 5-100%MeCN and 0.1M ammonium acetate solution).The product part is dissolved in methylene dichloride with resistates, water and salt water washing behind concentrating under reduced pressure.Organic layer drying (MgSO ₄), filter the back concentrating under reduced pressure, obtain title compound, be yellow solid.

¹H-NMR(CDCl ₃)：δ1.42-1.50(m，2H)，1.73-1.81(m，4H)，2.39(s，3H)，2.84-2.92(m，4H)，6.95(d，1H)，7.04-7.14(m，4H)，7.30-7.36(m，3H)，7.44(d，1H)，7.63(s，1H)。

MS：625(M+1)。HPLC: purity＞99%.

Free alkali synthetic universal method

Method A

Method B

Claims

1. the mesylate of a compound, half-1,5-napadisilate, 1,2-ethanedisulphonate, hydrochloride or hydrosulfate form, described compound is selected from:

(3) propane-1-sulfonic acid 4-[2-(2,4-two chloro-phenyl)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl]-phenyl ester;

But do not comprise pyridine-3-sulphonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] the phenyl ester hydrochloride.

2. one or more following compounds:

3. the mesylate of following formula I compound, half-1,5-napadisilate or 1,2-ethionic acid salt form:

Wherein

R ^aExpression halogen, C _1-3Alkyl or C _1-3Alkoxyl group;

M is 0,1,2 or 3;

N is 0,1,2 or 3;

R ³Expression:

A) radicals X-Y-NR ⁷R ⁸,

Wherein X is CO or SO ₂,

Y does not exist or represents optional by C _1-3The NH that alkyl replaces;

R ⁷And R ⁸Independent expression:

Optional by 1,2 or 3 C that replaces by the represented group of W _1-6Alkyl;

Perhaps R ⁷Expression H, R ⁸As above definition;

Described each group is optional to be replaced by 1,2 or 3 group Z;

Z represents C _1-3Alkyl, C _1-3Alkoxyl group, hydroxyl, halogen, trifluoromethyl, trifluoromethylthio, difluoro-methoxy, trifluoromethoxy, trifyl, nitro, amino, a C _1-3Alkylamino, two C _1-3Alkylamino, C _1-3Alkyl sulphonyl, C _1-3Carbalkoxy, carboxyl, cyano group, formamyl, a C _1-3Alkyl-carbamoyl, two C _1-3Alkyl-carbamoyl and ethanoyl; With

4. as each compound among the claim 1-3 of medicine.

5. pharmaceutical preparation, described pharmaceutical preparation comprise among the claim 1-3 each compound and pharmaceutically acceptable auxiliary, diluent or carrier.

6. each compound is used for the treatment of or prevents purposes in the medicine of following disease in preparation among the claim 1-3: obesity, mental disorder is psychosis for example, schizophrenia and bipolar disorder, anxiety disorder, anxiety-depression disease, dysthymia disorders, cognitive disorder, dysmnesia, compulsive disorder, apositia, exessive appetite, attention deficit disorder, epilepsy and relative disease, sacred disease, Parkinson's disease, Huntington Chorea and alzheimer's disease, Immunological diseases, cardiovascular disorder, dysgenesia, endocrine disturbance, septic shock, the respiratory system relative disease, the gastro-intestinal system relative disease, the persistence substance abuse, habituation and/or recurrence indication.

One kind the treatment following disease method: obesity, mental disorder, psychosis, schizophrenia, bipolar disorder, anxiety disorder, anxiety-depression disease, dysthymia disorders, cognitive disorder, dysmnesia, compulsive disorder, apositia, exessive appetite, attention deficit disorder, epilepsy and relative disease, sacred disease, Parkinson's disease, Huntington Chorea, alzheimer's disease, Immunological diseases, cardiovascular disorder, dysgenesia, endocrine disturbance, septic shock, the respiratory system relative disease, the gastro-intestinal system relative disease, the persistence substance abuse, habituation and/or recurrence indication, this method comprises among the claim 1-3 that the patient of needs pharmacologically effective dose is arranged each compound.

8. the compound that is used for the treatment of among the claim 1-3 of obesity each.