CN1898244A - Triazole derivatives as vasopressin antagonists - Google Patents

Abstract

Compounds of formula (I), or pharmaceutically acceptable derivatives thereof, wherein: V represents a direct link or -O-; Ring A represents an optionally substituted 5- to 7-membered saturated heterocyclic ring, or a phenylene group.

Description

As the boost triazole derivative of rope antagonist of blood vessel

Technical field

The present invention relates to triazole derivative and relate to the method for preparing this derivative, for the preparation of the intermediate of this derivative, comprise the purposes of composition and this derivative of this derivative.

Triazole derivative of the present invention is vasopressin antagonist. Particularly they are for the antagonist of V1a acceptor and have many treatment and use, especially for treatment dysmenorrhoea (primary and insecondary).

Background technology

In the menstrual disorder field, exist very large unsatisfied demand and according to estimates at the most 90% all woman that pass through be affected to a certain extent. At the most 42% woman since dysmenorrhoea to miss work or other movable and according to estimates as a result of at 1 year about 600,000,000 working hours { Coco of loss of the U.S., A.S. (1999) .Primary dysmenorrhoea.[Review] [30refs]. American Family Physician, 60,489-96.}.

The lower abdomen dysmenorrhoea is caused by the UBF of uterus muscle over-activity and minimizing. These physiopathologic changes cause the stomachache that is radiated to the back of the body and leg. This may cause that the woman feels to feel sick, headache and suffer insomnia. This patient's condition is known as dysmenorrhoea and can be categorized as primary or acquired dysmenorrhea.

When not identifying when causing this patient's condition unusual, be diagnosed as primary dysmenorrhea. This impact is 50% female population { Coco, A.S. (1999) .Primary dysmenorrhoea. [Review] [30refs] .American Family Physician, 60,489-96. at the most; Schroeder, B.﹠Sanfilippo, J.S. (1999) .Dysmenorrhoea and pelvic pain in adolescents.[Review] [78refs] .Pediatric Clinics of North America, 46,555-71}. There is basic gynecological disease, for example in the situation of endometriosis, pelvis inflammatory disease (PID), fibroma or cancer, will be diagnosed as acquired dysmenorrhea. Only about 25% woman who suffers from dysmenorrhoea is diagnosed as acquired dysmenorrhea. Dysmenorrhoea can with menorrhalgia together with generation, its accounted for Gynecologic Outpatients section referral about 12%.

Now, the woman (NSAID) who suffers from primary dysmenorrhea with nonsteroidal anti-inflammatory agent or oral contraceptive pill for curing. Under the situation of acquired dysmenorrhea, can perform the operation to correct basic gynecological disease.

The woman who suffers from dysmenorrhoea has greater than the same time viewed systemic vascular vasopressin level in healthy woman in the menstrual cycle. On uterine vascular vasopressin acceptor, to the inhibition of vasopressin pharmacological action, can prevent dysmenorrhoea.

Therefore compound of the present invention may be applicable to treat the disease, particularly attack of broad range, Alzheimer's, anorexia nervosa, anxiety, anxiety disorder, asthma, atherosclerotic, autism, angiocardiopathy (comprises angina pectoris, atherosclerotic, hypertension, in heart failure, oedema, hypernatronemia), cataract, central nervous system disease, cerebrovascular ischemia, cirrhosis, cognitive disorder, Cushing disease, depression, diabetes, dysmenorrhoea (primary and insecondary), vomiting (comprising motion sickness), endometriosis, gastrointestinal disease, glaucoma, gynecological disease, heart disease, intrauterine growth retardation, inflammation (comprising rheumatoid arthritis), ischemic, ischemic heart disease, lung neoplasm, urination disorder, imtermenstrual pain, neoplasm, renal toxicity, adult-onset diabetes, fat, besetment and behavior disorder, Ocular hypertension, disease (preclampsia) before the eclampsia, premature ejaculation, premature labor (the pregnant front childbirth of foot), lung disease, Raynaud's disease, kidney trouble, kidney is depleted, the sex sex dysfunction, septic shock, sleep-disorder, the spinal cord injury, thrombosis, urogenital infections or uriasis.

Interested especially is following disease or obstacle:

Disease, premature ejaculation, premature labor (the pregnant front childbirth of foot) and Raynaud's disease before anxiety, angiocardiopathy (comprising angina pectoris, atherosclerotic, hypertension, heart failure, oedema, hypernatronemia), dysmenorrhoea (primary and insecondary), endometriosis, vomiting (comprising motion sickness), intrauterine growth retardation, inflammation (comprising rheumatoid arthritis), imtermenstrual pain, the eclampsia.

Compound of the present invention, with their pharmaceutically acceptable salt and solvate, have following advantage: they be the V1a acceptor selective depressant (so may have the side effect of minimizing), with the Compound Phase ratio of prior art, they may have more rapidly the effect beginning, they may be more effective, they may act on longlyer, and the bioavilability that they are may tool larger or they may have other more desirable character.

Summary of the invention

According to the present invention, the compound of formula (I) is provided,

Or its pharmaceutically acceptable derivates, wherein:

X represents-[CH₂] _a-R or-[CH₂] _a-O-[CH ₂] _b-R；

A represents to be selected from 0 to 6 number;

B represents to be selected from 0 to 6 number;

R represents H, CF₃Or Het;

Het represents 5-or 6-unit is saturated, fractional saturation or heteroaromatic, it comprises (a) 1 to 4 nitrogen-atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms, optionally replaced by one or more groups that are independently selected from W;

Y represents one or more being independently selected from-[O]_c-[CH ₂] _d-R ¹Substituting group, its each appearance can be identical or different;

The each appearance of c independently expression is selected from 0 or 1 number;

The each appearance of d independently expression is selected from 0 to 6 number;

R ¹Each appearance represents H, halo, CF independently₃, CN or Het¹；

Het ¹Each appearance represents 5-or 6-membered unsaturated heterocycle independently, comprises (a) 1 to 4 nitrogen-atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms;

V represent direct key or-O-;

Ring A represents that 5-to 7-unit saturated heterocyclic, comprises (a) 1 to 4 nitrogen-atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms, or ring A represents phenylene; Ring A is optional by one or more C that are selected from_1-6The group of alkyl, phenyl or hydroxyl replaces;

Q represent direct key or-N (R²)-；

R ²Expression hydrogen or C_1-6Alkyl;

Z represents-[O]_e-[CH ₂] _f-R ³, benzyl ring (optional phenyl ring or the Het of being fused to², and optional by one or more groups replacements that are independently selected from W on the integrated group), or Het³(optional phenyl ring or the Het of being fused to⁴, and optional by one or more groups replacements that are independently selected from W on the integrated group);

R ³Expression C_1-6Alkyl (optional by one or more groups replacements that are independently selected from W), C_3-6Cycloalkyl, C_3-6Cycloalkenyl group, phenyl (optional by one or more groups replacements that are independently selected from W), Het⁵Or NR⁴R ⁵；

E represents to be selected from 0 or 1 number;

F represents to be selected from 0 to 6 number;

Het ²And Het⁵Represent independently that 5-or 6-unit are saturated, fractional saturation or heteroaromatic, comprise (a) 1 to 4 nitrogen-atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms, optionally replaced by one or more groups that are selected from W;

Het ³Expression 4 is to saturated, the fractional saturation of 6-unit or heteroaromatic, comprise (a) 1 to 4 nitrogen-atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms are optionally replaced by one or more groups that are selected from W;

Het ⁴Expression 6-unit heteroaromatic comprises (a) 1 to 4 nitrogen-atoms, and (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms are optionally replaced by one or more groups that are selected from W;

R ⁴And R⁵Represent independently hydrogen, C_1-6Alkyl, C_1-6Alkoxyl, C_3-8Cycloalkyl (the optional C that is fused to_3-8Cycloalkyl) or Het⁶；

R ⁴And R⁵Optional independently by one or more C that are selected from_1-6Alkyl, C_1-6Alkoxyl, C_3-8Cycloalkyl (the optional C that is fused to_3-8Cycloalkyl) or the group of phenyl replace;

Het ⁶Expression 5-or 6-unit is saturated, fractional saturation or heteroaromatic, comprise (a) 1 to 4 nitrogen-atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms are optionally replaced by one or more groups that are selected from W;

The each appearance of W represents halo, [O] independently_gR ⁶、SO ₂R ⁶、SR ⁶、SO ₂NR ⁶R ⁷、 [O] _h[CH ₂]iCF ₃、[O] _jCHF ₂, phenyl is (optional by halo, C_1-6Alkyl or C_1-6The alkoxyl replacement), CN, phenoxy group (choose wantonly and replaced by halogen), OH, benzyl, NR⁶R ⁷、NCOR ⁶, benzyloxy, oxo, CONHR⁶、NSO ₂R ⁶R ⁷、COR ⁶、C _1-6Alkylidene-NCOR⁷、 Het ⁷；

R ⁶Expression hydrogen, C_1-6Alkyl, C_3-6Cycloalkyl, C_3-6Cycloalkenyl group or C_1-6Alkylidene-O-C_1-6Alkyl;

R ⁷Expression hydrogen or C_1-6Alkyl;

I represents to be selected from 0 to 6 number

H represents to be selected from 0 or 1 number;

G represents to be selected from 0 or 1 number;

J represents to be selected from 0 or 1 number;

Het ⁷Expression 5-or 6-unit is saturated, fractional saturation or heteroaromatic comprises (a) 1 to 4 nitrogen-atoms, and (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms are optional by R⁶And/or R⁷And/or oxo group replaces.

The compound of formula (I ') is provided in substituting embodiment:

Or its pharmaceutically acceptable derivates, wherein:

X represents-[CH₂] _a-R or-[CH₂] _a-O-[CH ₂] _b-R；

A represents to be selected from 0 to 6 number;

B represents to be selected from 0 to 6 number;

R represents H, CF₃Or Het;

Het represents 5-or 6-unit heterocycle, comprises (a) 1 to 4 nitrogen-atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms;

Y represents-[O]_c-[CH ₂] _d-R ¹；

Y ' expression-[O]_c′-[CH ₂] _d′-R ¹；

C and c ' represent to be selected from 0 or 1 number independently;

D and d ' represent to be selected from 0 to 6 number independently;

R ¹And R¹' represent independently H, halo, CF₃Or Het¹；

Het ¹Expression 5-or 6-membered unsaturated heterocycle comprise (a) 1 to 4 nitrogen-atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms;

Ring A represents to comprise 5-or the 6-unit saturated heterocyclic of at least one nitrogen-atoms;

Z represents-[O]_e-[CH ₂] _f-R ²Benzyl ring (optional be fused to that benzyl ring or 5-or 6-unit are saturated, the unsaturated ring of part or heteroaromatic, and/or optional by one or more groups replacements that are independently selected from W), or 6-unit heteroaromatic (choose wantonly and be fused to benzyl ring or 6-unit heteroaromatic, and/or optional by one or more groups replacements that are independently selected from W);

R ²Expression C_1-6Alkyl or C_3-6Cycloalkyl;

E represents to be selected from 0 or 1 number;

F represents to be selected from 0 to 6 number;

W represents halo, [O]_gR ³、SO ₂R ³、SR ³、SO ₂NR ³R ⁴、[O] _h[CH ₂] _iCF ₃、 OCHF ₂, phenyl, CN, phenoxy group (optional replaced by halogen), OH, benzyl, NCOR³, benzyloxy, oxygen base, CONHR³、NSO ₂R ³R ⁴、COR ³、C _1-6Alkylidene-NCOR³、 Het ²；

R ³Expression hydrogen, C_1-6Alkyl, C_3-6Cycloalkyl or C_1-6Alkylidene-O-C_1-6Alkyl:

R ⁴Expression hydrogen or C_1-6Alkyl;

I represents to be selected from 0 to 6 number;

H represents to be selected from 0 or 1 number;

G represents to be selected from 0 or 1 number;

Het ²Expression 5-or 6-unit is saturated, part is unsaturated or aromatic heterocycle comprises (a) 1 to 4 nitrogen-atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms, and heterocyclic radical is optional by R³And/or R⁴And/or oxo group replaces.

In above-mentioned definition, halo represents fluoro, chloro, bromo or iodo. The alkyl, alkylidene and the alkoxyl that comprise the number carbon atom of wanting can be straight or branched. The example of alkyl comprise methyl, ethyl, just-propyl group, different-propyl group, just-butyl, different-butyl, the second month in a season-butyl and tert-butyl. The example of alkoxyl comprise methoxyl group, ethyoxyl, just-propoxyl group, different-propoxyl group, just-butoxy, different-butoxy, the second month in a season-butoxy and uncle-butoxy. The example of alkylidene comprises methylene, 1,1-ethylidene, 1,2-ethylidene, 1,1-propylidene, 1,2-propylidene, 1,3-propylidene and 2,2-propylidene. Het represents heterocyclic radical, its example comprises tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, THP trtrahydropyranyl, tetrahydro thiapyran base, piperidyl, 1,4-dioxane base, 1,4-thioxane base, morpholinyl, Isosorbide-5-Nitrae-dithiane base, piperazinyl, Isosorbide-5-Nitrae-azepine thiophene alkyl, 3,4-dihydro-2H-pyranose, 5,6-dihydro-2H-pyranose, 2H-pyranose, 1,2,3,4-tetrahydro pyridyl, 1,2,5,6-tetrahydro pyridyl, pyrrole radicals, furyl, thienyl, pyrazolyl, imidazole radicals, different  azoles base,  azoles base, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1-oxa--2,3-di azoly, 1-oxa--2,4-di azoly, 1-oxa--2,5-di azoly, 1-oxa--3,4-di azoly, 1-thia-2,3-di azoly, 1-thia-2,4-di azoly, 1-thia-2,5-di azoly, 1-thia-3,4-di azoly, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals and pyrazinyl.

Preferred compound represents CH for X wherein₂OCH ₃Compound. Be more preferably wherein that X represents-[CH₂] _aThe compound of R.

Preferred compound represents to be selected from the compound of 0 to 5 number for a wherein. Be more preferably the compound that a wherein represents to be selected from 0 to 4 number. Still be more preferably the compound that a wherein represents to be selected from 0 to 3 number. Still be more preferably the compound that a wherein represents to be selected from 0 to 2 number. The most preferred compound that represents to be selected from 1 number for a wherein.

Preferred compound represents the compound of H for R wherein. Preferred compound is the compound that R represents Het. Still be more preferably the compound that R wherein represents triazolyl.

Preferred compound represents one or two substituent compound for Y wherein. Preferred compound represents single substituent compound for Y wherein.

Preferred compound represents the compound of halo for Y wherein. Preferred compound represents the compound of chlorine and/or fluorine for Y wherein.

Preferred compound represents the compound of direct key for V wherein. Preferred compound is that wherein Q is the compound of direct key. Preferred compound is for wherein V and Q represent the compound of direct key.

Preferred compound is for wherein encircling the compound that A comprises 2 nitrogen-atoms. Preferred compound is for wherein encircling the compound that A comprises 1 nitrogen-atoms.

Preferred compound is for wherein encircling the compound that A represents the compound ring of 5-unit. Preferred compound represents the compound of 6-unit ring for wherein encircling A. Still preferred compound is for wherein encircling the compound that A represents piperidylidene.

Preferred compound is for wherein encircling A is connected to V via nitrogen-atoms compound. Preferred compound is for wherein encircling A is connected to Q via nitrogen-atoms compound. Preferred compound is for wherein encircling A is connected to Q and V via nitrogen-atoms compound.

Preferred compound represents Het for Z wherein³Compound. Het³Can represent the optional substituted group that is selected from indazolyl, indyl, indenyl, pyrazolyl, piperidyl, pyridine radicals, pyrimidine radicals, pyrrole radicals, thiazolyl, benzothienyl, benzothiazolyl, quinolyl, Benzoxazinyl, different  azoles base, imidazole radicals, furyl, benzofuranyl, cinnolines base, morpholinyl, chromene base, or derivatives thereof. Preferred compound represents the compound of phenyl for Z wherein.

Preferred compound for Z wherein through single or dibasic compound. Preferred compound wherein Z through mono-substituted compound.

Preferred compound be wherein Z through the compound of three-methyl fluoride replacement. Preferred compound is the compound that replaced by halogen of Z wherein. Preferred compound is the compound that replaces through chlorine and/or fluorine of Z wherein.

Particularly preferred compound according to the present invention is listed compound in the following embodiment part, and pharmaceutically acceptable salt. Particularly:

(3-chloro-phenyl)-and 4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidin-1-yl }-ketone;

(4-chloro-phenyl)-and 4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidin-1-yl }-ketone;

(5-chloro-2-fluoro-phenyl)-and 4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidin-1-yl }-ketone;

4-[4-(4-chloro-phenyl)-5-[1,2,3] and triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidin-1-yl }-(3,5-, two fluoro-phenyl)-ketone;

4-[4-(4-chloro-phenyl)-5-[1,2,3] and triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidin-1-yl }-(3-fluoro-phenyl)-ketone;

4-[4-(4-chloro-phenyl)-5-[1,2,3] and triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidin-1-yl }-(2,3-, two fluoro-phenyl)-ketone;

(3-chloro-2-fluoro-phenyl)-and 4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidin-1-yl }-ketone;

(3-chloro-4-fluoro-phenyl)-and 4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidin-1-yl }-ketone;

4-[4-(4-chloro-phenyl)-5-[1,2,3] and triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidin-1-yl }-(4-trifluoromethyl-phenyl)-ketone;

4-[4-(4-chloro-phenyl)-5-[1,2,3] and triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidin-1-yl }-(3-trifluoromethyl-phenyl)-ketone;

4-[4-(4-chloro-phenyl)-5-[1,2,3] and triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidin-1-yl }-(2-trifluoromethyl-phenyl)-ketone;

(3-chloro-5-fluoro-phenyl)-and 4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidin-1-yl }-ketone;

4-[4-(4-chloro-phenyl)-5-[1,2,3] and triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidin-1-yl }-(4-difluoromethyl-phenyl)-ketone;

4-[4-(4-chloro-phenyl)-5-[1,2,3] and triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidin-1-yl }-(1H-indazole-3-yl)-ketone;

And pharmaceutically acceptable derivates.

The salt, solvate, complex compound, polymorph, prodrug, stereoisomer, geometric isomer, tautomeric form and the isotopic variations that comprise formula (I) compound according to the pharmaceutically acceptable derivates of formula of the present invention (I) compound. Preferably, the pharmaceutically acceptable derivates of formula (I) compound comprises salt, solvate, ester and the acid amides of formula (I) compound. More preferably, the pharmaceutically acceptable derivates of formula (I) compound is salt and solvate.

The pharmaceutically acceptable salt of formula (I) compound comprises its acid-addition salts and alkali salt.

Suitable acid-addition salts forms from acid, and it forms atoxic salt. Example comprises acetate, aspartate, benzoate, benzene sulfonate, bicarbonate, disulfate, borate, camsilate, citrate, ethanedisulphonate, esilate, formates, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrogen bromide/bromide, hydrogen iodide/iodide, isethionate, D-and Pfansteihl salt, malate, maleate, malonate, mesylate, Methylsulfate, naphthoate (naphthylate), 2-naphthalene sulfonate, nicotine hydrochlorate, nitrate, Orotate, oxalates, palmitate, palmoate, phosphate, hydrophosphate, dihydric phosphate, glucarate, stearate, succinate, sulfate, D-and L-TARTARIC ACID salt, toluene fulfonate and trifluoroacetate.

Suitable alkali salt forms from alkali, and it forms atoxic salt. Example comprises aluminium salt, arginine salt, dibenzyl ethylenediamine salt, calcium salt, choline salt, diethyl amine salt, diethanolamine salt, glycinate, lysine salt, magnesium salts, meglumine salt, ethanolamine salt, sylvite, sodium salt, amino butanetriol salt and zinc salt.

For the summary of suitable salt, referring to Stahl and Wermuth, drug salts handbook: character, selection and purposes (Handbook of Pharmaceutical Salts:Properties, Selection and Use, Wei Si-VCH, Weinheim, Germany, 2002). As suitable, the pharmaceutically acceptable salt of formula (I) compound can be by compound and desired acid or the alkali preparation that mixes (I). Salt can out and by filtering to collect maybe can reclaim by evaporating solvent from precipitation. Degree of ionization in the salt can change to from fully ionization almost non-ionic.

The form that the form that compound of the present invention can non-solvent closes and solvent close exists. Use in this article term " solvate " to describe the molecular complex that comprises compound of the present invention and one or more pharmaceutically acceptable solvent molecules (for example, ethanol). When this solvent is water, use term " hydrate ".

Being included in the scope of the invention is for example inclusion compound of complex compound, medicine-main body inclusion complex, and wherein, in comparison with above-mentioned solvate, medicine and main body exist with stoichiometry or non-stoichiometry quantity. What also be included is the complex that comprises the medicine of two kinds or more kinds of organic and/or inorganic constituents that exist with stoichiometry or non-stoichiometry quantity. The gained complex compound is Ionized, partial ionization or non-ionic. The summary of this complex compound, referring to Haleblian, J Pharm Sci,64(8), 1269-1288 (in August, 1975).

Below all are mentioned formula (I) compound and pharmaceutically acceptable derivates thereof are comprised solvate and the complex compound of mentioning its salt, solvate and complex compound and salt thereof.

Formula of the present invention (I) compound comprises compound as defined above, and it is such as the polymorph of following definition, the compound of the isotope of prodrug and isomers (comprising optically-active, geometry and tautomeric isomers) and formula (I) element mark.

As described, the present invention includes all polymorphs of formula as defined above (I) compound.

" prodrug " of so-called formula (I) compound also within the scope of the invention. Therefore some itself have very little or even the derivative of formula (I) compound that do not have pharmacologically active when giving to health or on the health time, can changing into the compound with the formula (I) of activity of wanting, for example, pass through hydrolytic rupture. This derivative is called " prodrug ". The further information of using about prodrug can be found in " Pro-drugs as Novel Delivery Systems; the 14th; ACS Symposium Series (T.Higuchi and W Stella) and " Bioreversible Carriers in Drug Design "; Pergamon Press; in 1987 (E B Roche edits, American Pharmaceutical Association).

Can (for example) produce by the suitable degree of functionality that some part replacement that is described in " pro-moieties " of " Design of Prodrugs " (Elsevier, 1985) such as for example H Bundgaard known to those skilled in the art is present in formula (I) compound according to prodrug of the present invention.

Example according to prodrugs more of the present invention comprises:

(i) the compound of formula (I) comprise carboxylic functionality (under situation COOH), its ester, for example, with C₁-C ₈Alkyl displacement hydrogen;

(ii) the compound of formula (I) comprise the carbinol-functional degree (under situation OH), its ether, for example, with C₁-C ₆Alkanoyloxymethyl displacement hydrogen; With

(iii) compound in formula (I) comprises uncle or secondary amino group degree of functionality (NH₂Or-NHR, wherein under the situation of R ≠ H), its acid amides, for example, with C₁-C ₁₀Alkanoyl is replaced one or two hydrogen.

Substituent further example according to the example of previous example and other prodrug type can be found in the above-mentioned list of references.

At last, the compound of some formula (I) itself can be used as the prodrug of other formula (I) compound.

Being also contained in the scope of the invention is the metabolite of formula (I) compound, when in vivo forming.

Can there be two or more stereoisomers in formula (I) compound that comprises one or more asymmetric carbon atoms. Comprise under the situation of thiazolinyl or alkenylene at formula (I) compound, how much cis/trans (or Z/E) isomers are possible, comprise at compound in the situation of ketone for example or oximido or aromatics part, tautomerism (' tautomerism ') can occur. Single compound can manifest the isomerism that surpasses a type according to this.

Being included in the scope of the invention is all stereoisomers, geometric isomer and the tautomeric form of formula (I) compound, comprises compound and its one or more mixture of showing the isomerism that surpasses a type. What also be included is sour addition or alkali salt, and wherein counter ion is optically active, for example, D-lactate or 1B, or racemic, for example, DL-tartrate or DL-arginine.

The cis/trans isomers can oneself knows by those skilled in the art routine techniques, for example, fractional crystallization separates with chromatography.

The routine techniques of the preparation of indivedual enantiomters/separation comprises synthetic from the chirality of suitable optical voidness precursor or uses (for example) chirality HPLC resolution of racemic thing (or racemate of salt or derivative).

Perhaps, racemate (or racemic precursor) can with suitable optically active compound (for example, alcohol) or, comprise in the situation of acidity or alkali part at formula (I) compound, with acid or for example tartaric acid or the reaction of 1-phenylethylamine of alkali. The gained mixture of diastereomers can separate and one or two of diastereomer changes into the pure enantiomter of correspondence by method known to those skilled in the art by chromatography and/or fractional crystallization.

Chipal compounds of the present invention (with its chiral precursor) can use chromatography, HPLC typically, use the mobile phase that is formed by hydrocarbon (typically heptane or hexane) at asymmetric resin, comprise from 0 to 50% isopropyl alcohol, typically from 2% to 20%, with from 0 to 5% alkylamine, typically 0.1% diethylamine obtains with the enrichment enantiomeric form. Concentrated eluate provides the mixture of enrichment.

The alloisomerism aggregation can oneself knows by those skilled in the art routine techniques separate-referring to, for example, " spatial chemistry of organic compound (Stereochemistry of Organic Compounds) " (Wei Si, New York, 1994) of E L Eliel.

The present invention also comprises the isotopic variations of all pharmaceutically acceptable formula (I) compounds, wherein one or more atoms are had the same atoms ordinal number, but the different atomic substitutions of the atomic mass that atomic mass or mass number and occurring in nature are found or mass number.

Be fit to be included in the isotope that isotopic example in the compounds of this invention comprises hydrogen, for example²H and³H, carbon, for example¹¹C、 ¹³C and¹⁴C, nitrogen, for example¹³N and¹⁵N, oxygen, for example¹⁵O， ¹⁷O and¹⁶O, phosphorus, for example³²P, sulphur, for example³⁵S, fluorine, for example¹⁸F, iodine, for example¹²³I and¹²⁵I, and chlorine, for example³⁶Cl。

Some isotope-labeled formula (I) compound, for example incorporate into radioisotopic those, can be used in medicine and/or the research of substrate Tissue distribution. The radio isotope tritium, namely,³H, and carbon-14, namely,¹⁴C, in view of they incorporate into easily and the fast method that detects and can be used in this purpose especially.

By heavier isotope deuterium for example, namely,²H replaces, and some the treatment advantage that is caused by greater metabolic stability more can be provided, and for example in vivo the half-life increases or reduce dosage demand and therefore, can be in some cases preferably.

With the isotope of emission positive electron, for example¹¹C、 ¹⁸F、 ¹⁵O and¹³The replacement of N can be used in positron emission tomography (PET) research that checks substrate acceptor occupancy.

Isotope-labeled formula (I) compound can or be similar to this in the similar method of method described in appended embodiment and the preparation by routine techniques known to those skilled in the art usually, and the isotope-labeled reagent that use is fit to replaces the aforementioned nonisotopically labelled reagent that adopts and makes.

Pharmaceutically acceptable solvate according to the present invention comprises that the solvent of wherein crystallization can be replaced by isotope, for example D₂O，d ₆-acetone, d₆Those of-DMSO.

Compound of the present invention can be used in treatment. Therefore, further aspect of the present invention is formula (I) compound, or its pharmaceutically acceptable salt or solvate are as the purposes of medicine.

Compound exhibits of the present invention is as the activity of V1a antagonist. Particularly they can be used in the many patient's condition for the treatment of, comprise attack, Alzheimer's, anorexia nervosa, anxiety, anxiety disorder, asthma, atherosclerotic, autism, angiocardiopathy (comprises angina pectoris, atherosclerotic, hypertension, in heart failure, oedema, hypernatronemia), cataract, central nervous system disease, cerebrovascular ischemia, cirrhosis, cognitive disorder, Cushing disease, depression, diabetes, dysmenorrhoea (primary and insecondary), vomiting (comprising motion sickness), endometriosis, gastrointestinal disease, glaucoma, gynecological disease, heart disease, intrauterine growth retardation, inflammation (comprising rheumatoid arthritis), ischemic, ischemic heart disease, lung neoplasm, urination disorder, imtermenstrual pain, neoplasm, renal toxicity, adult-onset diabetes, fat, besetment and behavior disorder, ocular hypertension, disease before the eclampsia, premature ejaculation, premature labor (the pregnant front childbirth of foot), lung disease, Raynaud's disease, kidney trouble, kidney is depleted, the sex sex dysfunction, septic shock, sleep-disorder, the spinal cord injury, thrombosis, urogenital infections or uriasis. Sleep-disorder, spinal cord injury, thrombosis, urogenital infections or uriasis. Interested especially is dysmenorrhoea (primary and insecondary), more especially, and primary dysmenorrhea.

Therefore, further aspect of the present invention is for treating mammal (comprising the mankind) take the method for the treatment of as the obstacle of the indication of V1a antagonist, it comprise will the treatment effective dose formula (I) compound, or its pharmaceutically acceptable salt or solvate are administered to mammal. Especially, the compound of formula (I) can be used in treatment anxiety, angiocardiopathy (comprising angina pectoris, atherosclerotic, hypertension, heart failure, oedema, hypernatronemia), dysmenorrhoea (primary and insecondary), endometriosis, vomiting (comprising motion sickness), intrauterine growth retardation, inflammation (comprising rheumatoid arthritis), imtermenstrual pain, the front disease of eclampsia, premature ejaculation, premature labor (the pregnant front childbirth of foot) or Raynaud's disease. Even more particularly, they can be used in treatment dysmenorrhoea (primary or insecondary).

Further aspect of the present invention is formula (I) compound, or its pharmaceutically acceptable salt or solvate, is used for the treatment of in manufacturing to be the purposes in the medicine of the obstacle of the indication of V1a receptor antagonist.

All formulas (I) compound all can or pass through at embodiment part and the described ad hoc approach of preparation part by the step described in the following conventional method that proposes, or prepares by its conventional modification method. The present invention also comprises these methods of any or one or more preparation formula (I) compound, except any therein employed novel intermediates.

Unless be provided at herein in addition, otherwise:

WSCDI represents 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, and DCC represents N, and N '-dicyclohexylcarbodiimide, HOAT represent 1-hydroxyl-7-azepine BTA, and HOBT represents the I-hydroxybenzotriazole hydrate;

PyBOP  represents BTA-1-base oxygen base three (pyrrolidinyl) Phosphonium hexafluorophosphates, PyBrOP  represents bromo-three-pyrrolidinyl ,-Phosphonium hexafluorophosphates, and HBTU represents O-BTA-1-base-N, N, N ', N '-tetramethylurea cation hexafluorophosphate;

MCPBA represents meta-chlorine benzylhydroperoxide, and AcOH represents acetic acid, and HCl represents hydrochloric acid, and TFA represents that trifluoroacetic acid and p-TSA represent p-toluenesulfonic acid;

Et ₃N represents that triethylamine and NMM represent N-methylmorpholine;

K ₂CO ₃Expression potash and KO-^tBu represents uncle-butanols potassium;

NaOH, KOH and LiOH represent NaOH, potassium hydroxide and lithium hydroxide respectively;

BOc represents that uncle-butoxy carbonyl and CBz represent benzyloxycarbonyl group:

PTFE represents polytetrafluoro ethane;

MeI represents iodomethane;

MeTosylate represents p-toluenesulfonic acid methyl esters;

MeOH represents methyl alcohol, and EtOH represents that ethanol and n-BuOH are just representing-butanols;

EtOAc represents ethyl acetate, and MeCN represents acetonitrile, and THF represents oxolane, and DMSO represents methyl-sulfoxide, and DCM represents carrene, and DMF represents DMF, and NMP represents that METHYLPYRROLIDONE and DMA represent dimethylacetylamide;

Me represents methyl, and Et represents ethyl, and Cl represents chlorine, and OH represents hydroxyl; Cat represents catalyst or catalysis.

In following conventional method, unless indication is arranged in addition, otherwise R, R¹、R ²、R ³, ring A, V, X, Q, Z, Y, Y ', Het, Het¹And Het²Define about formula (I) compound such as the front. When Q represents NR², or Q is when representing to be connected to the direct key of the nitrogen-atoms in the ring A, and then the compound of formula (I) can be according to scheme 1 preparation.

PG represents suitable N protecting group, and typically benzyl, BOC or CBz are basic, and preferred BOC.

Scheme 1

The compound of formula (II) can be as described in WO 9703986 A1 19970206, or obtain by corresponding lower alkyl esters (for example methyl or ethyl) and the reaction of hydrazine under standard conditions, as giving an example in the following preparation.

Step (a): the compound of formula (III) can by hydrazine (II) and suitable acetal (for example DMA dimethylacetal) appropriate solvent for example among THF or the DMF in preparing through 18 hours reaction at the most between room temperature and about 60 ℃. Then the gained intermediate product can be about 18 hours of the lower processing of acid catalysis (for example p-TSA, or TFA), so that the compound of formula (III) to be provided in high boiling solvent (for example toluene or dimethylbenzene). Preferred condition: 1.5-2.0 equivalent acetal (N for example, N-dimethylacetamide dimethylacetal, triethyl orthopropionate), in THF or DMF in room temperature to 60 ℃ lower about 18 hours, then p-TSA or TFA (cat) were reflux in toluene 18 hours.

Step (b): triazole (IV) but formation through type (III) compound and suitable aniline in the presence of suitable acid catalyst, for example TFA or p-TSA, in suitable high boiling solvent (for example toluene or dimethylbenzene), the reaction under the temperature that raises and realizing. Preferred condition: 0.5-1.0 equivalent TFA, 1.0-2.0 equivalent aniline in toluene under the temperature of about backflow through 18 hours at the most.

Step (c): the protection use of going of compound (IV) is carried out such as the standard method that is described in " Protecting Groups in Organic Synthesis " by T.W.Greene and P.Wutz. When PG represented BOC, preferred condition was: the 4M HCl in two  alkane, in MeOH, two  alkane or DCM between room temperature and about 50 ℃, through 18 hours at the most; Or among the 2.2M HCl in MeOH under room temperature through 18 hours at the most;

Or the TFA in DCM was at room temperature about 1 hour.

Perhaps, when PG represented BOC, compound (V) can be by processing with excessive TFA, typically the 1.1-1.5 equivalent) and in toluene suitable aniline, under the reflux temperature of reaction, through 4 days and directly prepare from compound (III) at the most.

Step (d): the compound of formula (I) can pass through amine (V) and suitable acid or acid chlorideWherein T represents OH or Cl) reaction preparation. Coupling can be by using following arbitrary carrying out:

(i) acid chloride,

+ amine (V), with excessive soda acid in appropriate solvent; Or

(ii) sour ZCO₂H and conventional coupling agent+amine (V) randomly in the presence of catalyst, with excessive alkali in appropriate solvent.

Typically condition is as follows:

(i) acid chlorideAmine (V) is (randomly with excessive 3 ° of amine Et for example₃N, H ü nigShi alkali or NMM) in DCM or THF, not heating, 1 to 24 hour; Or

(ii) sour ZCO₂H, WSCDI/DCC and HOBT/HOAT, amine, excessive NMM, Et₃N or H ü nigShi alkali, at THF, DCM, among DMA or the EtOAc, under room temperature through 4 to 48 hours: or

Acid ZCO₂H, PYBOP /PyBrOP /O-BTA-1-base-N, N, N ', N '-tetramethylurea cation hexafluorophosphate, excess amine, excessive NMM, Et₃N or H ü nigShi alkali are in THF, DCM, DMA or EtOAc, at room temperature through 4 to 24 hours.

Preferred condition is:

1 equivalent amine (V), the 1.0-1.5 equivalent1.5-5 equivalent NMM, Et₃N or H ü nigShi alkali are in DCM, at room temperature through 18 hours at the most;

Or, 1 equivalent amine (V), 1.2 equivalent ZCO₂H, 1.2-1.5 equivalent HOBT, 1.2-1.5 equivalent WSCDI, 2-4 equivalent Et₃N, in DCM at room temperature through 24 hours;

Or, 1 equivalent amine (V), 1.2-1.5 equivalent ZCO₂H, 1.2-2.0 equivalent HBTU, 5 equivalent Et₃N or NMM in DMA or DCM, between room temperature and 60 ℃ through 24 hours at the most.

The compound of formula (IV), wherein Q represents NR², or Q represents to be connected to the direct key of the nitrogen-atoms in the ring A (it is connected to triazole ring via nitrogen-atoms successively), perhaps can be such as preparation as described in the following scheme 2, and be expressed as (IVA).

Scheme 2.

Step (e): the isothiocyanates (VI) that the compound of formula (VIIIA) can be by approximately waiting molal quantity and amine (VII) under the room temperature in appropriate solvent (for example EtOH or DCM) the reaction of warp between 2 and 72 hours prepare. Preferred condition: 1-1.1 equivalent (VI), 1 equivalent (VII), in EtOH or DCM, under room temperature through 0.5-2 hour.

Formula (VI) and compound (VII) are the commercial goods, but or the Application standard chemical transformation prepare from known compound.

Step (f): the compound of formula (IXA) can be by the preparation that methylates of thiocarbamide (VIIIA), it uses methylating agent (for example MeI or Me tosylate), in the presence of suitable alkali (routine KOt-Bu) in appropriate solvent (for example THF or ether) between 0 ℃ and the reflux temperature that reacts, through about 18 hours. Preferred condition: 1 equivalent (VIIIA), 1-1.2 equivalent KOt-Bu, 1-1.2 equivalent MeI or Me tosylate, in THF, between 10 ℃ and the room temperature through 18 hours at the most.

Step (g): the compound of formula (IVA) can pass through compound (IXA) and suitable hydrazides (XCONHNH₂) reaction preparation, its randomly under the acid catalysis (for example TFA or p-TSA) in appropriate solvent (for example THF or just-BuOH) in, between the reflux temperature of room temperature and reaction. Preferred condition: 0.5 equivalent TFA, excessive hydrazides (XCONHNH₂), in THF under refluxing through 18 hours at the most.

The compound of formula (VIIIA), wherein Q represents NR², or Q represents to be connected to the direct key of the nitrogen-atoms in the ring A (it is connected to triazole ring via nitrogen-atoms successively), perhaps can prepare shown in scheme 3.

Scheme 3.

The compound of formula (X) is the commercial goods, but or the Application standard chemical transformation prepare from known compound.

The compound of formula (XI) can be by preparing from isothiocyanates (VI) and amine (X) about the similar method of the described method of above-mentioned steps (e) with the front.

Step (h): the compound of formula (VIIIA) can use as be described in the standard method of " Protecting Groups in Organic Synthesis " by T.W.Greene and P.Wutz, by the protective effect acquisition of reactive nitrogen atom. When PG was BOC, preferred condition was: 1 equivalent amine (XI), and 1 equivalent bicarbonate di-tert-butyl, in DCM and two  alkane, at room temperature, through about 3 hours.

The compound of formula (VIII), wherein Q represents NR², or Q represents to be connected to the direct key of the nitrogen-atoms in the ring A (it is connected to triazole ring via nitrogen-atoms successively), can prepare described in scheme 4 and be expressed as (VIIIB).

Scheme 4.

Step (i): the compound of formula (XIV) can be by being similar to the method that before is described in step (d), by the coupling preparation of aniline (XIII) with acid (XII). Preferred condition: 1 angelic acid (XII), 1.1 equivalent amine (XIII), 1.2 equivalent WSCDI, 3 equivalent Et₃N in MeCN under room temperature through about 3 days.

Step (j): the compound of formula (VIIIB) is processed with suitable vulcanizing agent (for example Lawesson ' s reagent) by lower between the reflux temperature of room temperature and reaction in high boiling solvent (for example toluene), by the sulfurization preparation of compound (XIV). Preferred condition: 1 equivalent (XIV), 0.5 equivalent Lawesson ' s reagent in toluene is in room temperature with between refluxing, through 18 hours at the most.

The compound of formula (III), wherein Q represents NR², or Q represents to be connected to the direct key of the nitrogen-atoms in the ring A, perhaps can prepare shown in scheme 5.

Scheme 5.

Step (k): two-acyl group hydrazides (XV) can be by being similar to the method that before is described in the step (d), by coupling hydrazides (II) and acid, or acid chloride (Wherein T represents Cl or OH) preparation. Preferred condition: 1 equivalent hydrazides (II), 1.1 equivalent XCO₂H, 1.1 equivalent WSCDI, 1.1 equivalent HOBT, 1.2 equivalent Et₃N, in DMF at room temperature through 18 hours.

Step (l):  diazole (III) can pass through the cyclisation preparation of compound (XV), typically at acid catalysis (for example polyphosphoric acid, POCl₃, trifluoromethanesulfanhydride anhydride/pyridine, or the 1-methylimidazole) under, randomly in appropriate solvent (for example DCM), between the reflux temperature of 0 ℃ and reaction. Preferred condition: 1 equivalent (XV), excess pyridine or 1-methylimidazole, 1.5-2 equivalent trifluoromethanesulfanhydride anhydride, in DCM, between 0 ℃ and the room temperature through 3 hours at the most.

The compound of formula (XV) or can be by being similar to the method coupling acid (XII) that before is described in the step (d) and suitable hydrazides (XCONHNH₂) preparation. Preferred condition: 1 angelic acid (XII), 1 equivalent hydrazides, 1.02 equivalent WSDCI, in DCM between 0 ℃ and the room temperature.

The compound of formula (III), wherein X represents CH₂N-connects-Het, perhaps can prepare shown in scheme 6.

Scheme 6

Step (m): the compound of formula (XVI) can pass through the reaction of hydrazides (II) and chloracetyl chloride, in appropriate solvent (for example EtOAc or DCM) in suitable 3 ° of amine alkali (Et for example₃N or NMM) exist lower between 0 ℃ and room temperature, through preparation in about 18 hours. Preferred condition: 1 equivalent (II), 1 equivalent chloroacetic chloride, 1.1 equivalent NMM, in DCM, in 10 ℃ to room temperature, through 18 hours at the most.

The compound of formula (XVII) can prepare by being similar to the method cyclisation compound (XVI) that before is described in the step (l).

Step (n): the compound of formula (III) can be by the reaction of compound (XVII) with suitable Het (comprising reactive N atom), at suitable alkali (Et for example₃N or K₂CO ₃) exist down, in appropriate solvent (for example DMF or MeCN), between the reflux temperature of room temperature and reaction, through preparation in about 18 hours. Preferred condition: 1 equivalent (XVII), 1.4 equivalent K₂CO ₃, 2 equivalent Het, in DMF at room temperature, through 18 hours.

The compound of formula (I), wherein Q represents NR², or Q represents to be connected to the direct key of the nitrogen-atoms in the ring A, perhaps can prepare shown in scheme 7.

Ra represents C_1-4Alkyl or benzyl, and be preferably Me or Et.

Scheme 7

Step (o): the compound of formula (XIX) can be by being similar to the method that before is described in the step (d), by amine (XVIII) and suitably acid, or acid chloride (

T represents OH or Cl) reaction preparation. Preferred condition: 1 equivalent (XVIII), 0.9 equivalent ZCOCl, 1.1 equivalent Et₃N is in DCM, between 10 ℃ and the room temperature, through about 3 hours.

Step (p): the hydrazides of formula (XX) can be in appropriate solvent (for example EtOH or MeOH), processes ester (XIX) through 18 hours and prepare at the most with excessive hydrazine under the reflux temperature of reaction. Preferred condition: 1 equivalent (XIX), 2-4 equivalent hydrazine, in MeOH under refluxing, between 10 and 48 hours.

The compound of formula (XXI) can use the method that before is described in the step (k) that is similar to, by hydrazides (XX) withReaction preparation.

The compound of formula (XXII) can use the method that before is described in the step (l) that is similar to, by the cyclisation preparation of compound (XXI).

The compound of formula (I) can be described in abovementioned steps (b) from  diazole (XXII) and suitable aniline preparation.

Perhaps, the compound of formula (XXII) can be by being similar to the method that before is described in the step (a), by with suitable acetal (triethyl orthopropionate for example, N, the N-dimethylacetamide dimethylacetal) reaction directly prepares from compound (XX).

The compound of formula (XXII), wherein X represents CH₂-N-connects-Het, perhaps can prepare shown in scheme 8.

Scheme 8

The compound of formula (XXIII) can be by being similar to the method that before is described in the step (m), by the reaction preparation of hydrazides (XX) with chloracetyl chloride.

 diazole (XXIV) can be by being similar to the method that before is described in the step (l), by the cyclisation preparation of compound (XXIII).

Compound (XXII) can be described in abovementioned steps (n), by compound (XXIV) and the suitably reaction preparation of Het (comprising reactive N atom).

The compound of formula (I) wherein encircles A and is connected to triazole ring via nitrogen-atoms, perhaps can prepare shown in scheme 9.

Scheme 9

Formula (XXV) but compound be that commercial goods or Application standard chemical transformation prepare from commodity compound.

The compound of formula (XXVI) can be by being similar to the method that before is described in the step (e), by compound (XXV) and the suitably reaction preparation of isothiocyanates (VI).

The compound of formula (XXVII) can be by being similar to the method that before is described in the step (f), by the alkylation preparation of compound (XXVI).

The compound of formula (I) can be by compound (XXVII) and the suitably reaction preparation of hydrazides described in abovementioned steps (g).

The compound of formula (I), wherein Q represents to be connected to the direct key of the carbon atom among the ring A, and it is connected to triazole ring via the nitrogen-atoms among the ring A successively, and Z represents NR⁴R ⁵, can shown in scheme 10, prepare.

Ra represents C_1-4Alkyl or benzyl, and preferably Me or Et.

Scheme 10

Formula (XXVIII) but compound be that commercial goods or Application standard chemical transformation prepare from commodity compound.

The compound of formula (XXIX) can be by being similar to the method that before is described in the step (e), by compound (XXVIII) and the suitably reaction preparation of isothiocyanates (VI).

The compound of formula (XXX) can be by being similar to the alkylating preparation of the method ， Ji Women's-undergarments compound (XXIX) that before is described in the step (f).

The compound of formula (XXXI) can by as abovementioned steps (g) described in by compound (XXX) and suitable hydrazides reaction prepare.

Step (q): suitable acid or base catalyst are used in the hydrolysis of ester (XXXI), preferred suitably alkali metal base (for example NaOH, KOH or LiOH) in suitable aqueous solvent (for example at two  alkane or MeOH) between the reflux temperature of room temperature and reaction, between 2 and 48 hours. Preferred condition: 1 equivalent (XXXI), 5-10 equivalent NaOH solution, in two  alkane in room temperature with between refluxing, between 2 and 16 hours.

The compound of formula (I) can be by being similar to the method that before is described in the step (d), by the reaction preparation of Z-H (comprising reactive N atom) with acid (XXXII). Preferred condition: 1 angelic acid (XXXII), 1.5 equivalent amine (ZH), 4 equivalent Et₃N, 1.5 equivalent WSCDI, 1.5 equivalent HOBT, at room temperature in DCM, 24 hours.

The compound of formula (XXXII) or can standard conditions (5 equivalent KOH for example, 1 equivalent nitrile (XXXIII), under refluxing in ethanol/glycol dimethyl ether) lower hydrolysis by corresponding nitrile compound (XXXIII) is with preparing.

The compound of formula (XXXIII) can prepare shown in scheme 11.

Scheme 11

The compound of formula (XXXIII), wherein Q is that direct key and ring A are connected to triazole ring via nitrogen-atoms, can be by being similar to scheme 9 described methods, encircle from suitable isothiocyanates (VI) and the A that comprises nitrile,

Preparation.

The compound of formula (I), wherein V represents oxygen atom, can prepare shown in scheme 12.

Scheme 12

Step (r): the compound of formula (XXXV) can be by being similar to the method that before is described in the step (e), by hydrazides (XCONHNH₂) with the reaction of isothiocyanates (VI) preparation. Preferred condition: 1 equivalent isothiocyanates, 1 equivalent hydrazides, in EtOH at room temperature through 72 hours.

Step (s): the compound of formula (XXXVI) can pass through the cyclisation of compound (XXXV) under acid or alkali condition, preferred base catalysis (for example alkali metal hydroxide) is at aqueous solvent (for example in the water/EtOH), under the temperature that raises, through preparation in about 24 hours. Preferred condition: 1 equivalent (XXXV), 10 equivalent NaOH (aq) in EtOH under 80 ℃ through 18 hours.

Step (t): provide the alkylating of the compound (XXXVI) of compound (XXXVII) by being similar to the method that before is described in the step (f), to realize by processing with suitable alkylating agent (for example MeI or Me-tosylate). Preferred condition: 1 equivalent (XXXVI), 1 equivalent uncle KO-Bu, 1 equivalent Me-tosylate, in THF in room temperature and between refluxing through 3 hours.

Step (u): the compound of formula (XXXVIII) can be by obtaining in the about 18 hours oxidation of the compound (XXXVII) of processing with suitable oxidizing agent (for example mCPBA or hydrogen peroxide) in appropriate solvent (for example DCM) under the room temperature. Preferred condition: 1 equivalent (XXXVII), 4 equivalent mCPBA, in DCM at room temperature through 18 hours.

Step (v): the compound of formula (I) can be by the reaction of sulfoxide and alcohol excess (XXXIX), at suitable alkali (for example in the presence of NaH or uncle KO-Bu), in appropriate solvent (for example THF or ether), 0 and room temperature between 18 hours and prepare at the most. Preferred condition: 1 equivalent (XXXVIII), 2 equivalent NaH, 2 equivalents alcohol (XXXIX), in THF under room temperature 18 hours.

Formula (XXXIX) but compound be that commercial goods or Application standard chemical transformation prepare from commodity compound.

Some formula (I), (III), (IV), (V), (XXII) and compound (XXXI) can carry out functional group's change (for example alkylation, or hydrolysis) so that formula (I), (III), (IV), (V), (XXII) or alternate compounds (XXXI) to be provided respectively.

Be intended for use the compounds of this invention of medicinal usage can crystallization or amorphous products give. They can for example precipitation, crystallization, freeze drying, spray-drying or evaporation drying obtain such as solid plug, powder or film with for example by the method. Microwave or radiation frequency drying can be used for this purpose.

They can give individually or with one or more other compound combinations of the present invention or with one or more other medicines (or its any combination) combination. Usually, they will give with the form of the preparation of being combined with one or more pharmaceutically acceptable excipient. Term " excipient " uses in this article in order to describe the compounds of this invention any composition in addition. The selection of excipient will depend on to a great extent many factors for example special mode of administration, excipient on solubility and the impact of stability and the character of formulation.

Further aspect of the present invention is a kind of pharmaceutical preparation, and it comprises formula (I) compound or its pharmaceutically acceptable salt or solvate, and pharmaceutically acceptable excipient, diluent or carrier. A kind of pharmaceutical preparation that gives for prophylactically or when painful the beginning time is provided in further embodiment.

Being suitable for the pharmaceutical composition of sending of the compounds of this invention and their preparation method is aobvious and as can be known to those skilled in the art. Said composition and their preparation method can be found in (for example)Remington′s Pharmaceutical Sciences, the 19th version (Mack publishing company, 1995).

Compound of the present invention can give orally. Give to comprise orally and swallow, so that compound enters intestines and stomach, maybe can adopt through cheek or hypogloeeis to give, can directly enter in the blood flow from mouth by this approach compound.

The preparation that is suitable for giving comprises for example tablet of solid pharmaceutical preparation orally, comprise particle, liquid or powder capsule, lozenge (comprising liquid-filling), chew ingot, many-as and to receive-particle, gel, solid solution, liposome, film, vaginal plug, spray and liquid preparation.

Liquid preparation comprises suspension, solution, syrup and elixir. Said preparation can be in soft or hard shell capsules filler use and typically comprise carrier, for example, water, ethanol, polyethylene glycol, polypropylene glycol, methylcellulose or suitable oil and one or more emulsifying agents and/or suspending agent. Liquid preparation also can be by reconstruct (for example, from the parcel) preparation of solid.

Compound of the present invention also can dissolve fast, rapidly disintegrating dosage form for example is described in Expert Opinion in Therapeutic Patents by Liang and Chen,11(6), those among the 981-986 (2001) are used.

For Tabules, decide on dosage, medicine can account for formulation from 1 % by weight to 80 % by weight, more typically account for formulation from 5 % by weight to 60 % by weight. Except medicine, tablet comprises disintegrant usually. The example of disintegrant comprises hydroxypropyl cellulose, starch, pregelatinized starch and the mosanom that primojel, sodium carboxymethylcellulose, calcium carboxymethylcellulose, Ac-Di-Sol, Crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, low alkyl group replace. Usually, disintegrant will account for formulation from 1 % by weight to 25 % by weight, preferably account for from 5 % by weight to 20 % by weight.

Adhesive is commonly used to give the adhesion quality of tablet formulation. Suitably adhesive comprises microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and rubber polymer, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablet also can comprise diluent, for example lactose (monohydrate, spray-drying monohydrate, anhydrous etc.), sweet mellow wine, xylitol, glucose, sucrose, D-sorbite, microcrystalline cellulose, starch and dicalcium phosphate dihydrate.

Tablet also optionally comprises surfactant, for example lauryl sulfate sodium and polyoxyethylene sorbitan monoleate, and glidant for example silica and talcum. When existing, surfactant can account for tablet from 0.2 % by weight to 5 % by weight, and glidant can account for tablet from 0.2 % by weight to 1 % by weight.

Tablet also comprises lubricant for example dolomol, calcium stearate, zinc stearate, fumaric acid sodium stearyl ester usually, and the mixture of dolomol and lauryl sulfate sodium. Lubricant usually account for tablet from 0.25 % by weight to 10 % by weight, preferably from 0.5 % by weight to 3 % by weight.

Other possible composition comprises antioxidant, colouring agent, flavor enhancement, anticorrisive agent and taste-screening agent.

Typical tablet comprises at the most about 80% medicine, from about 10 % by weight to about 90 % by weight adhesives, and from about 0 % by weight to about 85 % by weight diluents, from about 2 % by weight to about 10 % by weight disintegrants, and from about 0.25 % by weight to about 10 % by weight lubricants.

The tablet admixture can directly compress or become tablet by the cylinder compressed shape. The part of tablet admixture or admixture or can be before film-making by wet type-, dry type-or fusing-granulate, fusing is condensed or extrude. Last preparation can comprise one layer or more and can be coated or not coated; Itself in addition can incapsulate.

The preparation of tablet is discussed at by H.Lieberman and L.LachmanPharmaceutical Dosage Forms：Tablets. the 1st (Marcel Dekker, New York, 1980).

The oral film that consumes that people or animal doctor use typically is pliable and tough water-soluble or water swelling film formulation, and it can dissolve rapidly or mucous membrane adheres to and typically comprise formula (I) compound, film-formation polymer, adhesive, solvent, NMF, plasticiser, stabilizing agent or emulsifying agent, viscosity-correction agent and solvent. Some compositions of preparation can be carried out more than one function.

The compound of formula (I) can be water-soluble or water-insoluble. Water miscible compound typically account for solute from 1 % by weight to 80 % by weight, more typically from 20 % by weight to 50 % by weight. More undissolved compound can account for the larger proportion of composition, typically accounts at the most 88 % by weight of solute. Perhaps, the compound of formula (I) can be the form of multiparticle pearl.

Film-formation polymer can be selected from natural polysaccharide, protein or synthetic water colloid and typically in the scope of 0.01 to 99 % by weight, more typically the scope in 30 to 80 % by weight exists.

Other possible composition comprises antioxidant, colouring agent, flavor enhancement and seasoning reinforcing agent, anticorrisive agent, saliva stimulant, cooling agent, cosolvent (comprising oils), lubricant, filler, anti-foaming agent, surfactant and taste-screening agent.

Membrane according to the invention typically can be by being coated on the evaporation drying preparation of the thin water-based film on peelable backing holder or the paper. This can carry out in baking box or tunnel, typically also with the coating drying machine, or mat freeze drying or vacuum.

The oral solid pharmaceutical preparation that gives can be mixed with immediately and/or revise release. Revise delivery formulations comprise delays-, continue-, pulse-, control-, target and sequencing release.

For the suitable correction delivery formulations of the object of the invention is described in United States Patent (USP) the 6th, 106, in No. 864. The details of other suitable release tech such as high-energy dispersion and infiltration and coating particle is found in the people's such as VermaPharmaceutical Technology On-line, 25 (2), 1-14 (2001). Use chewing gum to be described among the WO 00/35298 to realize that control discharges.

Compound of the present invention also can directly give to blood flow, to muscle, or to the internal. Be used for the proper method that stomach and intestine give outward comprise in intravenous, the artery, in the peritonaeum, in the sheath, in the ventricle, in the urethra, in the breastbone, in the encephalic, muscle and subcutaneous. The appropriate device that stomach and intestine give outward comprises pin (comprising micropin) syringe, needleless injector and infusion techniques.

Parenteral formulation typically is the aqueous solution, it can comprise for example salt of excipient, carbohydrate and buffer (preferably to 3 to 9 pH), but, use for some, they can more suitably be mixed with the sterilization non-aqueous solution or with suitable medium for example sterile pyrogen-free water merge the dried forms that uses.

The preparation of parenteral formulation under sterilising conditions for example, by freeze drying, can use standard drug technology known to those skilled in the art to finish easily.

The solubility that is used in formula (I) compound in the preparation of the outer solution of stomach and intestine can be by using suitable preparation technique, and for example incorporating solubility-improving agent into increases.

The preparation that gives outward for stomach and intestine can be mixed with immediately and/or revise release. Revise delivery formulations comprise delays-, continue-, pulse-, control-, target and sequencing release. Therefore compound of the present invention can be mixed with solid, semisolid or the thixotropic liquid of the implantation bank administration that the correction that is provided with providing reactive compound discharges. The example of said preparation comprise medicine coating this rise special fixture and poly-(dl-breast-altogether ethanol) acid (PGLA)-microballoon.

Compound of the present invention also can be administered to skin or mucous membrane partly, namely, and skin ground or transdermal ground. The exemplary formulations that is used for this purpose comprises gel, hydrogel adhesive, emulsion, solution, creme, ointment, face powder, dressing, foam, film, dermal patch, wafer, implant, sponge, fiber, bandage and microemulsion. Also can use liposome. Typical carrier comprises alcohol, water, mineral oil, atoleine, albolene, glycerine, polyethylene glycol and propane diols. Can merge penetration enhancers-referring to, for example, the J Pharm Sci of Finnin and Morgan, 88 (10), 955-958 (in October, 1999).

The device that other part gives comprises by electroporation, ionotherapy, iontophoresis (phonophoresis), ultrasonic importing (sonophoresis) and micropin or needleless (Powderject for example^TM、Bioject ^TMDeng) injected delivery.

The preparation that the part gives can be mixed with instant and/or revise and discharge. Revise delivery formulations comprise delays-, continue-, pulse-, control-, target and sequencing release.

But compound of the present invention also gives or gives by suction in the nose, typically with the form of dry powder (or separately, with mixture, for example, with the dried admixture of lactose, or the composition particle to mix, for example, with phosphatide, for example phosphatid ylcholine mixes) from Diskus or with aerosol spray from pressurizing vessel, pump, sprayer, atomizer (preferably making electricity consumption hydraulic pneumatic formula (electrohydrodynamics) produce the atomizer of mist), or sprayer is with or without and uses suitable propellant, for example 1,1,1,2-HFC-134a or 1,1,1,2,3,3,3-heptafluoro-propane. In order to use in the nose, powder can comprise bioadhesive agents, for example, and chitosan or cyclodextrin.

Pressurizing vessel, pump, sprayer, atomizer or sprayer comprise solution or the suspension of the compounds of this invention, it comprises for example ethanol, ethanol water or is suitable for the dispersion of active component, dissolvingization or prolongs the suitable substituting agent that discharges, propellant and option list surface-active agent as solvent, for example sorbitan trioleate, oleic acid, or lactic acid oligomer.

Before being used in dry powder or suspension preparation, the pharmaceutical product micro mist is changed into the size (typically being less than 5 microns) that is adapted to pass through inhalation delivery. This can pass through any suitable breaking method, for example spiral spray is milled, fluidised-bed spray is milled, form receive particle treatment with supercritical fluid, high pressure homogenizing or spray-drying and realize.

Capsule (utilizing (for example) gelatin or hydroxypropyl methylcellulose to make), bubble eye and the cartridge case that is used for inhalator or insufflator can be mixed with and comprise compound of the present invention, suitable powder matrix lactose or starch and the usefulness correction agent mixture of powders of l-leucine, sweet mellow wine or dolomol for example for example. Lactose can be the form of anhydrous or monohydrate, is preferably the latter. Other suitable excipient comprises glucan, glucose, maltose, D-sorbite, xylitol, fructose, sucrose and trehalose.

Being fit to be used in pharmaceutical solutions in the atomizer that electricity consumption hydraulic pneumatic formula produces mist can comprise the compounds of this invention of each driving 1 microgram to 20 milligram and drive volume and can change to 100 microlitres from 1 microlitre. Typical preparation can comprise compound, propane diols, aqua sterilisa, ethanol and the sodium chloride of formula (I). Can comprise in order to the replace solvents that replaces propane diols glycerine and polyethylene glycol.

Suitable flavouring, for example menthol and Levomenthol or sweetener, for example asccharin or saccharin sodium, can add to this to be intended for use to suck/preparation of the present invention that gives in the nose in.

The preparation that is used for suction/intranasal administration for example can use, and PGLA is mixed with immediately and/or revises release. Revise delivery formulations comprise delays-, continue-, pulse-, control-, target and sequencing release.

In Diskus and aerocolloidal situation, dosage unit determines with the valve of sending metered amounts. Every TDD typically can be in 0.01 microgram to 15 nanogram ranges, its can single dose give or, more normal, give with the dosage that separates all day.

But compound rectum ground of the present invention or vagina give interiorly, for example, and with the form of suppository, vaginal plug or bowel lavage. Cocoa butter is traditional suppository base, but as suitably can use various substitutes.

The preparation that is used for rectum/vagina administration can be mixed with immediately and/or revise release. Revise delivery formulations comprise delays-, continue-, pulse-, control-, target and sequencing release.

Compound of the present invention also can directly be administered to eyes or ear, typically in wait, pH-regulates, micronizing suspension in the sterile saline or the dropping liquid form of solution. Other preparation that suitable E ﹠ E gives comprise ointment, biology can decompose (for example absorbability gel sponge, collagen) and abiotic the decomposition (for example siloxanes) implant, wafer, eyeglass and particle or utricle system, for example nonionic surfactant vesicle (niosomes) or liposome. Polymer is cross linked polyacrylate, polyvinyl alcohol, hyaluronic acid, fibre-forming polymer for example, for example, and hydroxypropyl methylcellulose, hydroxyethylcellulose or methylcellulose, or assorted polysaccharide polymer, for example, gelan glue, can merge anticorrisive agent, for example benzalkonium chloride. Said preparation also can be sent by ionotherapy.

The preparation that is used for the administration of eye/ear can be mixed with instant and/or revise and discharge. Revise delivery formulations comprise delays-, continue-, pulse-, control-, target and sequencing release.

Compound of the present invention can with the soluble large molecule entity, for example cyclodextrin and its suitable derivative or contain the combination of polymers of polyethylene glycol, so as to improve when in any above-mentioned mode of administration, using they solubility, rate of dissolution, cover taste masking road, bioavilability and/or stability.

The drug-cyclodextrin complex compound for example, is found usually can be used in most formulation and administration path. Inclusion complex and non-inclusion complex both can use. As with the substituting of the direct complexing of medicine, can use cyclodextrin as auxiliary additive, namely as carrier, diluent or solubilizer. The most normal be used in these purposes be α-, β-and gamma-cyclodextrin, its example can be found among International Patent Application WO 91/11172, WO 94/02518 and the WO 98/55148.

Want as possible to give the combination of reactive compound, for example, in order to treat the purpose of specified disease or the patient's condition, within the scope of the invention be, two kinds or more kinds of pharmaceutical composition, at least its one of comprise according to compound of the present invention, can be combined into easily the form of the kit (kit) that is suitable for composition and gives altogether.

Therefore kit of the present invention comprises two kinds or more kinds of pharmaceutical composition that separates, at least its one of comprise according to formula of the present invention (I) compound, and be used for keeping dividually the device of said composition, for example container, the bottle that separates, or separate the paper tinsel bag. The example of such kit is for being used for the blister of being familiar with of package troche, capsule etc.

Kit of the present invention is suitable for giving different dosage form especially, for example outside the oral and stomach and intestine, is used for giving the composition that this separates at different spacing of doses, or is used for progressively increasing the composition that (titrating) is separated from each other. In order to help compliance, kit typically comprises the indication of administration and so-called memory aid can be provided.

For being administered to human patient, every TDD of the compounds of this invention typically 0.01 milligram to 50 milligrams scope, certainly, is decided on mode of administration. Every TDD can be single or separate doses gives and can drop under doctor's careful consideration outside the typical range that this paper gives.

These dosage are to have average about 65 kilograms of human individuals to 70 kilograms of weight as benchmark. The doctor can determine easily that weight drops on this extraneous curee (for example baby and the elderly's) dosage.

For fear of doubt, this paper indication " treatment " comprises healing, relaxing subtracts and prophylactic treatment.

Compound of the present invention can be tested in following screening:

1.0 V _1AFilter-binding assay

1.1 film preparation

Receptor binding assays is from stably showing human V_1AThe Chinese hamster ovary celI of acceptor, (CHO-hV_1A) carry out on the cell membrane of preparation. CHO-hV_1AClone be under permission agreement by joslyn hi-voltage city Case Western Reserve University School of Medicine, the Marc Thibonnier of Dept.of Medicine provides with open arms. CHO-V_1ARemain on 37 ℃ cell routine, at wet environment and 5%CO₂Down, in the DMEM/Hams F12 nutritional blend that is supplemented with 10% hyclone, 2mM Glu, 15mM HEPES and 400 ug/ml G418. For a large amount of manufacturings of cell ball, make to adhere to CHO-hV_1ACell is supplemented with 10% hyclone comprising, and grows into converging of 90-100% in 850 square centimeters of cylinder bottles of the culture medium of the DMEM/Hams F12 nutritional blend of 2mM Glu and 15mM HEPES. The CHO-hV that converges_1ACell is collected ice-cold PBS and is neutralized centrifugal in 1,000rpm with salt solution (PBS) washing of phosphate buffered. The cell ball is stored in-80 ℃ until use. The cell ball thaws on ice and by 50 mM Tris-HCl, pH 7.4,5mM MgCl₂Form and be supplemented with in the film preparation buffer solution of protease inhibitor cocktail (Roche) and homogenize. Cell homogenates is in 4 ℃, and centrifugal 10 minutes of 1000rpm removes supernatant and is stored on ice. Remaining ball such as before homogenize and centrifugal. Collect supernatant and under 4 ℃ in 25,000xg centrifugal 30 minutes. Ball is suspended in the Tris-HCl by 50mM again, and pH 7.4,5mM MgCl₂Be stored in-80 ℃ until use in the freezing buffer solution in forming with 20% glycerine and with little aliquot. Use Bradford reagent and BSA to measure protein concentration as standard items.

1.2 V1A filter membrane combination

Protein linearity according to saturated binding is carried out at the film of every new lot. The linear segment that is chosen in curve produces the film concentration of specific bond. Then use multiple concentration [³H]-arginine vasopressin, [³H]-AVP (0.05nM-100nM) carries out saturated binding and determines K_dAnd B_max。

Test compounds they to [³H]-AVP is bonded to CHO-hV_1AThe effect of film (³H-AVP; Specific activity 65.5Ci/ mM; NENLife Sciences). Be dissolved in compound in the methyl-sulfoxide (DMSO) and to comprise 50mM Tris-HCL pH 7.4,5mM MgCl₂Be diluted to the working concentration of 10%DMSO with the test buffer solution of 0.05%BSA. 25 microlitre compounds and 25 microlitres [³H]-AVP, (final concentration or be lower than the K of film batch decision_d, 0.5nM-0.6nM typically) add at the bottom of the 96-hole circle in the polypropylene board. Association reaction begins with the film that adds 200 microlitres and this plate is at room temperature vibrated 60 minutes lightly. By using Filtermate cell harvester (Packard Instruments) to filter rapidly cessation reaction through 96-hole GF/B UniFilter plate (it has been pre-soaked in 0.5% polymine to avoid peptide to adhere to). This filter comprises 50mM Tris-HCL pH 7.4 and 5mM MgCl with 1 milliliter₂Ice-cold wash buffer washing three times. Dry this plate and 50 microlitre Microscint-0 (Packard Instruments) are added in each hole. Seal this plate and count at TopCount microplate scintillation counter (Packard Instruments). Non-specific binding (NSB) is by using the unmarked d (CH of 1 μ M₂) ₅Tyr (Me) AVP, ([β-sulfydryl-β, β-cyclopentamethylene propiono, 0-Me-Tyr²，Arg ⁸]-vasopressin) (β MCPVP) (Sigma) measures. Use four parameter logarithmic equations, minimum of a value is forced to 0%, analyzes this radioligand in conjunction with data. The slope of efficiency curve does not have match and drops between-0.75 and-1.25. Calculate specific binding by deducting average N SB cpm from average total cpm. For test compounds, the quantitaes that is attached to the part of acceptor is % combination=(sample cpm-average N SB cpm)/specific binding cpm * 100. With plotted against concentration and the match sigmoid curve of % combination to test compounds. Use the Cheng-Prusoff equation to calculate and suppress dissociation constant (K_i)：K _i＝ IC ₅₀/(1+[L]/K _d), wherein [L] is for being present in concentration and the K of the part in the hole_dFor deriving from the dissociation constant of the radioligand that Scatchard draw to analyze.

2.0V _1AFunction test; By the FLIPR (AVP/V of fluorometric imaging plate reader (Molecular Devices)_1AThe Ca of-R mediation²⁺The inhibitory action that shifts

Use FLIPR at CHO-hV_1AMeasure calcium release in the cell, FLIPR allows to detect rapidly calcium behind receptor activation. CHO-hV_1AClone be under permission agreement by joslyn hi-voltage city Case Western Reserve University School of Medicine, the Marc Thibonnier of Dept.of Medicine provides with open arms. CHO-V_1ARemain on 37 ℃ cell routine, at wet environment and 5%CO₂Down, in the DMEM/Hams F12 nutritional blend that is supplemented with 10% hyclone, 2mM Glu, 15mM HEPES and 400 ug/ml G418. Cell is inserted with the density of 20,000 cells in every hole in the black sterilization 96-orifice plate with clear bottom to allow carrying out cellular assay and fluorescence measurement from the bottom in each hole in the afternoon before the test cell. Prepared the lavation buffer solution of the salt solution (DPBS) that comprises the DulbeccoShi phosphate buffered and 2.5mM probenecid the same day and by the loading dye that comprises 4 μ M Fluo-3-AM (being dissolved in DMSO and the pluronic acid) cell culture mediums (Molecular Probes) and 2.5mM probenecid and form in test freshly. Be dissolved in compound among the DMSO and be diluted in the test buffer solution that is formed by the DPBS that comprises 1%DMSO, 0.1%BSA and 2.5mM probenecid. This cell with every hole 100 microlitre loading dyes under 37 ℃ at wet environment and 5%CO₂Middle cultivation 1 hour. After dyestuff loads, use Denley plate washer to wash this cell three times with 100 microlitre lavation buffer solutions. In each hole, stay 100 microlitre lavation buffer solutions. Use FLIPR to measure fluorescence in the cell. Obtain the fluorescence reading with the test compounds that adds 50 microlitres with 2 seconds intervals after 30 seconds. Then carry out extra 155 measurements to detect any compound agonist activity with 2 seconds intervals. Then the arginine vasopressin (AVP) that adds 50 microlitres is so that the final test volume is 200 microlitres. Then collect further fluorescence reading with 1 second interval and continue 120 seconds. Form with peak fluorescence intensity (FI) is measured reaction. Characterize for pharmacology, deduct basic FI from each fluorescence reaction. For the AVP dose-effect curve, each reaction table is shown in this row % to the reaction of AVP maximum concentration. For IC₅₀Measure, each reaction table is shown % to the reaction of AVP. Use the Cheng-Prusoff equation IC50 value to be converted into the K of correction_bValue, it has considered agonist concentration, [A], activator EC₅₀And slope: K_b＝IC ₅₀ /(2+[A]/A ₅₀] ⁿ) ^1/n-1, wherein [A] is the concentration of AVP, A₅₀Be the EC from the AVP of dose-effect curve₅₀Slope with the n=AVP dose-effect curve.

Compound of the present invention can be individually or is given with one or more other compound combination of the present invention or with one or more other medicine (or its any combination) combination. Compound of the present invention can give with the oral contraceptive combination. Therefore of the present invention further aspect in, provide a kind of V1a of comprising antagonist and oral contraceptive as simultaneously, separately or order be used for the treatment of the drug products of the combination preparation of dysmenorrhoea. Compound of the present invention can make up the drug products that gives with the PDE5 inhibitor. Therefore of the present invention further aspect in, provide a kind of V1a of comprising antagonist and PDE5 inhibitor as simultaneously, separately or order be used for the treatment of the drug products of the combination preparation of dysmenorrhoea.

Can be used in the PDEV inhibitor that makes up with the V1a antagonist and comprise (but being not restricted to):

(i) at International Patent Application Publication No. WO 03/000691; WO 02/64590; WO 02/28865; WO 02/28859; WO 02/38563; WO 02/36593; WO 02/28858; WO 02/00657; WO 02/00656, and WO 02/10166; WO 02/00658; WO 01/94347; WO 01/94345; Mentioned PDE5 inhibitor among WO 00/15639 and the WO 00/15228;

(ii) United States Patent (USP) the 6th, 143, and 746; 6,143,747 and 6,043, mentioned PDE5 inhibitor in No. 252;

(iii) be disclosed in pyrazolo [4,3-d] pyrimidin-7-ones class among the EP-A-0463756; Be disclosed in pyrazolo [4,3-d] the pyrimidin-7-ones class among the EP-A-0526004; Be disclosed in pyrazolo [4,3-d] the pyrimidin-7-ones class in the disclosed International Patent Application WO 93/06104; Be disclosed in isomery pyrazolo [3,4-d] the pyrimidin-4-one class in the disclosed International Patent Application WO 93/07149; Be disclosed in the quinazoline-4-one class in the disclosed International Patent Application WO 93/12095; Be disclosed in pyrido [3,2-d] the pyrimidin-4-one class in the disclosed International Patent Application WO 94/05661; Be disclosed in the purine-6-one class in the disclosed International Patent Application WO 94/00453; Be disclosed in pyrazolo [4,3-d] the pyrimidin-7-ones class in the disclosed International Patent Application WO 98/49166; Be disclosed in pyrazolo [4,3-d] the pyrimidin-7-ones class in the disclosed International Patent Application WO 99/54333; Be disclosed in pyrazolo [4,3-d] the pyrimidin-4-one class among the EP-A-0995751; Be disclosed in pyrazolo [4,3-d] the pyrimidin-7-ones class in the disclosed International Patent Application WO 00/24745; Be disclosed in pyrazolo [4,3-d] the pyrimidin-4-one class among the EP-A-0995750; Be disclosed in the disclosed International Patent Application WO 95/19978 hexahydropyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diones; Be disclosed in pyrazolo [4,3-d] the pyrimidin-4-one class among the WO 00/27848; Be disclosed in imidazo [5,1-f] [1,2,4] triazine-ketone and the bicyclic compound that is disclosed in the disclosed International Patent Application WO 93/07124 in EP-A-1092719 and the disclosed International Patent Application WO 99/24433; Be disclosed in pyrazolo [4,3-d] the pyrimidin-7-ones class in the disclosed International Patent Application WO 01/27112; Be disclosed in pyrazolo [4,3-d] the pyrimidin-7-ones class in the disclosed International Patent Application WO 01/27113; Be disclosed in compound and the compound that is disclosed among the EP-A-1092719 among the EP-A-1092718; Be disclosed in the tricyclic compound among the EP-A-1241170; Be disclosed in the alkyl sulphone compound in the disclosed International Patent Application WO 02/074774; Be disclosed in the compound in the disclosed International Patent Application WO 02/072586; Be disclosed in the compound and the compound that is disclosed among the WO 02/074312 of disclosed International Patent Application WO 02/079203.

(iv) 5-[2-ethyoxyl-5-(4-methyl isophthalic acid-piperazine sulfonyl) phenyl preferably]-1-methyl-3-just-propyl group-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (silaenafil, for example sell with vigour (Viagra) ), be also referred to as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl)-and the 4-ethoxyl phenenyl] sulfonyl]-4-methyl piperazine (referring to EP-A-0463756); 5-(2-ethyoxyl-5-morpholinyl acetylphenyl)-1-methyl-3-just-propyl group-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to EP-A-0526004); 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-just-the propoxyl group phenyl]-2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 98/49166); 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 99/54333); (+)-3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxyl group-1 (R)-methyl ethoxy) pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, be also referred to as 3-ethyl-5-{5-[4-ethyl piperazidine-1-base sulfonyl]-2-([(1R)-and 2-methoxyl group-1-Methylethyl] the oxygen base) pyridin-3-yl }-2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 99/54333); 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl]-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, be also referred to as 1-{6-ethyoxyl-5-[3-ethyl-6,7-dihydro-2-(2-methoxy ethyl)-7-oxo-2H-pyrazolo [4,3-d] pyrimidine-5-yl]-the 3-pyridyl sulfonyl }-4-ethyl piperazidine (referring to WO 01/27113, embodiment 8); 5-[2-is different-butoxy-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(1-methyl piperidine-4-yl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 01/27113, embodiment 15); 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridine-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 01/27113, embodiment 66); 5-(5-acetyl group-2-propoxyl group-3-pyridine radicals)-3-ethyl-2-(1-isopropyl-3-azetidine base)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 01/27112, embodiment 124); 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidine base)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 01/27112, embodiment 132); (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3,4-methylenedioxyphenyl base) pyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone (Ta Dalafei (tadalafil), IC-351, sharp scholar (Cialis) ), i.e. the embodiment 78 of disclosed International Patent Application WO 95/19978 and 95 compound, and embodiment 1,3,7 and 8 compound; 2-[2-ethyoxyl-5-(4-ethyl-piperazine-1-base-1-sulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (watt ground that non-(vardenafil), LEVITRA ) is also referred to as 1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propyl imidazole also [5,1-f]-as-triazine-2-yl)-the 4-ethoxyl phenenyl] sulfonyl]-4-ethyl piperazidine, the i.e. embodiment 20,19 of disclosed International Patent Application WO 99/24433,337 and 336 compound; The compound (EISAI) of the embodiment 11 of disclosed International Patent Application WO 93/07124; Derive from Rotella D P, J.Med.Chem., 2000,43,1257 compound 3 and 14; 4-(4-chlorophenylmethyl) amino-6,7,8-trimethoxy quinazoline: N-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4,3-d]-pyrimidine-5-yl)-and 4-propoxyl group phenyl] sulfonyl]-1-methyl 2-pyrrolidines propionamide [" DA-8159 " (embodiment 68 of WO 00/27848)]; With 7,8-dihydro-8-oxo-6-[2-propoxy phenyl]-1H-imidazo [4,5-g] quinazoline and 1-[3-[1-[(4-fluorophenyl) methyl]-7,8-dihydro-8-oxo-1H-imidazo [4,5-g] quinazoline-6-yl]-the 4-propoxy phenyl] formamide.

(v) 4-bromo-5-(pyridine radicals methylamino)-6-[3-(4-chlorphenyl)-propoxyl group]-3 (2H) pyridazinone; 1-[4-[(1,3-benzodioxole-5-ylmethyl) amino]-6-chloro-2-quinoline azoles woods base]-4-piperidines-carboxylic acid, single sodium salt; (+)-cis-5,6a, 7,9,9,9a-, six hydrogen-2-[4-(trifluoromethyl)-phenyl methyl-5-methyl-ring penta-4,5] imidazo [2,1-b] purine-4 (3H) ketone; The husband draws XiLin (furazlocillin); Cis-2-hexyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydro ring, penta [4,5]-imidazo [2,1-b] purine-4-ketone; 3-acetyl group-1-(2-chlorophenylmethyl)-2-propyl indole-6-carboxylate; 3-acetyl group-1-(2-chlorophenylmethyl)-2-propyl indole-6-carboxylate; 4-bromo-5-(3-pyridine radicals methylamino)-6-(3-(4-chlorphenyl) propoxyl group)-3-(2H) pyridazinone; 1-methyl-5 (5-morpholinyl acetyl group-2-just-propoxy phenyl)-3-just-propyl group-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones; 1-[4-[(1,3-benzodioxole-5-ylmethyl) amino]-6-chloro-2-quinazolyl]-the 4-piperidine carboxylic acid, single sodium salt; Pharmaprojects number 4516 (Glaxo Wellcome); Pharmaprojects number 5051 (Bayer); Pharmaprojects number 5064 (Kyowa Hakko; Referring to WO 96/26940); Pharmaprojects number 5069 (Schering Plough); GF-196960 (Glaxo Wellcome); E-8010 and E-4010 (Eisai); Bay-38-3045﹠38-9456 (Bayer); FR229934 and FR226807 (Fujisawa); And Sch-51866.

It is incorporated in the compound of the general formula of the therapeutical active compound of the content of disclosed patent application and journal article and particularly claim and wherein card act herein in full by reference.

Preferred PDEV inhibitor is selected from silaenafil, Ta Dalafei, watt ground, and that is non-, DA-8159 and 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2; 6-dihydro-7H-pyrazolyl [4,3-d] pyrimidin-7-ones.

Most preferably the PDE5 inhibitor is silaenafil and pharmaceutically acceptable salt thereof. Sildenafil citrate is preferred salt.

Compound of the present invention can give with the combination of NO donor. Therefore of the present invention further aspect in, provide a kind of V1a of comprising antagonist and NO donor as simultaneously, separately or order be used for the treatment of the drug products of the combination preparation of dysmenorrhoea.

Compound of the present invention can with L-arginine, or arginine salt combination gives. Therefore of the present invention further aspect in, provide a kind of V1a of comprising antagonist and L-arginine as simultaneously, separately or order be used for the treatment of the drug products of the combination preparation of dysmenorrhoea.

Compound of the present invention can give with the combination of COX inhibitor. Therefore of the present invention further aspect in, provide a kind of V1a of comprising antagonist and COX inhibitor as simultaneously, separately or order be used for the treatment of the drug products of the combination preparation of dysmenorrhoea.

Can comprise (but being not restricted to) with the COX inhibitor that compound combination of the present invention uses:

(i) brufen, naproxen, benzene  Lip river is fragrant, Flurbiprofen, fenoprofen, fenbufen, Ketoprofen, indoprofen, pirprofen, Carprofen, the  promazine, Pu Bailuofen (prapoprofen), miroprofen, sulphur  Lip river is fragrant, suprofen, alminoprofen, Tiaprofenic Acid, Fluprofen, the bucloxic acid, Indomethacin, sulindac, tolmetin, the U.S. acid of assistant, Diclofenac, fenclofenac, alclofenac, ibufenac, Isoxepac, Furofenac, tiopinac, zidometacin, acetylsalicylic acid, Indomethacin, piroxicam, tenoxicam, frusemide, ketorolac, apazone, mefenamic acid, Tolfenamic Acid, Diflunisal, podophyllotoxin derivative, acemetacin, bend  former times health, floctafenine, Oxyphenbutazone, BUTE, proglumetacin, acemetacin, Fentiazac, clidanac, an Europe acid (oxipinac), mefenamic acid, meclofenamic acid, Flufenamic acid, Niflumic Acid, Flufenisal, Sudoxicam, Etodolac, Pai Puluofen (piprofen), salicylic acid, choline magnesium trisalicylate, salicylate, benorylate, Fentiazac, a gram acid (clopinac), feprazone, isoxicam and 2-fluoro-a-methyl [1,1 '-biphenyl]-4-acetic acid, 4-(nitre oxygen base) butyl ester is (referring to Wenk, Deng the people, Europ.J.Pharmacol.453:319-324 (2002));

(ii) Meloxicam, (CA number of registration 71125-38-7: be described in United States Patent (USP) the 4th, 233, in No. 299), or its pharmaceutically acceptable salt or prodrug;

(iii) be described in United States Patent (USP) the 6th, 271, the 1-benzopyran derivatives that is substituted in No. 253. Be described in addition United States Patent (USP) the 6th, 034,256 and 6,077, No. 850 with international publication number WO 98/47890 and WO 00/23433 in 1-benzopyran derivatives;

(iv) be described in United States Patent (USP) the 6th, 077, the chromene COX2 selective depressant in No. the 6th, 034,256, No. 850 and the United States Patent (USP);

(v) be described in compound among international patent application no WO 95/30656, WO 95/30652, WO 96/38418 and the WO 96/38442, and be described in European Patent Application No. and disclose compound in 799823 and pharmaceutically acceptable derivates thereof;

(vi) celecoxib (United States Patent (USP) the 5th, 466, No. 823), valdecoxib (United States Patent (USP) the 5th, 633, No. 272), deracoxib (deracoxib) (United States Patent (USP) the 5th, 521, No. 207), rofecoxib (United States Patent (USP) the 5th, 474, No. 995), etoricoxib (International Patent Application Publication No. WO 98/03484), JTE-522 (Japanese Unexamined Patent Publication No 9052882), or its pharmaceutically acceptable salt or prodrug;

(vii) parecoxib (be described in United States Patent (USP) the 5th, 932, No. 598 in), it is the treatment effective prodrug, particularly parecoxib sodium of three ring Cox-2 selective depressant valdecoxibs (be described in United States Patent (USP) the 5th, 633, No. 272 in);

(viii) ABT-963 (being described among the International Patent Application Publication No. WO 00/24719)

(ix) aulin (be described in United States Patent (USP) the 3rd, 840, No. 597 in), Flosulide (be discussed at J.Carter,Exp.Opin.Ther.Patents. 8(1) among the .21-29 (1997)), NS-398 (is disclosed in United States Patent (USP) the 4th, 885, in No. 367), SD 8381 (is described in United States Patent (USP) the 6th, 034, in No. 256), BMS-347070 (be described in United States Patent (USP) the 6th, 180, No. 651 in), S-2474 (being described in the European patent application publication No. 595546) and MK-966 (be described in United States Patent (USP) the 5th, in 968, No. 974);

(x) be disclosed in United States Patent (USP) the 6th, 395, No. 724, United States Patent (USP) the 6th, 077, No. 868, United States Patent (USP) the 5th, 994, No. 381, United States Patent (USP) the 6th, 362, No. 209, United States Patent (USP) the 6th, 080, No. 876, United States Patent (USP) the 6th, 133, No. 292, United States Patent (USP) the 6th, 369, No. 275, United States Patent (USP) the 6th, 127, No. 545, United States Patent (USP) the 6th, 130, No. 334, United States Patent (USP) the 6th, 204, No. 387, United States Patent (USP) the 6th, 071, No. 936, United States Patent (USP) the 6th, 001,843, number United States Patent (USP) the 6th, 040, No. 450, No. 96/03392, International Patent Application Publication WO, International Patent Application Publication No. WO 96/24585, United States Patent (USP) the 6th, 340, No. 694, United States Patent (USP) the 6th, 376, No. 519, United States Patent (USP) the 6th, 153, No. 787, United States Patent (USP) the 6th, 046, No. 217, United States Patent (USP) the 6th, 329, No. 421, United States Patent (USP) the 6th, 239, No. 137, United States Patent (USP) the 6th, 136, No. 831, United States Patent (USP) the 6th, 297, No. 282, United States Patent (USP) the 6th, 239, No. 173, United States Patent (USP) the 6th, 303, No. 628, United States Patent (USP) the 6th, 310, No. 079, United States Patent (USP) the 6th, 300, No. 363, United States Patent (USP) the 6th, 077, No. 869, United States Patent (USP) the 6th, 140, No. 515, United States Patent (USP) the 5th, 994, No. 379, United States Patent (USP) the 6th, 028, No. 202, United States Patent (USP) the 6th, 040, No. 320, United States Patent (USP) the 6th, 083, No. 969, United States Patent (USP) the 6th, 306, No. 890, United States Patent (USP) the 6th, 307, No. 047, United States Patent (USP) the 6th, 004, No. 948, United States Patent (USP) the 6th, 169, No. 188, United States Patent (USP) the 6th, 020, No. 343, United States Patent (USP) the 5th, 981, No. 576, United States Patent (USP) the 6th, 222, No. 048, United States Patent (USP) the 6th, 057, No. 319, United States Patent (USP) the 6th, 046, No. 236, United States Patent (USP) the 6th, 002, No. 014, United States Patent (USP) the 5th, 945, No. 539, United States Patent (USP) the 6th, 359, No. 182, International Patent Application Publication No. WO 97/13755, International Patent Application Publication No. WO 96/25928, International Patent Application Publication No. WO 96/374679, International Patent Application Publication No. WO 95/15316, International Patent Application Publication No. WO 95/15315, International Patent Application Publication No. WO 96/03385, international patent application no WO 95/00501, international patent application no WO 94/15932, International Patent Application Publication No. WO 95/00501, International Patent Application Publication No. WO 94/27980, International Patent Application Publication No. WO 96/25405, International Patent Application Publication No. WO 96/03388, International Patent Application Publication No. WO 96/03387, United States Patent (USP) the 5th, 344, No. 991, International Patent Application Publication No. WO 95/00501, International Patent Application Publication No. WO 96/16934, International Patent Application Publication No. WO 96/03392, International Patent Application Publication No. WO 96/09304, International Patent Application Publication No. WO 98/47890, and the compound among the International Patent Application Publication No. WO 00/24719 and pharmaceutically acceptable derivates.

The general formula of the therapeutical active compound of the content of any patent application and particularly claim and the compound of wherein giving an example its its all are incorporated in herein by reference.

The specific embodiment

The preparation of following preparation and embodiment formula (I) compound.

¹H nuclear magnetic resonance (NMR) spectrum is consistent with the structure of advising in all examples. Characterization displacement study (δ) provides with the umber from tetramethylsilane downfield per 1,000,000, uses the routine abbreviation of main peaks title: s for example, singlet; D, doublet; T, triplet; Q, quartet; M, multiplet; Br, broad peak. Mass spectrum (m/z) uses electrospray ionization (ESI) or APCI (APCI) record. Following abbreviation is used for common solvent: CDCl always₃, deteriochloroform; D₆-DMSO, the deuterium methyl-sulfoxide; CD₃OD, deuterium methyl alcohol; THF, oxolane. " ammonia " refers to have the concentrated solution of ammonia in water of proportion 0.88. In the situation of using thin-layered chromatography (TLC), it refers to use the silica gel tlc of silica gel 60F254 plate, R_fFor compound travel distance on the TLC plate divided by solvent front end travel distance. When using microwave, employed two microwaves are Emrys generator (Creator) and Ernrys release (Liberator), and both are supplied by individual chemical company (Personal Chemistry). Power bracket is the 15-300W at 2.45GHz. The actual power of supplying during reaction changes in order to keep fixing temperature.

Preparation 1:4-(5-methyl-[1,3,4]  diazole-2-yl)-piperidines-1-carboxylic acid uncle-butyl ester:

With (55.4 mMs of 8.1 milliliters dimethylformamide dimethyl acetals, 1.5 equivalent) be added to the 9.0 4-hydrazine carbonyl-piperidines that restrains-1-carboxylic acid uncle-butyl esters (referring to list of references WO 9703986 A1 19970206) (37 mMs, 1 equivalent) in the solution of 40 milliliters THF. Then reactant mixture stirred 4 hours in 50 ℃ under nitrogen. Under reduced pressure desolventizing, residue are dissolved in 40 milliliters the toluene and add 400 milligrams p-methyl benzenesulfonic acid. Mixture then under nitrogen in 100 ℃ the heating 18 hours, under reduced pressure remove volatile materials and residue and between the aqueous solution of carrene and sodium acid carbonate, distribute. Organic phase is by dried over mgso and filtration. Under reduced pressure remove volatile materials and by use methylene chloride/methanol (98: 2 v/v to 95: 5v/v) as the column chromatography purifying residue of the eluant, eluent white solid (81%) with title compounds that 8.07 grams are provided at silica gel.

¹H NMR(400MHz，CD ₃OD)：δ1.42(s，9H)，1.70(m，2H)，2.05(m， 2H)，2.50(s，3H)，3.00(m，2H)，3.15(m，1H)，4.05(m，2H)；LCMS： m/z APCl ⁺, 268[MH]; The discovery value; C, 58.26%; H, 7.96%; N, 15.78%; Cl₃H ₂₁N ₃O ₃Required value C, 58.41%, H, 7.92%, N, 15.72%.

Preparation 2a:4-[4-(4-chloro-phenyl)-5-methyl-4H-[1,2,4] triazole-3-yl]-piperidines:

The compound (15 mMs, 1 equivalent) of preparations 1 of 4.0 grams is dissolved in 100 milliliters the toluene. Add the parachloroanilinum (16.5 mMs, 1.1 equivalents) of 2.1 grams, then add 2 milliliters of TFA. Solution was in 110 ℃ of heating 16 hours, and the TFA and the solution that add 2 milliliters heated 48 hours in addition in 110 ℃. Then reaction mixture adds the aqueous solution and the decant organic phase of sodium acid carbonate. Water is with the potash alkalization and with carrene (50 milliliters) extraction four times. Dichloromethane solution provides the white solid of the title compound of 2.90 grams by dried over mgso and in a vacuum desolventizing.

¹H NMR(400MHz，CDCl ₃)：δ1.60-2.00(m)，2.20(s，3H)， 2.40-2.80(m，5H，)，3.10(m，2H)，7.10(d，2H)，7.55(d，2H)；LCMS： m/z APCl ⁺，277[MH] ⁺

Preparation 2b:4-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl] piperidine hydrochlorate

Hydrochloric acid in two  alkane (4M, 10 milliliters) is added in cooling (5 ℃) solution of preparation 1 compound (1.32 grams, 4.76 mMs) in methyl alcohol (30 milliliters), and make solution be warmed to room temperature and stirred 90 minutes in addition. Tlc analyzes and shows remaining raw material, stirs 4 hours in addition in hydrochloric acid (4M, 10 milliliters) and the reaction of two  alkane so add additionally. Under reduced pressure enriched mixture and residue and toluene (3x) azeotropic is to provide title compound, 1.4 grams.

¹H NMR(400MHz，DMSO-d ₆)：δ1.86(m，4H)，2.25(m，3H)， 2.80-2.97(m，3H)，3.22(m，2H)，7.64(m，2H)，7.77(d，2H)。

Preparation 3:1-(3-chloro-benzoyl)-piperidines-4-carboxylic acid, ethyl ester

With 4-piperidine carboxylate (ethyl isonipecotate) (27.6 grams, 175 mMs) solution in carrene (50 milliliters) is through dropwise being added to 3-chlorobenzoyl chloride (20 milliliters 160 mMs) and triethylamine (28 milliliters, 200 mMs) being cooled in the solution between 10 and 15 ℃ in carrene (500 milliliters) in 10 minutes. Then reaction was at room temperature stirred 3 hours and is under reduced pressure concentrated. Residue dilutes with ether, and solution is with 1N hydrochloric acid, sodium carbonate liquor (x3) and salt water washing. Then it pass through MgSO₄Drying and vapourisation under reduced pressure, the solid of generation title compound, 44.4 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.24(t，3H)，1.62-2.10(m，4H)， 2.58(m，1H)，2.98-3.16(m，2H)，3.70(m，1H)，4.15(q，2H)，4.49(m， 1H)，7.24(m，1H)，7.31-7.40(m，3H)。LRMS m/z(APCl) ⁺296[MH] ⁺。

Preparation 4:1-(3-chloro-benzoyl)-piperidines-4-carboxylic acid hydrazides

The ester of preparation 3 (44.4 grams, 0.15 mole) and the mixture of hydrazine hydrate (30 milliliters, 0.58 mole) in methyl alcohol (120 milliliters) heated 10 hours under refluxing, and then made cool to room temperature. Under reduced pressure enriched mixture and from the ethylacetate/ether crystallized product so that the solid of title compound to be provided, 32.5 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.62-1.98(m，4H)，2.36(m，1H)， 2.78-3.09(m，2H)，3.64-4.00(m，2H)，4.65(m，1H)，7.04(m，1H)， 7.26(m，1H)，7.36(m，3H)。LRMS：m/z(APCl)282[MH] ⁺。

Preparation 5:1-(3-chloro-benzoyl)-piperidines-4-carboxylic acid N '-(2-chloro-acetyl group)-hydrazides

With (4.3 milliliters of chloroacetic chlorides, 53 mMs) dropwise be added to hydrazides (10 grams of preparation 4 through 30 minutes, 35.5 mM) and N-methylmorpholine (5.4 grams, 53 mMs) in ice-cooling solution in carrene (200 milliliters), in order to keep interior temperature below 10 ℃. Then make reactant mixture be warmed to room temperature and stirred 18 hours in addition. Reaction is diluted with ethyl acetate, with saturated sodium bicarbonate solution, and then salt water washing. Solution is through MgSO₄Drying, under reduced pressure concentrated and residue grinds to provide the white solid of title compound, 10.2 grams with ether.

¹H NMR(400MHz，CD ₃OD)：δ1.66-1.84(m，3H)，1.98(m，1H)， 2.61(m，1H)，2.99(m，1H)，3.19(m，1H)，3.74(m，1H)，4.14(s，2H)， 4.60(m，1H)，7.35(dd，1H)，7.46(m，3H)。LRMS：m/z(ES) ⁺358[MH] ⁺。

Preparation 6:[4-(5-chloromethyl-[1,3,4]  diazole-2-yl)-piperidin-1-yl]-(3-chloro-phenyl)-ketone

With (9.45 milliliters of TFAAs, 57 mMs) compound (10.2 grams through dropwise being added to preparation 5 in 30 minutes, 28.5 mM) and the cooling solution (0 to 5 ℃) of pyridine (11.5 milliliters, 142.5 mMs) in carrene (300 milliliters) in. In case add fully, gained pink suspension stirred 90 minutes in addition in 10 ℃. Reactant mixture is poured in the saturated sodium bicarbonate solution (600 milliliters) and separating layer carefully. Organic phase is with further saturated sodium bicarbonate solution (x2) washing, through MgSO₄Drying, and with the decolouring charcoal treatment. Then filtering mixt and vapourisation under reduced pressure filtrate are to provide title compound, 13 grams.

¹H NMR(400MHz，CD ₃OD)：δ1.80-1.97(m，2H)，2.08(m，1H)， 2.22(m，1H)，3.15-3.40(m，3H)，3.76(m，1H)，4.56(m，1H)，4.84(s， 2H)，7.37(m，1H)，7.48(m，3H)。LRMS m/z(APCl ⁺)340[MH] ⁺

Preparation 7:4-[N '-(2-chloro-acetyl group)-hydrazine carbonyl]-piperidines-1-carboxylic acid uncle-butyl ester

With 4-hydrazine carbonyl-piperidines-1-carboxylic acid uncle-butyl ester (referring to list of references WO 2000039125, preparation 27) (25 grams, 103 mMs) be dissolved in the carrene (300 milliliters) and then add 4-methyl morpholine (12.5 milliliters, 113 mMs). Use the ice bath cooling mixture and dropwise add chloracetyl chloride (8.2 milliliters, 103 mMs). Then make reaction be warmed to room temperature and stirred 4 hours. Reactant mixture distributes with sodium bicarbonate aqueous solution, through dried over mgso, filters and the pale solid (29.6 gram) of evaporated filtrate to produce title compound.

LRMS m/z APCl ^--318[M-H] ^-

To prepare 8:4-(5-chloromethyl-[1,3,4]  di azoly-2-yl)-piperidines-1-carboxylic acid uncle-butyl ester

The hydrazides of preparation 7 (5.0 grams, 15.6 mMs) is suspended in the carrene (200 milliliters) and then added pyridine (6.4 milliliters, 78 mMs) before mixture is cooled to 10 ℃. Dropwise added TFAA (6.6 milliliters, 39 mMs) through 15 minutes, then mixture is at room temperature stirring 3 hours. Then reaction distributes with water (50 milliliters), and organic layer filters and vapourisation under reduced pressure filtrate through dried over mgso. By use methyl alcohol in carrene as the white solid (2.95 gram) of chromatography purification residue so that title compound to be provided of eluant, eluent (2: 98) at silica gel.

¹H NMR(400MHz，CD ₃OD)：δ1.45(s，9H)，1.74(m，2H)，2.19(m， 2H)，3.04(m，2H)，3.24(m，1H)，4.09(m，2H)，4.85(s，2H)。

Preparation 9a:4-(5-[1,2,3] triazole-2-ylmethyl-[1,3,4]  diazole-2-yl)-piperidines-1-carboxylic acid uncle-butyl ester and 4-(5-[1,2,3] triazol-1-yl methyl-[1,3,4]  diazole-2-yl)-piperidines-1-carboxylic acid uncle-butyl ester

The compound of preparation 8 (8 grams, 26.5 mMs), triazole (3.7 grams, 53 mMs) and the mixture of potash (5.2 grams, 38 mMs) in DMF (60 milliliters) stirred 18 hours under room temperature. Then filtering mixt reaches under reduced pressure concentrated filtrate. Residue is distributed between ethyl acetate and the salt solution, and separating layer and organic solution are through MgSO₄Dry mixture with under reduced pressure concentrating with the isomers that title compound is provided.

¹H NMR(400MHz，CD ₃OD): δ 1.43 (s, 9H), 1.62-1.78 (m, 2H), 2.02 (m, 2H), (3.00 m, 2H), 3.19 (m, 1H), 4.03 (m, 2H), 5.95,5.99 (2xs, 2H), [7.77 (s), 7.80 (d), the total 2H of 8.18 (s)].

Preparation 9b:4-(5-[1,2,3] triazole-2-ylmethyl-[1,3,4]  diazole-2-yl)-piperidines-1-carboxylic acid uncle-butyl ester

Carrene (500 milliliters) is added in the suspension of hydrazides (132.3 grams, 375 mMs) in 1-methylimidazole (120 milliliters) of preparation 170, and in ice/acetone bath, cool off gained solution. Dropwise added trifluoromethanesulfanhydride anhydride (92 milliliters, 561 mMs) through 2.5 hours, in order to reaction temperature is maintained below 0 ℃. In case add fully, reaction was stirred 20 minutes in addition. Then add 2M hydrochloric acid (350 milliliters) quencher reaction. Separately reach mutually with carrene (200 milliliters) aqueous layer extracted. The organic solution that merges is with the salt water washing, through MgSO₄Drying and vapourisation under reduced pressure. By use at silica gel carrene as the column chromatography purifying residue of eluant, eluent so that the oil of sticking title compound to be provided.

Preparation 10:(3-chloro-phenyl)-[4-(5-[1,2,3] triazole-2-ylmethyl-[1,3,4]  diazole-2-yl)-piperidin-1-yl]-ketone

The compound of preparation 6 (2 grams, 5.9 mM), (810 milligrams of triazoles, 11.75 mM) and the mixture of potash (1.2 gram, 8.85 mMs) in acetonitrile (20 milliliters) under room temperature, stirred 30 minutes, then in 50 ℃ of stirring another hours. To filter reactant mixture, with ethyl acetate washing and concentrated filtrate under reduced pressure. Remaining brown oil is distributed between ethyl acetate and the water, and separates layers and organic phase be with extra water, then salt water washing. Solution is through MgSO₄Drying and vapourisation under reduced pressure. By using carrene at silica gel: the column chromatography purification of crude product of methyl alcohol (100: 0 to 95: 5) is to provide title compound, (202 milligrams).

¹H NMR(400MHz，CD ₃OD)：δ1.76-1.90(m，2H)，2.02(m，1H)， 2.18(m，1H)，3.12-3.38(m，3H)，3.72(m，1H)，4.50(m，1H)，5.97(s， 2H)，7.37(dd，1H)，7.41-7.51(m，3H)，7.78(s，2H)。LRMS：m/z(ES ⁺) 373，375[MH] ⁺。

Preparation 11a:4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidines-1-carboxylic acid uncle-butyl ester

With (1 milliliter of trifluoroacetic acid, 13.2 mM) (8.8 restrain to add to the compound for preparing 9a, 26.5 mM) and the solution neutralization reaction mixture of 4-chloroaniline (5 gram, 39.75 mMs) in toluene (200 milliliters) under refluxing, stirred 5 hours. The mixture of cooling dilutes with carrene, then with 1N sodium hydroxide solution and salt water washing, and vapourisation under reduced pressure. By using carrene at silica gel: methyl alcohol: the column chromatography purifying of the gradient of 0.88 ammonia (100: 0: 0 to 90: 10: 1) and then use ethyl acetate: methyl alcohol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) again-the remaining brown oil of post analysis to be to provide title compound, (2.3 gram).

¹H NMR(400MHz，CD ₃OD)：δ1.42(s，9H)，1.68-1.82(m，4H)， 2.62-2.78(m，3H)，4.08(m，2H)，5.70(s，2H)，7.24(d，2H)，7.56(d， 2H)，7.59(s，2H)；LRMS：m/z(APCl ⁺)444[MH] ⁺。

Preparation 11b:4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidines-1-carboxylic acid uncle-butyl ester

With N-methylimidazole (4.66 gram, 56.75 mMs) and carrene (20 milliliters) add to derive from preparation 170 two-acyl group hydrazides (5.00 restrain 14.19 mMs) in, and gained solution is cooled to-20 ℃. Add Trifluoromethanesulfonic anhydride (6.00 grams, 21.28 mMs), temperature remains on below 0 ℃. Finish in case add, make reaction be warmed to room temperature and stir 15 hours. Reaction is with H₂O (10 milliliters) quencher separates mutually and water layer extracts with carrene (10 milliliters) again. The organic phase that merges is filtered through dried over mgso, and under vacuum distilled dichloromethane and replace to produce the toluene solution (～20 ml volumes) of intermediate  diazole with toluene. With 4-chloroaniline (1.90 gram, 14.90 mMs) then trifluoroacetic acid (0.81 gram, 7.09 mMs) add in the toluene solution and react on 85 ℃ and stirred 5.5 hours. Mixture cool to room temperature and stirred 5 minutes with 1.8N ammoniacal liquor (14 milliliters). Separate phase, then organic phase stirred 15 hours with tert-butyl methyl ether (20 milliliters) dilution. Collect the gained solid sediment by filtering, with tert-butyl methyl ether (2 * 5 milliliters) washing, produce the light brown solid (2.72 gram) of title compound.

¹H NMR(400MHz，CDCl3)：δ1.43(s，9H)，1.72(d，2H)，1.85(bm， 2H)，2.56(m，1H)，2.66(bm，2H)，4.09(bd，2H)，5.64(s，2H)，7.01(d， 2H)，7.43(d，2H)，7.50(s，2H)。

Preparation 12a:4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidines

4M hydrochloric acid in two  alkane (10 milliliters) is added in the solution of compound (2.3 gram, 5.2 mMs) in methyl alcohol (30 milliliters) of preparation 11a and reaction was at room temperature stirred 2 hours. Under reduced pressure concentrated solution is basified to pH 10 with carrene dilution residue with the 1N sodium hydroxide solution, and separately from this layer. Water with carrene again-extraction and the organic solution that merges is through MgSO₄Dry and under reduced pressure concentrated to provide the foam of title compound, (1.65 gram).

¹H NMR(400MHz，CD ₃OD)：δ1.79(m，4H)，2.48(m，2H)，2.65(m， 1H)，3.02(m，2H)，5.70(s，2H)，7.22(d，2H)，7.55(d，2H)，7.59(s， 2H)；LRMS：m/z(APCl ⁺)344[MH] ⁺

Preparation 12b:4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidines biconjugate-toluene fulfonate

Ethyl acetate (30 milliliters) is added to the compound (6.5 gram, 14.6 mMs) that derives from preparation 11b and the mixture neutralization reaction of p-toluenesulfonic acid monohydrate (8.4 grams, 44.2 mMs) at room temperature stirred 17 hours. Collect the gained solid sediment by filtering, with the white solid of ethyl acetate (20 milliliters) washing with the generation title compound, (9.32 gram).

¹H NMR(400MHz，DMSO-d ₆)：δ1.85(m，4H)，2.26(s，6H)，2.83(m， 3H)，3.24(m，2H)，5.68(s，2H)，7.10(d，4H)，7.32(d，2H)，7.47(d， 4H)，7.54(d，2H)，7.65(s，2H)，8.29(m，1H)，8.49(m，1H)。

LRMS：m/z(APCl ⁺)344[MH] ⁺

Preparation 13:1H-tetrazolium-1 guanidine-acetic acid methyl esters

Tetrazolium-1-guanidine-acetic acid (5 grams, 39 mMs) and the mixture of the 4M hydrochloric acid in two  alkane (100 microlitre) in methyl alcohol (50 milliliters) heated 18 hours under refluxing. The mixture of vapourisation under reduced pressure cooling is to provide title compound.

¹H NMR(400MHz，DMSO-d ₆)：δ3.74(s，3H)，5.58(s，2H)，9.39(s， 1H)；LCMS：m/z APCl ⁺143[MH] ⁺

Preparation 14:(3-methyl-different  azoles-5-yl)-chloroacetic chloride

With N, dinethylformamide (several), then ethanedioly chloride is (9.5 milliliters, 106 mMs) (5 restrain dropwise to be added to (3-methyl-different  azoles-5-yl)-acetic acid, 35.4 mM) in cooling (10 ℃) solution in carrene (50 milliliters), and make solution be warmed to room temperature. Reaction was stirred 3 hours in addition, and is then under reduced pressure concentrated. Residue and methylbenzene azeotropic are to provide title compound.

¹H NMR(400MHz，CDCl ₃)：δ2.30(s，3H)，4.32(s，2H)，6.18(s， 1H)。

Preparation 15:(2-methyl-1 H-imidazole-1-group) ethyl acetate

Add to potash (8.42 gram, 61 mMs) in the solution of glyoxal ethyline (5 grams, 61 mMs) in oxolane (100 milliliters) and suspension agitation 30 minutes. Adding bromoacetate (6.75 milliliters, 61 mMs) and reaction at room temperature stirred 30 minutes in addition. Filtering mixt is with carrene: methyl alcohol (90: 10) washing. Vapourisation under reduced pressure filtrate and by using carrene at silica gel: methyl alcohol: 0.88 ammonia (93: 7: 0.5) as the column chromatography purification of crude product of eluant, eluent to provide the oil of title compound, 5.28 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.26(t，3H)，2.35(s，3H)，4.22(q， 2H)，4.58(s，2H)，6.81(s，1H)，6.94(s，1H)。LCMS：m/z APCl ⁺ 169 [MH] ⁺。

Preparation 16:2-(1H-TETRAZOLE-1-yl) acethydrazide (acetohydrazide)

Hydrazine hydrate (3.2 gram, 63 mMs) is added in the solution of ester (3 grams, 21.1 mMs) in methyl alcohol (18 milliliters) of preparation 13 and mixture heating 18 hours under refluxing. Under reduced pressure the reaction of concentrated cooling and residue and methylbenzene azeotropic are to provide title compound.

¹H NMR(400MHz，DMSO-d ₆)：δ5.18(s，2H)，9.38(s，1H)。LCMS： m/z APCl ⁺143[MH] ⁺

Preparation 17:[1,2,3] triazol-1-yl-ethyl acetate and [1,2,3] triazole-2-base-ethyl acetate

1,2,3-triazoles (19.00 kilograms, 275 moles) was fed in the suspension of potash (42.15 kilograms, 305 moles) in ethanol (80 liters) through 30 minutes, and washes with ethanol (2 liters). Add at leisure bromoacetate (45.8 kilograms, 274 moles) in ethanol (30 liters) solution and wash with ethanol (2 liters). During during this period of time reaction temperature maintain＜20 ℃. Then make reactant mixture be warmed to room temperature and stirring is spent the night. Filtering suspension liquid; With ethanol (25 liters and 17 liters) debris concentrated filtrate under reduced pressure then. Concentrate be dissolved in the ethyl acetate (120 liters) and solution with 1N hydrochloric acid (1 * 40 liter, 7 * 20 liters, 4 * 15 liters) washing. The merging water washing liquor reaches and extracts with ethyl acetate (3 * 21 liters). Merge this organic phase, through dried over mgso, filter and be concentrated into and do to produce the mixture (25 kilograms) of title compound.¹H NMR spectroscopic analysis shows that this is 6: 5 mixtures of N-2/N-1 isomers.

¹H NMR(400MHz，CDCl ₃): δ 1.25 (m, 3H), 4.13 (q, 2H, the N-1 isomers), 4.25 (q, 2H, N-2 isomers), (5.20 s, 2H, N-1 isomers), (5.22 s, 2H, N-2 isomers), (7.70 s, 2H, N-2 isomers), (7.77 s, 2H, N-1 isomers).

Preparation 18:[1,2,3] triazole-2-base-acetic acid hydrazides

In cooling (＜10 ℃) solution of mixture (19 kilograms) in ethanol (69 liters) of the ester of the preparation 17 that hydrazine hydrate (8.65 kilograms, 270 moles) is added to, temperature remains on below 20 ℃ during the whole adding. Reactant mixture stirred 3 hours between 14 and 19 ℃, then added more ethanol (25 liters) and collected product by filtering, and washed with ethanol (10 liters). From ethanol (120 liters) recrystallization, follow from three purification of crude solids of methyl alcohol (150 liters, 120 liters and 90 liters) recrystallization to produce title compound (4.53 kilograms) after the drying in a vacuum.

¹H NMR(400MHz，DMSO-d ₆)：δ4.33(s，2H)，5.02(s，2H)，7.77(s， 2H)，9.40(s，1H)。

Preparation 19:2-(2-methyl-1 H-imidazole-1-group) acethydrazide

Title compound according to preparation 16 described similar steps, except using the hydrazine of 5 equivalents, and use isopropyl alcohol as beyond the reaction dissolvent, obtain white solid from preparing 15 compound.

¹H NMR(400MHz，CD ₃OD)：δ2.35(s，3H)，4.60(s，2H)，6.81(s， 1H)，6.99(s，1H)。LCMS：m/z APCl ⁺155[MH] ⁺

Preparation 20:2-(3-methyl isophthalic acid, 2,4- di azoly-5-yl) acethydrazide

Title compound according to preparation 16 described similar steps, except using the hydrazine of 8 equivalents, and use isopropyl alcohol as beyond the reaction dissolvent, from 3-methyl 1,2,4- diazole-5-base-methyl acetate (NL 7807076) obtains.

¹H NMR(400MHz，CDCl ₃)：δ2.42(s，3H)，3.86(s，2H)，6.89(brs， 1H)，8.18(brs，1H)。

Preparation 21:2-(pyrimidine-2-yloxy) acethydrazide

2-2-pyrimidinyl oxy ethyl acetate (GB2373186,, step I embodiment 368) (4.4 grams, 24.15 mMs) and the mixture of hydrazine hydrate (5 milliliters, 160 mMs) in isopropyl alcohol (30 milliliters) heated 1 hour under refluxing. Then cooling mixture and under reduced pressure concentrated and by using carrene at silica gel: methyl alcohol: the column chromatography purifying residue of 0.88 ammonia (100: 0: 0 to 100: 10: 1) is to provide title compound, 600 milligrams.

¹H NMR(400MHz，CDCl ₃)：δ4.98(s，3H)，7.04(m，1H)，8.58(d， 2H)；LCMS：m/z APCl ⁺ 169[MH] ⁺

The different  azoles of preparation 22:2-[(3-methyl-5-yl) acetyl group] uncle hydrazine carboxylic acid-butyl ester

(24 milliliters of triethylamines; 17 mMs) be added at leisure preparation 14 acid chloride (5.64 grams; 35.4 mM) in cooling (10 ℃) solution in carrene (200 milliliters); then adding carbazic acid uncle-butyl ester (5.6 grams, 42.5 mMs) and reaction at room temperature stirred 18 hours. Reaction is with ethyl acetate dilution and filtering precipitate. Concentrated filtrate and by using ethyl acetate at silica gel under reduced pressure: the column chromatography purifying residue of the gradient of pentane (50: 50 to 100: 0) is to provide title compound.

¹H NMR(400MHz，CDCl ₃)：δ1.47(s，9H)，2.30(s，3H)，3.77(s， 2H)，6.15(s，1H)，6.45(brs，1H)，7.59(br s，1H)。

Preparation 23:2-[3-(the different  azoles of 3,5-dimethyl-4-yl) propiono] uncle hydrazine carboxylic acid-butyl ester

Ethanedioly chloride (5.16 milliliters, 59.2 mMs) adds to β-(the different  azoles of 3,5-dimethyl-4-base) propionic acid (J.Org.Chem.59 (10); 1994; 2882) in (2.5 grams, 14.8 mMs) solution in carrene (50 milliliters) and DMF (1), and solution at room temperature stirred 30 minutes. Under reduced pressure enriched mixture and residue and carrene (5x) azeotropic is to provide brown liquid. Be dissolved in this liquid in the carrene (25 milliliters) and pursue part and add carbazic acid uncle-butyl ester (2.93 grams, 22.2 mMs). Mixture further at room temperature stirred 18 hours with carrene (23 milliliters) dilution and reaction. Enriched mixture under reduced pressure, residue is suspended in the carrene, filters gained sediment and vapourisation under reduced pressure filtrate. By using carrene at silica gel: methyl alcohol: the column chromatography purifying residue of the gradient of 0.88 ammonia (95: 5: 0.5 to 90: 10: 1) is to provide the oil of title compound, 3.08 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.45(s，9H)，2.21(s，3H)，2.36(m， 4H)，2.45(m，1H)，2.60-2.73(m，2H)，6.48(br s，1H)，7.42(br s， 1H)。LCMS：m/z ES ⁺306[MNa] ⁺

Preparation 24:2-(the different  azoles of 3-methyl-5-yl) acethydrazide hydrochloride

Mixture in the 4M hydrochloric acid of the compound of preparation 22 (1.6 grams, 6.3 mMs) in two  alkane (20 milliliters) and methyl alcohol (60 milliliters) at room temperature stirred 3 hours. Under reduced pressure concentrated solution filters the gained sediment to low volume, with washed with dichloromethane and dry to provide title compound, 810 milligrams.

¹H NMR(400MHz，DMSO-d ₆)：δ2.20(s，3H)，3.86(s，2H)，6.24(s， 1H)。LCMS：m/z APCl ⁺156[MH] ⁺

Preparation 25:3-(the different  azoles of 3,5-dimethyl-4-yl) propionyl hydrazine (prppanohydrazide) hydrochloride

The solution of the compound of preparation 23 (3.08 grams, 10.87 mMs) in 2.2M methanolic hydrochloric acid (50 milliliters) at room temperature stirred 18 hours. Under reduced pressure concentrated solution and residue and methylbenzene azeotropic. Crude product with pentane/ether then ether grind, and filter the gained solid to provide the white solid of title compound, 1.39 grams.

¹H NMR(400MHz，DMSO-d ₆)δ2.22(s，3H)，2.27(t，2H)，3.35(s， 3H)，2.66(t，2H)，6.75(brs，1H)。LCMS：m/z APCl ⁺184[MH] ⁺

Preparation 26:2-(hydrazine carbonyl) morpholine-4-carboxylic acid uncle-butyl ester

2, (WO 03/018579 for 4-morpholine carboxylic acid 4-(tert-butyl) 2-methyl ester, embodiment 1 part i) mixture of (2.03 grams, 8.3 mMs), hydrazine hydrate (1.2 milliliters, 24 mMs) and methyl alcohol (50 milliliters) heated 4 days under refluxing. The mixture of vapourisation under reduced pressure cooling, residue is distributed between water and the ethyl acetate, and separating layer. Organic phase is through MgSO₄Drying and vapourisation under reduced pressure are to provide title compound, 1.92 grams.

LCMS：m/z ES ⁺268[MNa] ⁺

Preparation 27:3-(hydrazine carbonyl) piperidines-1-carboxylic acid uncle-butyl ester

(75 milliliters of hydrazine hydrate, 1.5 mole) add to that piperidines-(US 2,002 0099035 for 1-3-dicarboxylic acids 1 tert-butyl 3-ethyl ester, embodiment 12) in (72 gram, 280 mMs) solution in ethanol (250 milliliters) and reaction heating 18 hours under refluxing. Under reduced pressure mixture and the residue of concentrated cooling are distributed between carrene and the water, and separating layer then. Water is with dichloromethane extraction, and the organic solution that merges is through MgSO₄Drying and vapourisation under reduced pressure. Product and ether azeotropic with provide title compound without coloring agent, 59.8 the gram.

¹H NMR(400MHz，CDCl ₃)：δ1.40-1.50(m，11H)，1.63(m，11H)， 1.83(m，2H)，2.25(m，1H)，2.97(m，1H)，3.16(m，1H)，3.78-3.98(m， 3H)，7.40-7.60(br s，1H)。

Preparation 28:1-(4-chlorobenzene formacyl) piperidines-4-carboxylic acid, ethyl ester

Title compound is according to obtaining yellow oil to preparation 3 described similar steps from 4-piperidine carboxylate and 4-chlorobenzoyl chloride.

¹H NMR(400MHz，CDCl ₃)：δ1.24(t，3H)，1.62-2.06(m，4H)， 2.59(m，1H)，3.03(m，2H)，3.72(m，1H)，4.17(q，2H)，4.54(m， 1H)，7.36(d，2H)，7.39(d，2H)。LCMS：m/z APCl ⁺296[MH] ⁺。

Preparation 29:1-(4-chlorobenzene formacyl) piperidines-4-carbonohydrazides

The solution of the compound of preparation 28 (148 grams, 0.5 mole) in methyl alcohol (400 milliliters) was in 70 ℃ of heating 30 minutes. Then add hydrazine hydrate (50 grams, 1.0 moles), and react on other 3 hours of 60 ℃ of stirrings. Tlc analyzes and shows remaining raw material, stirs 48 hours in addition so add extra hydrazine hydrate (50 milliliters, 1.0 moles) and react on 75 ℃. Under reduced pressure the mixture of concentrated cooling is suspended in carrene (1 liter) neutralization with residue and washs with water (2x). Organic solution is through MgSO₄Drying and vapourisation under reduced pressure are to provide the white solid of title compound, 119 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.65-1.94(m，4H)，2.35(m，1H)， 2.80-3.06(m，2H 3.79(m，1H)，4.65(m，1H)，7.10(s，1H)，7.38(m， 4H)。LCMS：m/z APCl ⁺282[MH] ⁺

Preparation 30:1-(4-chlorobenzene formacyl)-N '-(trifluoroacetyl group) piperidines-4-carbonohydrazides

(1.56 milliliters of TFAAs, 11.18 mM) dropwise be added to preparation 29 compound (3.0 grams, 10.65 mM) and (1.29 milliliters of N-methylmorpholines, 11.7 mM) ice-cooling solution in carrene (50 milliliters), and reaction was at room temperature stirred 18 hours. Filter the gained sediment, with washed with dichloromethane and dry to provide title compound, 1.78 grams.

¹H NMR(400MHz，DMSO-d ₆)：δ1.56(m，2H)，1.64-1.84(m，2H)， 2.56(m，1H)，2.85(m，1H)，3.08(m，1H)，3.58(m，1H)，4.40(m， 1H)，7.40(d，2H)，7.50(d，2H)，10.20(s，1H)，11.15(brs，1H)。

Preparation 31:1-(4-chlorobenzene formacyl)-N '-(ethyoxyl acetyl group) piperidines-4-carbonohydrazides

N-methylmorpholine (2.60 grams, 26.6 mM), then (WO 01/46150 for the ethyoxyl chloroacetic chloride, embodiment 33A) (1.09 grams, 8.87 mM) add to preparation 29 compound (2.5 grams, 8.87 mM) in the solution in carrene (70 milliliters), and reaction was at room temperature stirred 18 hours. Mixture is with water, and then ammonium chloride solution and last sodium carbonate liquor wash. It is through MgSO₄Drying and vapourisation under reduced pressure are to provide title compound.

¹H NMR(400MHz，CDCl ₃)：δ1.22(t，3H)，1.72-1.99(m，4H)， 2.56(m，1H)，2.86-3.06(m，2H)，3.60(q，2H)，3.80(m，1H)，4.04(s， 2H)，4.62(m，1H)，7.38(m，4H)，8.90(d，1H)，8.99(d，1H)。LCMS： m/z ES ⁺368，370[MH] ⁺

Preparation 32:1-(3-chlorobenzene formacyl)-N '-(ethyoxyl acetyl group) piperidines-4-carbonohydrazides

Title compound according to preparation 31 described similar steps, obtain 91% productive rate from preparing 4 compound and ethyoxyl chloroacetic chloride (WO 01/46150 embodiment 33A).

¹H NMR(400MHz，CDCl ₃)：δ1.22(t，3H)，1.72-2.00(m，4H)， 2.56(m，1H)，2.84-3.10(m，2H)，3.60(q，2H)，3.79(m，1H)，4.04(s， 2H)，4.62(m，1H)，7.26(m，1H)，7.38(m，3H)，8.61(d，1H)，8.75(d， 1H)。LCMS：m/z APCl ⁺368，370[MH] ⁺

Preparation 33:4-{[(4-chlorphenyl) amino] carbonyl } piperidines-1-carboxylic acid uncle-butyl ester

1-BOC-piperidines-4-carboxylic acid (100 grams, 437 mMs), the 4-chloroaniline (61.2 the gram, 480 mMs), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (100 the gram, 524 mMs) and triethylamine (182.6 milliliters, 1.31 moles) be dissolved in cold (10 ℃) acetonitriles (1.75 liters). Reactant mixture at room temperature stirred 54 hours and is then under reduced pressure concentrated. Residue is dissolved in the ethyl acetate and right and 2N hydrochloric acid distribution. Filter the gained sediment, again-being dissolved in the carrene, solution is through MgSO₄Drying and vapourisation under reduced pressure. Residue grinds to provide the white solid of the compound of wanting with ether. Separately filtrate, and organic layer is with 2N hydrochloric acid (2x) washing, through MgSO₄Drying and vapourisation under reduced pressure. Solid grinds to provide the white solid of further compound with ether, combined yield 99.4 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.46(s，9H)，1.68-1.80(m，2H)， 1.90(m，2H)，2.39(m，1H)，2.79(m，2H)，4.19(m，2H)，7.10(s，1H)， 7.26(d，2H)，7.46(d，2H)。LCMS：m/z APCl ⁺339[MH] ⁺

Preparation 34:4-{[(4-chlorphenyl) amino] thiocarbonyl (carbonothioyl) } piperidines-1-carboxylic acid uncle-butyl ester

The compound of preparation 33 (99.4 grams, 294 mMs) and the solution of Lawesson ' s reagent (30 grams, 74.3 mMs) in toluene (1 liter) heated 1 hour under refluxing, and then at room temperature stirred 18 hours in addition. Tlc analyze to show remaining raw material, so add extra Lawesson ' s reagent (11.1 mMs) and reaction heating another hour under refluxing. Under reduced pressure concentrate mixture and residue and the ethyl acetate azeotropic of cooling. Crude product grinds with hot ethyl acetate, filters gained solid and dry to provide the white solid of title compound, 53 grams.

LCMS：m/z APCl ^--353[M-H] ^-

Preparation 35:1-{[(4-chlorphenyl) amino] thiocarbonyl } piperidines-4-carboxylic acid, ethyl ester

Isothiocyanic acid 4-chlorobenzene ester (3.5 grams, 20.7 mMs) and the mixture of 4-piperidine carboxylate (3.19 milliliters, 20.7 mMs) in carrene (30 milliliters) stirred 1 hour under room temperature. Enriched mixture under reduced pressure, residue grinds with ether, and filters gained solid and dry to provide the white solid of title compound, 6.27 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.24(t，3H)，1.82(m，2H)，1.99(m， 2H)，2.60(m，1H)，3.34(m，2H)，4.19(q，2H)，4.38(m，2H)，7.09(d， 2H)，7.17(brs，1H)，7.30(d，2H)。LCMS：m/z APCl ⁺327[MH] ⁺

Preparation 36:N-(4-chlorphenyl)-3-methyl piperazine-1-thioformamide (carbothioamide)

Isothiocyanic acid 4-chlorobenzene ester (8.0 grams, 47.17 mM) solution in carrene (250 milliliters) dropwise was added in the ice-cooled solution of 2-methyl piperazine (9.45 grams, 94.33 mMs) in carrene (250 milliliters) through 30 minutes. In case add fully, reaction was at room temperature stirred one hour. Then with water (3x) washing reaction, through MgSO₄Dry and under reduced pressure concentrated, to produce the white solid of title compound, 11.8 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.08(d，3H)，2.70(m，1H)，2.88(m， 2H)，3.02(m，2H)，4.43(m，2H)，7.10(m，2H)，7.29(m，2H)。LCMS： m/z ES ⁺270.1[MH] ⁺。

Preparation 37:N-(4-chlorphenyl)-4-(2,2-dimethyl propylene acyl group)-3-methyl piperazine-1 thioformamide

Bicarbonate di-tert-butyl (9.30 grams, 42.6 mM) add to preparation 36 compound (11.5 grams, 42.6 mM) in the solution in carrene (300 milliliters) and two  alkane (100 milliliters), and reaction was at room temperature stirred 3 hours. Enriched mixture and from methyl alcohol recrystallization product under reduced pressure. Filter out the gained solid, and vapourisation under reduced pressure filtrate. Again from methyl alcohol recrystallization residue so that title compound to be provided, 9.64 grams.

¹H NMR(400MHz，DMSO-d ₆)：δ1.05(d，3H)，1.39(s，9H)， 3.17-3.36(m，2H)，3.58(m，1H)，3.77(m，1H)，4.14(m，1H)，4.40(m， 2H)，7.32(m，4H)，9.36(s，1H)。LCMS：m/z APCl ⁺370[MH] ⁺

Preparation 38:N-(4-chlorphenyl)-4-(2,2-dimethyl propylene acyl group)-2-methyl piperazine-1-thioformamide

4-chlorphenyl thiocyanates (5.1 grams, 30 mMs) and the solution of 4-N-BOC-2-methyl piperazine (6.0 grams, 30 mMs) in carrene (250 milliliters) stirred 2 hours under room temperature. The vapourisation under reduced pressure reactant mixture is to provide the white foam of title compound.

LCMS：m/z APCl ⁺370[MH] ⁺

Preparation 39:1-{[(4-chlorphenyl) amino] thiocarbonyl }-4-methyl piperazine-4-carboxylic acid, ethyl ester

Isothiocyanic acid 4-chlorobenzene ester (2.36 grams, 13.98 mM), stirred 30 minutes under room temperature with the mixture of 4-methyl piperazine-4-carboxylic acid, ethyl ester (US 2002/0086887, embodiment 532C) (2.17 grams, 12.71 mMs) in carrene (50 milliliters). Mixture is distributed between carrene and the salt solution, and separates layers. Organic phase is passed through MgSO₄Drying and vapourisation under reduced pressure. By using carrene on the silica gel: the column chromatography purification of crude product of ethyl acetate (100: 0 to 90: 10) is to provide the white solid of title compound, 3.46 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.22(m，6H)，1.58(m，2H)，2.18(m， 4H)，3.30(m，2H)，4.19(q，2H)，4.24(m，1H)，7.09(d，2H)，7.28(d， 2H)；LCMS：m/z APCl ⁺ 341[MH] ⁺

Preparation 40:N-(4-chlorphenyl)-4-cyano group-4-Phenylpiperidine-1-thioformamide

(1.4 milliliters of triethylamines, 10 mMs) (1.69 restrain to add to isothiocyanic acid 4-chlorobenzene ester, 10 mMs) and 4-cyano group-4-Phenylpiperidine hydrochloride (2.22 grams, 10 mMs) in the suspension in carrene (100 milliliters), and then reaction at room temperature stirred 20 minutes. Mixture is with 2N hydrochloric acid, then salt water washing, and it passes through MgSO₄Drying and vapourisation under reduced pressure are to provide the white solid of title compound, 3.62 grams.

¹H NMR(400MHz，CDCl ₃)：δ2.18(m，4H)，3.50(m，2H)，4.78(m， 2H)，7.08(d，2H)，7.27-7.48(m，7H)。

Preparation 41 to 44:

Isothiocyanic acid 4-chlorobenzene ester (1 equivalent) and suitable amine (1 equivalent) are at ethanol (0.8-1.28 milliliter mM^-1) in mixture at room temperature stirred 30 minutes. Then the vapourisation under reduced pressure reactant mixture is to provide the white solid of title compound.

Preparation 45:4-{[(4-chlorphenyl) amino] thiocarbonyl }-Isosorbide-5-Nitrae-phenodiazine Ban (diazepane)-1-carboxylic acid uncle-butyl ester

Isothiocyanic acid 4-chlorobenzene ester (5.0 grams, 29.95 mMs), and the mixture of BOC-homopiperazine (homopiperazine) (6.0 grams, 29.95 mMs) in ethanol (50 milliliters) at room temperature stirred 2 hours. Vapourisation under reduced pressure mixture, residue are distributed between ethyl acetate and the water and separates layers. Organic phase is through MgSO₄Drying and vapourisation under reduced pressure are to produce the white foam of title compound.

¹H NMR(400MHz，CD ₃OD)：δ1.45(s，9H)，1.98(m，2H)，3.43(m， 2H)，3.64(m，2H)，3.94-4.10(m，4H)，7.28(s，4H)。LCMS：m/z APCl ⁺ 370[MH] ⁺。

Preparation 46:4-[(Z)-and [(4-chlorphenyl) imino group] (methyl mercapto) methyl] piperidines-1-carboxylic acid uncle-butyl ester

Uncle-butanols potassium (20.1 grams, 0.18 mole) is added in cooling (10 ℃) solution of compound (53 grams, 0.15 mole) in oxolane (1 liter) of preparation 34, in order to temperature is maintained at 10 ℃ by part. Dropwise add iodomethane (11.2 milliliters, 0.18 mole), in order to temperature is maintained at 10 ℃, and then make reaction be warmed at leisure room temperature. Reaction was stirred 90 minutes in addition, then added water quencher reaction. Reaction is with the ethyl acetate dilution with water washing. Separate phase, water layer is with other ethyl acetate extraction, and the organic solution that merges is passed through MgSO₄Drying and vapourisation under reduced pressure. Residual oil is adsorbed on the silica gel and by using pentane at silica gel: so that the oil of title compound to be provided, it is crystallization when leaving standstill as the column chromatography purifying of eluant, eluent for ethyl acetate (75: 25).

¹H NMR(400MHz，CDCl ₃)：δ1.43(s，9H)，1.57-1.82(m，5H)， 2.35(s，3H)，2.42-2.62(m，1H)，2.78(m，1H)，4.16(m，2H)，6.65(d， 2H)，7.26(d，2H)。LCMS：m/z ES ⁺391[MNa] ⁺。

Preparation 47:1-[(Z)-and [(4-chlorphenyl) imino group] (methyl mercapto) methyl] piperidines-4-carboxylic acid, ethyl ester

Uncle-butanols potassium (2.58 restrain 23.1 mMs) pursues in the solution of compound (6.27 grams, 19.2 mMs) in oxolane (100 milliliters) that partly is added to preparation 35 and reacts stirring 10 minutes. Adding iodomethane (1.44 milliliters, 23.1 mMs) and reaction at room temperature stirred 30 minutes in addition. Reaction is with the ether dilution with the salt water washing. Vapourisation under reduced pressure organic solution, and by use at silica gel carrene as the column chromatography purifying gained orange solid of eluant, eluent to provide the oil of title compound, 3.6 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.25(t，3H)，1.78(m，2H)，1.98(m， 2H)，2.04(s，3H)，2.56(m，1H)，3.01(m，2H)，4.12-4.23(m，4H)， 6.80(d，2H)，7.20(d，2H)；LCMS：m/z ES ⁺341[MH] ⁺。

Preparation 48:1-[(Z)-[(4-chlorphenyl) imino group] (methyl mercapto) methyl]-4-methyl piperazine-4-carboxylic acid, ethyl ester

Title compound according to preparation 47 described similar steps, except product not with the column chromatography purifying on the silica gel, obtain 75% productive rate from preparing 39 compound and iodomethane.

¹H NMR(400MHz，CDCl ₃)：δ1.25(m，6H)，1.50(m，2H)，2.04(s， 3H)，2.18(m，2H)，3.19(m，2H)，3.98(m，2H)，4.19(q，2H)，6.80(m， 2H)，7.20(d，2H)；LCMS：m/z ES ⁺355[MH] ⁺。

Preparation 49 to 55:

Uncle-butanols potassium (1.1 equivalent) follows p-toluenesulfonic acid methyl esters (1.1 equivalent) and adds to and be selected from preparation 37,38,40-42 and 45 the solution of compound (1 equivalent) in oxolane and reaction was at room temperature stirred 2 hours. Under reduced pressure enriched mixture and residue are distributed between ethyl acetate and the water, and separates layers and organic solution are with water (3x) washing, through MgSO₄Drying and vapourisation under reduced pressure are to produce title compound.

The A=reaction was at room temperature stirred 18 hours, and product is extraly by using carrene at silica gel: methyl alcohol is as the column chromatography purifying of eluant, eluent.

Preparation uncle 56:4-[(-butoxy carbonyl) amino-N-(4-chlorphenyl) piperidines-1-isothiocyanic acid (carbimidothioate) methyl esters

Uncle-butanols potassium (12.8 gram, 114 mMs) adds in the suspension of compound (42.3 grams, 114 mMs) in oxolane (400 milliliters) of preparation 44 and suspension at room temperature stirred 10 minutes. Adding p-toluenesulfonic acid methyl esters (21.29 grams, 114 mMs) and reaction stirred 10 minutes. Adding extra uncle-butanols potassium (641 milligrams, 5.7 mMs) and p-toluenesulfonic acid methyl esters (1.08 grams, 5.7 mMs) and reaction stirred 10 minutes in addition. With ether dilution mixture, with water (200 milliliters) and salt water washing, then pass through MgSO₄Drying and vapourisation under reduced pressure are to provide title compound.

¹H NMR(400MHz，CDCl ₃)：δ1.34-1.52(m，11H)，2.00(m，2H)， 2.05(s，3H)，3.04(m，2H)，3.68(br s，1H)，4.19(m，2H)，4.50(br s， 1H)，6.80(d，2H)，7.20(d，2H)。LCMS：m/z ES ⁺384[MH] ⁺。

Preparation 57:4-[5-(methoxy)-1,3,4- diazole-2-yl] piperidines-1-carboxylic acid uncle-butyl ester

Uncle-butanols potassium (3.40 gram, 30.3 mMs) adds in the solution of compound (7.62 grams, 25.25 mMs) in methyl alcohol (120 milliliters) of preparation 8 and reaction was at room temperature stirred 18 hours. Tlc analyzes and shows remaining raw material, stirs 2 hours so add extra uncle-butanols potassium (1 gram, 8.9 mMs) and react on 50 ℃. Under reduced pressure enriched mixture and residue are distributed between ethyl acetate and the ammonium chloride solution. Separates layers, organic phase is through MgSO₄Drying and vapourisation under reduced pressure are to provide the yellow oil of title compound, 7.30 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.45(s，9H)，1.82(m，2H)，2.08(m， 2H)，2.96(m，2H)，3.08(m，1H)，3.44(s，3H)，4.10(m，2H)，4.61(s， 2H)。LCMS：m/z APCl ⁺298[MH] ⁺。

Preparation 58:4-{5-[(2,2,2-trifluoro ethoxy) methyl]-1,3,4- diazole-2-yl } piperidines-1-carboxylic acid uncle-butyl ester

Uncle-butanols potassium (1.8 grams, 41.8 mMs) adds in the solution of 2,2,2-trifluoroethanol (4.64 grams, 46.4 mMs) in oxolane (100 milliliters) and solution at room temperature stirred 10 minutes. Then the compound (7.0 grams, 23.2 mMs) and the mixture that add preparation 8 heated 2 hours in 50 ℃. Reaction is to add ammonium chloride solution quencher, then decant organic layer and vapourisation under reduced pressure. Residue again-be dissolved in the ethyl acetate, solution is with the salt water washing, through MgSO₄Dry then vapourisation under reduced pressure is to provide the yellow oil of title compound, 8.15 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.43(s，9H)，1.80(m，2H)，2.06(m， 2H)，2.97(m，2H)，3.10(m，1H)，3.96(q，2H)，4.12(m，2H)，4.82(s， 2H)。

Preparation 59:4-[5-(methylol)-1,3,4- diazole-2-yl] piperidines-1-carboxylic acid uncle-butyl ester

Potassium acetate (5.2 grams, 53.0 mMs) adds in the solution of compound (8 grams, 26.5 mMs) in acetonitrile (150 milliliters) of preparation 8, and reacts on 80 ℃ of heating 18 hours. Under reduced pressure mixture and the residue of concentrated cooling are distributed between water and the ethyl acetate, and separates layers. Organic phase is with the salt water washing, through MgSO₄Drying and vapourisation under reduced pressure. Residual oil is dissolved in the methyl alcohol (120 milliliters), and adds sodium carbonate (5.6 grams, 53.0 mMs) and water (1 milliliter). Mixture at room temperature stirred 2 hours and its vapourisation under reduced pressure then. Residue is distributed between ethyl acetate and the water. Organic layer is with the salt water washing, through MgSO₄Drying and vapourisation under reduced pressure are to provide the white solid of title compound, 7.16 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.45(s，9H)，1.81(m，2H)，2.04(m， 2H)，2.17(m，1H)，2.97(m，2H)，3.08(m，1H)，4.11(m，2H)，4.82(s， 2H)。LCMS：m/z ES ⁺306[MNa] ⁺。

Preparation 60:4-[5-(morpholine-4-ylmethyl)-1,3,4- diazole-2-yl] piperidines-1-carboxylic acid uncle-butyl ester

The compound of preparation 8 (10 grams, 33.1 mMs), morpholine (4.3 milliliters, 49.7 mMs) and the mixture of potash (9.2 grams, 66.2 mMs) in acetonitrile (300 milliliters) stirred 4 hours in 80 ℃. The under reduced pressure mixture of concentrated cooling, and residue is distributed between water and the ethyl acetate. Organic phase is through MgSO₄Drying and vapourisation under reduced pressure are to provide the orange oil of title compound, 12.06 grams.

¹H NMR(400MHz，CD ₃OD)：δ1.45(s，9H)，1.65-1.78(m，2H)， 2.04(m，2H)，2.58(m，4H)，3.00(m，2H)，3.10(m，1H)，3.68(t，2H)， 3.81(s，2H)，4.06(m，2H)。LCMS：m/z ES ⁺353[MH] ⁺。

Preparation 61:4-{[2-(ethyoxyl acetyl group) diazanyl] carbonyl } piperidines-1-carboxylic acid uncle-butyl ester

4-hydrazine carbonyl-piperidines-(WO 2000039125 for 1-carboxylic acid uncle-butyl ester, preparation 27) (3 grams, 12.33 mM), (1.28 milliliters of ethoxyacetic acids, 13.56 mM), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (2.6 the gram, 13.56 mM), the I-hydroxybenzotriazole hydrate (1.83 the gram, 13.56 mM) and (2.1 milliliters of triethylamines, 14.8 mM) at N, the mixture in the N-dimethyl formamide (15 milliliters) stirred under room temperature 18 hours. Under reduced pressure enriched mixture and residue are distributed between ethyl acetate and the aqueous sodium carbonate. Separates layers, organic phase is through MgSO₄Drying and vapourisation under reduced pressure are to provide the oil of title compound, crystallization when it leaves standstill.

¹H NMR(400MHz，CDCl ₃)：δ1.24(t，3H)，1.45(s，9H)，1.58-1.78(m， 2H)，1.81(m，2H)，2.38(m，1H)，2.74-2.82(m，2H)，3.60(q，2H)， 4.04-4.21(m，2H)，8.26(br s，1H)，8.82(br s，1H)。LCMS：m/z APCl ⁺ 330[MH] ⁺。

Preparation 62:4-{[2-(3,3,3-trifluoropropyl acyl group) diazanyl] carbonyl } piperidines-1-carboxylic acid uncle-butyl ester

Title compound according to preparation 61 described similar steps, obtain from 4-hydrazine carbonyl-piperidines-1-carboxylic acid uncle-butyl ester (WO 2000039125, preparation 27) and 3,3,3-trifluoroacetic acid.

¹H NMR(400MHz，CD ₃OD)：δ1.44(s，9H)，1.60(m，2H)，1.80(m， 2H)，2.43(m，1H)，2.81(m，2H)，3.22(q，2H)，4.10(m，2H)。LCMS： m/z APCl ^-352[M-H] ^-。

Preparation 63:4-[5-(ethoxyl methyl)-1,3,4- diazole-2-yl] piperidines-1-carboxylic acid uncle-butyl ester

Pyridine (4 milliliters, 49.3 mMs) dropwise is added in the ice-cooling solution of compound (4.06 grams, 12.33 mMs) in carrene (60 milliliters) of preparation 61. Then stirred one hour in 0 ℃ through dropwise adding trifluoromethanesulfanhydride anhydride (4.2 milliliters, 24.6 mMs) and solution in 20 minutes. Then it at room temperature stir another hour. Use sodium bicarbonate aqueous solution alkalization mixture to pH 4, and with dichloromethane extraction. The organic extract that merges is through MgSO₄Drying, and under reduced pressure concentrated. By using carrene at silica gel: methyl alcohol: the column chromatography purification of crude product of 0.88 ammonia (97: 3: 0.3) is to provide the yellow oil of title compound, 1.25 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.23(t，3H)，1.44(s，9H)，1.81(m， 2H)，2.04(m，2H)，2.96(m，2H)，3.10(m，1H)，3.60(q，2H)，4.14(m， 2H)，4.66(s，2H)。LCMS：m/z APCl ⁺312[MH] ⁺。

Preparation 64:4-[5-(2,2,2-trifluoroethyl)-1,3,4- diazole-2-yl] piperidines-1-carboxylic acid uncle-butyl ester

Title compound according to preparation 63 described similar steps, obtain faint yellow solid from preparing 62 compound.

¹H NMR(400MHz，CDCl ₃)：δ1.42(s，9H)，1.81(m，2H)，2.04(m， 2H)，2.98(m，2H)，3.08(m，1H)，3.76(q，2H)，4.10(m，2H)。LCMS： m/z APCl ⁺ 358[MNa] ⁺。

Preparation 65:1-(4-chlorobenzene formacyl)-4-(1,3,4- diazole-2-yl) piperidines

DMF dimethylacetal (5.71 gram, 47.9 mMs) adds in the solution of compound (9.0 grams, 31.94 mMs) in DMF (100 milliliters) of preparation 29 and reacts on 50 ℃ and stirred 3 hours. Under reduced pressure enriched mixture and residue are suspended in the toluene (150 milliliters). Add p-toluenesulfonic acid (1 gram, 5.26 mMs) and react on 110 ℃ of heating 18 hours. Reaction is with ethyl acetate (100 milliliters) dilution, and with salt solution, water and then primary brine wash. Solution is through MgSO₄Drying is vapourisation under reduced pressure then. Use silica gel cartridge case and carrene: methyl alcohol (100: 0 to 90: 10) as the column chromatography purification of crude product of eluant, eluent to provide the white solid of title compound, 4.25 grams.

LCMS：m/z APCl ⁺292[MH] ⁺

Preparation 66:1-(3-chlorobenzene formacyl)-4-(1,3,4- diazole-2-yl) piperidines

DMF dimethylacetal (5.71 gram, 47.9 mMs) adds in the solution of compound (9.0 grams, 31.94 mMs) in oxolane (6 milliliters) of preparation 4 and reacts on 50 ℃ and stirred 3 hours. Tlc analyzes and shows surplus raw material, therefore adds extra DMF dimethylacetal (15 mMs) and continuation and stirs 2 hours in addition. Under reduced pressure enriched mixture and residue are suspended in the toluene (32 milliliters). Add p-toluenesulfonic acid (1 gram, 5.26 mMs) and react on 110 ℃ of heating 18 hours. Reaction with saturated sodium bicarbonate solution (2x) and salt water washing, is then passed through Na with ethyl acetate (100 milliliters) dilution₂SO ₄Drying and vapourisation under reduced pressure. By using carrene at silica gel: methyl alcohol: the column chromatography purification of crude product of the gradient of 0.88 ammonia (100: 0: 0 to 90: 10: 1) is to provide title compound.

¹H NMR(400MHz，CDCl ₃)：δ1.95(m，2H)，2.04-2.28(m，2H)， 3.12-3.30(m，3H)，3.80(m，1H)，4.58(m，1H)，7.28(m，2H)，7.39(m， 2H)，8.40(s，1H)。LCMS：m/z APCl ⁺ 292[MH] ⁺。

Preparation 67:1-(4-chlorobenzene formacyl)-4-(5-methyl isophthalic acid, 3,4- diazole-2-yl) piperidines

N, dinethylformamide dimethylacetal (6.38 grams, 47.9 mMs) adds to the compound (9.0 grams, 31.94 mMs) of preparation 29 at N, in the solution in the dinethylformamide (20 milliliters), and reaction was at room temperature stirred 1 hour. Then it stirred 2 hours in addition in 40 ℃. With toluene (150 milliliters) dilution mixture, be heated to 110 ℃, then add p-toluenesulfonic acid (400 milligrams, 2.22 mMs). React on 110 ℃ of heating 18 hours, then cooling and under reduced pressure concentrated. Residue is dissolved in the ethyl acetate, and with ammonium chloride solution and salt water washing, then it is through MgSO₄Drying and vapourisation under reduced pressure are to provide the oil of title compound, 9.75 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.81-1.97(m，2H)，2.00-2.22(m， 2H)，2.56(s，3H)，3.18(m，3H)，3.90(m，1H)，4.58(m，1H)，7.38(m， 4H)。LCMS：m/z APCl ⁺306[MH] ⁺。

Preparation 68:1-(4-chlorobenzene formacyl)-4-(5-ethyl-1,3,4- diazole-2-yl) piperidines

Triethyl orthopropionate (1.63 grams, 9.23 mMs) adds in the solution of compound (2.0 grams, 7.1 mMs) in DMF (10 milliliters) of preparation 29, and stirs 3 hours in 60 ℃. Tlc analyzes and shows remaining raw material, stirs 18 hours in addition so add extra triethyl orthopropionate (0.5 gram, 2.83 mMs) and react on 60 ℃. Enriched mixture under reduced pressure, residue are suspended in the toluene (15 milliliters) and add trifluoroacetic acid (5). Reaction was heated 18 hours under refluxing, then cooling and under reduced pressure concentrated. By using silica gel cartridge case and carrene: methyl alcohol (100: 0 to 95: 5) as the column chromatography purification of crude product of eluant, eluent to provide the oil of title compound, 1.6 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.38(t，3H)，1.90(m，2H)， 2.00-2.21(m，2H)，2.85(q，2H)，3.19(m，3H)，，3.80(m，1H)，4.58(m， 1H)，7.38(m，4H)。LCMS：m/z ES ⁺320，322[MH] ⁺。

Preparation 69:1-(3-chlorobenzene formacyl)-4-[5-(ethoxyl methyl)-1,3,4- diazole-2-yl] piperidines

Pyridine (1.8 grams, 22.84 mMs) then trifluoromethanesulfanhydride anhydride (3.22 grams, 11.42 mMs) adds in the ice-cooling solution of compound (2.80 grams, 7.61 mMs) in carrene (50 milliliters) of preparation 32. Then stirring reaction 2 hours at room temperature. Mixture is with ammonium chloride solution (3x), and then saturated aqueous sodium carbonate washing is through MgSO₄Dry reaching with activated carbon treatment. Then filter this mixture and vapourisation under reduced pressure filtrate. By using silica gel cartridge case and carrene: the column chromatography purification of crude product of the gradient of methyl alcohol (100: 0 to 95: 5) is to provide the yellow oil of title compound, 566 milligrams.

¹H NMR(400MHz，CDCl ₃)：δ1.23(t，3H)，1.83-2.24(m，3H)， 3.14-3.26(m，4H)，3.62(q，2H)，3.80(m，1H)，4.59(m，1H)，4.67(s， 2H)，7.25(m，1H)，7.40(m，3H)。LCMS：m/z APCl ⁺350[MH] ⁺。

Preparation 70:1-(4-chlorobenzene formacyl)-4-[5-(ethoxyl methyl)-1,3,4- diazole-2-yl] piperidines

Title compound according to preparation 69 described similar steps, obtain crystalline solid from preparing 31 compound.

¹H NMR(400MHz，CDCl ₃)：δ1.23(t，3H)，1.83-1.99(m，2H)， 2.04-2.22(m，2H)，3.14-3.26(m，3H)，3.62(q，2H)，3.79-3.90(m，1H)， 4.59(m，1H)，4.67(s，2H)，7.40(m，4H)。LCMS：m/z APCl ⁺350[MH] ⁺。

Preparation 71:1-(4-chlorobenzene formacyl)-4-[5-(trifluoromethyl)-1,3,4- diazole-2-yl] piperidines

Trifluoromethanesulfanhydride anhydride (1.98 milliliters, 11.7 mMs) adds in the compound (1.77 grams, 4.69 mMs) and the ice-cooling solution of pyridine (1.53 milliliters, 18.74 mMs) in carrene (40 milliliters) of preparation 30. Then make mixture be warmed to room temperature and stirred 18 hours. Reaction is diluted with carrene, with 2N hydrochloric acid, then washs with saturated sodium bicarbonate aqueous solution. It is through MgSO₄Drying and vapourisation under reduced pressure. By using carrene at silica gel: the column chromatography purification of crude product of the gradient of methyl alcohol (99: 1 to 96: 4) is to provide the brown oil of title compound, 620 milligrams.

¹H NMR(400MHz，CDCl ₃)：δ1.60(m，1H)，1.97(m，3H)，2.20(m， 2H)，3.20(m，2H)，3.34(m，1H)，7.39(m，4H)。LCMS：m/z APCl ⁺ 360[MH] ⁺。

Preparation 72 to 74:

The compound that shows down following general structure:

According to preparation 67 described similar steps from DMA dimethylacetal and suitable hydrazides preparation.

A=uses 3-hydrazine carbonyl-pyrrolidines-1-carboxylic acid uncle-butyl ester (deriving from CB Research and Development company).

Preparation 75:1-(3-chlorobenzene formacyl)-4-[5-(1H-pyrazol-1-yl methyl)-1,3,4- diazole-2-yl] piperidines

The compound of preparation 6 (1 gram, 2.94 mM), (400 milligrams of pyrazoles, 5.9 mM) and the mixture of potash (610 milligrams, 4.4 mMs) in acetonitrile (10 milliliters) and DMF (10 milliliters) in 100 ℃ of lower stirrings 18 hours. Filter the mixture of cooling, reach under reduced pressure concentrated filtrate. With ethyl acetate dilution residue, with water (2x), and the salt water washing. Then it pass through MgSO₄Dry. By using carrene at silica gel: methyl alcohol: the column chromatography purification of crude product of 0.88 ammonia (100: 0: 0 to 95: 5: 0.5) is to provide title compound, 550 milligrams.

¹H NMR(400MHz，CD ₃OD)：δ1.76-1.92(m，3H)，1.99-2.22(m， 3H)，3.18(m，1H)，3.70(m，1H)，4.50(m，1H)，5.63(s，2H)，6.35(d， 1H)，6.38(d，1H)，7.37(d，1H)，7.44(m，2H)，7.52(s，1H)，7.80(s， 1H)；LCMS：m/z ES ⁺372[MH] ⁺

Preparation 76:4-[4-(4-chlorphenyl)-5-(2-morpholine-4-base ethyl)-4H-1,2,4-triazole-3-yl] piperidines-1-carboxylic acid uncle-butyl ester

Trifluoroacetic acid (0.35 milliliter, 4.3 mMs) adds to 4-morpholine propionic acid hydrazides (Comptes Rendus des Seances de I ' acadamie des Sciences, the Serie C in oxolane (18 milliliters); Sciences Chimiques 1976; 282 (17); 857-60) the compound of (1.5 restrain 8.7 mMs) and preparation 46 (2.7 grams, 7.25 mMs), and reaction was heated 8 hours under refluxing. With the mixture of carrene dilution cooling, with the washing of 1N sodium hydroxide solution, and vapourisation under reduced pressure. By using carrene at silica gel: methyl alcohol: the column chromatography purification of crude product of the gradient of 0.88 ammonia (100: 0: 0 to 10: 10: 1) is to produce title compound, 2.2 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.45(s，9H)，1.59-1.95(m，4H)， 2.40(m，4H)，2.58(m，1H)，2.61-2.80(m，6H)，3.64(m，4H)，4.10(m， 2H)，7.19(d，2H)，7.57(d，2H)；LCMS：m/z APCl ⁺ 476，478[MH] ⁺。

Preparation 77 to 87:

The compound that shows down general structure:

According to preparation 76 described similar steps from preparing 46 compound and suitable hydrazides preparation.

The preparation numbering	Data
		77	X=2-OXo-1-pyrrolidine ylmethyl1H NMR(400MHz，CDCl 3)：δ1.42(s，9H)，1.71(m，2H)，1.77-2.00(m，4H)，   2.20(t，2H)，2.56-2.74(m，3H)，3.45(t，2H)，4.06(m，2H)，4.42(s，2H)，7.19   (d，2H)，7.54(d，2H).LCMS：m/z APCl +460[MH] +
78 A	X=imidazoles-1-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.41(s，9H)，1.70(m，2H)，1.83(m，2H)，2.55   (m，1H)，2.65(m，2H)，4.10(m，2H)，5.17(s，2H)，6.78(s，1H)，6.90(d，2H)，   7.01(s，1H)，7.19(s，1H)，7.52(d，2H).LCMS：m/z APCl +443[MH] +
		79 B	X=2-methyl-1 H-imidazole-1-group methyl1H NMR(400MHz，CDCl 3)：δ1.43(s，9H)，1.70(m，2H)，1.84(m，2H)，2.01   (s，3H)，2.52(m，1H)，2.66(m，2H)，4.10(m，2H)，5.02(s，2H)，6.55(s，1H)，   6.85(m，3H)，7.53(d，2H).LCMS：m/z APCl +457[MH] +
80	X=-1,2,4-triazol-1-yl methyl1H NMR(400MHz，CDCl 3)：δ1.42(s，9H)，1.76(m，2H)，1.86(m，2H)，2.55-   2.75(m，3H)，4.12(m，2H)，5.39(s，2H)，7.12(d，2H)，7.57(d，2H)，7.82(s，   1H)，8.05(s，1H).   LCMS：m/z APCl +444[MH] +
		81	X=tetrazolium-1-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.43(s，9H)，1.63-1.95(m，4H)，2.58-2.75(m，   3H)，4.11(m，2H)，5.60(s，2H)，7.15(d，2H)，7.59(d，2H)，8.81(s，1H).   LCMS：m/z ES +445[MH] +
82 C	X=3-methyl-isoxazole-5-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.37(s，9H)，1.60-1.82(m，4H)，2.14(s，3H)，   2.45-2.65(m，3H)，3.96-4.05(m，4H)，5.82(s，1H)，7.06(d，2H)，7.44(d，   2H).LCMS：m/z APCl +458[MH] +
		83	The X=3-methyl isophthalic acid, 2,4-oxadiazole-5-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.44(s，9H)，1.62-1.95(m，4H)，2.32(s，3H)，   2.70(m，3H)，4.10(m，2H)，4.24(s，2H)，7.18(d，2H)，7.54(d，2H).LCMS：   m/z APCl +459[MH] +

84	X=pyrimidine-2-yloxy methyl1H NMR(400MHz，CDCl 3)：δ1.41(s，9H)，1.59-76(m，2H)，1.86(m，2H)，   2.58-2.76(m，3H)，4.10(m，2H)，5.39(s，2H)，6.95(m，1H)，7.26(d，2H)，   7.43(d，2H)，8.42(s，2H).LCMS：m/z APCl +471，473[MH] +
		85	X=2-piperidin-1-yl ethyl1H NMR(400MHz，CDCl 3)：δ1.39-1.78(m，19H)，1.78-1.86(m，2H)，2.28-   3.04(m，3H)，2.56-2.82(m，6H)，4.08(m，2H)，7.19(d，2H)，7.58(d，2H).   LCMS：m/z APCl +474[MH] +
86 C	X=2-pyridine-2-base ethyl1H NMR(400MHz，CDCl 3)：δ1.42(s，9H)，1.66(m，2H)，1.78-1.90(m，2H)，   2.56(m，1H)，2.60-2.74(m，2H)，2.98(t，2H)，3.26(t，2H)，4.06(m，2H)，7.03   (d，2H)，7.12(m，1H)，7.18(d，1H)，7.50(d，2H)，7.58(m，1H)，8.42(d，1H).   LCMS：m/z APCl +468[MH] +
		87	X=2-(3,5-dimethyl isoxazole-4-yl) ethyl1H NMR(400MHz，CDCl 3)：δ1.42(s，9H)，1.70(m，2H)，1.79-1.93(m，5H)，   2.04(s，3H)，2.54(m，1H)，2.60-2.80(m，4H)，4.10(m，2H)，5.32(s，2H)，   6.90(d，2H)，7.56(d，2H).LCMS：m/z APCl +486[MH] +

A=uses 1-imidazoles-1-guanidine-acetic acid hydrazides; Such as BOll.Chim Farm.114 (2); 70-72; Preparation described in 1975.

The B=reaction was stirred 18 hours under refluxing.

C=uses 1 equivalent hydrazides.

Preparation 88:{1-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl] piperidin-4-yl } carbamic acid uncle-butyl ester

Acethydrazide (16.9 grams, 228 mMs) then (4.4 milliliters of trifluoroacetic acids, 57.1 mM) add in the solution of preparation 56 compound (43.6 grams, 114 mMs) in oxolane (250 milliliters) and mixture heating 7 hours under refluxing. Then with the mixture of liquor ammoniae dilutus wash cooling, this layer and with the further aqueous phase extracted of ethyl acetate separately. The organic solution that merges is through MgSO₄Drying and vapourisation under reduced pressure. Residue grinds with ether (100 milliliters) and removes gained crystallization and dry to provide title compound, 32.4 grams in a vacuum by filtration.

¹H NMR(400MHz，CDCl ₃)：δ1.32(m，2H)，1.40(s，9H)，1.85(m， 2H)，2.22(s，3H)，2.84(m，2H)，3.24(m，2H)，3.52(m，1H)，4.44(m， 1H)，7.24(d，2H)，7.51(d，2H)；LCMS：m/z APCl ⁺ 392[MH] ⁺。

Preparation 89:4-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl]-Isosorbide-5-Nitrae-phenodiazine Ban-1-carboxylic acid uncle-butyl ester

Title compound according to preparation 88 described similar steps, except using 2 equivalent acethydrazides, from preparing 55 compound and acethydrazide acquisition, 75% productive rate.

¹H NMR(400MHz，CDCl ₃)：δ1.41(s，9H)，1.58(m，11H)，1.72(m， 1H)，3.02(m，1H)，3.20(m，1H)，3.24-3.44(m，5H)，3.52(m，2H)， 4.24(s，2H)，7.38(m，2H)，7.50(d，2H)；LCMS：m/z APCl ⁺ 422[MH] ⁺

Preparation 90:1-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl] piperidines-4-carboxylic acid, ethyl ester

(0.84 milliliter of trifluoroacetic acid, 10.85 mM) (2.41 restrain to follow acethydrazide, 32.6 mM) add in the solution of preparation 47 compound (7.38 grams, 21.7 mMs) in oxolane (100 milliliters) and mixture heating 3 hours under refluxing. The mixture of cooling is distributed between ethyl acetate and the ammoniacal liquor and separates layers. With salt water washing organic phase, through MgSO₄Drying and vapourisation under reduced pressure. Crude product grinds to provide the white solid of title compound with ether, 5.04 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.22(t，3H)，1.60(m，2H)，1.83(m， 2H)，2.22(s，3H)，2.38(m，1H)，2.82(m，2H)，3.28(m，2H)，4.14(q， 2H)，7.25(d，2H)，7.55(d，2H)；LCMS：m/z APCl ⁺ 349[MH] ⁺。

Preparation 91:1-[4-(4-chlorphenyl)-5-(2H-1,2,3-triazole-2-ylmethyl)-4H-1,2,4-triazole-3-yl] piperidines-4-carboxylic acid, ethyl ester

(0.41 milliliter of trifluoroacetic acid, 5.3 mM) add to preparation 18 hydrazides (3.6 grams, 10.6 mM) and the solution of preparation 47 compound (2.24 grams, 15.9 mMs) in oxolane (50 milliliters) in, and reaction heating 15 hours under refluxing. The mixture of cooling is distributed between ethyl acetate and the salt solution and separates layers. Filter organic phase, through MgSO₄Drying and vapourisation under reduced pressure are to provide gluey title compound.

¹H NMR(400MHz，CDCl ₃)：δ1.21(t，3H)，1.58(m，2H)，1.82(m， 2H)，2.38(m，1H)，2.86(m，2H)，3.38(m，2H)，4.12(q，2H)，5.59(s， 2H)，7.15(d，2H)，7.40(d，2H)，7.50(s，2H)。

Preparation 92:1-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl]-4-methyl piperidine-4-carboxylic acid, ethyl ester

Title compound is according to obtaining the clean oil of 86% productive rate to preparation 91 described similar steps from preparing 48 compound and acethydrazide.

¹H NMR(400MHz，CDCl ₃)：δ1.18(s，3H)，1.23(t，3H)，1.40(m， 2H)，2.00(m，2H)，2.23(s，3H)，2.90(m，2H)，3.18(m，2H)，4.14(q， 2H)，7.26(d，2H)，7.57(d，2H)；LCMS：m/z APCl ⁺ 363[MH] ⁺。

Preparation 93:4-[4-(4-chlorphenyl)-5-(methoxy)-4H-1,2,4-triazole-3-yl]-2-methyl piperazine-1-carboxylic acid uncle-butyl ester

Methoxyl group acethydrazide (1.95 gram, 18.75 mMs) adds in the solution of compound (4.80 grams, 12.50 mMs) in oxolane (200 milliliters) of preparation 49 and solution stirred 10 minutes. Add trifluoroacetic acid (710 milligrams, 6.25 mMs), and reaction was stirred at room temperature lower 18 hours. Enriched mixture and by using silica gel cartridge case and carrene under reduced pressure: methyl alcohol (100: 0 to 90: 10) is as eluant, eluent, with the column chromatography purification of crude product that uses ethyl acetate to repeat as eluant, eluent to provide the foam of title compound, 1.84 grams.

¹H NMR(400MHz，CDCl ₃)：δ0.98(d，3H)，1.42(s，9H)， 2.82-3.05(m，4H)，3.24(m，1H)，3.34(s，3H)，3.80(m，1H)，4.18(m， 1H)，4.34(s，2H)，7.40(d，2H)，7.64(d，2H)；LCMS：m/z APCl ⁺ 363 [MH] ⁺。

Preparation 94:4-[4-(4-chlorphenyl)-5-(methoxy)-4H-1,2,4-triazole-3-yl]-3-methyl piperazine-1-carboxylic acid uncle-butyl ester

Title compound according to preparation 93 described similar steps, except reaction heating under refluxing, obtain 67% productive rate from preparing 50 compound.

LCMS：m/z APCl ⁺ 363[MH] ⁺

Preparation 95:4-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl] piperazine-1-carboxylic acid uncle-butyl ester

The compound (32.46 grams, 88 mMs) that acethydrazide (6.51 gram, 88 mMs) adds to preparation 52 just-solution in the butanols (250 milliliters) in and reaction refluxing under heating 18 hours. Reaction was heated other 5 days and is added periodically extra acethydrazide (altogether 36.5 grams) under refluxing. Under reduced pressure the mixture of concentrated cooling reaches by using carrene at silica gel: methyl alcohol: the column chromatography purifying residue of 0.88 ammonia (95: 5: 0.5) is to provide the white foam of title compound.

¹H NMR(400MHz，CDCl ₃)：δ1.42(s，9H)，2.24(s，3H)，3.01(m， 4H)，3.38(m，4H)，7.25(d，2H)，7.54(d，2H)。LCMS：m/z APCl ⁺ 378[MH] ⁺。

Preparation 96:1-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl]-4-Phenylpiperidine-4-nitrile

The compound (3.3 grams, 8.93 mMs) that acethydrazide (1.65 gram, 22.3 mMs) adds to preparation 51 just-solution in the butanols (5 milliliters) in and reaction refluxing under heating 2 days. Under reduced pressure mixture and the residue of concentrated cooling are attached on the silica gel in advance. Then by using carrene at silica gel: methyl alcohol: the column chromatography purifying of 0.88 ammonia (95: 5: 0.5), and product grinds to provide the title compound of solid with ethyl acetate.

¹H NMR(400MHz，CDCl ₃)：δ1.97-2.16(m，4H)，2.24(s，3H)， 3.35(m，2H)，3.42(m，2H)，7.22-7.45(m，7H)，7.56(d，2H)；LCMS： m/z ES ⁺400[MNa] ⁺。

Preparation 97:4-[4-(4-chlorphenyl)-5-(methoxy)-4H-1,2,4-triazole-3-yl] piperidines-1-carboxylic acid uncle-butyl ester

Trifluoroacetic acid (2.14 grams, 18.83 mM) add to preparation 57 compound (7.0 grams, 23.54 mM) and the solution of 4-chloroaniline (3.60 gram, 28.24 mMs) in toluene (50 milliliters) in and reactant mixture heating 18 hours under refluxing. Under reduced pressure the solution of concentrated cooling reaches by using silica gel cartridge case and carrene: the column chromatography purifying residue of the gradient of methyl alcohol (100: 0 to 90: 10) is to provide the oil of title compound, 4.25 grams.

¹H NMR(400MHz，CD ₃OD)：δ1.45(s，9H)，1.67-1.83(m，4H)， 2.68-2.83(m，3H)，3.32(s，3H)，4.08(m，2H)，4.39(s，2H)，7.46(d， 2H)，7.63(d，2H)；LCMS：m/z APCl ⁺407[MH] ⁺。

Preparation 98:4-[4-(4-chlorphenyl)-5-(methylol)-4H-1,2,4-triazole-3-yl] piperidines-1-carboxylic acid uncle-butyl ester

The compound of preparation 59 (6.8 grams, 24 mMs), 4-chloroaniline (4.3 grams, 33.7 mMs) and the mixture of trifluoroacetic acid (0.9 milliliter, 12 mMs) in toluene (40 milliliters) are in 100 ℃ of lower stirrings 18 hours. The mixture of vapourisation under reduced pressure cooling and residue is dissolved in the carrene neutralization washs with the 2M sodium hydroxide solution. Organic solution is through MgSO₄Dry and under reduced pressure concentrated. By using ethyl acetate at silica gel: methyl alcohol: the column chromatography purification of crude product of 0.88 ammonia (95: 5: 0.5 to 90: 10: 1) is to provide the white solid of title compound, 7.1 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.42(s，9H)，1.75(m，2H)，1.82(m， 2H)，2.59-2.76(m，3H)，3.00(br s，1H)，4.10(m，2H)，4.58(s，2H)， 7.30(d，2H)，7.58(d，2H)；LCMS：m/z APCl ⁺393[MH] ⁺。

Preparation 99 to 101:

The compound of following demonstration general structure:

According to preparing from suitable compound and the 4-chloroaniline that is selected from preparation 60,63 and 64 to preparation 98 described similar steps.

The preparation numbering	Data
		99 A	The X=ethoxyl methyl1H NMR(400MHz，CDCl 3)：δ1.09(t，3H)，1.43(s，9H)，1.68(m，2H)，2.59-   2.78(m，3H)，3.42(q，2H)，4.14(m，2H)，4.42(s，2H)，7.24(d，2H)，7.57(d，   2H).LCMS：m/z APCl +421[MH] +
100 A	X=2,2,2-trifluoroethyl1H NMR(400MHz，CDCl 3)：δ1.42(s，9H)，1.72(m，2H)，1.87(m，2H)，2.58   (m，1H)，2.66(m，2H)，3.45(q，2H)，4.10(m，2H)，7.19(d，2H)，7.60(d，2H).     LCMS：m/z APCl +445[MH] +
		101 B	X=morpholine-4-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.41(s，9H)，1.65-1.96(m，4H)，2.38(m，4H)，   2.58-2.77(m，3H)，3.57(m，4H)，4.08(m，2H)，7.23(d，2H)，7.56(d，2H).   LCMS：m/z APCl +462[MH] +

A=uses the trifluoroacetic acid of 0.8 equivalent.

B=uses the trifluoroacetic acid of 1 equivalent.

Preparation 102:2-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl] morpholine-4-carboxylic acid uncle-butyl ester

Title compound according to preparation 98 described similar steps, except the trifluoroacetic acid and 2 equivalent 4-chloroanilines that use 1 equivalent, obtain the oil of 75% productive rate from preparing 72 compound and 4-chloroaniline.

LCMS：m/z APCl ⁺ 393[MH] ⁺

Preparation 103:3-[4-(4-chloro-2-methyl phenyl)-5-methyl-4H-1,2,4-triazole-3-yl] piperidines-1-carboxylic acid uncle-butyl ester

4-chloro-2-methyl aniline (3.78 grams, 26.3 mM) and p-toluenesulfonic acid (50 milligrams) adds in the solution of preparation 73  diazole (2.33 grams, 8.9 mMs) in dimethylbenzene (10 milliliters) and reaction heating 24 hours under refluxing. By using ethyl acetate at silica gel: methyl alcohol: the column chromatography of carrene (100: 0: 0 to 0: 5: 95) is the reaction of purifying cooling directly. Product and carrene azeotropic are to provide the purple crystal solid of title compound.

¹H NMR(400MHz，CDCl ₃)：δ1.39(m，10H)，1.69(m，11H)， 1.80-1.97(m，2H)，1.98，2.01(s，2xs，3H)，2.17(s，3H)，2.32(m， 1H)，2.59-3.17(m，2H)，4.10(m，2H)，7.05，7.12(m，1H)，7.38(t， 1H)，7.44(d，1H)；LCMS：m/z APCl ⁺391[MH] ⁺。

Preparation 104:3-[4-(4-chloro-2-methyl phenyl)-5-methyl-4H-1,2,4-triazole-3-yl] pyrrolidines-1-carboxylic acid uncle-butyl ester

The compound of preparation 74 (1.50 grams, 5.92 mMs), trifluoroacetic acid (528 microlitres, 7.1 mMs) and the mixture of 4-chloroaniline (1.68 grams, 11.8 mMs) in toluene (20 milliliters) were in 110 ℃ of lower heating 18 hours. Under reduced pressure the mixture of concentrated cooling reaches by using carrene at silica gel: methyl alcohol: the column chromatography purifying residue of the gradient of triethylamine (98: 1.5: 0.5 to 90: 10: 1 to 80: 20: 1) is to provide title compound, 810 milligrams.

¹H NMR(400MHz，CDCl ₃)：δ1.44(s，9H)，2.01(s，3H)，2.22(m， 5H)，2.94-3.70(m，5H)，7.08(m，1H)，7.37-7.46(m，2H)；LCMS： m/z APCl ⁺ 377[MH] ⁺。

Preparation 105:4-[4-(4-chloro-2-anisyl)-5-methyl-4H-1,2,4-triazole-3-yl] piperidines-1-carboxylic acid uncle-butyl ester

The compound of preparation 1 (2 grams, 7.5 mMs), 4-chloro-2-aminoanisole (Bioorganic and Medicinal Chemistry Letters, 1999; 9 (19); 2805-2810) (1.77 grams, 11.2 mMs) and the mixture of trifluoroacetic acid (0.29 milliliter, 3.7 mMs) in toluene (20 milliliters) stirred 5 hours in 85 ℃. The mixture of cooling washs with the ethyl acetate dilution with the 2M sodium hydroxide solution. The aqueous solution is with the organic solution process Na of carrene (2x) extraction and merging₂SO ₄Drying is then under reduced pressure concentrated. By using carrene at silica gel: methyl alcohol: the column chromatography purification of crude product of 0.88 ammonia (100: 0: 0 to 90: 10: 1) is to provide title compound, 2 grams.

¹H NMR(400MHz，CD ₃OD)：δ1.46(s，9H)，1.63-1.84(m，4H)， 2.18(s，3H)，2.59-2.81(m，3H)，3.86(s，3H)，4.05(m，2H)，7.20(dd， 1H)，7.39(m，2H)；LCMS：m/z APCl ⁺ 407[MH] ⁺。

Preparation 106:4-[4-(2,4-dichlorophenyl)-5-methyl-4H-1,2,4-triazole-3-yl] piperidines-1-carboxylic acid uncle-butyl ester

Title compound according to and preparation 105 described similar steps, except using 2 equivalent aniline, prepare from preparing 1  diazole and 2,4-dichloroaniline.

¹H NMR(400MHz，CDCl ₃)：δ1.42(s，9H)，1.65-1.94(m，4H)， 2.20(s，3H)，2.42(m，1H)，2.61-2.78(m，2H)，4.10(m，2H)，7.22(d， 1H)，7.46(d，1H)，7.66(s，1H)。

Preparation 107 to 116:

Suitable aniline (Y ' Y-PhNH₂) (1-1.1 equivalent) then trifluoroacetic acid (0.5 equivalent) add to the compound (1 equivalent) of preparation 9 (1.6 milliliters mMs of toluene^-1) solution in and under refluxing, add thermal reaction mixture. Reaction makes the mixture cooling with the tlc monitoring and in case finish (45 minutes to 9 hours). Then reaction passes through MgSO with liquor ammoniae dilutus and salt water washing₄Drying and vapourisation under reduced pressure. By using carrene at silica gel: methyl alcohol (95: 5) as the column chromatography purification of crude product of eluant, eluent so that title compound to be provided.

The preparation numbering	Data
		107	Y＝H；Y’＝H；   1H NMR(400MHz，CDCl 3)：δ1.42(s，9H)，1.74(m，2H)，1.87(m，2H)，   2.51-2.73(m，3H)，4.08，(m，2H)，5.63(s，2H)，7.05(d，2H)，7.40-7.55(5H，   m).LCMS：m/z ES +432[MNa] +
108	Y＝4-OCH 3；Y’＝H；   1H NMR(400MHz，CDCl 3)：δ1.42(s，9H)，1.74(m，2H)，1.86(m，2H)，   2.53-2.71(m，3H)，3.84(s，3H)，4.08(m，2H)，5.61(s，2H)，6.91(d，2H)，   6.96(d，2H)，7.50(s，2H)LCMS：m/z ES +462[MNa] +
		109	Y＝4-F；Y’＝H；   1H NMR(400MHz，CDCl 3)：δ1.42(s，9H)，1.72(m，2H)，1.89(m，2H)，2.56   (m，1H)，2.65(m，2H)，4.09(m，2H)，5.62(s，2H)，7.06(d，1H)，7.13(m，   2H)，7.48(s，2H).LCMS：m/z ES +428[MNa] +
110 A	Y＝4-Br；Y’＝H；   1H NMR(400MHz，CDCl 3)：δ1.46(s，9H)，1.74(m，2H)，1.92(m，2H)，2.59   (m，1H)，2.68(m，2H)，4.12(m，2H)，5.66(s，2H)，6.98(d，2H)，7.52(s，   2H)，7.61(d，2H).LCMS：m/z ES +510[MNa] +
		111	Y＝4-CF 3；Y’＝H；   1H NMR(400MHz，CDCl 3)：δ1.42(s，9H)，1.74(m，2H)，1.90(m，2H)，   2.54(m，1H)，2.65(m，2H)，4.10(m，2H)，5.67(s，2H)，7.21(d，2H)，7.47   (s，2H)，7.73(d，2H).LCMS：m/z ES +500[MNa] +

112	Y＝4-CH 3；Y’＝H；   1H NMR(400MHz，CDCl 3)：δ1.42(s，9H)，1.74(m，2H)，1.87(m，2H)，2.41   (s，3H)，2.54-2.73(m，3H)，4.07(m，2H)，6.94(d，2H)，7.26(d，2H)，7.52   (s，2H).LCMS：m/z ES +446[MNa] +
		113	Y＝4-CN；Y’＝H；   1H NMR(400MHz，CDCl 3)：δ1.42(s，9H)，1.72(m，2H)，1.92(m，2H)，2.55   (m，1H)，2.66(m，2H)，4.09(m，2H)，5.68(s，2H)，7.28(d，2H)，7.52(s，   2H)，7.79(d，2H).LCMS：m/z ES +435[MH] +
114 A	Y＝4-Cl；Y’＝2-CH 3；   1H NMR(400MHz，CDCl 3)：δ1.45(s，9H)，1.62-1.78(m，3H)，1.86(s，3H)，   2.00(m，1H)，2.41(m，1H)，2.67(m，2H)，4.01-4.18(m，2H)，5.52(d，1H)，   5.67(d，1H)，6.87(d，1H)，7.25(d，1H)，7.34(s，1H)，7.48(s，2H)   LCMS：m/z ES +458[MH] +
		115	Y＝4-Cl；Y’＝3-F；   1H NMR(400MHz，CDCl 3)：δ1.44(s，9H)，1.73(m，2H)，1.89(m，2H)，2.57   (m，1H)，2.68(m，2H)，4.11(m，2H)，5.67(s，2H)，6.84-6.92(m，2H)，7.46-   7.54(m，3H).LCMS：m/z ES +462[MH] +
116	Y＝4-Cl；Y’＝3-Cl；   1H NMR(400MHz，CDCl 3)：δ1.42(s，9H)，1.73(m，2H)，1.88(m，2H)，2.55   (m，1H)，2.70(m，2H)，4.08(m，2H)，5.67(s，2H)，6.97(d，1H)，7.07(d，   1H)，7.52(s，2H)，7.55(d，1H).LCMS：m/z ES +478[MH] +

Use the aniline of 1.5 equivalents in the A=reaction.

Preparation 117:4-[4-(4-chlorphenyl)-5-({ [(methyl mercapto) thiocarbonyl] oxygen base } methyl)-4H-1,2,4-triazole-3-yl] piperidines-1-carboxylic acid uncle-butyl ester

Sodium hydride (60% dispersion in mineral oil, 112 milligrams, 2.8 mM) add in the ice-cooling solution of preparation 98 compound (1 gram, 2.55 mMs) in oxolane (20 milliliters) and solution at room temperature stirred one hour. Add carbon disulfide (230 microlitres, 3.83 mMs) and then add iodomethane (238 microlitres, 3.83 mMs), and reaction was at room temperature stirred 2 hours in addition. Add water (1 milliliter), under reduced pressure enriched mixture and residue are distributed between carrene and the sodium bicarbonate aqueous solution. Organic phase is through MgSO₄Drying and vapourisation under reduced pressure. By using carrene at silica gel: methyl alcohol: the column chromatography purification of crude product of the gradient of 0.88 ammonia (97: 3: 0.3 to 95: 5: 0.5) is to provide the light white yellow solid of title compound, 460 milligrams.

¹H NMR(400MHz，CDCl ₃)：δ1.42(s，9H)，1.77(m，2H)，1.90(m， 2H)，2.54(s，3H)，2.58-2.77(m，3H)，4.13(m，2H)，5.56(s，2H)， 7.20(d，2H)，7.57(d，2H)；LCMS：m/z APCl ⁺483[MH] ⁺。

Preparation 118 to 137:

4M hydrochloric acid in two  alkane (8 to 30 equivalent) add to be selected from preparation 76,77,80 to 85 and 105 to 116 suitably through the piperidines (1 equivalent) of protection (9 to 22.5 milliliters mMs of methyl alcohol^-1) in the solution neutralization reaction at room temperature stir between 1.5 and 3 hours. Enriched mixture under reduced pressure, residue is distributed between carrene and the 1M sodium hydroxide solution and separates layers. Organic solution is through MgSO₄Drying and vapourisation under reduced pressure are to provide title compound.

The preparation numbering	Data
		118 A	Y＝4-Cl；Y’＝2-Cl；X＝CH 3   1H NMR(400MHz，CD 3OD)：δ2.05-2.22(m，4H)，2.58(s，3H)，3.10(m，3H)，   3.45(m，2H)，7.78(d，1H)，7.84(m，1H)，8.00(s，1H).   LCMS：m/z APCl +311[MH] +
119 A	Y＝4-Cl；Y’＝2-OCH 3；X＝CH 3   1H NMR(400MHz，CD 3OD)：δ2.00-2.22(m，4H)，2.62(s，3H)，3.08(m，3H)，   3.44(m，2H)，3.95(s，3H)，7.30(d，1H)，7.50(s，1H)，7.61(d，1H).   LCMS：m/zAPCl +307[MH] +
		120	Y=4-Cl; Y '=H; X=2-OXo-1-pyrrolidine ylmethyl1H NMR(400MHz，CDCl 3)：δ1.70-1.90(m，4H)，1.98(m，2H)，2.21(m，2H)，   2.58(m，3H)，3.14(m，2H)，3.45(t，2H)，4.42(s，2H)，7.18(d，2H)，7.58(d，   2H).LCMS：m/z APCl +360[MH] +

121	Y=4-Cl; Y '=H; X=1,2,4-triazol-1-yl methyl1H NMR(400MHz，CDCl 3)：δ1.80-1.98(m，4H)，2.17-2.30(m，1H)，2.62(m，   2H)，3.22(m，2H)，5.38(s，2H)，7.04(d，2H)，7.52(d，2H)，7.82(s，1H)，8.03   (s，1H).LCMS：m/z APCl +344[MH] +
		122	Y=H; Y '=H; X=1,2,3-triazole-2-ylmethyl1H NMR(400MHz，CD 3OD)：δ1.83-1.96(m，4H)，2.65-2.85(m，3H)，3.25(d，   2H)，5.66(s，2H)，7.23(d，2H)，7.43-7.60(5H，m)   LCMS：m/z ES +310[MH] +
123	Y=4-F; Y '=H; X=1,2,3-triazole-2-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.75(m，2H)，1.85(m，2H)，2.53(m，3H)，3.16   (d，2H)，5.62(s，2H)，7.02(d，2H)，7.12(t，2H)，7.49(s，2H).LCMS：m/z ES +   328[MH] +
		124	Y=4-Br; Y '=H; X=1,2,3-triazole-2-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.79(m，2H)，1.87(m，2H)，2.54-2.65(m，3H)，   5.64(s，2H)，6.93(d，2H)，7.52(s，2H)，7.59(d，2H).LCMS：m/z ES +388   [MH] +
125	Y=4-Cl; Y '=3-F; X=1,2,3-triazole-2-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.80(m，2H)，1.93(m，2H)，2.54-2.66(m，3H)，   3.22(d，2H)，5.66(s，2H)，6.80-6.88(m，2H)，7.47-7.53(m，3H).LCMS：m/z   ES +362[MH] +
		126	Y=4-Cl; Y '=3-Cl; X=1,2,3-triazole-2-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.80(m，2H)，1.91(m，2H)，2.52-2.66(m，3H)，   3.20(d，2H)，5.66(s，2H)，6.94(d，1H)，7.07(d，1H)，7.52(s，2H)，7.54(d，   1H).LCMS：m/z ES +378[MH] +
127	Y＝4-CF 3 Y '=H; X=1,2,3-triazole-2-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.76(m，2H)，1.87(m，2H)，2.56(m，3H)，3.14   (d，2H)，5.66(s，2H)，7.20(d，2H)，7.46(s，2H)，7.64(d，2H).LCMS：m/z ES +   378[MH] +
		128	Y＝4-Cl；Y’＝2-CH 3 X=1,2,3-triazole-2-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.68-1.87(m，5H)，1.91-2.15(m，2H)，2.45(m，   1H)，1.55-1.72(m，2H)，3.17(d，1H)，3.28(d，1H)，5.47(d，1H)，5.64(d，1H)，   6.84(d，1H)，7.20(d，1H)，7.31(d，1H)，7.46(s，2H).LCMS：m/z ES +358   [MH] +

129	Y＝4-CH 3 Y '=H; X=1,2,3-triazole-2-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.74-1.98(m，4H)，2.43(s，3H)，2.55-2.68(m，   3H)，3.20(d，2H)，5.60(s，2H)，6.92(d，2H)，7.24(d，2H)，7.51(s，2H).   LCMS：m/z ES +324[MH] +
		130	Y＝4-OCH 3 Y '=H; X=1,2,3-triazole-2-ylmethyl1H NMR(400MHz，CD 3OD)：δ1.72-1.79(m，4H)，2.45(m，2H)，2.65(m，1H)，   3.00(d，2H)，3.82(s，3H)，5.62(s，2H)，7.00(d，2H)，7.11(d，2H)，7.57(s，   2H).LCMS：m/z ES +340[MH] +
131	Y=4-CN; Y '=H; X=1,2,3-triazole-2-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.61-1.95(m，4H)，2.44-2.60(m，3H)，3.16(m，   2H)，5.66(s，2H)，7.21(d，2H)，7.48(s，2H)，7.76(d，2H).LCMS：m/z ES +   335[MH] +
		132 A	Y=4-Cl; Y '=H; X=tetrazolium-1-ylmethyl1H NMR(400MHz，DMSO-d 6)：δ1.80-1.98(m，4H)，2.80(m，3H)，3.20(m，   2H)，3.56(s，4H)，5.77(s，2H)，7.43(d，2H)，7.60(d，2H)，8.75(br s，1H)，   8.94(br s，1H)，9.18(s，1H).LCMS：m/z ES +345，347[MH] +
133 A	Y=4-Cl; Y '=H; X=3-methyl-isoxazole-5-ylmethyl1H NMR(400MHz，CD 3OD)：δ2.05(m，2H)，2.20(m，2H)，3.00(m，2H)，3.18   (m，1H)，3.38(m，2H)，3.54(s，3H)，4.25-(s，2H)，7.48(m，2H)，7.58(d，2H).   LCMS：m/z APCl +358[MH] +
		134 A	Y=4-Cl; Y '=H; The X=3-methyl isophthalic acid, 2,4-oxadiazole-5-ylmethyl1H NMR(400MHz，CD 3OD)：δ2.12(m，4H)，2.34(s，3H)，3.02(m，2H)，3.15   (m，1H)，3.43(m，2H)，3.64(s，2H)，7.57(m，2H)，7.68(d，2H).LCMS：m/z   APCl +359[MH] +
135	Y=4-Cl; Y '=H; X=pyrimidine-2-yloxy methyl1H NMR(400MHz，CDCl 3)：δ2.05(m，4H)，2.80-2.95(m，3H)，3.46(m，2H)，   5.40(m，2H)，6.98(m，1H)，7.20-7.34(m，1H)，7.41-7.58(m，3H)，8.44(m，   2H).LCMS：m/z APCl +371[MH] +
		136	Y=4-Cl; Y '=H; X=2-piperidin-1-yl ethyl1H NMR(400MHz，CDCl 3)：δ1.41(m，2H)，1.56(m，4H)，1.78-1.97(m，4H)，   2.20-2.40(m，6H)，2.60-2.78(m，5H)，3.22(m，2H)，7.18(d，2H)，7.57(d，   2H).LCMS：m/z APCl +374[MH] +

137	Y=4-Cl; Y '=H; X=morpholine-4-base ethyl1H NMR(400MHz，CDCl 3)：δ1.70-1.90(m，4H)，2.38(m，4H)，2.58(m，3H)，   2.70(s，4H)，3.14(m，2H)，3.61(m，4H)，7.18(d，2H)，7.57(d，2H).LCMS：   m/z APCl +376[MH] +

Then A=vapourisation under reduced pressure reactant mixture processes to separate the hydrochloride of title compound.

Preparation 138 to 141:

Be selected from preparation 78 to 79 and 86 to 87 suitably through protection piperidines (1 equivalent) from (13 milliliters mMs of 2.2M methanolic hydrochloric acids^-1) in solution at room temperature stirred 18 hours. Under reduced pressure enriched mixture and residue and methylbenzene azeotropic. Crude product is distributed between carrene and the 1M sodium hydroxide solution and separates layers. Organic solution is through MgSO₄Drying and vapourisation under reduced pressure are to provide title compound.

A=vapourisation under reduced pressure reactant mixture, and and methylbenzene azeotropic. Product grinds with ethyl acetate, filters and dry hydrochloride with the generation title compound.

Preparation 142:4-[4-(4-chlorphenyl)-5-(methoxy)-4H-1,2,4-triazole-3-base 4-[] piperidines

4M hydrochloric acid in two  alkane (60 milliliters) adds in the solution of preparation 97 compound (3.75 grams, 9.22 mMs) in two  alkane (50 milliliters) and reaction was at room temperature stirred 3 hours. Vapourisation under reduced pressure mixture and residue again-be dissolved in carrene neutralization with ammoniacal liquor, then salt water washing. Organic solution is through MgSO₄Drying and vapourisation under reduced pressure. By using silica gel cartridge case and carrene: methyl alcohol: 0.88 ammonia (90: 10: 1) as the column chromatography purification of crude product of eluant, eluent to provide title compound, 1.99 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.80-1.98(m，4H)，2.57-2.70(m， 3H)，3.20(m，2H)，3.25(s，3H)，4.38(s，2H)，7.22(d，2H)，7.57(d， 2H)。LCMS：m/z APCl ⁺307[MH] ⁺。

Preparation 143:4-[4-(4-chlorphenyl)-5-(ethoxyl methyl)-4H-1,2,4-triazole-3-yl] piperidine hydrochlorate

4M hydrochloric acid in two  alkane (20 milliliters) adds in preparation 99 the solution of compound (990 milligrams, 2.35 mMs) in two  alkane (20 milliliters) and reaction was at room temperature stirred 18 hours. Vapourisation under reduced pressure mixture and residue and carrene azeotropic are to provide title compound, 910 milligrams.

¹H NMR(400MHz，CD ₃OD)：δ1.02(t，3H)，1.80(m，4H)，2.55(m， 2H)，2.76(m，1H)，3.05(m，2H)，3.38(q，2H)，4.42(s，2H)，7.45(d， 2H)，7.63(d，2H)；LCMS：m/z APCl ⁺ 321[MH] ⁺。

Preparation 144:1-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl] piperazine dihydrochloride

4M hydrochloric acid in two  alkane (13.75 milliliters) adds in the solution of preparation 95 compound (4.12 grams, 110 mMs) in carrene (50 milliliters) and reaction was at room temperature stirred 30 minutes. Vapourisation under reduced pressure mixture and dry to provide the white solid of title compound, 3.8 grams in a vacuum.

¹H NMR(400MHz，CDCl ₃)：δ2.23(s，3H)，2.80(m，4H)，3.05(m， 4H)，7.25(d，2H)，7.50(d，2H)。

Preparation 145:1-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl] piperidines-4-amine dihydrochloride

The suspension of the compound of preparation 88 (32.3 grams, 82.5 mMs) in methyl alcohol (250 milliliters) and the 4N hydrochloric acid in two  alkane (40 milliliters) was warmed to 50 ℃ through 3 hours. Enriched mixture and residue pulping in oxolane (50 milliliters) under reduced pressure. Filter gained solid and dry so that title compound to be provided in a vacuum.

¹H NMR(400MHz，CD ₃OD)：δ1.65(m，2H)，1.96(m，2H)，2.36(s， 3H)，3.07(m，2H)，3.36(m，1H)，3.47(m，2H)，7.66(d，2H)，7.75(d， 2H)。LCMS：m/z APCl ⁺292[MH] ⁺。

Preparation 146:3-[4-(4-chloro-2-tolyl)-5-methyl-4H-1,2,4-triazole-3-yl] piperidines

4M hydrochloric acid (5 milliliters) adds in preparation 103 the solution of compound (846 milligrams, 2.16 mMs) in two  alkane (10 milliliters) and reaction was at room temperature stirred 18 hours. Tlc analyzes and shows remaining raw material, so the 4M hydrochloric acid (5 milliliters) and the reaction that additionally are added in the two  alkane are at room temperature stirred another hour. Then concentrated reaction mixture and use carrene at silica gel by column chromatography under reduced pressure: methyl alcohol: 0.88 ammonia (90: 10: 1) purification of crude product. Product and carrene and ether azeotropic are to provide the canescence foam of title compound.

¹H NMR(400MHz，CDCl ₃)：δ1.49(m，1H)，1.68-1.93(m，3H)， 1.97(s，3H)，2.16(s，3H)，2.59(m，1H)，2.80(m，1H)，3.03(m，1H)， 3.16(m，1H)，7.06(2xd，1H)，7.35(2xm，1H)，7.42(2xd，1H)；LCMS： m/z APCl ⁺ 291[MH] ⁺。

Preparation 147:4-(4-chloro-2-tolyl)-3-methyl-5-pyrrolidin-3-yl-4H-1,2,4-triazole

Solution in the 4M hydrochloric acid of compound in two  alkane (20 milliliters) of preparation 104 stirred 4 hours under room temperature. Mixture is distributed between ethyl acetate and the 2N sodium hydroxide solution, and separates layers. Organic solution is passed through MgSO₄Drying and vapourisation under reduced pressure are to provide title compound.

¹H NMR(400MHz，CDCl ₃)：δ2.00(m，5H)，2.20(m，5H)， 2.80-3.02(m，2H)，3.10-3.27(m，1H)，7.05(d，1H)，7.38(d，1H)， 7.41(s，1H)；LCMS：m/z APCl ⁺277[MH] ⁺。

Preparation 148:1-[4-(4-chlorphenyl)-5-(methoxy)-4H-1,2,4-triazole-3-yl]-Isosorbide-5-Nitrae-phenodiazine Ban

4M hydrochloric acid (30 milliliters) in two  alkane (25 milliliters) adds in the solution of preparation 89 compound (5.45 grams, 12.93 mMs) in two  alkane (30 milliliters) and reaction was at room temperature stirred 18 hours. Under reduced pressure concentrated reaction mixture and residue are distributed between water and the ether. Then separates layers uses NaOH alkalization water to reach with carrene (3x) extraction solution. The organic extract that merges passes through MgSO₄Dry to provide the title compound of foam, 3.84 grams.

¹H NMR(400MHz，CD ₃OD)：δ1.78(m，2H)，2.84(m，4H)，3.21(s， 3H)，3.30(m，4H)，4.24(s，2H)，7.50(d，2H)，7.60(d，2H)；LCMS： m/z APCl ⁺322[MH] ⁺。

Preparation 149:1-[4-(4-chlorphenyl)-5-(methoxy)-4H-1,2,4-triazole-3-yl]-the 2-methyl piperazine

Title compound obtains from preparing 94 compound according to preparation 148 described steps, and 95% productive rate is yellow oil.

¹H NMR(400MHz，CDCl ₃)：δ1.14(d，3H)，2.10(br s，1H)，2.60(m， 1H)，2.82(m，2H)，2.97(m，1H)，3.07(m，2H)，3.35(s，3H)，4.28(d， 1H)，4.40(d，1H)，7.38(d，2H)，7.50(d，2H)；LCMS：m/z APCl ⁺322 [MH] ⁺。

Preparation 150:1-[4-(4-chlorphenyl)-5-(methoxy)-4H-1,2,4-triazole-3-yl]-the 3-methyl piperazine

Trifluoroacetic acid (25 milliliters) adds in the solution of the ice of preparation 93 compound (2.80 grams, 6.63 mMs) in carrene (25 milliliters)-cooling and solution at room temperature stirred one hour. Under reduced pressure enriched mixture and residue are dissolved in the ethyl acetate again, then wash with the 1N sodium hydroxide solution. Organic solution is passed through MgSO₄Drying and vapourisation under reduced pressure. By using silica gel cylinder and carrene: methyl alcohol: the column chromatography purification of crude product of the gradient of 0.88 ammonia (100: 0: 0 to 90: 10: 1) is to provide the oil of title compound, 780 milligrams.

¹H NMR(400MHz，CDCl ₃)：δ1.19(d，3H)，2.98(m，2H)， 3.02-3.23(m，5H)，3.36(s，3H)，4.34(s，2H)，7.40(d，2H)，7.52(d， 2H)；LCMS：m/z APCl ⁺ 322[MH] ⁺。

Preparation 151:4-[4-(4-chloro-2-methyl phenyl)-5-methyl-4H-1,2,4-triazole-3-yl] piperidines

The compound of preparation 1 (3 grams, 11.2 mM), the 4-chloro-2-methyl aniline (2.4 the gram, 16.8 mM) and the mixture of trifluoroacetic acid (0.8 milliliter, 11.2 mMs) in toluene (30 milliliters) stirred 18 hours in room temperature, 110 ℃ are lower. Under reduced pressure the mixture of concentrated cooling adds 2M sodium hydroxide solution (10 milliliters) and mixture and methylbenzene azeotropic. By using carrene at silica gel: methyl alcohol: the column chromatography purification of crude product of 0.88 ammonia (95: 5: 0.5 to 80: 20: 3) is to provide the pale foam of title compound, 1.45 grams.

¹H NMR(400MHz，CD ₃OD)：δ1.81(m，2H)，1.92(m，2H)，2.00(s， 3H)，2.19(s，3H)，2.60-2.78(m，3H)，3.20(m，2H)，7.38(d，1H)， 7.46(d，1H)，7.59(s，1H)；LCMS：m/z APCl ⁺291[MH] ⁺。

Preparation 152:4-[4-(4-chloro-2-fluorophenyl)-5-methyl-4H-1,2,4-triazole-3-yl] piperidines two trifluoroacetates

(900 milligrams of the compounds of preparation 1,3.4 mM), (109.1 milligrams of 4-chloro-2-fluoroanilines, 0.75 mM) and the mixture of trifluoroacetic acid (288 microlitres, 3.74 mMs) in toluene (8 milliliters) in 110 ℃ of lower stirrings 72 hours. Under reduced pressure the mixture of concentrated cooling adds 0.88 ammonia and reaches under reduced pressure enriched mixture. Residue and methylbenzene azeotropic and by using carrene at silica gel: methyl alcohol: the column chromatography purification of crude product of the gradient of 0.88 ammonia (90: 10: 1 to 80: 20: 3) to provide the white foam of title compound, 985 milligrams.

¹H NMR(400MHz，CDCl ₃)：δ2.02-2.30(m，7H)，2.80(m，1H)， 3.10(m，2H)，3.59(m，2H)，3.86(m，1H)，7.26(m，1H)，7.40(m， 2H)，9.34(brs，1H)，10.10(brs，1H)；LCMS：m/z APCl ⁺295[MH] ⁺。

Preparation 153:4-{4-(4-chlorphenyl)-5-[(2,2,2-trifluoro ethoxy) methyl]-4H-1,2,4-triazole-3-yl } piperidines

Trifluoroacetic acid (2.49 grams, 21.8 mM) (3.63 restrain to add to the 4-chloroaniline, 28.4 mM) and the solution of preparation 58 compound (8.0 grams, 21.9 mMs) in toluene (50 milliliters) in, and reaction heating 48 hours under refluxing. Tlc analyzes as showing remaining raw material, so add extra trifluoroacetic acid (8 milliliters) and reaction was heated other 4 hours under refluxing. With the mixture of water extraction cooling, use the potassium hydroxide alkalization aqueous solution then to extract with carrene (4 * 100 milliliters). The organic extract that merges is through MgSO₄Drying and vapourisation under reduced pressure. By using silica gel cartridge case and carrene: methyl alcohol: the column chromatography purification of crude product of the gradient of 0.88 ammonia (100: 0: 0 to 85: 15: 1.5) is to produce title compound, 4.34 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.86-2.04(m，4H)，2.78(m，3H)， 3.37(m，2H)，3.82(q，2H)，4.22-4.41(brs，1H)，4.58(s，2H)，7.22(d， 2H)，7.58(d，2H)；LCMS：m/z ES ⁺375.1[MH] ⁺。

Preparation 154:4-{4-(4-chlorphenyl)-5-[(trifluoromethoxy) methyl]+4H-1,2,4-triazole-3-yl } piperidines

With (0.35 milliliter of hydrogen fluoride-pyridine, 13.2 mM), then will prepare (160 milligrams of 117 compounds, 0.33 mM) solution in carrene (1 milliliter) adds to 1 under-78 ℃, 3-two bromos-2, the solution of 4-dimethyl hydantoin (283 milligrams, 1.0 mMs) in carrene (5 milliliters) is. Then made reaction be warmed to room temperature through 30 minutes stirs another hour. Mixture is with the washing of 1N sodium hydroxide solution, through MgSO₄Drying and vapourisation under reduced pressure. By using carrene at silica gel: methyl alcohol: 0.88 ammonia (90: 10: 1) as the column chromatography purification of crude product of eluant, eluent to provide the yellow oil of title compound, 45 milligrams.

LCMS：m/z APCl ⁺361[MH] ⁺

Preparation 155:4-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl] benzonitrile

Trifluoroacetic acid (600 microlitres, 8.1 mMs) adds to 4-chloroaniline (2.1 grams, 16.2 mMs) and 4-(5-methyl isophthalic acid, 3,4- diazole-2-yl) benzonitrile (Journal f ü r Praktische Chemie, 1994; 336 (8): 678-85) (3.0 grams, 16.2 mMs) suspension neutralization reaction in oxolane (50 milliliters) heated 22 hours under refluxing. The mixture of cooling is distributed between ethyl acetate (300 milliliters) and 20%0.88 ammoniacal liquor (120 milliliters), then separates layers. Organic phase is through MgSO₄Drying and vapourisation under reduced pressure. Residue grinds to provide the white crystalline solid of title compound with the ethyl acetate of ether and minimum volume, 2.82 grams.

¹H NMR(400MHz，CDCl ₃)：δ2.38(s，3H)，7.19(d，2H)，7.55(m， 4H)，7.60(d，2H)；LCMS：m/z ES ⁺295[MH] ⁺。

Preparation 156:4-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl] benzoic acid

Potassium hydroxide (2.6 grams, 46.0 mM) solution in water (10 milliliters) adds in the solution of compound (2.7 grams, 9.2 mMs) in glycol dimethyl ether (40 milliliters) of preparation 155 and reaction heating 18 hours under refluxing. Adding ethanol (50 milliliters) and reaction heated under refluxing 72 hours in addition. The mixture of cooling is acidified to pH6 and under reduced pressure concentrated. Use carrene: methyl alcohol: 0.88 ammonia (84: 14: 2) extracted residues, then filtering suspension liquid, and vapourisation under reduced pressure filtrate. Product grinds with ether, filters with dry so that the white solid of title compound to be provided.

¹H NMR(400MHz，CD ₃OD)：δ2.38(s，3H)，7.19(m，4H)，7.58(d， 2H)，7.90(d，2H)；LCMS：m/z ES ^-312[M-H] ^-。

Preparation 157:4-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl] chlorobenzoyl chloride

With (3 milliliters of ethanedioly chlorides, 32 mMs) then with N, dinethylformamide (5) adds in the solution of acid (2 grams, 6.4 mMs) in carrene (200 milliliters) of preparation 156, and mixture at room temperature stirred 2 hours. Filtering mixt, vapourisation under reduced pressure filtrate reaches residue and carrene (3 * 200 milliliters) azeotropic so that the orange oil of title compound, 2.01 grams to be provided.

¹H NMR(400MHz，CDCl ₃)：δ2.78(s，3H)，7.58(d，2H)，7.63(d， 2H)，7.74(m，2H)，8.06(d，2H)。

Preparation 158:1-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl] piperidines-4-carboxylic acid

The ester of preparation 90 (4 grams, 10.4 mMs) and the solution of 4N NaOH (13 milliliters, 52 mMs) in two  alkane (20 milliliters) stirred 2 hours under room temperature. Mixture is distributed between water and the ethyl acetate and separates phase. Use 2N hcl acidifying water layer to pH 4, filter the gained sediment and with water washing. Solid grinds with ether, filters with dry so that the white solid of title compound to be provided in a vacuum.

¹H NMR(400MHz，CD ₃OD)：δ1.52-1.61(m，2H)，1.81(m，2H)， 2.21(s，3H)，2.40(m，1H)，2.81(m，2H)，3.21-3.36(m，2H)，7.47(d， 2H)，7.62(d，2H)。

Preparation 159:1-[4-(4-chlorphenyl)-5-(2H-1,2,3-triazole-2-ylmethyl)-4H-1,2,4-triazole-3-yl] piperidines-4-carboxylic acid

Title compound according to preparation 158 described similar steps, except in reaction, using 10 Equivalent Hydrogen sodium oxide molybdenas, obtain white solid from preparing 91 ester.

¹H NMR(400MHz，CD ₃OD)：δ1.48-1.60(m，2H)，1.81(m，2H)， 2.40(m，1H)，2.82(m，2H)，3.32(m，2H)，5.64(s，2H)，7.30(d，2H)， 7.50(d，2H)，7.58(s，2H)；LCMS：m/z APCl ⁺ 388[MH] ⁺。

Preparation 160:1-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl]-4-methyl piperidine-4-carboxylic acid

The ester of preparation 92 (1.45 grams, 4.0 mMs) and the mixture of 4N sodium hydroxide solution (5 milliliters, 20 mMs) in two  alkane (50 milliliters) stirred 16 hours under refluxing. Tlc analyzes demonstration and is left raw material, thus add additional hydrogen sodium oxide molybdena (4N, 5 milliliters, 20 mMs), and reaction was heated under backflow 18 hours in addition. The mixture of cooling is distributed between ethyl acetate and the water, and separates layers. Use 2N hcl acidifying water to extract to pH 3.5 and with ethyl acetate (2x). The organic extract that merges is through MgSO₄Drying and vapourisation under reduced pressure. Product grinds with ethyl acetate. Filter gained solid and dry to provide the white solid of title compound, 800 milligrams.

¹H NMR(400MHz，CD ₃OD)：δ1.18(s，3H)，1.38(m，2H)，1.99(m， 2H)，2.21(s，3H)，2.92(m，2H)，3.16(m，2H)，7.49(d，2H)，7.63(d， 2H)。LCMS：m/z APCl ⁺ 335[MH] ⁺。

Preparation 161:N-(4-chlorphenyl)-2-(2H-1,2,3-triazole-2-base acetyl group) hydrazine thioformamide

4-chlorphenyl isothiocyanates (8.58 grams, 50.6 mMs) at room temperature stirred 72 hours by suspension and the mixture of hydrazides (7.0 grams, 50.6 mMs) in ethanol (200 milliliters) that part is added to preparation 18. Filter the gained sediment, with ether washing and dry to provide the white solid of title compound, 14.5 grams.

¹H NMR(400MHz，CD ₃OD)：δ5.30(s，2H)，7.36(d，2H)，7.44(d， 2H)，7.78(s，2H)。

Preparation 162:4-(4-chlorphenyl)-5-(2H-1,2,3-triazole-2-ylmethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thioketones

The compound of preparation 161 (14.5 grams, 46.5 mMs) and the solution of 2M sodium hydroxide solution (232 milliliters, 465 mMs) in ethanol (36 milliliters) are in 80 ℃ of lower stirrings 18 hours. Use the mixture of concentrated hydrochloric acid acidifying cooling to pH 9, then it extracts with carrene (6 * 250 milliliters). The organic solution that vapourisation under reduced pressure merges is to provide the white solid of title compound, 7.5 grams.

¹H NMR(400MHz，CDCl ₃)：δ5.54(s，2H)，7.05(d，2H)，7.42(d， 2H)，7.58(s，2H)。

Preparation 163:2-{[4-(4-chlorphenyl)-5-(methyl mercapto)-4H-1,2,4-triazole-3-yl] methyl }-2H-1,2,3-triazole

Uncle-butanols potassium (2.9 gram, 25.6 mMs) adds in the solution of compound (7.5 grams, 25.6 mMs) in oxolane (250 milliliters) of preparation 162 and suspension at room temperature stirred 30 minutes. Add methyl tosylate (4.8 grams, 25.7 mMs) and mixture and heated 45 minutes under refluxing, then at room temperature heating is 2 hours in addition. Mixture is with carrene (1000 milliliters) dilution, and with saturated ammonium chloride solution (300 milliliters) and salt solution (300 milliliters) washing, then it pass through MgSO₄Drying and vapourisation under reduced pressure. By using carrene at silica gel: methyl alcohol (85: 15) as the column chromatography purification of crude material of eluant, eluent to provide title compound, 4.9 grams.

¹H NMR(400MHz，CDCl ₃)：δ2.70(s，3H)，5.64(s，2H)，7.02(d， 2H)，7.41(d，2H)，7.54(s，2H)。LCMS：m/z ES ⁺329[MNa] ⁺。

Preparation 164:2-{[4-(4-chlorphenyl)-5-(methyl sulphonyl)-4H-1,2,4-triazole-3-yl] methyl }-2H-1,2,3-triazole

Meta-chlorine benzylhydroperoxide (3.4 gram, 19.56 mMs) adds in the solution of compound (1.5 grams, 4.90 mMs) in carrene (60 milliliters) of preparation 163 and reaction was at room temperature stirred 18 hours. Mixture dilutes with carrene, then with saturated sodium bicarbonate solution (300 milliliters) and salt solution (200 milliliters) washing. Organic solution is through Na₂SO ₄Dry and under reduced pressure concentrated. Residual solid is washed with ethanol, and is then dry to provide the white solid of title compound, 1.40 grams in a vacuum.

¹H NMR(400MHz，CDCl ₃)：δ3.46(s，3H)，5.69(s，2H)，7.18(d， 2H)，7.41(d，2H)，7.57(s，2H)；LCMS：m/z ES ⁺361[MNa] ⁺。

Preparation 165:4-chloro-2-ethoxy nitrobenzene

Caustic alcohol (in ethanol 21%, 8.6 milliliter, 26 mMs) dropwise is added in the solution of 4-chloro-2-fluoronitrobenzene (3 grams, 17.1 mMs) in ethanol (20 milliliters), and in case adds and finish reaction and stir another hour. Under reduced pressure enriched mixture with ethyl acetate dilution residue, reaches solution with water (x2), then salt water washing. Solution is through MgSO₄Drying and vapourisation under reduced pressure are to provide the solid of title compound, 3.45 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.49(t，3H)，4.19(q，2H)，7.00(d， 1H)，7.05(s，1H)，7.81(d，11H)。

Preparation 166:4-chloro-2-ethoxy aniline

The nitro compound of preparation 165 (3.30 grams, 16.4 mM), iron powder (2.7 the gram, 49 mMs) and the mixture of calcium chloride (810 milligrams, 7.4 mMs) in water (5 milliliters) and ethanol (30 milliliters) in lower the heating 3.5 hours of refluxing. Filter the mixture of cooling through Celite , and concentrated filtrate under reduced pressure. Residue is distributed between water and the ethyl acetate, separates layers, and organic phase is further with the salt water washing. Solution is through MgSO₄Drying and vapourisation under reduced pressure. Crude product is by using pentane at silica gel: the column chromatography purifying of the gradient of ethyl acetate (100: 0 to 0: 100) is to provide the oil of title compound, 2.4 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.42(t，3H)，402(q，2H)，6.61(d， 1H)，6.76(m，2H)。

Preparation 167:1-(5-chloro-2-nitrobenzene methyl) pyrrolidines

Pyrrolidines (4 milliliters, 48.5 mMs) adds in the solution of 5-chloro-2-nitrobenzaldehyde (6 grams, 32.2 mMs) in carrene (150 milliliters) and solution at room temperature stirred 30 minutes. Then cooling solution in ice reaches by partly adding sodium triacetoxy borohydride (10.3 grams, 48.5 mMs). Finish in case add, reaction was at room temperature stirred 4 hours. Reaction is washed with sodium carbonate liquor, through MgSO₄Drying and vapourisation under reduced pressure. By using ethyl acetate at silica gel: the column chromatography purifying residual oil of pentane (86: 14) is to provide the faint yellow solid of title compound, 6.3 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.82(m，4H)，2.58(m，2H)，3.98(s， 2H)，7.37(d，1H)，7.80(s，1H)，7.87(d，1H)。LCMS：m/z APCl ⁺ 241[MH] ⁺。

Preparation 168:4-chloro-2-(pyrrolidin-1-yl methyl) aniline

The compound of preparation 167 (6.2 grams, 25.8 mMs) and raney (Raney^) hydrogenation 2 hours under 40psi and room temperature of the mixture of nickel (400 milligrams) in ethanol (200 milliliters). Mixture filters and vapourisation under reduced pressure filtrate through Arbocel . By using carrene at silica gel: methyl alcohol: the column chromatography purifying residue of the gradient of 0.88 ammonia (95: 5: 0.5 to 90: 10: 1) is to provide the solid of title compound, 3.95 grams.

¹H NMR(400MHz，CDCl ₃)：δ1.78(m，4H)，2.48(m，2H)，3.59(s， 2H)，4.65-4.90(br s，2H)，6.56(d，1H)，6.98(s，1H)，7.00(d，1H)。 LCMS：m/z APCl ⁺ 211[MH] ⁺。

Preparation 169:4-{[4-(4-chlorphenyl)-5-piperidin-4-yl-4H-1,2,4-triazole-3-yl] methyl } morpholine

Preparation 101 compound (8.6 grams, 18.6 mMs) in two  alkane (50 milliliters) and the solution of the 4M hydrochloric acid in two  alkane (30 milliliters) under room temperature, stirred 18 hours. Vapourisation under reduced pressure solution and residue are distributed between 2N sodium hydroxide solution and the ethyl acetate. Filter gained solid and dry to provide the white solid of title compound, 1.2 grams. Separate filtrate, with the dichloromethane extraction water layer, and the organic solution that merges is through MgSO₄Drying and vapourisation under reduced pressure are to provide additional product, 1.11 grams.

LCMS：m/z APCl ⁺362[MH] ⁺。

Preparation 170:4-{[2-(2H-1,2,3-triazole-2-base acetyl group) diazanyl] carbonyl } piperidines-1-carboxylic acid uncle-butyl ester

The suspension of hydrazides (18.5 grams, 130.8 mMs) in carrene (150 milliliters) of N-BOc-4-piperidine carboxylic acid (isonipecotic acid) (30.0 grams, 130.8 mMs) and preparation 18 is in N₂In ice bath, cool off down. Funnel adds 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (25.6 grams, 133.5 mMs) and funnel washs with extra carrene (10 milliliters) via adding. Gained solution is warmed to room temperature. In case react completely, add isopropyl alcohol (150 milliliters) and homogeneous solution and be concentrated in a vacuum about 165 milliliters, be heated to about 70 ℃, and make cool to room temperature and stirring. Filter in a vacuum the thick white slurries of gained, wash with 50 ℃ of lower dryings are to produce the white solids of title compound in a vacuum with isopropyl alcohol (15 milliliters and 30 milliliters), 25.3 restrain (55%). The lower liquid that concentrates inherent filtration of decompression is to low volume, and the gained syrup processed and stir intensely to produce thick slurries in two minutes with water (50 milliliters). After the granulating that spends the night, filter (filtering rapidly) slurries, with water (2 * 10 milliliters) debris and lower dry to produce additional product, 8.5 grams (18%) in 50 ℃ in a vacuum.

¹H NMR(CDCl ₃)：δ1.42(s，9H)，1.50-1.85(m，4H)，2.41(m，1H)， 2.73(t，2H)，4.12(d，2H)，5.21(s，2H)，7.70(s，2H)，9.15(d，1H)， 9.75(d，1H)。

Embodiment 1 to 162:

The embodiment 1 of synthetic following explanation to 162 as the storehouse. Use following solution:

Carboxylic acid, ZCO₂H is dissolved in the dimethylacetylamide (anhydrous) and adds 3.75% triethylamine, 0.2M concentration.

The amine solvent of preparation 2a adds 3.75% triethylamine, 0.2M concentration in DMA (anhydrous).

HBTU is dissolved among the DMA (anhydrous), 0.2M concentration.

(the gentle sonicated of N.B. in tepidarium (temperature＜40 ℃), is used for dissolved monomer, wherein if required).

Experimental procedure:

Reaction scale is (experimental detail of 20 micromole's reaction and display, therefore scale can regulate in this scope) between every hole 20 and 30 micromoles. Reaction is carried out in polypropylene 96 orifice plates.

A) amine aqueous solution (0.1 milliliter, 20 micromoles, 1 equivalent) adds in this hole

B) carboxylic acid solution (0.15 milliliter, 30 micromoles, 1.5 equivalents) adds in this hole

C) HBTU solution (0.15 milliliter, 30 micromoles, 1.5 equivalents) adds in each hole

D) polypropylene 96 orifice plates seal and are clipped between the pair of metal plate with PTFE and rubber packing.

E) plate in 60 ℃ of heating 6 hours, is then stayed cool overnight in the baking box in baking box.

F) when cooling, plate is not clamped and is placed among the Genevac with desolventizing.

G) this sample again-be dissolved in the DMSO/ water (9: 1) (500 microlitre), and remove by filter any particulate material.

H) carry out purifying by RP-HPLC.

The HPLC purification condition:

Post: Phenomenex Luna C18,10 microns, 150 * 10 millimeters id

Temperature: room temperature

Eluant, eluent A: 0.05% diethylamine in water

Eluant, eluent B: acetonitrile

Sample dissolution exists: 90% methyl-sulfoxide in the water.

Use has the sample Gilson LC pump initial conditions of the Gilson Autosampler loading of 550 microlitre volume injected:

Solvent

A％  80.0

B％  20.0

Flow velocity (ml/min) 8.000

Gilson LC pump gradient timetable:

Time	A％	B％	Flow velocity (ml/min)
				0.00   0.20   7.00   9.00   9.10   10.50	80.0   80.0   5.0   5.0   80.0   80.0	20.0   20.0   95.0   95.0   20.0   20.0	8.000   8.000   8.000   8.000   8.000   8.000

Gilson 119uv detector in the monitoring of 254 nanometers:

Collector is set in 225 nanometers

Doubling sensitivity 200

Peak sensitiveness 80

Peak width 0.3 minute.

HPLC analysis condition and mass spectrometry details:

Post: Phenomenex Luna C18,5 microns, 30 * 4.6 millimeters id.

Eluant, eluent A: 0.05% diethylamine in water

Eluant, eluent B: acetonitrile

Sample dissolution exists: 90% methyl-sulfoxide in the water

Use has the sample Waters 1525 binary LC pump initial conditions that the Gilson Quad Z of the volume injected of 5 microlitres loads:

Solvent

A％                        95.0

B％                        5.0

Flow velocity (ml/min) 2.5 (each passage)

Temperature (℃) room temperature

LC pump gradient timetable:

The gradient timetable comprises 4 records, and it is:

Time	A％	B％	Flow velocity
				0.00   3.00   3.50	95.0   5.0   95.0	5.0   95.0   5.0	2.500   2.500   2.500

Total run time 4.50 minutes

Detect:

Waters 2488 dual wavelength detectings

UV1 (nanometer) 225

UV2 (nanometer) 255

With

ELSD:PolymerLabs, temperature: 75 ℃, gas flow rate: 1.2 bar

Mass spectrograph:

Waters ZQ 20004 mode MUX,

ES+ taper voltage: 26v capillary: 3.85 kilovolts

ES-taper voltage :-30v capillary :-3.00 kilovolts

Desolventizing gas: 800 liter/mins of clocks

Come source temperature: 300 ℃.

Sweep limits 160-1000Da

Implement numbering	Z	The discovery value of the mass ion of product	The HPLC retention time (minute)
				1	2-methoxyl group-pyridin-3-yl	412.15	1.55
2	The 3-trifluoromethyl-phenyl	449.13	2
				3	2-methoxyl group-phenyl	411.15	1.35
4	2-methane sulfonyl-phenyl	459.12	1.6
				5	3-methane sulfonyl-phenyl	459.12	1.55
6	Phenyl	381.14	1.72
				7	3-methoxyl group-phenyl	411.15	1.67
8	4-fluoro-phenyl	399.13	1.74
				9	2-chloro-phenyl	415.1	1.8
10	4-chloro-phenyl	415.1	1.92
				11	4-methane sulfonyl-phenyl	459.12	1.49
12	2,4-, two chloro-phenyl	449.06	1.99
				13	3,4-, two chloro-phenyl	449.06	2.04
14	2,5-, two chloro-phenyl	449.06	1.99
				15	4-ethyoxyl-phenyl	425.17	1.77
16	4-methyl mercapto-phenyl	427.13	1.85
				17	4-chloro-2-methoxyl group-phenyl	445.11	1.89
18	2-ethyoxyl-phenyl	425.17	1.84
				19	Isoquinolyl-1	432.15	1.6
20	2,6-dimethyl-phenyl	409.17	1.82
				21	Quinoline-2-base	432.15	1.74
22	Quinolyl-4	432.15	1.6
				23	Quinoline-3-base	432.15	1.57
24	2-chloro-6-fluoro-phenyl	433.09	1.54
				25	2,3-, two chloro-phenyl	449.06	1.95

26	2,5-, two fluoro-phenyl	417.12	1.82
				27	2,5-dimethoxy-phenyl	441.16	1.55
28	2,3-, two fluoro-phenyl	417.12	1.8
				29	2,4-, two fluoro-phenyl	417.12	1.8
30	3,4-, two fluoro-phenyl	417.12	1.85
				31	4-isopropyl-phenyl	423.19	2
32	6-methyl-pyridin-3-yl	396.15	1.45
				33	4-fluoro-naphthalene-1-base	449.15	2
34	3,5-, two fluoro-phenyl	417.12	1.87
				35	3-amino-sulfonyl-4-chloro-phenyl	494.07	1.5
36	1H-benzimidazole-5-base	421.15	1.37
				37	2-chloro-4-fluoro-phenyl	433.09	1.85
38	4-trifluoromethoxy-phenyl	465.12	2.07
				39	1H-BTA-5-base	422.14	1.34
40	4-methoxy yl-quinoline-2-base	462.16	1.82
				41	2-fluoro-4-trifluoromethyl-phenyl	467.12	2.04
42	2,3,6-, three fluoro-phenyl	435.11	1.87
				43	2-methyl-pyridin-3-yl	396.15	1.32
44	2,4,5-, three fluoro-phenyl	435.11	1.85
				45	4-propyl group-phenyl	423.19	2.15
46	2-fluoro-3-trifluoromethyl-phenyl	467.12	1.92
				47	3-fluoro-2-methyl-phenyl	413.15	1.82
48	2,4-, two chloro-5-fluoro-phenyl	467.05	2.05
				49	3-fluoro-4-methoxyl group-phenyl	429.14	1.8
50	4-isopropoxy-phenyl	439.18	1.89
				51	4-propoxyl group-phenyl	439.18	2.02
52	3-chloro-4-fluoro-phenyl	433.09	1.95
				53	2,6-dimethoxy-pyridin-3-yl	442.16	1.7

54	2-fluoro-5-methyl-phenyl	413.15	1.85
				55	3-fluoro-5-trifluoromethyl-phenyl	467.12	2.09
56	4-difluoro-methoxy-phenyl	447.13	1.79
				57	Xenyl-2-base	457.17	2.02
58	4-amino-sulfonyl-phenyl	460.11	1.45
				59	3-chloro-phenyl	415.1	1.9
60	4-cyano group-phenyl	406.14	1.6
				61	2,3-dimethoxy-phenyl	441.16	1.68
62	2,6-dimethoxy-phenyl	441.16	1.68
				63	3,5-dimethoxy-phenyl	441.16	1.82
64	3-fluoro-4-methyl-phenyl	413.15	1.8
				65	3-fluoro-phenyl	399.13	1.75
66	3-methoxyl group-4-methyl-phenyl	425.17	1.9
				67	Naphthalene-1-base	431.16	1.95
68	Pyridin-3-yl	382.14	1.3
				69	Pyridine-2-base	382.14	1.42
70	6-methyl-pyridine-2-base	396.15	1.52
				71	Meta-tolyl	395.16	1.85
72	P-tolyl	395.16	1.74
				73	4-fluoro-3-methoxyl group-phenyl	429.14	1.79
74	3-chloro-4-methyl-phenyl	429.12	2
				75	5-chloro-2-methyl-phenyl	429.12	1.97
76	3-chloro-2,6-dimethoxy-phenyl	475.12	1.82
				77	3-chloro-2-fluoro-phenyl	433.09	1.89
78	2-phenoxy group-pyridin-3-yl	474.16	1.82
				79	2-trifluoromethoxy-phenyl	465.12	1.99
80	3-ethyoxyl-phenyl	425.17	1.79
				81	3-chloro-4-methoxy-phenyl	445.11	1.85

82	3,5-dimethoxy-4 '-methyl-phenyl	455.18	1.99
				83	4-chloro-3-methyl-phenyl	429.12	2.05
84	2-chloro-3,4-dimethoxy-phenyl	475.12	1.72
				85	3-cyclopentyloxy-4-methoxyl group-phenyl	495.21	2
86	4-methoxyl group-3-propoxyl group-phenyl	469.19	1.89
				87	3-isopropoxy-4-methoxyl group-phenyl	469.19	1.85
88	3-butoxy-4-methoxyl group-phenyl	483.21	1.95
				89	4-trifluoromethyl-pyridin-3-yl	450.12	1.65
90	6-(2,2,2-, three fluoro-ethyoxyls)-pyridin-3-yl	480.13	1.95
				91	2-(4-fluoro-phenoxy group)-pyridin-3-yl	492.15	1.9
92	2-chloro-3-trifluoromethyl-phenyl	483.09	1.97
				93	2-difluoro-methoxy-phenyl	447.13	1.82
94	3-difluoro-methoxy-phenyl	447.13	1.89
				95	6-trifluoromethyl-pyridin-3-yl	450.12	1.84
96	2-methyl-[1,8] naphthyridines-3-base	447.16	1.32
				97	2-methyl-[1,6] naphthyridines-3-base	447.16	1.42
98	2,3-dihydro-benzofuran-7-base	423.15	1.57
				99	2-chloro-3-methyl-phenyl	429.12	1.92
100	4-methoxyl group-3-methyl-phenyl	425.17	1.92
				101	2-ethyoxyl-pyridin-3-yl	426.16	1.6
102	2-ethyoxyl-naphthalene-1-base	475.18	2.02
				103	3-(dimethylamino) sulfonyl-phenyl	488.14	1.72
104	2-propoxyl group-pyridin-3-yl	440.18	1.84
				105	2-(4-chloro-phenoxy group)-pyridin-3-yl	508.12	1.93
106	2-methyl isophthalic acid H-benzimidazole-5-base	435.16	1.4
				107	6-hydroxyl-pyridine-2-base	398.13	1.32
108	2-(5-methyl-[1,2,4]  diazole-3-	464.15	1.45

	Base)-pyridin-4-yl
				109	4-(5-methyl-[1,2,4]  diazole-3-yl)-phenyl	463.16	1.67
110	4-(5-ethyl-[1,2,4]  diazole-3-yl)-phenyl	477.17	1.92
				111	3-(5-methyl-[1,2,4]  diazole-3-yl)-phenyl	463.16	1.68
112	3-(5-ethyl-[1,2,4]  diazole-3-yl)-phenyl	477.17	1.9
				113	2-hydroxyl-pyridin-4-yl	398.13	1.25
114	2-benzyl-phenyl	471.19	2.17
				115	3,5-, two chloro-phenyl	449.06	2
116	3-chloro-2-methyl-phenyl	429.12	1.93
				117	2,3-dihydro-benzofuran-5-base	423.15	1.74
118	2-(3-methyl-[1,2,4]  diazole-5-yl)-pyridin-4-yl	464.15	1.49
				119	3-hydroxy-2-methyl-phenyl	411.15	1.54
120	2-fluoro-5-trifluoromethyl-phenyl	467.12	2.02
				121	4-methoxyl group-2-methyl-phenyl	425.17	1.82
122	3-methoxyl group-2-methyl-phenyl	425.17	1.82
				123	2-hydroxy-5-methyl base-phenyl	411.15	1.68
124	3,5-, two chloro-4-hydroxyls-phenyl	465.06	1.57
				125	2-hydroxyl-3-isopropyl-phenyl	439.18	2.93
126	1H-indoles-6-base	420.15	1.75
				127	3-hydroxyl-phenyl	397.14	1.6
128	3-methoxyl group-naphthalene-2-base	461.17	1.9
				129	3-hydroxyl-4-methoxyl group-phenyl	427.15	1.54
130	4-chlorine-2-hydroxyl-phenyl	431.1	1.77

131	3,4-dimethoxy-2-methyl-phenyl	455.18	1.79
				132	6-(acetylamino)-pyridin-3-yl	439.16	1.35
133	2,6-dimethoxy-4 '-methyl-phenyl	455.18	1.8
				134	2-benzyloxy-phenyl	487.18	2.07
135	6-methoxy yl-quinoline-2-base	462.16	1.82
				136	Quinoxalin-6-yl	433.15	1.42
137	1,2-dimethyl-1H-benzimidazole-5-base	449.18	1.49
				138	1H-indoles-5-base	420.15	1.7
139	2-(3,5-dimethyl-1H-pyrazoles-4-yl)-5-methoxyl group-phenyl	505.2	1.6
				140	8-methyl-2-oxo-1,2-EEDQ-6-base	462.16	1.45
141	3-amino-sulfonyl-phenyl	460.11	1.5
				142	4-(3-methyl-6-oxo-3-piperidyl)-phenyl	492.21	1.54
143	2-(2-methoxyl group-ethyoxyl)-phenyl	455.18	1.62
				144	2-hydroxy-4-methyl-phenyl	411.15	1.68
145	3-chloro-4-hydroxyl-phenyl	431.1	1.64
				146	3-hydroxy-4-methyl-phenyl	411.15	1.75
147	3-methoxyl group-5-(methyl sulphonyl) amino-phenyl	504.14	1.57
				148	2-{[(2, the 2-dimethyl propyl) amino] carbonyl }-phenyl	494.22	1.85
149	5-acetyl group-2-ethoxy pyridine-3-base	468.17	1.7
				150	2-(2-methoxyl group-ethyoxyl)-pyridine-3-base	456.17	1.62
151	Isoquinolin-4-base	432.15	1.52

152	2-ethyoxyl-3-methoxyl group-phenyl	455.18	1.8
				153	4-[(1R)-1-(acetylamino) ethyl]-phenyl	466.19	1.47
154	4-pyrimidine-4-yl-phenyl	459.16	1.6
				155	3-methyl-2-propoxyl group-phenyl	453.2	2
156	4-ethyoxyl-pyridin-3-yl	426.16	1.5
				157	2-chloro-4-sulfonyloxy methyl amino-phenyl	508.09	1.64
158	2-ethyoxyl-5-methane sulfonyl-phenyl	503.14	1.68
				159	4-hydroxyl-2-(2,2,2-, three fluoro-ethyoxyls)-phenyl	495.13	1.65
160	4-hydroxyl-2-methoxyl group-phenyl	427.15	1.52
				161	4-cyano group-pyridine-2-base	407.13	1.55
162	2-pyridin-4-yl-3H-benzimidazole-5-base	498.17	1.5

Embodiment 163:(3-chloro-phenyl)-4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidin-1-yl }-ketone

Derive from (202 milligrams of preparation 10 compounds, 0.54 mM), (140 milligrams of 4-chloroanilines, 1.1 mM) and the mixture of trifluoroacetic acid (42 microlitres, 0.54 mM) in toluene (2 milliliters) under microwave 170 ℃ the heating 20 minutes. The mixture of cooling dilutes with ethyl acetate, with 1N sodium hydroxide solution and salt water washing, then passes through Na₂SO ₄Dry and under reduced pressure concentrated. By using carrene at silica gel: methyl alcohol: the column chromatography purified product of 0.88 ammonia (100: 0: 0 to 90: 10: 1) is to provide title compound, (234 milligrams).

¹H NMR(400MHz，CD ₃OD)：δ1.80-1.97(m，4H)，2.86(m，2H)， 3.08(m，1H)，3.70(m，1H)，4.58(m，1H)，5.72(s，2H)，7.26(m，2H)， 7.32(m，1H)，7.41-7.54(m，5H)，7.59(s，2H)。

LRMS：m/z(APCl) ⁺482[MH] ⁺。

Embodiment 164:(4-chloro-phenyl)-4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidin-1-yl }-ketone

4-chlorobenzoyl chloride (49 microlitres, 0.38 mM) add to (120 milligrams of compounds that derive from preparation 12a, 0.35 mM) and N-methylmorpholine (77 microlitres, 0.70 mM) in the mixture in carrene (2 milliliters), then mixture at room temperature stirred 2 hours. Reaction is diluted with carrene, with 1N sodium hydroxide solution washing and water washing liquor with carrene again-extract. The organic solution that vapourisation under reduced pressure merges is to produce oil. This oil is by using carrene at silica gel: methyl alcohol: the column chromatography purifying of 0.88 ammonia (90: 10: 1) is to provide the white solid of title compound, (160 milligrams).

¹H NMR(400MHz，DMSO-d ₆)：δ1.60-1.82(m，4H)，2.70-3.04(m， 3H)，3.54(m，1H)，4.33(m，1H)，5.66(s，2H)，7.34(d，2H)，7.39(d， 2H)，7.48(d，2H)，7.57(d，2H)，7.64(s，2H)；LRMS：m/z(APCl ⁺) 482[MH] ⁺。

Embodiment 165a:{4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]+piperidin-1-yl }-(3,5-, two fluoro-phenyl)-ketone

Title compound obtains 92% productive rate according to embodiment 164 described steps from compound and 2, the 4-difluoro benzoyl chloride that derives from preparation 12a.

¹H NMR(400MHz，CD ₃OD)：δ1.80-1.98(m，4H)，2.84(m，2H)， 3.09(m，1H)，3.65(m，1H)，4.58(m，1H)，5.72(s，2H)，7.05(m，3H)， 7.24(m，2H)，7.57(d，2H)，7.59(s，2H)；

LRMS：m/z(APCl ⁺)484[MH] ⁺。

Embodiment 165b:{4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidin-1-yl }-(3,5-, two fluoro-phenyl)-ketone

Triethylamine (3.2 milliliters, 23.0 mMs) adds in the slurries of two salt (4.89 grams, 7.12 mMs) in carrene (25 milliliters) that derive from preparation 12b, produces yellow solution. At the ice bath cooling solution, then add 3,5-difluoro benzoyl chloride (0.95 milliliter, 8.09 mMs). Then stirring reaction 30 minutes adds water (20 milliliters). After stirring in addition 20 minutes, separately phase, and organic phase is continuously with aqueous citric acid solution, water, sodium bicarbonate aqueous solution and the washing of half-saturated brine. Then through the transparent dichloromethane solution of dried over mgso and concentrated to produce white foam. Produce the white solid of title compound from the recrystallization of ethyl acetate, (2.69 gram), identical with the material of preparation as described in embodiment 165a.

Embodiment 166 to 167:

Suitable acid chloride (1.2 equivalent) adds to preparation 2 amine (1 equivalent) and N-methylmorpholine (1.5 equivalent) (5.5 milliliters mMs of carrene^-1) in the solution neutralization reaction at room temperature stirred 4 hours. Add three-(2-amino-ethyl) amine polystyrene (3.85 mMs/gram) and reaction and stir another hour. Add saturated ammonium chloride solution, then stirred the mixture 20 minutes and use the hydrophobic film separates layers. Organic phase is washed with saturated sodium bicarbonate solution, and separates layers and vapourisation under reduced pressure organic solution are to provide title compound.

The embodiment numbering	Z	Productive rate (%)	Data
				166	Neopentyl	39	1H NMR(400MHz，CDCl 3)：δ1.00(s，9H)，1.71(m，2H)，   1.82(m，1H)，1.98(m，1H)，2.20(s，2H)，2.24(s，3H)，   2.57(m，1H)，2.65(m，1H)，3.00(m，1H)，3.98(m，1H)，   4.57(m，1H)，7.20(d，2H)，7.57(d，2H).LCMS：m/z   APCl +375[MH] +
167	Cyclopropyl	39	1H NMR(400MHz，CDCl 3)：δ0.73(m，2H)，0.94(m，2H)，   1.70(m，3H)，1.88(m，1H)，2.02(m，1H)，2.22(s，3H)，   2.58-2.75(m，2H)，3.08(m，1H)，4.23(m，1H)，4.44(m，   1H)，7.20(d，2H)，7.58(d，2H).LCMS：m/z APCl +347   [MH] +

Embodiment 168 to 173:

Suitable amine; or amine salt; be selected from preparation 12a, 100,118,119,143 and 152 (1 equivalent), suitable acid chloride (W-PhCOCl) (1.2 to 1.4 equivalent) and N-ethyl diisopropylamine (4 equivalent) are (16 milliliters mMs of carrene^-1) in mixture under room temperature, stirred 2 hours. Then add three-(2-amino-ethyl) amine polystyrene and mixture and stir another hour. Then with 1N sodium hydroxide solution purging compound, with carrene (2x) extraction water solution and the concentrated organic solution that merges under reduced pressure. By using ethyl acetate at silica gel: methyl alcohol: 0.88 ammonia (90: 10: 1) is as the column chromatography purification of crude product of eluant, eluent, so that title compound to be provided.

The embodiment numbering	Data
		168	W＝3-F，4-CH 3；Y＝4-Cl；Y’＝2-Cl；X＝CH 3   1H NMR(400MHz，CDCl 3)：δ1.77-1.99(m，4H)，2.19(s，3H)，2.26(s，3H)，   2.59(m，1H)，2.84-3.02(m，2H)，3.83(m，1H)，4.55(m，1H)，7.02(m，2H)，   7.18-7.28(m，2H)，7.48(m，1H)，7.66(s，1H).LCMS：m/z APCl +447[MNa] +
169 A	W＝3-F，4-CH 3；Y＝4-Cl；Y′＝2-F；X＝CH 3   1H NMR(400MHz，CDCl 3)：δ1.75-2.00(m，4H)，2.24(m，6H)，2.63(m，1H)，   2.92(m，2H)，3.81(m，1H)，4.56(m，1H)，7.02(m，2H)，7.19(m，1H)，7.40(m，   3H).LCMS：m/z APCl +431[MH] +
		170	W＝3，5-di-Cl；Y＝4-Cl；Y’＝2-OCH 3；X＝CH 3   1H NMR(400MHz，CD 3OD)：δ1.70-2.00(m，4H)，2.17(s，3H)，2.72-2.92(m，   2H)，3.1(m，1H)，3.62(m，1H)，3.84(m，3H)，4.56(m，1H)，7.20(m，1H)，7.39   (m，4H)，7.58(s，1H).LCMS：m/z APCl +480[MH] +
171 A	W＝2-F，3-Cl；Y＝4-Cl；Y′＝H；X＝CH 2OCH 2CH 3；   1H NMR(400MHz，CDCl 3)：δ1.08(t，3H)，1.64-1.81(m，2H)，1.84-2.01(m，   2H)，2.79(m，1H)，2.85-3.17(m，2H)，3.41(q，2H)，3.62(m，1H)，4.41(s，2H)，   4.62(m，1H)，7.17(m，1H)，7.23(m，3H)，7.43(m，1H)，7.58(d，2H).LCMS：   m/z APCl +477[M] +
		172 A	W＝4-Cl；Y＝4-Cl；Y’＝H；X＝CH 2CF 3；   1H NMR(400MHz，CDCl 3)：δ1.81(m，2H)，1.98(m，2H)，2.70(m，1H)，2.80-   3.02(m，2H)，3.44(q，2H)，3.81(m，1H)，4.59(m，1H)，7.19(d，2H)，7.38(m，   4H)，7.60(d，2H).LCMS：m/z APCl +483[M] +
173 B	W＝2-OCF 3 Y=4-Cl; Y '=H; X=[1,2,3]-triazole-2-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.76(m，1H)，1.79-2.02(m，3H)，2.68(m，1H)，   2.82-3.02(m，2H)，3.58(m，1H)，4.59(m，1H)，5.62(s，2H)，6.99(m，2H)，   7.22-7.42(m，6H)，7.50(s，2H).LCMS：m/z APCl +532[MH] +

A=uses 4 equivalent triethylamines, and crude product is not processed with the amine that polymer is supported.

The N-ethyl diisopropylamine that B=uses 10 equivalent polymer to support replaces the N-ethyl diisopropylamine.

Embodiment 174 to 187:

Suitable acid chloride (W-PhCOCl) (1.0 to 1.5 equivalent) adds to suitable amine hydrochlorate, or amine, is selected from preparation 120 to 121,132,134 to 135,137,139 to 142,151,153 to 154 and 169 (1 equivalents) and triethylamine (1.2 to 5 equivalent) (10 to 25 milliliters mMs of carrene^-1) in solution in. Reaction was at room temperature stirred 18 hours. Mixture is then with the carrene dilution, and it is with saturated sodium carbonate solution, and then with the ammonium chloride solution washing, then it is under reduced pressure concentrated. By using carrene at silica gel: methyl alcohol (100: 0 to 90: 10) as the column chromatography purification of crude product of eluant, eluent so that title compound to be provided.

The embodiment numbering	Data
		174 A	W＝3-Cl；Y＝4-Cl；Y’＝2-CH 3；X＝CH 3   1H NMR(400MHz，CDCl 3)：δ1.65-2.02(m，7H)，2.18(s，3H)，2.55(m，1H)，   2.78-3.01(m，2H)，3.79(m，1H)，4.58(m，1H)，7.03(m，1H)，7.20-7.39(m，   5H)，7.41(s，1H).LCMS：m/z APCl +451[MNa] +
175 B	W＝3，5-di-Cl；Y＝4-Cl；Y’＝H；X＝CH 2OCH 3   1H NMR(400MHz，CD 3OD)：δ1.81-1.98(m，4H)，2.86(m，2H)，3.12(m，   1H)，3.20(s，3H)，3.64(m，1H)，4.38(s，2H)，4.58(m，1H)，7.40(s，2H)，   7.46(d，2H)，7.58(s，1H)，7.62(d，2H).LCMS：m/z APCl +479，481[MH] +
		176 A	W＝4-Cl；Y＝4-Cl；Y’＝H；X＝CH 2OCF 3   1H NMR(400MHz，CDCl 3)：δ1.81(m，2H)，1.98(m，2H)，2.78(m，1H)，   2.96(m，2H)，3.75-3.90(m，1H)，4.40-4.60(m，1H)，4.97(s，2H)，7.21(m，   2H)，7.37(m，4H)，7.59(d，2H).LCMS：m/z APCl +499[M] +
177 B	W＝3，5-di-F；Y＝4-Cl；Y′＝H；X＝CH 2OCH 2CF 3   1H NMR(400MHz，CDCl 3)：δ1.80-2.02(m，4H)，2.79(m，1H)，2.83-3.05   (m，2H)，3.80(m，3H)，4.58(m，3H)，6.85(m，3H)，7.22(d，2H)，7.57(d，   2H).LCMS：m/z APCl +515[MH] +

178	W=3-Cl; Y=4-Cl; Y '=H; X=(2-oxo-pyrrolidine-1-yl) methyl;1H NMR(400MHz，CDCl 3)：δ1.78-2.00(m，6H)，2.22(t，2H)，2.75(m，1H)，   2.97(m，2H)，3.48(t，2H)，3.80(m，1H)，4.42(s，2H)，4.58(m，1H)，7.00   (d，2H)，7.23(d，1H)，7.38(m，3H)，7.58(d，2H).LCMS：m/z APCl +499，   501[MH] +
		179 A	W=3,5-di-Cl; Y=4-Cl; Y '=H; X=morpholine-4-ylmethyl;1H NMR(400MHz，CDCl 3)：δ1.78-2.02(m，4H)，2.40(m，4H)，2.78(m，   1H)，2.78-3.04(m，2H)，3.41(s，2H)，3.58(m，4H)，3.78(m，1H)，4.58(m，   1H)，7.23(m，5H)，7.56(d，2H).LCMS：m/z APCl +534[M] +
180	W=3-F; Y=4-Cl; Y '=H; X=1H-tetrazolium-1-ylmethyl;1H NMR(400MHz，CDCl 3)：δ1.60-1.83(m，4H)，2.60-2.78(m，2H)，3.00   (m，1H)，3.90(m，1H)，4.50(m，1H)，5.58(s，2H)，6.98(m，2H)，7.50(m，   2H)，7.29(m，1H)，7.60(d，2H)，8.79(s，1H).LCMS：m/z ES +481，483   [MH] +
		181	W=3-Cl; Y=4-Cl; Y '=H; X=2-methyl-imidazo-3-yl methyl;1H NMR(400MHz，CDCl 3)：δ1.77-1.83(m，2H)，1.89-2.00(m，2H)，2.14(s，   3H)，2.64(m，2H)，2。94(m，1H)，3.82(m，1H)，4.58(m，1H)，5.08(s，2H)，   6.60(s，1H)，6.96(m，3H)，7.24(m，1H)，7.32-7.40(m，3H)，7.58(d，2H).   LCMS：m/z APCl +495，497[MH] +
182	W=3-Cl; Y=4-Cl; Y '=H; X=3-methyl-[1,2,4] oxadiazole-5-ylmethyls1H NMR(400MHz，CDCl 3)：δ1.80(m，2H)，1.98(m，2H)，2.30(s，3H)，2.76   (m，1H)，2.95(m，2H)，3.80(m，1H)，4.22(s，2H)，4.58(m，1H)，7.19(d，   2H)，7.24(d，1H)，7.37(m，3H)，7.52(d，2H).LCMS：m/z APCl +497，499   [MH] +
		183	W=3,5-di-F; Y=4-Cl; Y '=H; X=[1,2,4]-triazole-1-methyl1H NMR(400MHz，CDCl 3)：δ1.82(m，2H)，2.00(m，2H)，2.75(m，1H)，   2.80-3.08(m，2H)，3.80(m，1H)，4.58(m，1H)，5.40(s，2H)，6.89(m，3H)，   7.15(m，2H)，7.58(d，2H)，7.82(s，1H)，8.04(s，1H).LCMS：m/zAPCl +   484，486[MH] +
184 B	W=2-F, 3-Cl; Y=4-Cl; Y '=H; X=pyrimidine-2-yloxy methyl1H NMR(400MHz，CDCl 3)：δ1.75(m，2H)，1.97(m，2H)，2.81(m，1H)，   2.88-3.15(m，2H)，3.62(m，1H)，4.62(m，1H)，5.43(s，2H)，6.98(m，1H)，   7.16(m，1H)，7.25(m，1H)，7.36(d，2H)，7.44(m，3H)，8.44(d，2H).   LCMS：m/z APCl +527[M] +

185	W=2-F, 3-Cl; Y=4-Cl; Y '=H; X=2-pyridine-2-base-ethyl1H NMR(400MHz，CDCl 3)：δ1.58-1.98(m，4H)，2.75(m，1H)，2.90-3.00   (m，2H)，3.04-3.18(m，2H)，3.42(m，2H)，3.61(m，1H)，4.60(m，1H)，7.10-   7.27(m，6H)，7.42(m，1H)，7.56(d，2H)，7.82(m，1H)，8.48(s，1H).   LCMS：m/z APCl +524[MH] +
		186	W=3-Cl; Y=4-Cl; Y '=H; X=2-morpholine-4-base ethyl;1H NMR(400MHz，CDCl 3)：δ1.80(m，2H)，1.97(m，2H)，2.40(m，4H)，   2.64-3.02(m，7H)，3.59-3.90(m，5H)，4.58(m，1H)，7.19(d，2H)，7.24(m，   2H)，7.36(m，2H)，7.58(d，2H).LCMS：m/z APCl +514[M] +
187	W=5-Cl, 2-F; Y=4-Cl; Y '=H; X=2-(3,5-dimethyl ,-isoxazole-4-bases)-ethyl;1H NMR(400MHz，CDCl 3)：δ1.75-1.98(m，7H)，2.04(s，3H)，2.63-2.80(m，   5H)，2.86-3.08(m，2H)，3.62(m，1H)，4.59(m，1H)，6.75(m，2H)，7.01(m，   1H)，7.37(m，2H)，7.57(d，2H).LCMS：m/z APCl +542，544[MH] +

A=uses ethyl acetate: methyl alcohol: 0.88 ammonia is as the post eluant, eluent.

B=uses 2 equivalent N-methylmorpholines to replace triethylamine.

C=uses 3 equivalent N-methylmorpholines to replace triethylamine.

Embodiment 188:4-[4-(4-chlorphenyl)-5-(1H-imidazoles-1-ylmethyl)-4H-1,2,4-triazole-3-yl]-1-(3,3-dimethyl butyrate acyl group) piperidines

Title compound obtains from preparing 138 compound and isoveryl chloride according to embodiment 174 to 187 described steps.

¹H NMR(400MHz，CDCl ₃)：δ1.01(s，9H)，1.70-1.85(m，2H)， 1.98(m，3H)，2.22(m，2H)，2.55-2.66(m，2H)，3.00(m，1H)，4.00(m， 1H)，4.59(m，1H)，5.18(s，2H)，6.60(s，1H)，6.90(m，2H)，7.00(s， 1H)，7.52(m，2H)；LCMS：m/z APCl ⁺ 441[MH] ⁺。

Embodiment 189 to 198:

Suitable acid chloride, ZCOCl, (1.0 equivalent) add to and are selected from preparation 122 to 131 suitable amine (1 equivalent) and triethylamine (1.1 equivalent) (4 milliliters mMs of carrene^-1) in solution in. Reaction was at room temperature stirred 1 hour. Then it with the water dilution, stirred 5 minutes, then filters through the cartridge case that is separated. Under reduced pressure concentrated organic solution reaches by using ethyl acetate at silica gel: carrene: methyl alcohol (100: 0: 0 to 0: 95: 5) is as the column chromatography purification of crude product of eluant, eluent. This product and ether azeotropic spume with the white that title compound is provided.

The embodiment numbering	Data
		189	Z=3-chloro-2-fluorophenyl; Y=H; Y '=H;1H NMR(400MHz，CDCl 3)：δ1.68-2.07(m，4H)，2.75(m，1H)，2.92(m，   1H)，3.01(m，1H)，3.61(m，1H)，4.60(m，1H)，5.64(s，2H)，7.06(d，2H)，   7.13(t，1H)，7.38-7.57(m，7H).LCMS：m/z ES +488[MNa] +
190	Z=3-chlorphenyl Y=4-OCH3；Y’＝H；   1H NMR(400MHz，CDCl 3)：δ1.75-2.20(m，4H)，2.79(m，1H)，2.93(m，   2H)，3.80(m，1H)，3.84(s，3H)，4.56(m，1H)，5.66(s，2H)，6.94(m，2H)，   7.01(m，2H)，7.26(m，1H)，7.28-7.40(m，3H)，7.51(s，2H).LCMS：m/z   ES +500[MNa] +
		191	Z=3-chloro-2-fluorophenyl; Y=4-F; Y '=H;1H NMR(400MHz，CDCl 3)：δ1.72-2.07(m，4H)，2.77(m，1H)，2.90(m，   1H)，3.02(m，1H)，3.62(m，1H)，4.61(m，1H)，5.64(s，2H)，7.05-7.19(m，   6H)，7.41(t，1H)，7.49(s，2H).LCMS：m/z ES +503[MNa] +
192	Z=3-chloro-2-fluorophenyl; Y=4-Br; Y '=H;1H NM R(400MHz，CDCl 3)：δ1.71-2.06(m，4H)，2.72(m，1H)，2.94(m，   1H)，3.05(m，1H)，3.63(m，1H)，4.62(m，1H)，5.65(s，2H)，6.95(d，2H)，   7.14(t，1H)，7.27(m，1H)，7.43(t，1H)，7.49(s，2H)，7.60(d，2H).LCMS：   m/z ES +546[MH] +

193	Z=3-chloro-2-fluoro-phenyl; Y=4-CF3；Y’＝H；   1H NMR(400MHz，CDCl 3)：δ1.75-2.15(m，4H)，2.76-2.94(m，2H)，3.05   (m，1H)，3.62(m，1H)，4.67(m，1H)，5.76(s，2H)，7.14(dd，1H)，7.20-7.30   (m，2H)，7.36-7.50(m，4H)，7.75(d，2H).LCMS：m/z ES +556[MNa] +
		194	The Z=3-chlorphenyl; Y=4-CH3；Y’＝H；   1H NMR(400MHz，CDCl 3)：δ1.88(m，2H)，2.06(m，2H)，2.42(s，3H)，   2.79-3.00(m，3H)，3.80(m，1H)，4.59(m，1H)，5.70(s，2H)，7.07(d，2H)，   7.23-7.40(m，6H)，7.53(s，2H).LCMS：m/z ES +484[MNa] +
195	Z=3-chloro-2-fluoro-phenyl; Y=4-CN; Y '=H;1H NMR(400MHz，CDCl 3)：δ1.67-2.00(m，4H)，2.67(m，1H)，2.80-3.08   (m，2H)，3.60(m，1H)，4.58(m，1H)，5.64(s，2H)，7.11(t，1H)，7.16-7.25   (m，3H)，7.41(t，1H)，7.46(s，2H)，7.75(d，2H).LCMS：m/z ES +513   [MNa] +
		196	Z=3-chloro-2-fluoro-phenyl; Y=4-Cl; Y '=2-CH3；   1H NMR(400MHz，CDCl 3)：δ1.68-1.98(m，6H)，2.07(m，1H)，2.60(m，   1H)，1.80-3.13(m，2H)，3.60(d，1H)，4.60(d，1H)，5.55(d，1H)，5.67(d，   1H)，6.86-7.50(m，8H).LCMS：m/z ES +536[MNa] +
197	The Z=3-chlorphenyl; Y=4-Cl; Y '=3-F;1H NMR(400MHz，CDCl 3)：δ1.84(m，2H)，2.00(m，2H)，2.72(m，1H)，   2.94(m，2H)，3.83(m，1H)，4.55(m，1H)，5.67(s，2H)，6.90(d，2H)，7.26-   7.41(m，4H)，7.50-7.56(m，3H).LCMS：m/z ES +500[MH] +
		198	Z=3-chloro-2-fluoro-phenyl; Y=4-Cl; Y '=3-Cl;1H NMR(400MHz，CDCl 3)：δ1.80(m，1H)，1.86-2.05(m，3H)，2.74(m，   1H)，2.92(m，1H)，3.04(m，1H)，3.61(m，1H)，4.61(m，1H)，5.70(s，2H)，   7.05-7.16(m，3H)，7.27(br s，1H)，7.40(t，1H)，7.50(s，2H)，7.55(d，1H)   LCMS：m/z ES +534[MNa] +

Embodiment 199 to 201:

Suitable acid, ZCO₂H (1.2 equivalent), I-hydroxybenzotriazole hydrate (1.2 equivalent), triethylamine (2 to 4 equivalent) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (1.2 equivalent) and be selected from preparation 2 and 143 suitable amine, or amine hydrochlorate (1 equivalent) is (26 milliliters mMs of carrene^-1) in mixture under room temperature, stirred 24 hours. Then with 2N sodium hydroxide solution washing reaction and vapourisation under reduced pressure organic solution. By using ethyl acetate at silica gel: methyl alcohol: the column chromatography purification of crude product of the gradient of 0.88 ammonia (100: 0: 0 to 95: 5: 0.5) is to provide title compound.

The embodiment numbering	Data
		199	Z=cyclopropyl methyl; X=CH2OCH 2CH 3   1H NMR(400MHz，CDCl 3)：δ0.18(m，2H)，0.58(m，2H)，1.06(t，3H)，   1.70-1.90(m，3H)，2.00(m，2H)，2.22(m，2H)，2.59-2.77(m，2H)，3.02   (m，1H)，3.40(q，2H)，3.92(m，1H)，4.40(s，2H)，4.55(m，1H)，7.22(d，   2H)，7.54(d，2H).LCMS：m/z APCl +403[MH] +
200 A	Z=5-5-flumethiazine-2-base; X=CH2OCH 2CH 3   1H NMR(400MHz，CDCl 3)：δ1.08(t，3H)，1.79-2.04(m，4H)，2.60(m，   1H)，2.95-3.17(m，2H)，3.20(q，2H)，3.78(m，1H)，4.41(s，2H)，4.59   (m，1H)，7.22(d，2H)，7.57(d，2H)，7.77(d，1H)，7.95(d，1H)，8.55(s，   1H).LCMS：m/z APCl +494[MH] +
		201 B	Z=1H-indazole-3-base; Y=4-Cl; Y '=H; X=CH3   1H NMR(400MHz，CDCl 3)：δ1.65-1.88(m，4H)，2.15(s，3H)，2.80-2.97   (m，2H)，3.08(m，1H)，4.42-4.62(m，2H)，7.20(dd，1H)，7.40(dd，1H)，   7.57(m，3H)，7.65(d，2H)，7.90(d，1H)，13.42(s，1H).LCMS：m/z   APCl +421[MH] +

A=use 5-(trifluoromethyl)-2-Pyridinecarboxylic Acid and it can be such as J.Org.Chem. (Europe) 2003; (8); Prepare described in the 1559-1568.

B=reaction is carried out in the presence of not at I-hydroxybenzotriazole hydrate and triethylamine.

Embodiment 202 to 204:

Suitable acid, ZCO₂H, (1.5 equivalent), O-BTA-1-base-N, N, N ', N '-tetramethylurea cation hexafluorophosphate (2 equivalent), N-methylmorpholine (5 equivalent) and be selected from preparation 2 and 133 suitable amine hydrochlorate (1 equivalent) (8 milliliters mMs of carrene^-1) in solution under room temperature, stirred 24 hours. Then with sodium hydroxide solution washing reaction and vapourisation under reduced pressure organic solution. By using carrene at silica gel: methyl alcohol: the column chromatography purification of crude product of the gradient of 0.88 ammonia (100: 0: 0 to 90: 10: 1) is to provide title compound.

The embodiment numbering	Data
		202	Z=4-chloro-3-fluorophenyl; X=CH3；   1H NMR(400MHz，CD 3OD)：δ1.79-1.99(m，4H)，2.23(s，3H)，2.85(m，   2H)，3.11(m，1H)，3.70(m，1H)，4.58(m，1H)，7.22(d，1H)，7.37(d，   1H)，7.45(d，2H)，7.58(m，1H)，7.64(d，2H).LCMS：m/z APCl +433   [M] +
203	Z=2,3,4-trifluorophenyl; X=CH3；   1H NMR(400MHz，CD 3OD)：δ1.82(m，3H)，1.98(m，1H)，2.22(s，3H)，   2.89(m，2H)，3.15(m，1H)，3.60(m，1H)，4.60(m，1H)，7.12(m，2H)，   7.44(m，2H)，7.66(m，2H).LCMS：m/z APCl +435[M] +
		204	Z=1H-indazole-3-base; X=3-methyl-isoxazole-5-base methyl;1H NMR(400MHz，CDCl 3)：δ.1.80-2.15(m，5H)，2.18(s，3H)，2.75(m，   1H)，2.80-2.92(m，2H)，3.17(m，1H)，4.04(s，2H)，4.62-4.81(m，2H)，   4.86(s，1H)，7.15(m，3H)，7.30(dd，1H)，7.50(m，3H)，8.00(d，1H)，   11.90(br s，1H).LCMS：m/z ES +500，502[M] +

Embodiment 205 to 207:

Suitable acid, ZCO₂H, (1.2 equivalent), O-BTA-1-base-N, N, N ', N '-tetramethylurea cation hexafluorophosphate (1.2 equivalent), N-methylmorpholine (1.4 equivalent) and be selected from preparation 2 and 136 suitable amine (1 equivalent) (7 to 10 milliliters mMs of carrene^-1) in solution under room temperature, stirred 24 hours. Then reaction is distributed between sodium hydroxide solution and the carrene, and separates layers. With ammonium chloride solution washing organic solution, through MgSO₄Drying is its vapourisation under reduced pressure then. By using carrene at silica gel: methyl alcohol: the column chromatography purification of crude product of the gradient of 0.88 ammonia (100: 0: 0 to 90: 10: 1) is to provide title compound.

The embodiment numbering	Data
		205 A	Z=3-difluoromethyl-phenyl; X=[1,2,3]-triazole-2-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.78-2.02(m，4H)，2.70(m，1H)，2.95(m，   2H)，3.80(m，1H)，4.58(m，1H)，5.63(s，2H)，6.50-6.80(t，1H)，7.01(d，   2H)，7.42-7.58(m，8H).LCMS：m/z APCl +498，500[MH] +
206 B，C	Z=4-difluoromethyl-phenyl; X=[1,2,3]-triazole-2-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.78(m，2H)，1.97(m，2H)，2.66(m，1H)，   2.90(m，2H)，3.78(m，1H)，4.58(m，1H)，5.61(s，2H)，6.46-6.78(t，1H)，   6.98(d，2H)，7.22(s，2H)，7.39-7.57(m，8H).LCMS：m/z APCl +498，500   [MH] +
		207	Z=1H-indazole-3-base; X=2-piperidin-1-yl-ethyl;1H NMR(400MHz，CDCl 3)：δ1.38(m，2H)，1.50(m，4H)，1.74-2.18(m，   4H)，2.30(m，4H)，2.72(m，6H)，2.88(m，1H)，3.19(m，1H)，4.61-4.88   (m，2H)，7.18(m，3H)，7.30(m，1H)，7.54(m，3H)，8.02(d，1H).LCMS：   m/z-APCl +518[M] +

A=uses 3-difluoromethyl benzoic acid. It can be according to Tetrahedron 31; 1977; The 391-410 preparation.

B=uses 4-difluoromethyl benzoic acid. It can be according to Tetrahedron 31; 1977; The 391-410 preparation.

C=is from isopropyl alcohol crystallized product extraly, and uses the N-methylmorpholine of 2.8 equivalents.

Embodiment 208 to 210:

Be selected from preparation 66 and 67 suitable  diazole (1 equivalent), derive from the suitable aniline of preparation 166 and 168 or commodity 4-chloro-2-(trifluoromethoxy) aniline (1.5 to 2.0 equivalent) and trifluoroacetic acid (0.5 to 1.0 equivalent) (2.5 to 9.5 milliliters mMs of toluene^-1) in mixture in 110 ℃ the heating 18 hours. The mixture of cooling is distributed between carrene and the sodium carbonate liquor, and separates layers then. Organic phase is through MgSO₄Drying and vapourisation under reduced pressure. By using carrene at silica gel: methyl alcohol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) as the column chromatography purification of crude product of eluant, eluent so that title compound to be provided.

The embodiment numbering	Data
		208	The Z=3-chlorphenyl; Y=4-Cl; Y '=2-OCH2CH 3；X＝H；   1H NMR(400MHz，CD 3OD)：δ1.23(t，3H)，1.78-1.98(m，4H)，2.92(m，   2H)，3.16(m，1H)，3.70(m，1H)，4.14(q，2H)，4.58(m，1H)，7.18(d，1H)，   7.34(m，2H)，7.42(m，3H)，8.43(s，1H).LCMS：m/z APCl +445[M] +
209	Z=3-chlorphenyl; Y=4-Cl; Y '=2-OCF3；X＝H；   1H NMR(400MHz，CD 3OD)：δ1.80-1.98(m，4H)，2.84-2.99(m，2H)，   3.10-3.20(m，1H)，3.72(m，1H)，4.60(m，1H)，7.37(d，1H)，7.44(m，   3H)，7.70(m，2H)，7.78(s，1H)，8.62(s，1H).LCMS：m/z APCl +485[M] +
		210	The Z=4-chlorphenyl; Y=4-Cl; Y '=2-pyrrolidin-1-yl methyl; X=CH3；   1H NMR(400MHz，CDCl 3)：δ1.64-1.84(m，7H)，2.18(s，3H)，2.37(m，   4H)，2.58(m，1H)，2.78-2.99(m，2H)，3.16-3.20(m，2H)，3.64-3.95(m，   1H)，4.45-4.70(m，1H)，7.09(m，1H)，7.30-7.44(m，5H)，7.62(s，1H).   LCMS：m/z APCl +498[M] +

Embodiment 211 to 216:

Be selected from suitable  diazole (1 equivalent), aniline (1.5 to 2.0 equivalent) and the trifluoroacetic acid (0.5 to 1.0 equivalent) of preparation 66 to 69,71 and 75 (1.0 to 2.5 milliliters mMs of toluene^-1) in mixture under microwave in 170 to 185 ℃ the heating 20 minutes. By using carrene at the silica gel cartridge case: methyl alcohol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) as the column chromatography purification of crude solution of eluant, eluent so that title compound to be provided.

The embodiment numbering	Data
		211	The Z=3-chlorphenyl; Y=4-Cl; Y '=2-OCH2CF 3；X＝H；   1H NMR(400MHz，CDCl 3)：δ1.78-2.02(m，4H)，2.80(m，1H)，2.95-3.06   (m，2H)，3.81(m，1H)，4.40(q，2H)，4.58(m，1H)，7.17(s，1H)，7.25(m，   3H)，7.38(m，3H)，8.18(s，1H).LCMS：m/z APCl +499[M] +
212 A	The Z=4-chlorphenyl; Y=4-Cl; Y '=H; X=CF3；   1H NMR(400MHz，CDCl 3)：δ1.82(m，2H)，2.00(m，2H)，2.76(m，1H)，   2.83-3.02(m，2H)，3.83(m，1H)，4.60(m，1H)，7.22(d，2H)，7.37(d，2H)，   7.40(d，2H)，7.60(d，2H).LCMS：m/z APCl +469[M] +
		213	The Z=3-chlorphenyl; Y=4-Cl; Y '=H; X=CH2OCH 2CH 3；   1H NMR(400MHz，CDCl 3)：δ1.08(t，3H)，1.78-1.90(m，2H)，1.92-2.02   (m，2H)，2.78(m，1H)，2.80-3.02(m，2H)，3.41(q，2H)，3.80(m，1H)，   4.41(s，2H)，4.60(m，1H)，7.24(m，3H)，7.36(m，2H)，7.57(d，2H).   LCMS：m/z APCl +459[M] +
214	The Z=4-chlorphenyl; Y=4-CH3；Y′＝2-CH 3；X＝CH 3；   1H NMR(400MHz，CDCl 3)：δ1.68-2.00(m，7H)，2.14(s，3H)，2.40(s，   3H)，2.58(m，1H)，2.78-2.98(m，2H)，3.78(m，1H)，4.54(m，1H)，6.97   (m，1H)，7.15(m，1H)，7.20(s，1H)，7.30(d，2H)，7.36(d，2H).LCMS：   m/z APCl +409[MH] +
		215	The Z=4-chlorphenyl; Y=4-Cl; Y '=2-CH3；X＝CH 2CH 3；   1H NMR(400MHz，CDCl 3)：δ1.20(t，3H)，1.68-2.02(m，6H)，2.14(m，   1H)，2.38-2.58(m，3H)，2.79-2.98(m，2H)，3.80(m，1H)，4.58(m，1H)，   7.04(m，1H)，7.26-7.39(m，5H)，7.41(s，1H).LCMS：m/z ES +443，446   [MH] +
216	The Z=3-chlorphenyl; Y=4-Cl; Y '=H; X=pyrazol-1-yl methyl;1H NMR(400MHz，CD 3OD)：δ1.80-1.97(m，4H)，2.82(m，2H)，3.06(m，   1H)，3.69(m，1H)，4.58(m，1H)，5.41(s，2H)，6.18(s，1H)，7.20(m，2H)，   7.30(m，2H)，7.38-7.57(m，5H).LCMS：m/z APCl +481[M] +

The A=crude product mixture is distributed between ethyl acetate and the 2N hydrochloric acid, then with saturated sodium bicarbonate solution washing organic solution and vapourisation under reduced pressure.

Embodiment 217 to 222:

Be selected from preparation 158 and 159 suitable acid (1 equivalent), I-hydroxybenzotriazole hydrate (1.5 equivalent), triethylamine (4 equivalent) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (1.5 equivalent) (3.5 milliliters mMs of carrene^-1) solution add to suitable amine (HNR⁴R ⁵) (1.5 equivalent) (2.5 milliliters mMs of carrene^-1) in neutralize at room temperature stirring reaction 24 hours of solution. Then with ammonium chloride solution washing reaction and vapourisation under reduced pressure organic solution. By using carrene at silica gel: methyl alcohol: the column chromatography purification of crude product of the gradient of 0.88 ammonia (100: 0: 0 to 95: 5: 0.5) is to provide title compound.

The embodiment numbering	Data
		217 A	R 4＝H；R 5=dicyclo [1.1.1] penta-1-base; X=CH3；   1H NMR(400MHz，CDCl 3)：δ1.58-1.78(m，4H)，1.86(m，3H)，2.02(m，5H)，   2.22(s，3H)，2.79(m，2H)，3.32(m，2H)，5.90(s，1H)，7.24(d，2H)，7.54(d，   2H).LCMS：m/z APCl +386[MH] +
218	R 4＝H；R 5=t-butyl; X=[1,2,3]-triazole-2-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.29(s，9H)，1.55-1.74(m，4H)，1.99-2.09(m，   1H)，2.80(m，2H)，3.38(m，2H)，5.23(m，1H)，5.59(s，2H)，7.10(d，2H)，   7.40(d，2H)，7.52(s，2H).LCMS：m/z APCl +443[MH] +
		219	NR 4R 5=azetidine-1-base; X=[1,2,3]-triazole-2-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.56-1.68(m，4H)，2.18-2.30(m，3H)，2.80(m，   2H)，3.37(m，2H)，3.98(t，2H)，4.16(t，2H)，5.59(s，2H)，7.10(d，2H)，7.40   (d，2H)，7.55(s，2H).LCMS：m/z ES +427[MH] +
220	NR 4R 5=pyrrolidin-1-yl; X=[1,2,3]-triazole-2-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.59-1.76(m，4H)，1.82(m，2H)，1.95(m，2H)，   2.41(m，1H)，2.82(m，2H)，3.36-3.46(m，6H)，5.59(s，2H)，7.15(d，2H)，   7.40(d，2H)，7.55(s，2H).LCMS：m/z ES +441[MH] +

221	NR 4R 5=morpholine-4-base; X=[1,2,3]-triazole-2-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.58-1.78(m，4H)，2.56(m，1H)，2.82(m，2H)，   3.38(m，2H)，3.44(m，2H)，3.60(m，2H)，3.62(m，4H)，5.60(s，2H)，7.12(d，   2H)，7.40(d，2H)，7.52(s，2H).LCMS：m/z ES +457[MH] +
		222	R 4＝H；R 5=2-phenylethyl; X=[1,2,3]-triazole-2-ylmethyl1H NMR(400MHz，CDCl 3)：δ1.52-1.68(m，4H)，2.04(m，1H)，2.79(m，4H)，   3.36(m，2H)，3.47(m，2H)，5.40(m-1H)，5.59(s，2H)，7.10(d，2H)，7.17(d，   2H)，7.20-7.36(m，3H)-7.40(d，2H)，7.54(s，2H).LCMS：m/z ES +491[MH] +

A=1-dicyclo [1.1.1] amylamine hydrochloride is (referring to list of references J.O.C.2001; 66 (19); 6282-6285).

Embodiment 223:1-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl]-N-isopropyl-4-methyl piperidines-4-formamide

Ethanedioly chloride (0.04 milliliter, 0.55 mM) adds in the solution of acid (50 milligrams, 0.15 mM) in carrene (50 milliliters) of preparation 160, and solution at room temperature stirred 20 minutes. Add extra ethanedioly chloride (0.02 milliliter, 0.27 mM), and solution stirred 10 minutes in addition. Then vapourisation under reduced pressure solution and residue and carrene (3x) azeotropic. The oil residue is dissolved in the carrene (10 milliliters). Isopropylamine (0.19 milliliter, 2.25 mMs) is added in the solution and then at room temperature stirred the mixture 18 hours. Then with the ammonium chloride solution washing reaction, through MgSO₄Drying is vapourisation under reduced pressure then. By using carrene at silica gel: methyl alcohol: 0.88 ammonia (95: 5: 1) is as the column chromatography purifying residue of eluant, eluent. Product grinds to provide the solid of title compound with ether, 30 milligrams.

¹H NMR(400MHz，CDCl ₃)：δ1.15(m，9H)，1.42(m，2H)，1.95(m， 2H)，2.22(s，3H)，3.02(m，2H)，3.18(m，2H)，4.03(m，1H)，5.38(m， 1H)，7.26(d，2H)，7.57(d，2H)；LCMS：m/z APCl ⁺376[MH] ⁺。

Embodiment 224:N-{1-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl] piperidin-4-yl } benzamide

With triethylamine (105 microlitres, 0.75 mM) then with chlorobenzoyl chloride (79.6 microlitres, 0.69 mM) add in the solution of amine (200 milligrams, 0.69 mM) in carrene (5 milliliters) of preparation 145, and reaction was at room temperature stirred 5 minutes. Add water (5 milliliters) and stirring the mixture intensely 5 minutes. Then use and be separated the cartridge case filtering mixt and under reduced pressure concentrate organic layer. Residue then with the ether azeotropic to provide the white solid of title compound, 278 milligrams.

¹H NMR(400MHz，CD ₃OD)：δ1.55(m，2H)，1.86(m，2H)，2.22(s， 3H)，2.93(m，2H)，3.52(m，2H)，3.97(m，1H)，7.42(t，2H)，7.45-7.53(m， 3H)，7.63(d，2H)，7.75(d，2H)；LCMS：m/z APCl ⁺ 418[MNa] ⁺。

Embodiment 225:1-benzoyl-4-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl] piperazine

(150 milligrams in I-hydroxybenzotriazole hydrate, 1.1 mM), (225 milligrams of 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, 1.17 mM), (0.4 milliliter of triethylamine, 2.7 mM) and (250 milligrams of preparation 144 amine, 0.9 mM) be added to continuously in the solution of benzoic acid (110 milligrams, 0.9 mM) in carrene (10 milliliters). Then reaction was at room temperature stirred 18 hours. Mixture is distributed between 2M sodium hydroxide solution and the carrene, then separates phase. With the further aqueous layer extracted of carrene, and the organic solution of vapourisation under reduced pressure merging. By using carrene at silica gel: methyl alcohol: the column chromatography purification of crude product of the gradient of 0.88 ammonia (100: 0: 0 to 95: 5: 0.5) is to provide the white foam of title compound, 182 milligrams.

¹H NMR(400MHz，CDCl ₃)：δ2.22(s，3H)，3.08(m，4H)， 3.38-3.78(m，4H)，7.25(d，2H)，7.39(m，4H)，7.54(d，3H)。LCMS： m/z APCl ⁺382[MH] ⁺ Microanalysis discovery value: C, 61.66; H, 5.32; N, 17.42. C₂₀H _2OC1N ₅O；0.14CH ₂Cl ₂Required value C, 61.43; H, 5.19; N, 17.79%.

Embodiment 226:4-benzoyl-1-[4-(4-chlorphenyl)-5-(methoxy)-4H-1,2,4-triazole-3-yl]-the 2-methyl piperazine

Triethylamine (100 microlitres, 0.71 mM), then chlorobenzoyl chloride (82 microlitres, 0.71 mM) adds to (150 milligrams of preparation 149 compounds, 0.47 mM) in the solution in carrene (10 milliliters), and then reaction was at room temperature stirred 18 hours. Mixture washs with sodium bicarbonate solution, separates layers and vapourisation under reduced pressure organic solution. By using ethyl acetate at silica gel: methyl alcohol: 0.88 ammonia (95: 5: 0.5) as the column chromatography purification of crude product of eluant, eluent to provide the white solid of title compound, 120 milligrams.

¹H NMR(400MHz，CDCl ₃)：δ1.01-1.16(m，3H)，3.18-3.23(m， 3H)，3.30(s，3H)，3.39-3.48(m，3H)，3.83(m，1H)，4.04(m，1H)， 4.28(d，1H)，4.38(d，1H)，7.39(m，7H)，7.52(d，2H)；LCMS：m/z APCl ⁺426[MH] ⁺。

Embodiment 227:1-(4-chlorobenzene formacyl)-4-[4-(4-chlorphenyl)-5-(methoxy)-4H-1,2,4-triazole-3-yl]-the 2-methyl piperazine

Title compound according to embodiment 226 described steps from preparing the preparation of 150 compound and 4-chlorobenzoyl chloride, 37% productive rate.

¹H NMR(400MHz，CDCl ₃)：δ1.08(d，3H)，2.94-3.39(m，8H)， 4.34(s，2H)，7.25(d，2H)，7.39(m，4H)，7.54(d，2H)；LCMS：m/z APCl ⁺460[M] ⁺。

Embodiment 228:1-[4-(4-chlorphenyl)-5-(methoxy)-4H-1,2,4-triazole-3-yl]-4-(3-fluoro benzoyl)-Isosorbide-5-Nitrae-phenodiazine Ban

Title compound according to embodiment 224 described steps from preparing the preparation of 148 compound and 3-fluorobenzoyl chloride, 84% productive rate.

¹H NMR(400MHz，CDCl ₃)：δ1.68-1.80(m，2H)3.17(m，1H)， 3.25(s，3H)，3.39(m，4H)，3.58(m，1H)，3.65(m，1H)，3.78(m，1H)， 4.22(d，2H)，7.02(d，1H)，7.10(m，2H)，7.22-7.42(m，3H)，7.49(m， 2H)；LCMS：m/z APCl ⁺ 444[M] ⁺。

Embodiment 229:4-(2-chlorobenzene formacyl)-2-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl] morpholine

Trifluoroacetic acid (5 milliliters) adds in cooling (5 ℃) solution of preparation 102 compound (1.3 grams, 3.43 mMs) in carrene (5 milliliters), and agitating solution 2 hours at room temperature then. Under reduced pressure then enriched mixture adds triethylamine (450 milligrams, 4.47 mMs) and carrene (30 milliliters). This solution (10 milliliters) of a part is processed and was then at room temperature stirred 2 hours with 2-chlorobenzoyl chloride (1.26 mMs). Add three-(2-amino-ethyl) amine polystyrene (500 milligrams) and stirred the mixture other 24 hours. Then with aqueous ammonium chloride solution dilution mixture, use the hydrophobic film separates layers and directly use silica gel cartridge case and carrene: methyl alcohol (100: 0 to 95: 5) as eluant, eluent purifying organic solution so that title compound to be provided.

¹H NMR(400MHz，CDCl ₃) (rotational isomer): δ 2.23,2.34 (2xs, 3H), 3.00-3.62 (m, 3H), 3.64-4.00 (m, 2H), 4.11-4.40 (m, 1H), 4.58,4.90 (2xm, 1H), 7.17-7.40 (m, 6H), 7.56 (m, 2H); LCMS:m/z ES⁺439[MNa] ⁺。

Embodiment 230:1-(2-chlorobenzene formacyl)-3-[4-(4-chloro-2-tolyl)-5-methyl-4H-1,2,4-triazole-3-yl] piperidines

Triethylamine (79 microlitres, 0.57 mM) is then added to 2-chlorobenzoyl chloride (66 microlitres, 0.52 mM) in the solution of compound (150 milligrams, 0.52 mM) in carrene (5 milliliters) of preparation 146. Then mixture at room temperature stirred 18 hours. After this with water (5 milliliters) diluting reaction, and stirred the mixture rapidly 30 minutes. Then separates layers, vapourisation under reduced pressure organic solution, and from ether azeotropic product to provide the white foam of title compound, 193 milligrams.

¹H NMR(400MHz，CDCl ₃)：δ1.38-1.82(m，3H)，1.82-2.22(m， 8H)，2.54-2.87(m，1H)，3.03-3.50(m，2H)，4.80(m，1H)，6.94-7.50(m， 7H)；LCMS：m/z ES ⁺451[MNa] ⁺。

Embodiment 231:3-[1-(2-chlorobenzene formacyl) pyrrolidin-3-yl]-4-(4-chloro-2-tolyl)-5-methyl-4H-1,2,4-triazole

(97 milligrams of the compounds of preparation 147,0.35 mM), 2-chlorobenzoyl chloride (40.4 microlitres, 0.32 mM) and the mixture of N-methylmorpholine (58 microlitres, 0.53 mM) in carrene (5 milliliters) under room temperature, stirred 18 hours. Then react with carrene (20 milliliters) dilution, with 2N hydrochloric acid (20 milliliters) and saturated sodium bicarbonate solution (20 milliliters) washing. Then organic solution pass through by MgSO₄Dry and under reduced pressure concentrated. Residual oil grinds with ether, filters the gained solid, and is then dry to provide title compound, 55 milligrams.

¹H NMR(400MHz，CDCl ₃) (rotational isomer): δ 1.84-2.62 (m, 8H), 3.00-3.20 (m, 1H), 3.22-3.42 (m, 1H), 3.44-3.79 (m, 2H), 3.81-3.98 (m, 1H), 7.20-7.50 (m, 7H); LCMS:m/z APCl⁺415[MH] ⁺。

Embodiment 232:N-{1-[4-(4-chlorphenyl)-5-(2H-1,2,3-triazole-2-ylmethyl)-4H-1,2,4-triazole-3-yl] pyrrolidin-3-yl }-the N-methylacetamide

Title compound is according to preparing 93 described steps from preparing 54 and 18 compound acquisition, 50% productive rate.

¹H NMR(400MHz，CDCl ₃) (rotational isomer): δ 1.78-1.90 (m, 2H), 2.04 (s, 3H), 2.74 (s, 1H), 2.80 (s, 3H), 2.98 (m, 1H), 3.04-3.18 (m, 2H), 3.22-3.38 (m, 2H), 4.40,5.21 (2xm, 1H), (5.55 m, 2H), 7.03 (d, 2H), (7.38 d, 2H), 7.52 (s, 2H); LCMS:m/z ES⁺423[MNa] ⁺。

Embodiment 233:1-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl]-4-Phenylpiperidine-4-formamide

Sulfuric acid (930 milligrams, 95%, 9.5 mM) adds in the solution of compound (700 milligrams, 1.9 mMs) in acetic acid (1.5 milliliters) of preparation 96, and then reacts on 100 ℃ of lower heating 3 days. Then the mixture of cooling extracts with carrene (4x) by adding carefully 0.88 ammonia quencher. Then organic layer so that the salt water washing merges passes through MgSO₄Drying and vapourisation under reduced pressure. From the ethyl acetate crystallized product to provide title compound, 282 milligrams.

¹H NMR(400MHz，CDCl ₃)：δ2.06(m，2H)，2.20(s，3H)，2.32(m， 2H)，3.05-3.20(m，4H)，5.20(m，2H)，7.24(m，3H)，7.38(m，4H)， 7.52(d，2H)；LCMS：m/z ES ⁺396[MH] ⁺。

Embodiment 234:4-{[4-(4-chlorphenyl)-5-(2H-1,2,3-triazole-2-ylmethyl)-4H-1,2,4-triazole-3-yl] the oxygen base } piperidines-1-carboxylic acid uncle-butyl ester

Oxolane (2 milliliters) adds in the sodium hydride (24 milligrams, 60% in the mineral oil), and it is with pentane (2 milliliters) prewashing, and stirred suspension at room temperature. Then adding 4-hydroxyl-1-piperidine carboxylic acid uncle-butyl ester (119 milligrams, 0.6 mM) and mixture at room temperature stirred 30 minutes in addition. The compound (100 milligrams, 0.3 mM) and the reaction that add preparation 164 were at room temperature stirred 18 hours in addition. Then reaction is distributed between carrene (20 milliliters) and the salt solution (20 milliliters) separates layers and vapourisation under reduced pressure organic phase. Residue is dissolved in the carrene (6 milliliters), adds PS-DIEA (Argonaut Technologies) (638 milligrams) and triethylamine (0.5 milliliter, 3.6 mMs). Then stirred the mixture 18 hours. Filtering mixt is with saturated potassium carbonate solution washing and vapourisation under reduced pressure filtrate. By using carrene at silica gel: methyl alcohol (99: 1) is as the column chromatography purification of crude product of eluant, eluent. Product further uses Phenomenex Luna C18 post and 0.1% aqueous formic acid by HPLC: acetonitrile/0.1% formic acid (80: 20 to 5: 95) purifying is to provide title compound, 34 milligrams.

¹H NMR(400MHz，CD ₃OD)：δ1.40(m，9H)，1.62(m，2H)，1.98(m， 2H)，3.30-3.59(m，4H)，4.90-5.02(m，1H)，5.61(s，2H)，7.18(d，2H)， 7.40(d，2H)，7.50(m，2H)。

Embodiment 235:N-(tert-butyl)-4-[4-(4-chlorphenyl)-5-methyl-4H-1,2,4-triazole-3-yl] benzamide

With (223 milligrams of uncle-butylamine hydrochlorides; 2.0 mM); then will prepare (150 milligrams of 157 acid chlorides; 0.4 mM) solution in carrene (3 milliliters); adding to the solution neutralization reaction of triethylamine (300 microlitres, 2.0 mMs) in carrene (2 milliliters) at room temperature stirred one hour. Then mixture is distributed between carrene and the aqueous citric acid solution and separates phase. The organic solution process MgSO that water layer further extracts with carrene (2 * 25 milliliters) and merges₄Drying and vapourisation under reduced pressure. By using carrene at silica gel: methyl alcohol: 0.88 ammonia (93: 7: 1) as the column chromatography purification of crude product of eluant, eluent to provide title compound, 122 milligrams.

¹H NMR(400MHz，CDCl ₃)：δ1.42(s，9H)，2.40(s，3H)，5.98(br s，1H)，7.19(d，2H)，7.41(d，2H)，7.50(d，2H)，7.61(d，2H)；LCMS： m/z ES ⁺391[MNa] ⁺。

Embodiment 236 to 395:

Suitable acid, ZCO₂H, (0.25 milliliter, at N, 0.2M solution in the dinethylformamide, 50 micromoles), if necessary, with triethylamine (7 microlitres, every salt equivalent 50 micromoles) neutralization is then with O-(7-azepine BTA-yl)-N, N, N ', (0.1 milliliter of N '-tetramethylurea cation hexafluorophosphoric acid salting liquid, 0.525M, 52.5 micromoles) process. Then solution processed with the amine (0.25 milliliter, the 0.2M solution in the DMF, 50 micromoles) of triethylamine (28 microlitres, 0.20 mM) and preparation 12 in 96 deep hole polypropylene microtiter plates. Seal this plate and descend stirring 16 hours in 40 ℃. Then the vapourisation under reduced pressure reactant mixture reaches by using Watera XTerra MS C18 post, and acetonitrile: the HPLC purifying residue of 10mM carbonic hydroammonium (being adjusted to pH 10 with ammonium hydroxide) (5: 95 to 98: 2), so that desired compound to be provided.

Time	％A	％B	％D
				0 minute 3.5 minutes 4.0 minutes	94   4.5   4.5	5   95   95	1   0.5   0.4

The embodiment numbering	Z	MS[MH] +	Retention time (minute)
				236	5-methyl isophthalic acid-phenyl-1H-pyrazoles-4-base	529	2.26
237	5-Methyl-1H-indole-2-base	502	2.56
				238	3-(1H-indol-3-yl) propyl group	530	2.17
239	1-benzyl-1H-pyrazoles-4-base	529	2
				240	3-(2-fluorophenyl)-1H-pyrazoles-5-base	533	2.08
241	3-(4-aminomethyl phenyl)-1H-pyrazoles-5-base	529	2.17
				242	2-(phenyl methyl) thiazole-4-yl	546	2.26
243	5-methyl isophthalic acid H-indazole-3-base	503	2.04
				244	(2,5,7-trimethyl-1H-indol-3-yl) methyl	544	2.3
245	4,5,6,7-tetrahydrochysene-2-methyl-2H-indazole-3-base	507	1.95
				246	1H-indazole-1-ylmethyl	503	1.95
247	3-(2,5-3,5-dimethylphenyl) propyl group	519	2.47

248	(1S)-1-(dimethylamino)-2-phenylethyl	520	2.04
				249	(2,5-dimethyl-1,3-thiazoles-4-yl) methyl	498	1.87
250	(4-methoxyphenyl)-5-methyl isophthalic acid H-pyrazoles-4-yl]	559	2.04
				251	1-(1-cyclopentene-1-yl) butyl	495	2.47
252	Hexamethylene-3-alkene-1-base	453	2.04
				253	(1,3-dimethyl-1H-thieno [2,3-c] pyrazoles-5-yl)	523	1.91
254	(2S)-1-(uncle-butoxy carbonyl) piperidin-2-yl	556	2.3
				255	Benzo [b] thiene-3-yl-	505	2.21
256	4-(5- azoles base) phenyl	516	1.87
				257	3-(2-methyl-4-thiazolyl) phenyl	546	2.13
258	2-phenoxypyridines-5-base	542	2.21
				259	2-methyl 4-phenyl pyrimidine-5-base	541	1.95
260	5-methoxyl group-indoles-2-base	518	2.13
				261	The 4-chlorophenylmethyl	497	2.43
262	1-benzyl ring amyl group	517	2.69
				263	3-(4-fluorophenyl)-3-oxopropyl	523	2.03
264	1,2,3,4-naphthane-2-base	503	2.23
				265	Cyclopenta (phenyl) methyl	531	2.52
266	Biphenyl-4-ylmethyl	539	2.37
				267	1-(4-chlorophenoxy)-1-Methylethyl	541	2.5
268	1-(3-chlorophenoxy) ethyl	527	2.23
				269	2-methyl isophthalic acid-phenyl butyl	519	2.49
270	(1-naphthoxy) methyl	529	2.13
				271	(2,3-dimethyl phenoxy) methyl	507	2.2
272	3-(4-aminomethyl phenyl) propyl group	505	2.18
				273	1H-indoles-1-base ethyl	516	2.12

274	(thiophenyl) methyl	495	2.08
				275	1-(4-chlorphenyl) ethyl	511	2.27
276	2,3-dihydro-1H-indenes-2-ylmethyl	503	2.23
				277	The 2-[(4-chlorphenyl) sulfenyl] propyl group	558	2.47
278	2-chloro-4-fluorobenzene methyl	515	2.13
				279	(1R)-1-phenyl-propyl group	491	2.22
280	3-methoxyl group cyclohexyl	485	1.81
				281	1-benzyl-2, the 2-dimethyl propyl	533	2.52
282	1-methyl-2-phenylethyl	491	2.15
				283	(benzyloxy) methyl	493	1.96
284	3-(4-chlorphenyl)-3-oxopropyl	539	2.17
				285	[(4-chlorphenyl) sulfenyl] methyl	529	2.27
286	(benzylthio) methyl	509	2.12
				287	The 3-chlorophenylmethyl	497	2.1
288	1,1-diphenyl-ethyl	553	2.5
				289	2,2-diphenyl-ethyl	553	2.39
290	(2,3-dichlorophenoxy) methyl
				291	4-fluorobenzene methyl	548	2.29
292	The 2-mehtoxybenzyl	481	1.98
				293	2-(2-methoxyphenyl) ethyl	493	1.91
294	2,8-, two-methylquinoline-4-base	507	2.16
				295	(2-naphthoxy) methyl	528	2.21
296	The 2-naphthyl methyl	529	2.29
				297	2-phenoxy group ethyl	513	2.26
298	1-(2-fluorophenyl) cyclopenta	493	2.11
				299	5-methoxyl group-1-oxo-dihydro indenes-2-ylmethyl	535	2.36
300	(3-methyl benzoyl) amino methyl	520	1.89

301	Instead-the 4-methylcyclohexyl	469	2.26
				302	3-phenyl 3-oxo-1 methyl-propyl	519	2.09
303	2-(2-aminomethyl phenyl) ethyl	491	2.21
				304	1-methyl-indol-3-yl methyl	516	2.14
305	Diphenyl methyl	539	2.38
				306	1-(4-chlorphenyl)-1-Methylethyl	525	2.41
307	1-methyl isophthalic acid-phenylethyl	491	2.26
				308	1-ethyleneoxy-1-phenyl methyl	521	2.01
309	Hexamethylene-1-alkene-1-ylmethyl	467	2.12
				310	(2R)-the 2-phenyl propyl	491	2.19
311	[(4-fluorophenyl) sulfenyl] methyl	513	2.14
				312	(2R)-1-(uncle-butoxy carbonyl) piperidin-2-yl	556	2.26
313	3-(2,3-dihydro-Isosorbide-5-Nitrae-benzo two  alkene-6-yl) propyl group	549	2.14
				314	6-chloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazine-4-base	568	2.11
315	2-(4-fluorophenoxy) ethyl	511	2.16
				316	2-hydroxy quinoxaline-3-base	517	1.57
317	The different  azoles of 5-methyl-3-phenyl-4-base	530	2.07
				318	Isoquinolyl-1	500	1.87
319	The 2-Phenoxyphenyl	541	2.29
				320	Quinoline-2-base	500	1.97
321	Quinolyl-4	500	1.8
				322	Quinoline-3-base	500	1.87
323	The 2-naphthyl	499	2.21
				324	5-butyl-pyridinium-2-base	506	2.22
325	The 3-benzoyloxy phenyl	553	2.21
				326	1H-benzimidazole-6-base	489	1.55

327	9-oxo-9H-fluorenes-1-base	551	2.16
				328	4-methoxy quinoline-2-base	530	2.07
329	1-benzofuran-2-base	489	2.16
				330	2-(4-methyl benzoyl) phenyl	567	2.31
331	7-methoxyl group-1-benzofuran-2-base	519	2.17
				332	2,6-dimethoxy-pyridine-3-base	510	2.3
333	2,5-dimethyl-3-furyl	467	2.26
				334	Xenyl-2-base	525	2.52
335	5-methyl-2-thienyl	469	2.3
				336	2-phenoxypyridines-3-base	542	2.17
337	1,3-benzothiazol-6-yl	506	2.08
				338	3-phenyl cinnolines-4-base	577	1.76
339	3-tert-butyl-1-methyl isophthalic acid H-pyrazoles-5-base	509	2.26
				340	2,1,3-benzo  diazole-5-base	491	2.26
341	5-bromo-2,3-dihydro-1-benzofuran-7-base	570	2.43
				342	1-(4-chlorobenzene base) cyclopropyl	523	2.27
343	The different  azoles of 5-isobutyl group-3-base	496	2.23
				344	3-(1H-pyrazol-1-yl) phenyl	515	1.91
345	3,5-dimethyl indole-2-base	516	2.32
				346	4-(uncle-butoxy carbonyl) morpholine-3-ylmethyl	572	1.98
347	3-isobutyl group-1H-pyrazoles-5-base	495	1.96
				348	The different  azoles of 5-propyl group-3-base	482	2.1
349	2,4-dimethyl-1,3-thiazoles-5-base	498	1.61
				350	2-methylquinoline-4-base	514	1.81
351	6-chloro-imidazoles is [1,2-a] pyridine-2-base also	523	1.71
				352	3-phenyl-1H-pyrazoles-5-base	515	1.96
353	3-isopropyl-1H-pyrazoles-5-base	481	1.66
				354	4,5,6,7-tetrahydrochysene-2-indazole-3-base	493	1.81

355	2,3-dimethyl-1H-indoles-5-base	516	2.05
				356	3,5-dimethyl-1H-pyrroles-2-base	466	1.96
357	3-(3,5-dimethyl-1H-pyrazol-1-yl) phenyl	543	2
				358	3-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] phenyl	557	1.98
359	3 '-fluorine biphenyl base-4-base	543	2.37
				360	4-phenyl-1,3-thiazoles-2-base	546	2.17
361	4-(1H-pyrazol-1-yl) phenyl	515	1.9
				362	5,7-dimethyl-pyrazoles is [1,5-a] pyrimidine-2-base also	518	1.76
363	The different  azoles of 3-phenyl-5-base	516	2.2
				364	2,3-dihydro-1-benzofuran-2-base	491	2
365	1H-benzimidazole-1-ylmethyl	503	1.73
				366	5-(4-methoxyphenyl)-2-furyl	545	2.25
367	1,3-benzothiazole-2-base ethyl	534	2.03
				368	2-methyl-5-propyl group pyrazole-3-yl	495	1.96
369	1-benzyl-2-oxo-1,2-dihydropyridine-3-base	556	1.85
				370	1-benzyl-6-oxo-1,6-dihydropyridine-3-base	556	1.75
371	2-phenyl-1,3-thiazoles-4-base	532	2.22
				372	4-methyl-2-phenyl-1,3-thiazoles-5-base	546	2.18
373	8-methoxyl group-2H-chromene-3-base	533	2.02
				374	2H-chromene-3-base	503	2.12
375	6-methoxyl group-2H-chromene-3-base	533	2.1
				376	4-(uncle-butoxy carbonyl) morpholine-3-base	558	1.95
377	4-methoxyl group-3-thiophene base	485	1.85

378	4-(1H-imidazoles-1-yl) phenyl	515	1.68
				379	2-methyl isophthalic acid H-benzimidazole-5-base	503	1.51
380	2,3-dihydro-1H-indenes-2-base	489	2.15
				381	Trans-2-benzyl ring third-1-base	489	2.15
382	1-Methyl-1H-indole-2-base	502	2.18
				383	1-Methyl-1H-indole-3-base	502	2.02
384	5-fluoro-1H-indoles-2-base	506	2.13
				385	6-methyl-4-oxo-4H-chromene-2-base	531	2.02
386 A	3-isopropyl-1-methylpyrazole-5-base	495	1.95
				387 B	5-bromo-2-methoxypyridine-3-base	559	2.03
388 C	5-methyl-2-phenyl-1H-imidazol-4 yl	529	1.95
				389 D	3-(1-oxo-1,3-dihydro)-2H-iso-indoles-2-yl) propyl group	532	1.82
390 E	1-ethyl piperidines-2-base	484	1.91
				391 F	3-[(pyrimidine-2-base sulphur base) methyl] phenyl	573	2.08
392 G	4-[(pyridine-2-base sulphur base) methyl] phenyl	572	2.17
				393 H	6-cyclohexyl-2-oxo-1,2,3,6-tetrahydrochysene pyrimidine-4-base	551	2.04
394 I	5-oxo-1-propyl pyrrole alkane-3-base	498	1.74
				395 J	The different  azoles of 5-propyl group-4-base	482	2

A=uses 3-isopropyl-1-methyl isophthalic acid H-pyrazoles-5-carboxylic acid; Referring to DE 3029281.

B=uses the acid of 5-bromo-2-methoxyl group nicotine, referring to EP 306251, and preparation 1.

C=uses 5-methyl-2-phenyl-1H-imidazoles-4-carboxylic acid, referring to J.Chem Soc.1948; 1969.

D=3-(1-oxo-1,3-dihydro-2H-iso-indoles-2-yl) propionic acid is referring to J.Med.Chem.83; 26 (2); 243.

E=uses 1-ethyl piperidines-2-carboxylic acid, referring to Journal of Inorganic and Nuclear medicine; 1978; 40 (6); 1103-6.

F=uses 3-[(pyrimidine-2-base sulphur base) methyl] benzoic acid, referring to J.Indian Chem.Soc. (97); 74 (7); 575.

G=uses 4-[(pyridine-2-base sulphur base) methyl] benzoic acid, referring to US 4325959, embodiment 2.

H=uses 6-cyclohexyl-2-oxo-1,2,3, and 6-tetrahydrochysene pyrimidine-4-carboxylic acid is referring to J.O.C.2000; 65 (20); 6777.

I=uses 5-oxo-1-propyl pyrrole alkane-3-carboxylic acid, referring to WO 200202614.

J=uses the different  azoles of 5-propyl group-4-carboxylic acid, referring to J.Het.Chem.1991; 28 (2) 453.

Embodiment 396 to 403:

Derive from the N-ethyl diisopropylamine (10 equivalent) of the suitable amine (1 equivalent) of preparation 12a, suitable acyl group chlorine (1.2 to 1.4 equivalent) and polymer support (16 milliliters mMs of carrene^-1) in mixture under room temperature, stirred 2 hours. Add three-(2-amino-ethyl) amine polystyrene and stirred the mixture one hour. It is then with 1N NaOH solution washing. The aqueous solution is with carrene (2x) extraction and under reduced pressure concentrate the organic solution that merges. By using ethyl acetate at silica gel: methyl alcohol: 0.88 ammonia (90: 10: 1) provides title compound as the column chromatography method purification of crude product of wash-out agent.

The embodiment numbering	Data
		396	W＝2-CF 3；   1H NMR(400MHz，CDCl 3)：δ1.61-1.76(m，1H)，1.79-1.98(m，3H)，2.62-2.80   (m，1H)，2.84-2.97(m，2H)，3.42(m，1H)，4.60(m，1H)，5.62(d，2H)，6.99(m，   2H)，7.20-7.55(m，6H)，7.59(m，1H)，7.66(m，1H).LCMS：m/z APCl +516   [MH] +
397	W＝3-CF 3；   1H NMR(400MHz，CDCl 3)：δ1.80(m，2H)，1.98(m，2H)，2.70(m，1H)，2.88-   3.02(m，2H)，3.72(m，1H)，4.57(m，1H)，5.62(s，2H)，7.00(m，2H)，7.22(d，   2H)，7.25-7.59(m，4H)，7.65(m，2H).LCMS：m/zAPCl +516[MH] +

398	W＝4-CF 3；   1H NMR(400MHz，CD 3OD)：δ1.78-1.96(m，4H)，2.82(m，2H)，3.00-3.14(m，   1H)，3.62(m，1H)，4.58(m，1H)，5.67(s，2H)，7.22(m，2H)，7.50(d，2H)，7.58   (m，4H)，7.77(d，2H).LCMS：m/z APCl +516[MH] +
		399 A	W＝2-F，5-Cl；   1H NMR(400MHz，CDCl 3)：δ1.78-2.00(m，4H)，2.70(m，1H)，2.91(m，1H)，   3.01(m，1H)，3.62(m，1H)，4.58(m，1H)，5.63(s，2H)，7.01(m，3H)，7.30(m，   2H)，7.42(d，2H)，7.50(s，2H).LCMS：m/z APCl +500[MH] +
400 B	W＝3-F   1H NMR(400MHz，CDCl 3)：δ1.66-1.81(m，2H)，1.98(m，2H)，2.66(m，1H)，   2.80-2.96(m，2H)，3.74-3.82(m，1H)，4.45-4.60(m，1H)，5.62(s，2H)，6.99-   7.12(m，4H)，7.15(s，1H)，7.37(m，1H)，7.42(d，2H)，7.49(s，2H).LCMS：   m/z APCl +466[MH] +
		401 B	W＝2，3-di-F   1H NMR(400MHz，CDCl 3)：δ1.74-2.00(m，4H)，2.72(m，1H)，2.79(m，1H)，   3.01(m，1H)，3.62(m，1H)，4.60(m，1H)，5.62(s，2H)，7.01(m，2H)，7.07-   7.21(m，3H)，7.42(d，2H)，7.52(s，2H).LCMS：m/z APCl +484[MH] +
402 B	W＝2-F，3-Cl   1H NMR(400MHz，CDCl 3)：δ1.62-2.00(m，4H)，2.70(m，1H)，2.82-3.06(m，   2H)，3.60(m，1H)，4.60(m，1H)，5.62(s，2H)，7.00(m，2H)，7.15(m，1H)，7.24   (m，1H)，7.41(m，3H)，7.45(s，2H).LCMS：m/z APCl +500[MH] +
		403 B	W＝4-F，3-Cl；   1H NMR(400MHz，CDCl 3)：δ1.74-1.85(m，2H)，1.98(m，2H)，2.70(m，1H)，   2.82-2.98(m，2H)，3.70-3.88(m，1H)，4.40-4.58(m，1H)，5.63(s，2H)，7.02   (m，2H)，7.17(m，1H)，7.23(m，1H)，7.42(m，3H)，7.49(s，2H).LCMS：m/z   APCl +500[MH] +

The N-ethyl diisopropylamine that A=uses 2.5 equivalent triethylamines to replace polymer to support.

The N-ethyl diisopropylamine that B=uses 2 equivalent N-methylmorpholines to replace polymer to support.

Embodiment 404 to 405:

Suitable acid, ZCO₂H (1.2 equivalent), O-BTA-1-base-N, N, N ', N '-tetramethyl urea cation hexafluorophosphate (1.2 equivalent), N-methylmorpholine (1.4 equivalent) and the amine (1 equivalent) that derives from preparation 12a are at carrene (7-10 milliliter mM^-1) in solution under room temperature, stirred 24 hours. Reaction is distributed between NaOH solution and the carrene, and separates layers then. Wash organic solution with ammonium chloride solution, through MgSO₄Drying and vapourisation under reduced pressure. By using carrene at silica gel: methyl alcohol: the column chromatography method purification of crude product of the gradient of 0.88 ammonia (100: 0: 0 to 90: 10: 1) is to provide title compound.

The embodiment numbering	Data
		404	Z=3-fluoro-5-chlorobenzene base;1H NMR(400MHz，CDCl 3)：δ1.80(m，2H)，1.98(m，2H)，2.70(m，1H)，   2.95(m，2H)，3.78(m，1H)，4.48(m，1H)，5.63(s，2H)，6.99(m，3H)，7.15   (m，2H)，7.42(d，2H)，7.50(s，2H).LCMS：m/z APCl +500[M] +
405	Z=indazole-3-base;1H NMR(400MHz，DMSO-d 6)：δ1.63-1.82(m，4H)，2.78-2.90(m，2H)，   3.18(m，1H)，4.45(m，1H)，4.62(m，1H)，5.77(s，2H)，7.18(m，1H)，   7.32-7.40(m，3H)，7.58(m，3H)，7.63(s，2H)，7.90(d，1H).LCMS：m/z   ES -486[M-H] -

As mentioned above when screening 1.0 (V_1AFilter membrane is in conjunction with test) in when test, all above-mentioned compounds of giving an example all show the Ki value less than 500nM.

The example of special compound is described as follows:

The embodiment numbering	Ki(nM)
		165	2.98
206	2.43
		399	1.99
405	1.11

Claims (23)

1. the compound of formula (I),

Or its pharmaceutically acceptable derivates, wherein:

X represents-[CH₂] _a-R or-[CH₂] _a-O-[CH ₂] _b-R；

A represents to be selected from 0 to 6 number;

B represents to be selected from 0 to 6 number;

R represents H, CF₃Or Het;

Het represents 5-or 6-unit is saturated, fractional saturation or heteroaromatic, it comprises (a) 1 to 4 nitrogen-atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms, optionally replaced by one or more groups that are independently selected from W;

Y represents one or more being independently selected from-[O]_c-[CH ₂] _d-R ¹Substituting group, its each appearance can be identical or different;

The each appearance of c independently expression is selected from 0 or 1 number;

The each appearance of d independently expression is selected from 0 to 6 number;

R ¹Each appearance represents H, halogen generation, CF independently₃, CN or Het¹；

Het ¹Each appearance represents 5-or 6-membered unsaturated heterocycle independently, comprises (a) 1 to 4 nitrogen-atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms;

V represent direct key or-O-;

Ring A represents that 5-to 7-unit saturated heterocyclic, comprises (a) 1 to 4 nitrogen-atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms; Perhaps encircle A and represent inferior phenyl; Ring A is optional by one or more C that are selected from_1-6The group of alkyl, phenyl or hydroxyl replaces;

Q represent direct key or-N (R²)-；

R ²Expression hydrogen or C_1-6Alkyl;

Z represents-[O]_e-[CH ₂] _f-R ³, benzyl ring (optional phenyl ring or the Het of being fused to², and optional by one or more groups replacements that are independently selected from W on the integrated group), or Het³(optional phenyl ring or the Het of being fused to⁴, and optional by one or more groups replacements that are independently selected from W on the integrated group);

R ³Expression C_1-6Alkyl (optional by one or more groups replacements that are independently selected from W), C_3-6Cycloalkyl, C_3-6Cycloalkenyl group, phenyl (optional by one or more groups replacements that are independently selected from W), Het⁵Or NR⁴R ⁵；

E represents to be selected from 0 or 1 number;

F represents to be selected from 0 to 6 number;

Het ²And Het⁵Represent independently that 5-or 6-unit are saturated, fractional saturation or heteroaromatic, comprise (a) 1 to 4 nitrogen-atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms, optionally replaced by one or more groups that are selected from W;

Het ³Expression 4 is to saturated, the fractional saturation of 6-unit or heteroaromatic, comprise (a) 1 to 4 nitrogen-atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms are optionally replaced by one or more groups that are selected from W;

Het ⁴Expression 6-unit heteroaromatic comprises (a) 1 to 4 nitrogen-atoms, and (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms are optionally replaced by one or more groups that are selected from W;

R ⁴And R⁵Represent independently hydrogen, C_1-6Alkyl, C_1-6Alkoxyl, C_3-8Cycloalkyl (the optional C that is fused to_3-8Cycloalkyl) or Het⁶；

R ⁴And R⁵Optional independently by one or more C that are selected from_1-6Alkyl, C_1-6Alkoxyl, C_3-8Cycloalkyl (the optional C that is fused to_3-8Cycloalkyl) or the group of phenyl replace;

Het ⁶Expression 5-or 6-unit is saturated, fractional saturation or heteroaromatic, comprise (a) 1 to 4 nitrogen-atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms are optionally replaced by one or more groups that are selected from W;

The each appearance of W represents halogen generation, [O] independently_gR ⁶、SO ₂R ⁶、SR ⁶、SO ₂NR ⁶R ⁷、 [O] _h[CH ₂] _iCF ₃、[O] _jCHF ₂, phenyl is (optional by halogen generation, C_1-6Alkyl or C_1-6The alkoxyl replacement), CN, phenoxy group (choose wantonly and replaced by halogen), OH, benzyl, NR⁶R ⁷、NCOR ⁶, benzyloxy, oxo, CONHR⁶、NSO ₂R ⁶R ⁷、COR ⁶、C _1-6Alkylidene-NCOR⁷、 Het ⁷；

R ⁶Expression hydrogen, C_1-6Alkyl, C_3-6Cycloalkyl, C_3-6Cycloalkenyl group or C_1-6Alkylidene-O-C_1-6Alkyl;

R ⁷Expression hydrogen or C_1-6Alkyl;

I represents to be selected from 0 to 6 number

H represents to be selected from 0 or 1 number;

G represents to be selected from 0 or 1 number;

J represents to be selected from 0 or 1 number;

Het ⁷Expression 5-or 6-unit is saturated, fractional saturation or heteroaromatic comprises (a) 1 to 4 nitrogen-atoms, and (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms are optional by R⁶And/or R⁷And/or bridge oxygen base replaces.

2. according to claim 1 compound, wherein X represents-[CH₂] _a-R。

3. according to claim 2 compound, wherein R represents Het.

4. arbitrary compound in 3 according to claim 1, wherein Y represents halogen generation.

5. arbitrary compound in 4 according to claim 1, wherein V represents direct key.

6. arbitrary compound in 5 according to claim 1, wherein Q represents direct key.

7. arbitrary compound in 6 according to claim 1 wherein encircles A and represents six-member ring.

8. arbitrary compound in 7 according to claim 1, wherein Z represents phenyl.

9. arbitrary compound in 8 according to claim 1, wherein Z is replaced by halogen.

10. according to claim 1 compound, it is selected from

(3-chloro-phenyl)-and 4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidines-1-yl }-ketone;

(4-chloro-phenyl)-and 4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidines-1-yl }-ketone;

(5-chloro-2-fluoro-phenyl)-and 4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidines-1-yl }-ketone;

4-[4-(4-chloro-phenyl)-5-[1,2,3] and triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidines-1-yl }-(3,5-, two fluoro-phenyl)-ketone;

4-[4-(4-chloro-phenyl)-5-[1,2,3] and triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidines-1-yl }-(3-fluoro-phenyl)-ketone;

4-[4-(4-chloro-phenyl)-5-[1,2,3] and triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidines-1-yl }-(2,3-, two fluoro-phenyl)-ketone;

(3-chloro-2-fluoro-phenyl)-and 4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidines-1-yl }-ketone;

(3-chloro-4-fluoro-phenyl)-and 4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidines-1-yl }-ketone;

4-[4-(4-chloro-phenyl)-5-[1,2,3] and triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidines-1-yl }-(4-three methyl fluorides-phenyl)-ketone;

4-[4-(4-chloro-phenyl)-5-[1,2,3] and triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidines-1-yl }-(3-three methyl fluorides-phenyl)-ketone;

4-[4-(4-chloro-phenyl)-5-[1,2,3] and triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidines-1-yl }-(2-three methyl fluorides-phenyl)-ketone;

(3-chloro-5-fluoro-phenyl)-and 4-[4-(4-chloro-phenyl)-5-[1,2,3] triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidines-1-yl }-ketone;

4-[4-(4-chloro-phenyl)-5-[1,2,3] and triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidines-1-yl }-(4-difluoromethyl-phenyl)-ketone;

4-[4-(4-chloro-phenyl)-5-[1,2,3] and triazole-2-ylmethyl-4H-[1,2,4] triazole-3-yl]-piperidines-1-yl }-(1H-indazole-3-yl)-ketone;

And pharmaceutically acceptable derivates.

11. according to claim 1 in 10 arbitrary compound as the purposes of medicine.

12. treatment comprises human mammiferous method, is used for the treatment of the obstacle for V1a indication short of money anti-dose, comprises according to claim 1 arbitrary the compound in 10 for the treatment of effective amount.

13. treatment comprises human mammiferous method, be used for the treatment of anxiety, cardiovascular disease (comprising angina pectoris, atherosclerotic, hypertension, heart failure, oedema, hypernatronemia), dysmenorrhoea (primary and insecondary), uterus endometrium ectopia, vomiting (comprising that motion is sick), sub-intrauterine growth retardation, inflammation (comprising rheumatoid arthritis), through between disease, premature ejaculation, premature labor (the pregnant front childbirth of foot) or Raynaud's disease before the pain, eclampsia, the method comprises according to claim 1 arbitrary the compound in 10 for the treatment of effective amount to suffering from this sick patient.

14. according to claim 12 or the method for claim 13, obstacle wherein is dysmenorrhoea (primary or insecondary).

15. arbitrary compound is used for the treatment of purposes in the medicine of obstacle in manufacturing in 10 according to claim 1, described obstacle is V1a indication short of money anti-dose.

16. according to claim 1 in 10 arbitrary compound manufacturing be used for the treatment of anxiety, cardiovascular disease (comprising angina pectoris, atherosclerotic, hypertension, heart failure, oedema, hypernatronemia), dysmenorrhoea (primary and insecondary), uterus endometrium ectopia, vomiting (comprising that motion is sick), sub-intrauterine growth retardation, inflammation (comprising rheumatoid arthritis), through between the purposes in the medicine of disease, premature ejaculation, premature labor (sufficient pregnant front childbirth) and Raynaud's disease before the pain, eclampsia.

17. according to claim 15 or the purposes of claim 16, wherein said obstacle is dysmenorrhoea (primary or insecondary).

18. a medicine preparation, it comprises according to claim 1 in 10 arbitrary compound, and pharmaceutically acceptable excipient, diluent or carrier.

19. (A) according to claim 1 arbitrary compound and (B) combination of another kind pharmacological component in 10.

20. combination according to claim 19, wherein (B) is oral contraceptive, PDEV inhibitor, COX inhibitor, NO-donor or L-arginine.

21. according to claim 19 or claim 20 be combined in make to be used for the treatment dysmenorrhoea simultaneously, order or the purposes in the medicine of the combined therapy of administration separately.

22. the method for the treatment of dysmenorrhoea, it comprises that curee to this treatment of needs gives according to claim 19 or a certain amount of (A) and the combination (B) of claim 20, (A) of described amount and (B) to combine be effective.

23. a drug products, it comprises according to claim 19 or (A) and the composition (B) of claim 20, as in treatment dysmenorrhoea (primary or insecondary) simultaneously, the combination preparation that separates or use in order.