CN1898244B - Triazole derivatives as vasopressin antagonists - Google Patents

Abstract

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

Description

Triazole derivatives as vasopressin antagonists

technical field

The present invention relates to triazole derivatives and to processes for the preparation of the derivatives, intermediates for the preparation of the derivatives, compositions comprising the derivatives and uses of the derivatives.

The triazole derivatives of the present invention are vasopressin antagonists. In particular they are antagonists of the Via receptor and have many therapeutic applications, especially for the treatment of dysmenorrhea (primary and secondary).

Background technique

There is a large unmet need in the field of menstrual disorders and it is estimated that up to 90% of all menstruating women are affected in some way. Up to 42% of women miss work or other activities due to menstrual pain and it is estimated that approximately 600 million work hours are lost a year in the United States as a result {Coco, A.S. (1999). Primary dysmenorrhoea. [Review] [30refs]. American Family Physician, 60, 489-96.}.

Lower abdominal pain is caused by overactive uterine muscles and reduced blood flow to the uterus. These pathophysiological changes cause abdominal pain that radiates to the back and legs. This can cause the woman to feel sick, have headaches and suffer from insomnia. This condition is called dysmenorrhea and can be classified as primary or secondary dysmenorrhea.

Primary dysmenorrhea is diagnosed when no abnormality causing the condition is identified. This affects up to 50% of the female population {Coco, A.S. (1999). Primary dysmenorrhoea. [Review] [30refs]. American Family Physician, 60, 489-96.; pelvic pain inadolescents. [Review] [78refs]. Pediatric Clinics of North America, 46, 555-71}. Secondary dysmenorrhea is diagnosed in the presence of underlying gynecological conditions such as endometriosis, pelvic inflammatory disease (PID), fibroids, or carcinoma. Only about 25% of women with dysmenorrhea are diagnosed with secondary dysmenorrhea. Dysmenorrhea, which can occur in conjunction with menorrhagia, accounts for approximately 12% of treatment schedules in gynecological outpatient departments.

Currently, women with primary dysmenorrhea are treated with non-steroidal anti-inflammatory drugs or oral contraceptive pills (NSAIDs). In the case of secondary dysmenorrhea, surgery may be performed to correct the underlying gynecological condition.

Women with dysmenorrhea have circulating vasopressin levels greater than that observed in healthy women at the same time in the menstrual cycle. Inhibition of the pharmacological action of vasopressin at uterine vasopressin receptors prevents dysmenorrhea.

The compounds of the present invention are therefore potentially useful in the treatment of a wide range of diseases, in particular aggressive behavior, Alzheimer's disease, anorexia nervosa, anxiety, anxiety disorders, asthma, atherosclerosis, autism, cardiovascular disease ( Including angina pectoris, atherosclerosis, hypertension, heart failure, edema, hypernatremia), cataract, central nervous system disease, cerebrovascular ischemia, liver cirrhosis, cognitive impairment, Cushing's disease, depression, diabetes , dysmenorrhea (primary and secondary), vomiting (including motion sickness), endometriosis, gastrointestinal disease, glaucoma, gynecological disease, cardiac disease, intrauterine growth retardation, inflammation (including rheumatoid Arthritis), ischemia, ischemic heart disease, lung tumors, voiding disorders, menstrual pain, neoplasms, nephrotoxicity, non-insulin-dependent diabetes mellitus, obesity, obsessive-compulsive disorder, ocular hypertension, preeclampsia Preclampsia, premature ejaculation, premature labor (delivery before full pregnancy), lung disease, Raynaud's disease, kidney disease, renal failure, male or female sexual dysfunction, septic shock, sleep disturbance, spinal cord injury, thrombosis, genitourinary tract infection or urolithiasis.

Of particular interest are the following diseases or disorders:

Anxiety, cardiovascular disease (including angina, atherosclerosis, hypertension, heart failure, edema, hypernatremia), dysmenorrhea (primary and secondary), endometriosis, vomiting (including motion sickness), intrauterine growth retardation, inflammation (including rheumatoid arthritis), menstrual pain, preeclampsia, premature ejaculation, preterm labor (delivery before term), and Raynaud's disease.

The compounds of the present invention, and their pharmaceutically acceptable salts and solvates, have the advantage that they are selective inhibitors of V1a receptors (so may have reduced side effects), compared with compounds of the prior art , they may have a more rapid onset of action, they may be more potent, they may act longer, they may have greater bioavailability or they may have other more desirable properties.

Contents of the invention

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

or a pharmaceutically acceptable derivative thereof, wherein:

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

a represents a number selected from 0 to 6;

b represents a number selected from 0 to 6;

R represents H, CF ₃ or Het;

Het represents a 5- or 6-membered saturated, partially saturated or aromatic heterocycle containing (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, optionally substituted by one or more groups independently selected from W;

Y represents one or more substituents independently selected from -[O] _c -[CH ₂ ] _d -R ¹ , each occurrence of which may be the same or different;

each occurrence of c independently represents a number selected from 0 or 1;

each occurrence of d independently represents a number selected from 0 to 6;

Each occurrence of R ¹ independently represents H, halo, CF ₃ , CN or Het ¹ ;

Each occurrence of Het ¹ independently represents a 5- or 6-membered unsaturated heterocycle containing (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atoms or 1 sulfur atom and 1 or 2 nitrogen atoms;

V means direct key or -O-;

Ring A represents a 5- to 7-membered saturated heterocyclic ring containing (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom And 1 or 2 nitrogen atoms, or Ring A represents phenylene; Ring A is optionally substituted by one or more groups selected from C _1-6 alkyl, phenyl or hydroxyl;

Q means direct bond or -N(R ² )-;

R ² represents hydrogen or C _1-6 alkyl;

Z represents -[O] _e- [CH ₂ ] _f -R ³ , phenyl ring (optionally fused to benzene ring or Het ² , and the group as a whole is optionally replaced by one or more independently selected from W group substitution), or Het ³ (optionally fused to a benzene ring or Het ⁴ , and the group as a whole is optionally substituted by one or more groups independently selected from W);

R ³ represents C _1-6 alkyl (optionally substituted by one or more groups independently selected from W), C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl (optionally substituted by One or more groups independently selected from W, Het ⁵ or NR ⁴ R ⁵ ;

e represents a number selected from 0 or 1;

f represents a number selected from 0 to 6;

Het ² and Het ⁵ independently represent a 5- or 6-membered saturated, partially saturated or aromatic heterocyclic ring comprising (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or ( c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, optionally substituted by one or more groups selected from W;

Het ³ represents a 4 to 6-membered saturated, partially saturated or aromatic heterocyclic ring containing (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom Or 1 sulfur atom and 1 or 2 nitrogen atoms, optionally substituted by one or more groups selected from W;

Het ⁴ represents a 6-membered aromatic heterocycle containing (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 Or 2 nitrogen atoms, optionally substituted by one or more groups selected from W;

R ⁴ and R ⁵ independently represent hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl (optionally fused to C _3-8 cycloalkyl) or Het ⁶ ;

R ⁴ and R ⁵ are optionally independently replaced by one or more selected from C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl (optionally fused to C _3-8 cycloalkane group) or phenyl group substitution;

Het ⁶ represents a 5- or 6-membered saturated, partially saturated or aromatic heterocycle containing (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, optionally substituted by one or more groups selected from W;

Each occurrence of W independently represents halo, [O] _g R ⁶ , SO ₂ R ⁶ , SR ⁶ , SO ₂ NR ⁶ R ⁷ , [O] _h [CH ₂ ] _i CF ₃ , [O] _j CHF ₂ , phenyl (optionally substituted by halo, C _1-6 alkyl or C _1-6 alkoxy), CN, phenoxy (optionally substituted by halogen), OH, benzyl, NR ⁶ R ⁷ , NCOR ⁶ , benzyloxy, oxo, CONHR ⁶ , NSO ₂ R ⁶ R ⁷ , COR ⁶ , C _1-6 alkylene-NCOR ⁷ , Het ⁷ ;

R ⁶ represents hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl or C _1-6 alkylene-OC _1-6 alkyl;

R ⁷ represents hydrogen or C _1-6 alkyl;

i represents a number selected from 0 to 6

h represents a number selected from 0 or 1;

g represents a number selected from 0 or 1;

j represents a number selected from 0 or 1;

Het ⁷ represents a 5- or 6-membered saturated, partially saturated or aromatic heterocycle containing (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, optionally substituted by R ⁶ and/or R ⁷ and/or bridged oxo.

In an alternative embodiment a compound of formula (I') is provided:

or a pharmaceutically acceptable derivative thereof, wherein:

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

a represents a number selected from 0 to 6;

b represents a number selected from 0 to 6;

R represents H, CF ₃ or Het;

Het represents a 5- or 6-membered heterocycle containing (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms;

Y represents -[O] _c -[CH ₂ ] _d -R ¹ ;

Y' represents -[O] _c ′-[CH ₂ ] _d ′-R ¹ ′;

c and c' independently represent a number selected from 0 or 1;

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

R ¹ and R ¹ ' independently represent H, halo, CF ₃ or Het ¹ ;

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

Ring A represents a 5- or 6-membered saturated heterocyclic ring containing at least one nitrogen atom;

Z represents -[O] _e- [ _CH2 ] _f - ^R2 , a phenyl ring (optionally fused to a phenyl ring or a 5- or 6-membered saturated, partially unsaturated or aromatic heterocycle, and/ or optionally substituted by one or more groups independently selected from W), or a 6-membered aromatic heterocycle (optionally fused to a phenyl ring or a 6-membered aromatic heterocycle, and/or optionally substituted by one or more groups independently selected from W);

R ² represents C _1-6 alkyl or C _3-6 cycloalkyl;

e represents a number selected from 0 or 1;

f represents a number selected from 0 to 6;

W represents halo, [O] _g R ³ , SO ₂ R ³ , SR ³ , SO ₂ NR ³ R ⁴ , [O] ^h [CH ₂ ] _i CF ₃ , OCHF ₂ , phenyl, CN, phenoxy (optionally substituted by halogen), OH, benzyl, NCOR ³ , benzyloxy, oxy, CONHR ³ , NSO ₂ R ³ R ⁴ , COR ³ , C _1-6 alkylene-NCOR ³ , Het ² ;

^R represents hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 alkylene-OC _1-6 alkyl:

R ⁴ represents hydrogen or C _1-6 alkyl;

i represents a number selected from 0 to 6;

h represents a number selected from 0 or 1;

g represents a number selected from 0 or 1;

Het ² represents a 5- or 6-membered saturated, partially unsaturated or aromatic heterocyclic group comprising (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 Oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, heterocyclic group is optionally substituted by R ³ and/or R ⁴ and/or bridged oxo.

In the above definitions, halo means fluoro, chloro, bromo or iodo. Alkyl, alkylene and alkoxy groups containing the desired number of carbon atoms may be straight or branched. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and tert-butyl. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and tert-butoxy. Examples of alkylene groups include methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene and 2,2-Propylene. Het represents a heterocyclic group, examples of which include tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1 , 4-Oxathianyl, Morpholinyl, 1,4-Dithianyl, Piperazinyl, 1,4-Azathianyl, 3,4-Dihydro-2H-pyranyl , 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2,3,4-tetrahydropyridyl, 1,2,5,6-tetrahydropyridyl, pyrrolyl, furan Base, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1- Oxa-2,3-oxadiazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-oxadiazolyl, 1-thia-2,4-oxadiazolyl, 1-thia-2,5-oxadiazolyl, 1-thia-3,4-oxadiazolyl group, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

Preferred compounds are those wherein X _{represents CH2OCH3} . More preferred are compounds wherein X represents -[ _CH2 ] _aR .

Preferred compounds are those wherein a represents a number selected from 0 to 5. More preferred are compounds wherein a represents a number selected from 0 to 4. Still more preferred are compounds wherein a represents a number selected from 0 to 3. Still more preferred are compounds wherein a represents a number selected from 0 to 2. Most preferred are compounds wherein a represents a number selected from one.

Preferred compounds are those wherein R represents H. More preferred compounds are those wherein R represents Het. Still more preferred are compounds wherein R represents triazolyl.

Preferred compounds are those wherein Y represents one or two substituents. More preferred compounds are those wherein Y represents a single substituent.

Preferred compounds are those wherein Y represents halo. More preferred compounds are those wherein Y represents chlorine and/or fluorine.

Preferred compounds are those wherein V represents a direct bond. Preferred compounds are those wherein Q is a direct bond. More preferred compounds are those wherein both V and Q represent direct bonds.

Preferred compounds are those wherein Ring A contains 2 nitrogen atoms. More preferred compounds are those wherein ring A contains 1 nitrogen atom.

Preferred compounds are those wherein ring A represents a 5-membered compound ring. More preferred compounds are those wherein ring A represents a 6-membered ring. Still more preferred compounds are those wherein ring A represents piperidinylene.

Preferred compounds are those wherein ring A is attached to V via a nitrogen atom. More preferred compounds are those wherein ring A is linked to Q via a nitrogen atom. Preferred compounds are those wherein ring A is linked to Q and V via a nitrogen atom.

Preferred compounds are those wherein Z represents Het ³ . Het ³ may represent an optionally substituted group selected from indazolyl, indolyl, indenyl, pyrazolyl, piperidinyl, pyridyl, pyrimidinyl, pyrrolyl, thiazolyl, benzothienyl, benzothiazole group, quinolinyl, benzoxazinyl, isoxazolyl, imidazolyl, furyl, benzofuryl, cinnolinyl, morpholinyl, chromenyl, or a derivative thereof. More preferred compounds are those wherein Z represents phenyl.

Preferred compounds are those wherein Z is mono- or disubstituted. More preferred compounds are those wherein Z is monosubstituted.

Preferred compounds are those wherein Z is substituted with tri-fluoromethyl. More preferred compounds are those wherein Z is substituted by halogen. More preferred compounds are compounds wherein Z is substituted with chlorine and/or fluorine.

Particularly preferred compounds according to the invention are those listed in the Examples section below, and pharmaceutically acceptable salts thereof. in particular:

(3-chloro-phenyl)-{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4 ]triazol-3-yl]-piperidin-1-yl}-methanone;

(4-chloro-phenyl)-{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4 ]triazol-3-yl]-piperidin-1-yl}-methanone;

(5-chloro-2-fluoro-phenyl)-{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1 , 2,4] Triazol-3-yl]-piperidin-1-yl}-methanone;

{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]- Piperidin-1-yl}-(3,5-difluoro-phenyl)-methanone;

{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]- Piperidin-1-yl}-(3-fluoro-phenyl)-methanone;

{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]- Piperidin-1-yl}-(2,3-difluoro-phenyl)-methanone;

(3-chloro-2-fluoro-phenyl)-{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1 , 2,4] Triazol-3-yl]-piperidin-1-yl}-methanone;

(3-chloro-4-fluoro-phenyl)-{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1 , 2,4] Triazol-3-yl]-piperidin-1-yl}-methanone;

{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]- Piperidin-1-yl}-(4-trifluoromethyl-phenyl)-methanone;

{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]- Piperidin-1-yl}-(3-trifluoromethyl-phenyl)-methanone;

{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]- Piperidin-1-yl}-(2-trifluoromethyl-phenyl)-methanone;

(3-chloro-5-fluoro-phenyl)-{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1 , 2,4] Triazol-3-yl]-piperidin-1-yl}-methanone;

{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]- Piperidin-1-yl}-(4-difluoromethyl-phenyl)-methanone;

{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]- Piperidin-1-yl}-(1H-indazol-3-yl)-methanone;

and pharmaceutically acceptable derivatives thereof.

Pharmaceutically acceptable derivatives of compounds of formula (I) according to the present invention include salts, solvates, complexes, polymorphs, prodrugs, stereoisomers, geometric isomers of compounds of formula (I) variants, tautomeric forms and isotopic variants. Preferably, pharmaceutically acceptable derivatives of compounds of formula (I) include salts, solvates, esters and amides of compounds of formula (I). More preferably, the pharmaceutically acceptable derivatives of the compounds of formula (I) are salts and solvates.

Pharmaceutically acceptable salts of compounds of formula (I) include acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate, bisulfate, borate, camphorsulfonate, citrate, edisylate, ethyl Sulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, seabenzoate, hydrochloride/chloride, bromide Hydrogen/bromide, hydrogen iodide/iodide, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, formazan Sulfate, naphthylate, 2-naphthalenesulfonate, nicotine, nitrate, orotate, oxalate, palmitate, palmoate, phosphate, hydrogen phosphate, diphosphate Hydrogen salt, glucarate, stearate, succinate, sulfate, D- and L-tartrate, tosylate and trifluoroacetate.

Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum salts, arginine salts, dibenzylethylenediamine salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinate salts, lysine salts, magnesium salts, meglumine salts, Ethanolamine, potassium, sodium, tromethamine and zinc salts.

For a review of suitable salts see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weiss-VCH, Weinheim, Germany, 2002. A pharmaceutically acceptable salt of a compound of formula (I) can be prepared by mixing a compound of (I) with the desired acid or base, as appropriate. The salt can precipitate out of solution and be collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in a salt can vary from completely ionized to nearly non-ionized.

The compounds of the invention can exist in unsolvated as well as solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (eg, ethanol). When the solvent is water, the term "hydrate" is used.

Included within the scope of the present invention are complexes such as clathrates, drug-host inclusion complexes, wherein, in contrast to the above-mentioned solvates, the drug and the host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of drugs comprising two or more organic and/or inorganic components present in stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized or non-ionized. For a review of this complex, see Haleblian, J Pharm Sci, 64 (8), 1269-1288 (August 1975).

All references below to compounds of formula (I) and pharmaceutically acceptable derivatives thereof include references to salts, solvates and complexes thereof and solvates and complexes of salts thereof.

The compounds of formula (I) of the present invention include compounds as defined above, their polymorphs as defined below, prodrugs and isomers (including optical, geometric and tautomeric isomers) and formula (I) ) isotopically labeled compounds.

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

So-called "prodrugs" of the compounds of formula (I) are also within the scope of the present invention. Thus certain derivatives of compounds of formula (I) which themselves have little or even no pharmacological activity, when administered into or onto the body, can be converted into compounds of formula (I) having the desired activity, for example, by hydrolysis crack. Such derivatives are called "prodrugs". Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems, Volume 14, ACSSymposium Series (T. Higuchi and W Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (ed. E B Roche , American Pharmaceutical Association).

The prodrugs according to the present invention may, for example, be substituted by certain parts of the "pro-moieties" present in the formula ( I) Appropriate functionality in the compound to produce.

Examples of some prodrugs according to the invention include:

(i) where the compound of formula (I) contains a carboxylic acid functionality (—COOH), its ester, for example, with C ₁ -C ₈ alkyl replacing hydrogen;

(ii) where the compound of formula (I) contains an alcohol functionality (—OH), its ether, for example, replaces the hydrogen with C ₁ -C ₆ alkanoyloxymethyl; and

(iii) where a compound of formula (I) contains a primary or secondary amino functionality (-NH ₂ or -NHR, where R≠H), its amide, for example, with C ₁ -C ₁₀ alkanoyl replacing one or two hydrogens.

Further examples of substituents according to the preceding examples and examples of other prodrug types can be found in the above references.

Finally, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

Also included within the scope of the present invention are metabolites of the compounds of formula (I), when formed in vivo.

Compounds of formula (I) containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. Where compounds of formula (I) contain alkenyl or alkenylene groups, geometric cis/trans (or Z/E) isomers are possible, where compounds contain e.g. ketone or oxime groups or aromatic moieties tautomerism ('tautomerism') can occur. A single compound may thus exhibit more than one type of isomerism.

Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism and mixtures of one or more thereof . Also included are acid addition or base salts where the counterion is optically active, e.g., D-lactate or L-lysine, or racemic, e.g., DL-tartrate or DL-arginine acid.

The cis/trans isomers can be separated by conventional techniques known to those skilled in the art, eg, fractional crystallization and chromatography.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from appropriate optically pure precursors or resolution of racemates (or racemates of salts or derivatives using, for example) chiral HPLC ).

Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound (e.g. alcohol) or, where the compound of formula (I) contains an acidic or basic moiety, with an acid or base such as tartaric acid or 1 -Phenylethylamine reaction. The resulting diastereomeric mixtures may be separated by chromatography and/or fractional crystallization and one or both of the diastereomers converted into the corresponding pure enantiomers by methods known to those skilled in the art.

The chiral compounds of the invention (and their chiral precursors) can be chromatographically, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon (typically heptane or hexane) containing from 0 to 50 % isopropanol, typically from 2% to 20%, and from 0 to 5% alkylamine, typically 0.1% diethylamine, are obtained in enantiomerically enriched form. Concentrating the eluate provides an enriched mixture.

Stereoisomeric aggregates can be separated by conventional techniques known to those skilled in the art - see, e.g., E L Eliel, "Stereochemistry of Organic Compounds" (Weiss, New York, 1994).

The present invention also includes all pharmaceutically acceptable isotopic variations of the compounds of formula (I), wherein one or more atoms have the same atomic number, but the atomic mass or mass number is different from the atomic mass or mass number found in nature atomic replacement.

Examples of isotopes suitable for inclusion in compounds of the invention include isotopes of hydrogen such as ² H and ³ H, carbon such as ¹¹ C, ¹³ C and ¹⁴ C, nitrogen such as ¹³ N and ¹⁵ N, oxygen such as ¹⁵ O, ¹⁷ O and ¹⁶ O, phosphorus such as ³² P, sulfur such as ³⁵ S, fluorine such as ¹⁸ F, iodine such as ¹²³ I and ¹²⁵ I, and chlorine such as ³⁶ Cl.

Certain isotopically-labeled compounds of formula (I), for example those incorporating radioactive isotopes, are useful in drug and/or substrate tissue distribution studies. The radioisotopes tritium, ie ³ H, and carbon-14, ie ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and rapid method of detection.

Substitution by heavier isotopes such as deuterium, i.e., ² H, may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements and thus, may in some cases be preferred.

Substitution with positron-emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, allows for positron emission tomography (PET) studies to examine substrate acceptor occupancy.

Isotope-labeled compounds of formula (I) can generally be replaced by a suitable isotope-labeled reagent by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples and preparations. It is prepared using non-isotopically labeled reagents.

Pharmaceutically acceptable solvates according to the invention include those in which the solvent of crystallization may be isotopically substituted, eg _D2O , _d6 -acetone, _d6 -DMSO.

The compounds of the invention may be used in therapy. Accordingly, a further aspect of the invention is the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as a medicament.

Compounds of the invention show activity as Via antagonists. In particular they are useful in the treatment of a number of conditions including aggressive behavior, Alzheimer's disease, anorexia nervosa, anxiety, anxiety disorders, asthma, atherosclerosis, autism, cardiovascular disease (including angina, atherosclerosis sclerosis, hypertension, heart failure, edema, hypernatremia), cataract, central nervous system disease, cerebrovascular ischemia, liver cirrhosis, cognitive impairment, Cushing's disease, depression, diabetes, dysmenorrhea (primary and secondary), vomiting (including motion sickness), endometriosis, gastrointestinal disorders, glaucoma, gynecological disorders, cardiac disorders, intrauterine growth retardation, inflammation (including rheumatoid arthritis), deficient Blood, ischemic heart disease, lung tumor, voiding disorder, menstrual pain, vegetation, nephrotoxicity, non-insulin-dependent diabetes mellitus, obesity, obsessive-compulsive and behavioral disorder, ocular hypertension, preeclampsia, premature ejaculation, Preterm labor (delivery before full term), lung disease, Raynaud's disease, kidney disease, kidney failure, male or female sexual dysfunction, septic shock, sleep disturbance, spinal cord injury, blood clots, genitourinary tract infection, or urolithiasis. Sleep disturbance, spinal cord injury, blood clots, genitourinary tract infection, or urolithiasis. Of particular interest are dysmenorrhea (primary and secondary), more particularly, primary dysmenorrhea.

Accordingly, a further aspect of the present invention is a method of treating a mammal (including a human) for a disorder for which a Via antagonist is an indication, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof or a solvate administered to a mammal. In particular, compounds of formula (I) are useful in the treatment of anxiety, cardiovascular diseases (including angina, atherosclerosis, hypertension, heart failure, edema, hypernatremia), dysmenorrhea (primary and secondary ), endometriosis, vomiting (including motion sickness), intrauterine growth retardation, inflammation (including rheumatoid arthritis), intermenstrual pain, preeclampsia, premature ejaculation, preterm labor (delivery before term) or Raynaud's disease. Even more particularly, they are useful in the treatment of dysmenorrhea (primary or secondary).

A further aspect of the invention is the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a disorder for which a Via receptor antagonist is an indication.

All compounds of formula (I) can be prepared by the procedures described in the general methods set forth below or by the specific methods described in the Examples section and Preparations section, or by conventional modifications thereof. The invention also encompasses any or one or more of these processes for the preparation of compounds of formula (I), in addition to any novel intermediates employed therein.

Unless otherwise provided herein, otherwise:

WSCDI means 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, DCC means N, N'-dicyclohexylcarbodiimide, HOAT means 1-hydroxy-7-nitrogen Heterobenzotriazole, and HOBT means 1-hydroxybenzotriazole hydrate;

表示苯并三唑-1-基氧基三(吡咯烷基)鳞六氟磷酸盐，PyBrOP表示溴代-三-吡咯烷基-鳞六氟磷酸盐，和HBTU表示O-苯并三唑-1-基-N，N，N’，N’-四甲基脲阳离子六氟磷酸盐；PyBOP

Represents benzotriazol-1-yloxytris(pyrrolidinyl)phosphonium hexafluorophosphate, PyBrOP stands for bromo-tris-pyrrolidinyl-phosphonium hexafluorophosphate, and HBTU stands for O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium cation hexafluorophosphate;

mCPBA means m-chloroperbenzoic acid, AcOH means acetic acid, HCl means hydrochloric acid, TFA means trifluoroacetic acid and p-TSA means p-toluenesulfonic acid;

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

K ₂ CO ₃ means potassium carbonate and KO- ^t Bu means potassium tert-butoxide;

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

BOc represents tert-butoxycarbonyl and CBz represents benzyloxycarbonyl:

PTFE means polytetrafluoroethylene;

MeI represents methyl iodide;

MeTosylate means p-toluenesulfonate methyl ester;

MeOH means methanol, EtOH means ethanol and n-BuOH means n-butanol;

EtOAc represents ethyl acetate, MeCN represents acetonitrile, THF represents tetrahydrofuran, DMSO represents dimethyl sulfoxide, DCM represents dichloromethane, DMF represents N,N-dimethylformamide, NMP represents N-methyl-2-pyrrolidone and DMA means dimethylacetamide;

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

In the following general procedures, unless otherwise indicated, R, R ¹ , R ² , R ³ , ring A, V, X, Q, Z, Y, Y', Het, Het ¹ and Het ² are as before for formula (I) Compound definition. When Q represents NR ² , or Q represents a direct bond to a nitrogen atom within ring A, then compounds of formula (I) can be prepared according to Scheme 1 .

PG represents a suitable N protecting group, typically a benzyl, BOC or CBz group, and preferably BOC.

plan 1

Compounds of formula (II) can be obtained as described in WO 9703986 A1 19970206, or by reaction of the corresponding lower alkyl ester (eg methyl or ethyl) with hydrazine under standard conditions, as exemplified in the preparations below.

Step (a): the compound of formula (III) can be obtained by hydrazine (II) and suitable acetal (such as N,N-dimethylacetamide dimethyl acetal) in suitable solvent such as THF or DMF at room temperature and about Prepared by reacting at 60°C for up to 18 hours. The resulting intermediate can then be treated in a high boiling solvent such as toluene or xylene under acid catalysis (eg p-TSA, or TFA) for about 18 hours to provide compounds of formula (III). Preferred conditions: 1.5-2.0 equivalents of acetal (such as N, N-dimethylacetamide dimethyl acetal, triethyl orthopropionate), in THF or DMF at room temperature to 60 ° C for about 18 hours, Then p-TSA or TFA(cat), refluxed in toluene for 18 hours.

Step (b): The formation of triazole (IV) can be achieved by the compound of formula (III) with a suitable aniline in the presence of a suitable acid catalyst, such as TFA or p-TSA, in a suitable high boiling point solvent (such as toluene or xylene), reaction at elevated temperature. Preferred conditions: 0.5-1.0 equivalents of TFA, 1.0-2.0 equivalents of aniline in toluene at about reflux temperature for up to 18 hours.

Step (c): Deprotection of compound (IV) is performed using standard methods as described by T.W. Greene and P. Wutz in "Protecting Groups in Organic Synthesis". When PG represents BOC, the preferred conditions are: 4M HCl in dioxane, in MeOH, dioxane, or DCM between room temperature and about 50°C for up to 18 hours; or 2.2M HCl in MeOH at room temperature for up to 18 hours;

or TFA in DCM for about 1 hr at room temperature.

Alternatively, when PG represents BOC, compound (V) can be synthesized from compound (III) by treatment with excess TFA, typically 1.1-1.5 equivalents) and the appropriate aniline in toluene at the reflux temperature of the reaction over a period of up to 4 days. directly prepared.

其中T表示OH或Cl)的反应制备。偶合可通过使用下列任一进行：Step (d): The compound of formula (I) can be obtained by amine (V) and suitable acid or acid chloride (

Wherein T represents the reaction preparation of OH or Cl). Coupling can be performed by using any of the following:

(i) acid chlorides, + amine (V), with excess acid-base in a suitable solvent; or

(ii) Acid _ZCO2H with conventional coupler + amine (V) optionally in the presence of a catalyst, with excess base in a suitable solvent.

Typical conditions are as follows:

(i) acid chloride , amine (V) (optionally with excess 3° amine such as _Et3N , Hünig's base or NMM) in DCM or THF without heating, 1 to 24 hours; or

_{or _}

/PyBrOP

/O-苯并三唑-1-基-N，N，N’，N’-四甲基脲阳离子六氟磷酸盐，过量胺，过量的NMM、Et₃N或Hünig氏碱，在THF、DCM、DMA或EtOAc中，在室温下经4到24小时。Acid ZCO ₂ H, PYBOP

/PyBrOP

/O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium cation hexafluorophosphate, excess amine, excess NMM, Et ₃ N or Hünig's base, in THF, in DCM, DMA or EtOAc at room temperature for 4 to 24 hours.

The preferred conditions are:

，1.5-5当量NMM、Et₃N或Hünig氏碱在DCM中，在室温下经至多18小时；1 equivalent of amine (V), 1.0-1.5 equivalents

, 1.5-5 equivalents of NMM, _Et3N or Hünig's base in DCM at room temperature for up to 18 hours;

Or, 1 equivalent of amine (V), 1.2 equivalents of ZCO ₂ H, 1.2-1.5 equivalents of HOBT, 1.2-1.5 equivalents of WSCDI, 2-4 equivalents of Et ₃ N in DCM at room temperature for 24 hours;

Alternatively, 1 eq amine (V), 1.2-1.5 eq _ZCO2H , 1.2-2.0 eq HBTU, 5 eq _Et3N or NMM in DMA or DCM between room temperature and 60 °C for up to 24 hours.

Compounds of formula (IV), wherein Q represents NR ² , or Q represents a direct bond to a nitrogen atom within ring A (which in turn is bonded to the triazole ring via a nitrogen atom), or can be prepared as described in Scheme 2 below, and denoted as (IVA).

Scenario 2.

Step (e): Compounds of formula (VIIIA) can be synthesized by approximately equimolar amounts of isothiocyanate (VI) and amine (VII) in a suitable solvent (e.g. EtOH or DCM) at room temperature for 2 and 72 hours The reaction between preparation. Preferred conditions: 1-1.1 equiv of (VI), 1 equiv of (VII) in EtOH or DCM at room temperature for 0.5-2 hours.

Compounds of formula (VI) and (VII) are commercially available or can be prepared from known compounds using standard chemical transformations.

Step (f): Compounds of formula (IXA) can be prepared by methylation of thiourea (VIIIA) using a methylating agent (e.g. MeI or Me tosylate) in a suitable base (e.g. KOt-Bu) Between 0° C. and the reflux temperature of the reaction in the presence of a suitable solvent such as THF or ether for about 18 hours. Preferred conditions: 1 equiv of (VIIIA), 1-1.2 equiv of KOt-Bu, 1-1.2 equiv of MeI or Me tosylate in THF between 10°C and room temperature for up to 18 hours.

Step (g): Compounds of formula (IVA) can be prepared by reaction of compound (IXA) with an appropriate hydrazide (XCONHNH ₂ ), optionally under acid catalysis (eg TFA or p-TSA) in a suitable solvent (eg THF or n-BuOH), between room temperature and the reflux temperature of the reaction. Preferred conditions: 0.5 equivalents of TFA, excess hydrazide ( _XCONHNH2 ) in THF at reflux for up to 18 hours.

Compounds of formula (VIIIA), wherein Q represents NR ² , or Q represents a direct bond to a nitrogen atom within ring A which in turn is bonded to the triazole ring via a nitrogen atom, or can be prepared as shown in Scheme 3.

Option 3.

Compounds of formula (X) are commercially available or can be prepared from known compounds using standard chemical transformations.

Compounds of formula (XI) can be prepared from isothiocyanates (VI) and amines (X) by methods analogous to those described above for step (e) above.

Step (h): Compounds of formula (VIIIA) can be obtained by protection of the reactive nitrogen atom using standard methods as described by T.W. Greene and P. Wutz in "Protecting Groups in Organic Synthesis". When PG is BOC, the preferred conditions are: 1 equivalent of amine (XI), 1 equivalent of di-tert-butyl bicarbonate in DCM and dioxane at room temperature for about 3 hours.

Compounds of formula (VIII), wherein Q represents NR ² , or Q represents a direct bond to a nitrogen atom within ring A (which in turn is bonded to the triazole ring via a nitrogen atom), can be prepared as described in Scheme 4 and represent is (VIIIB).

Option 4.

Step (i): Compounds of formula (XIV) can be prepared by coupling anilines (XIII) with acids (XII) in analogy to methods previously described for step (d). Preferred conditions: 1 eq acid (XII), 1.1 eq amine (XIII), 1.2 eq WSCDI, 3 eq _Et3N in MeCN at room temperature for about 3 days.

Step (j): Compound of formula (VIIIB) undergoes sulfidation of compound (XIV) by treatment with a suitable sulfiding agent (eg Lawesson's reagent) in a high boiling point solvent (eg toluene) between room temperature and the reflux temperature of the reaction preparation. Preferred conditions: 1 equivalent of (XIV), 0.5 equivalents of Lawesson's reagent in toluene, between room temperature and reflux, over a period of up to 18 hours.

Compounds of formula (III), wherein Q represents NR ² , or Q represents a direct bond to a nitrogen atom within ring A, or can be prepared as shown in Scheme 5.

Option 5.

Step (k): The di-acylhydrazide (XV) can be obtained by coupling the hydrazide (II) with an acid, or an acid chloride ( , wherein T represents Cl or OH) preparation. Preferred conditions: 1 eq hydrazide (II), 1.1 eq _XCO2H , 1.1 eq WSCDI, 1.1 eq HOBT, 1.2 eq _Et3N in DMF at room temperature for 18 hours.

Step (l): Oxadiazole (III) can be prepared by cyclization of compound (XV), typically in the presence of acid catalysis (e.g. polyphosphoric acid, POCl ₃ , trifluoromethanesulfonic anhydride/pyridine, or 1-methylimidazole ), optionally in a suitable solvent (eg DCM), between 0 °C and the reflux temperature of the reaction. Preferred conditions: 1 eq. (XV), excess pyridine or 1-methylimidazole, 1.5-2 eq. trifluoromethanesulfonic anhydride in DCM, between 0° C. and room temperature for up to 3 hours.

Compounds of formula (XV) can alternatively be prepared by coupling acid (XII) with the appropriate hydrazide ( _XCONHNH2 ) analogously to the method previously described in step (d). Preferred conditions: 1 equiv of acid (XII), 1 equiv of hydrazide, 1.02 equiv of WSDCI in DCM between 0 °C and room temperature.

Compounds of formula (III), wherein X represents _CH2N -attached-Het, may alternatively be prepared as shown in Scheme 6.

Option 6

Step (m): Compounds of formula (XVI) can be obtained by reaction of hydrazide (II) with chloroacetyl chloride in a suitable solvent (eg EtOAc or DCM) in the presence of a suitable 3° amine base (eg _Et3N or NMM) Prepared between 0°C and room temperature over about 18 hours. Preferred conditions: 1 equiv of (II), 1 equiv of acetyl chloride, 1.1 equiv of NMM in DCM at 10° C. to room temperature over up to 18 hours.

Compounds of formula (XVII) can be prepared by cyclizing compounds (XVI) analogously to the methods previously described in step (1).

Step (n): Compounds of formula (III) can be reacted by compound (XVII) with an appropriate Het (containing a reactive N atom) in the presence of an appropriate base (eg Et ₃ N or K ₂ CO ₃ ) in an appropriate Preparation in a solvent such as DMF or MeCN between room temperature and the reflux temperature of the reaction over about 18 hours. Preferred conditions: 1 eq (XVII), 1.4 eq _K2CO3 , 2 eq Het in DMF at room _temperature over 18 hours.

Compounds of formula (I), wherein Q represents NR ² , or Q represents a direct bond to a nitrogen atom within ring A, or can be prepared as shown in Scheme 7.

Ra represents C _1-4 alkyl or benzyl, and is preferably Me or Et.

Option 7

Step (o): Compounds of formula (XIX) can be obtained by reacting amine (XVIII) with a suitable acid, or acid chloride ( , T represents the reaction preparation of OH or Cl). Preferred conditions: 1 eq (XVIII), 0.9 eq ZCOCl, _1.1 eq Et3N in DCM between 10 °C and room temperature over about 3 hours.

Step (p): Hydrazides of formula (XX) can be prepared by treating esters (XIX) with excess hydrazine in a suitable solvent such as EtOH or MeOH at the reflux temperature of the reaction for up to 18 hours. Preferred conditions: 1 equiv of (XIX), 2-4 equiv of hydrazine in MeOH at reflux between 10 and 48 hours.

的反应制备。Compounds of formula (XXI) can be obtained by combining hydrazide (XX) with

reaction preparation.

Compounds of formula (XXII) can be prepared by cyclization of compounds (XXI) using methods analogous to those previously described in step (1).

Compounds of formula (I) can be prepared from oxadiazole (XXII) and the appropriate aniline as described in step (b) above.

Alternatively, the compound of formula (XXII) can be synthesized by dimethyl acetalization with a suitable acetal (eg triethyl orthopropionate, N,N-dimethylacetamide) in a manner similar to that previously described in step (a). Aldehydes), prepared directly from compound (XX).

Compounds of formula (XXII), wherein X represents _CH2 -N-attached-Het, may alternatively be prepared as shown in Scheme 8.

Option 8

Compounds of formula (XXIII) can be prepared by reaction of hydrazide (XX) with chloroacetyl chloride analogously to the method previously described in step (m).

Oxadiazole (XXIV) can be prepared by cyclization of compound (XXIII) similarly to the method previously described in step (1).

Compound (XXII) can be prepared by reacting compound (XXIV) with an appropriate Het (containing a reactive N atom) as described in the aforementioned step (n).

Compounds of formula (I), wherein Ring A is attached to the triazole ring via a nitrogen atom, may alternatively be prepared as shown in Scheme 9.

Option 9

Compounds of formula (XXV) are commercially available or can be prepared from commercial compounds using standard chemical transformations.

Compounds of formula (XXVI) can be prepared by reacting compound (XXV) with an appropriate isothiocyanate (VI) in analogy to the method previously described in step (e).

Compounds of formula (XXVII) can be prepared by alkylation of compounds (XXVI) analogously to methods previously described in step (f).

Compounds of formula (I) can be prepared by reaction of compound (XXVII) with an appropriate hydrazide as described in step (g) above.

A compound of formula (I), wherein Q represents a direct bond to a carbon atom in ring A, which in turn is connected to the triazole ring via a nitrogen atom in ring A, and Z represents NR ⁴ R ⁵ , can be represented as shown in Scheme 10 shows preparation.

Ra represents C _1-4 alkyl or benzyl, and preferably Me or Et.

Scheme 10

Compounds of formula (XXVIII) are commercially available or can be prepared from commercial compounds using standard chemical transformations.

Compounds of formula (XXIX) can be prepared by reaction of compound (XXVIII) with an appropriate isothiocyanate (VI) analogously to the method previously described in step (e).

Compounds of formula (XXX) can be prepared by alkylation of compounds (XXIX) in a manner similar to that previously described in step (f).

Compounds of formula (XXXI) can be prepared by reacting compound (XXX) with an appropriate hydrazide as described in step (g) above.

Step (q): Hydrolysis of the ester (XXXI) using a suitable acid or base catalyst, preferably a suitable alkali metal base (such as NaOH, KOH or LiOH) in a suitable aqueous solvent (such as in dioxane or MeOH) at room temperature and reaction between 2 and 48 hours at reflux temperature. Preferred conditions: 1 equiv of (XXXI), 5-10 equiv of NaOH solution in dioxane between room temperature and reflux for between 2 and 16 hours.

Compounds of formula (I) can be prepared by reaction of ZH (containing a reactive N atom) with acid (XXXII) analogously to the method previously described in step (d). Preferred conditions: 1 eq acid (XXXII), 1.5 eq amine (ZH), 4 eq _Et3N , 1.5 eq WSCDI, 1.5 eq HOBT at room temperature in DCM for 24 hours.

Compounds of formula (XXXII) can alternatively be prepared by hydrolysis of the corresponding nitrile compound (XXXIII) under standard conditions (e.g. 5 equivalents of KOH, 1 equivalent of nitrile (XXXIII) at reflux in ethanol/ethylene glycol dimethyl ether) .

Compounds of formula (XXXIII) can be prepared as shown in Scheme 11.

Scheme 11

Compounds of formula (XXXIII), wherein Q is a direct bond and ring A is attached to the triazole ring via a nitrogen atom, can be obtained from appropriate isothiocyanates (VI) and nitrile-containing A ring, preparation.

Compounds of formula (I), wherein V represents an oxygen atom, can be prepared as shown in Scheme 12.

Scheme 12

Step (r): Compounds of formula (XXXV) can be prepared by reaction of hydrazide ( _XCONHNH2 ) with isothiocyanate (VI) analogously to the method previously described in step (e). Preferred conditions: 1 equivalent of isothiocyanate, 1 equivalent of hydrazide in EtOH at room temperature for 72 hours.

Step (s): Compounds of formula (XXXVI) can be cyclized by compound (XXXV) under acid or base conditions, preferably base-catalyzed (eg alkali metal hydroxide) in an aqueous solvent (eg water/EtOH) , prepared at elevated temperature over about 24 hours. Preferred conditions: 1 eq (XXXV), 10 eq NaOH (aq) in EtOH at 80 °C for 18 h.

Step (t): Alkylation of compound (XXXVI) to provide compound (XXXVII) can be carried out analogously to the method previously described in step (f) by adding a suitable alkylating agent such as MeI or Me-toluenesulfonate acid ester) treatment. Preferred conditions: 1 eq (XXXVI), 1 eq KO tert-Bu, 1 eq Me-tosylate in THF between RT and reflux for 3 hours.

Step (u): Compound of formula (XXXVIII) can be obtained by oxidation of compound (XXXVII) treated with a suitable oxidizing agent such as mCPBA or hydrogen peroxide in a suitable solvent such as DCM for about 18 hours at room temperature. Preferred conditions: 1 equiv of (XXXVII), 4 equiv of mCPBA in DCM at room temperature for 18 hours.

Step (v): The compound of formula (I) can be reacted by sulfoxide with excess alcohol (XXXIX), in the presence of a suitable base (such as NaH or KO tert-Bu), in a suitable solvent (such as THF or ether), Prepare between 0 and room temperature for up to 18 hours. Preferred conditions: 1 equiv (XXXVIII), 2 equiv NaH, 2 equiv alcohol (XXXIX), in THF at room temperature for 18 hours.

Compounds of formula (XXXIX) are commercially available or can be prepared from commercial compounds using standard chemical transformations.

Certain compounds of formula (I), (III), (IV), (V), (XXII) and (XXXI) can undergo functional group interconversion (e.g., alkylation, or hydrolysis) to provide formula (I), respectively ), (III), (IV), (V), (XXII) or (XXXI) alternative compounds.

Compounds of the invention intended for pharmaceutical use may be administered in crystalline or amorphous form. They can be obtained, for example, as solid plugs, powders or films by such methods as precipitation, crystallization, freeze-drying, spray-drying or evaporative drying. Microwave or radiation frequency drying can be used for this purpose.

They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or any combination thereof). Typically, they will be administered in a formulation in combination with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than a compound of the invention. The choice of excipient will depend largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

A further aspect of the present invention is a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient, diluent or carrier. In a further embodiment there is provided a pharmaceutical formulation for administration prophylactically or when affliction begins.

Pharmaceutical compositions suitable for the delivery of the compounds of the invention and methods for their preparation will be apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences. , 19th Edition (Mack Publishing Company, 1995).

The compounds of the invention can be administered orally. Oral administration can involve swallowing, allowing the compound to enter the gastrointestinal tract, or buccal or sublingual administration can be employed, whereby the compound enters the bloodstream directly from the mouth.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing granules, liquids, or powders, troches (including liquid-filled), chewable lozenges, multi- and nano-particulates, gels, solid solutions, Liposomes, films, pessaries, sprays and liquid formulations.

Liquid preparations include suspensions, solutions, syrups and elixirs. The formulations can be used as fillers in soft or hard capsules and typically contain a carrier such as water, ethanol, polyethylene glycol, polypropylene glycol, methylcellulose or a suitable oil and one or more emulsifying agents and / or suspending agent. Liquid preparations can also be prepared by reconstitution (eg, from packets) of solids.

The compounds of the invention can also be administered in fast dissolving, fast disintegrating dosage forms such as those described by Liang and Chen in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 (2001).

For tablet dosage forms, depending on the dosage, the drug may comprise from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight of the dosage form. Tablets usually contain disintegrants in addition to the drug. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline Cellulose, lower alkyl substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Typically, the disintegrant will comprise from 1% to 25% by weight of the dosage form, preferably from 5% to 20% by weight.

Binders are often used to impart cohesive qualities to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycols, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and phosphoric acid Calcium hydrogen dihydrate.

Tablets may also optionally contain surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactant can comprise from 0.2% to 5% by weight of the tablet, and the glidant can comprise from 0.2% to 1% by weight of the tablet.

Tablets also usually contain lubricating agents such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Lubricants generally comprise from 0.25% to 10% by weight of the tablet, preferably from 0.5% to 3% by weight.

Other possible ingredients include antioxidants, coloring agents, flavoring agents, preservatives and taste-masking agents.

A typical tablet contains up to about 80% drug, from about 10% to about 90% binder by weight, from about 0% to about 85% diluent by weight, from about 2% to about 10% disintegrant by weight , and from about 0.25% to about 10% by weight lubricant.

Tablet blends can be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded prior to tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.

The formulation of tablets is discussed by H. Lieberman and L. Lachman in Pharmaceutical Dosage Forms: Tablets . Volume 1 (Marcel Dekker, New York, 1980).

Consumable oral films for human or veterinary use are typically flexible water-soluble or water-swellable film dosage forms which are rapidly dissolving or mucoadherent and typically comprise a compound of formula (I), a film-forming polymer, a binder, a solvent , humectants, plasticizers, stabilizers or emulsifiers, viscosity-correctors and solvents. Some components of the formulation may perform more than one function.

Compounds of formula (I) may be water soluble or water insoluble. The water soluble compound typically comprises from 1% to 80% by weight of the solute, more typically from 20% to 50% by weight. The less soluble compound may comprise a larger proportion of the composition, typically up to 88% by weight of the solute. Alternatively, the compound of formula (I) may be in the form of multiparticulate beads.

Film-forming polymers may be selected from natural polysaccharides, proteins or synthetic hydrocolloids and are typically present in the range of 0.01 to 99% by weight, more typically in the range of 30 to 80% by weight.

Other possible ingredients include antioxidants, colorants, flavoring agents and flavor enhancers, preservatives, salivary stimulants, cooling agents, co-solvents (including oils), lubricants, fillers, anti-foaming agents, surfactants and Taste-masking agent.

Films according to the invention are typically prepared by evaporative drying of thin aqueous films coated on a release backing support or paper. This can be done in an oven or tunnel, typically with a coat dryer, or by freeze drying or vacuum.

Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

Suitable modified release formulations for the purposes of the present invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and infiltrated and coated particles are found in Verma et al., Pharmaceutical Technology On-line , 25(2), 1-14 (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298.

The compounds of the invention may also be administered directly into the bloodstream, into a muscle, or into an internal organ. Suitable methods for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffers (preferably to a pH of 3 to 9), however, for some applications they may be more suitably formulated as sterile non-aqueous solutions Or in dry form for use with a suitable vehicle, eg sterile pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by freeze-drying, is readily accomplished using standard pharmaceutical techniques known to those skilled in the art.

The solubility of compounds of formula (I) for use in the formulation of parenteral solutions may be increased through the use of appropriate formulation techniques, for example, the incorporation of solubility-enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. The compounds of the present invention may thus be formulated as solid, semi-solid, or thixotropic liquids for administration into implanted depots providing modified release of the active compound. Examples of such formulations include drug-coated stents and poly(dl-lacto-co-glycolic) acid (PGLA)-microspheres.

The compounds of the invention may also be administered topically to the skin or mucous membranes, ie, dermally or transdermally. Typical formulations used for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers , bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, Finnin and Morgan, J Pharm Sci, 88(10), 955-958 (October 1999).

Other devices for local administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free (eg, Powderject ^™ , Bioject ^™, etc.) injection.

Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

The compounds of the invention may also be administered intranasally or by inhalation, typically in dry powder form (or alone, in admixture, e.g., with lactose dry blend, or in mixed ingredient particles, e.g., with phospholipids, e.g. Acylcholine mix) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, nebulizer, nebulizer (preferably one using electrohydrodynamics to produce a fine mist), or a nebulizer, with or No suitable propellants such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane were used. For intranasal use, powders may contain bioadhesives, eg, chitosan or cyclodextrin.

Pressurized container, pump, nebulizer, nebuliser, or nebulizer containing a solution or suspension of a compound of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable substitute for dispersion, solubilization, or prolonged release of the active ingredient , a propellant as a solvent and optionally a surfactant such as sorbitan trioleate, oleic acid, or oligolactic acid.

The drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns) prior to use in dry powder or suspension formulations. This can be achieved by any suitable comminution method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (made with, for example, gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a compound of the invention, a suitable powder base such as lactose or starch Powder mix with potency modifiers such as l-leucine, mannitol, or magnesium stearate. Lactose may be in anhydrous or monohydrate form, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

Solution formulations suitable for use in nebulizers using electrohydropneumatics to generate a fine mist may contain from 1 microgram to 20 mg of a compound of the invention per actuation and the actuation volume may vary from 1 microliter to 100 microliters. A typical formulation may contain a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycols.

Suitable flavoring agents, such as menthol and levomenthol, or sweetening agents, such as saccharin or sodium saccharin, may be added to the formulations of the invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a metered amount. The total daily dosage may typically range from 0.01 micrograms to 15 milligrams, which may be given in a single dose or, more usually, in divided doses throughout the day.

The compounds of the invention can be administered rectally or intravaginally, for example, in the form of suppositories, pessaries, or enemas. Cocoa butter is the traditional suppository base, but various alternatives may be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops as micronized suspensions or solutions in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and nonbiodegradable (e.g., silicone) implants, wafers, lenses, and particles or small cellular systems, such as nonionic surfactant vesicles (niosomes) or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, fiber polymers, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers, for example, Gelan gum, may incorporate preservatives such as benzalkonium chloride. The formulation can also be delivered by iontophoresis.

Formulations for ophthalmic/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

The compounds of the present invention may be combined with soluble macromolecular entities such as cyclodextrins and their appropriate derivatives or polyethylene glycol-containing polymers in order to improve their solubility, dissolution rate when used in any of the above modes of administration , taste masking, bioavailability and/or stability.

Drug-cyclodextrin complexes, for example, find general use in most dosage forms and routes of administration. Both inclusion complexes and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrins can be used as auxiliary additives, ie as carriers, diluents, or solubilizers. Most commonly used for these purposes are α-, β- and γ-cyclodextrins, examples of which can be found in International Patent Applications WO 91/11172, WO 94/02518 and WO 98/55148.

Whenever it may be desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the invention that two or more pharmaceutical compositions, at least one of which comprises a compound according to the invention , may be conveniently combined into the form of a kit suitable for co-administration of the compositions.

The kit of the present invention thus comprises two or more separate pharmaceutical compositions, at least one of which comprises a compound of formula (I) according to the present invention, and means for separately retaining the compositions, such as a container, a separate bottle, or separate foil pouch. An example of such a kit is the familiar blister pack for packaging tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different dosage forms, eg oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions with each other. To aid compliance, kits typically contain directions for administration and may be provided with so-called memory aids.

For administration to human patients, the total daily dose of the compounds of the invention will typically range from 0.01 mg to 50 mg, depending, of course, on the mode of administration. The total daily dosage may be administered in single or divided doses and may, at the discretion of the physician, fall outside the typical ranges given herein.

These dosages are based on a human individual having an average weight of about 65 kg to 70 kg. A physician will readily be able to determine dosage for subjects whose weight falls outside this range, such as infants and the elderly.

For the avoidance of doubt, references herein to "treatment" include curative, relieving and prophylactic treatments. Compounds of the invention can be tested in the following screens:

1.0V _1A filter binding test

1.1 Membrane preparation

Receptor binding assays were performed on membranes prepared from CHO cells stably expressing the human V _1A receptor, (CHO-hV _1A ). The CHO-hV _1A cell line was kindly provided by Marc Thibonnier, Dept. of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH under a license agreement. CHO-V _1A cells were routinely maintained at 37°C in a humidified _environment with 5% CO in DMEM/Hams supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 15 mM HEPES, and 400 μg/ml G418 F12 Nutrient Blend. For mass production of cell pellets, make adherent CHO-hV _1A cells in 850 cm roller bottles containing medium containing a DMEM/Hams F12 nutrient mixture supplemented with 10% fetal bovine serum, 2 mM L-glutamine, and 15 mM HEPES. Grow to 90-100% confluency. Confluent CHO-hV _1A cells were washed with phosphate-buffered saline (PBS), collected into ice-cold PBS and centrifuged at 1,000 rpm. Cell pellets were stored at -80°C until use. Cell pellets were thawed on ice and homogenized in membrane preparation buffer consisting of 50 mM Tris-HCl, pH 7.4, 5 mM _MgCl2 supplemented with protease inhibitor cocktail (Roche). The cell homogenate was centrifuged at 1000 rpm for 10 minutes at 4°C, the supernatant was removed and stored on ice. The remaining pellet was homogenized and centrifuged as before. The supernatant was collected and centrifuged at 25,000 xg for 30 minutes at 4°C. Pellets were resuspended in freezing buffer consisting of 50 mM Tris-HCl, pH 7.4, 5 mM _MgCl2 and 20% glycerol and stored in small aliquots at -80°C until use. Protein concentrations were determined using Bradford reagent and BSA as standards.

1.2V _1A filter combined

Protein linearity according to saturation binding studies was performed on each new batch of membranes. Choose the membrane concentration that produces specific binding in the linear portion of the curve. Saturation binding studies and determination of K _d and B _max were then performed using various concentrations of [ ³ H]-arginine vasopressin, [ ³ H]-AVP (0.05 nM-100 nM).

Compounds were tested for their effect on [ ³ H]-AVP binding to CHO-hV _1A membranes ( ³ H-AVP; specific activity 65.5 Ci/mmol; NEN Life Sciences). Compounds were dissolved in dimethyl sulfoxide (DMSO) and diluted to a working concentration of 10% DMSO in assay buffer containing 50 mM Tris-HCL pH 7.4, 5 mM MgCl ₂ and 0.05% BSA. 25 microliters of compound and 25 microliters of [ ^3H ]-AVP, (final concentration at or below membrane batch determined _Kd , typically 0.5nM-0.6nM) were added to 96-well round bottom polypropylene plates. Binding reactions were initiated with the addition of 200 microliters of membrane and the plate was shaken gently for 60 minutes at room temperature. Reactions were terminated by rapid filtration using a Filtermate cell harvester (Packard Instruments) through 96-well GF/BUniFilter plates that had been pre-soaked in 0.5% polyethyleneimine to avoid peptide adhesion. The filter was washed three times with 1 mL of ice-cold wash buffer containing 50 mM Tris-HCL pH 7.4 and 5 mM _MgCl2 . The plate was dried and 50 microliters of Microscint-0 (Packard Instruments) was added to each well. The plate was blocked and counted on a TopCount microplate scintillation counter (Packard Instruments). Non-specific binding (NSB) by using 1 μM unlabeled d(CH ₂ ) ₅ Tyr(Me)AVP, ([β-mercapto-β, β-cyclopentamethylenepropionyl, 0-Me-Tyr ² , Arg ⁸ ]-vasopressin) (βMCPVP), (Sigma) assay. The radioligand binding data were analyzed using a four parameter logarithmic equation with minimum forced to 0%. The slope of the valid curve was not fitted and fell between -0.75 and -1.25. Specific binding was calculated by subtracting mean NSB cpm from mean total cpm. For test compounds, the amount of ligand bound to the receptor is expressed as % binding = (cpm sample - cpm mean NSB) / cpm specific binding x 100. Plot % binding versus concentration of test compound and fit a sigmoid curve. The inhibitory dissociation constant (K _i ) was calculated using the Cheng-Prusoff equation: K _i =IC ₅₀ /(1+[L]/K _d ), where [L] is the concentration of ligand present in the well and K _d is Dissociation constants for radioligands from Scatchard plot analysis.

2.0 V _1A functional assay; inhibition of AVP/V _1A -R mediated ^Ca transfer by FLIPR (Fluorescent Imaging Plate Reader (Molecular Devices)

Intracellular calcium release was measured in CHO-hV _1A cells using FLIPR, which allows rapid detection of calcium following receptor activation. The CHO-hV _1A cell line was kindly provided by Marc Thibonnier, Dept. of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH under a license agreement. CHO-V _1A cells were routinely maintained at 37°C in a humidified _environment with 5% CO in DMEM/Hams supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 15 mM HEPES, and 400 μg/ml G418 F12 Nutrient Blend. Cells were plated in black sterile 96-well plates with clear bottoms at a density of 20,000 cells per well the afternoon before assaying cells to allow cell inspection and fluorescence measurements from the bottom of each well. Washing buffer containing Dulbecco's phosphate-buffered saline (DPBS) and 2.5 mM probenecid was freshly prepared on the day of the experiment and cell culture medium (Molecular Probes) and a loading dye consisting of 2.5 mM probenecid. Compounds were dissolved in DMSO and diluted in assay buffer consisting of DPBS containing 1% DMSO, 0.1% BSA and 2.5 mM probenecid. The cells were loaded with dye at 100 μl per well and incubated at 37° C. in a humidified environment with 5% CO ₂ for 1 hour. After dye loading, the cells were washed three times with 100 microliters of wash buffer using a Denley plate washer. Leave 100 µl of wash buffer in each well. Intracellular fluorescence was measured using FLIPR. Fluorescence readings were taken at 2 second intervals after 30 seconds with the addition of 50 microliters of test compound. An additional 155 measurements were then taken at 2 second intervals to detect any compound agonistic activity. 50 microliters of arginine vasopressin (AVP) was then added to make a final assay volume of 200 microliters. Further fluorescence readings were then collected at 1 second intervals for 120 seconds. Responses were measured as peak fluorescence intensity (FI). For pharmacological characterization, the base FI was subtracted from each fluorescent response. For AVP dose response curves, each response is expressed as % of response to the highest concentration of AVP in that row. For _IC50 determinations, each response is expressed as a % response to AVP. IC50 values were converted to corrected _Kb values using the Cheng-Prusoff equation, which takes into account agonist concentration, [A], agonist _EC50 and slope: _Kb = _IC50 /(2+[A]/ _A50 ] ⁿ ) ^1/n- 1, where [A] is the concentration of AVP, _A50 is the _EC50 of AVP from the dose-response curve and n=slope of the AVP dose-response curve.

A compound of the invention may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or any combination thereof). The compounds of the invention may be administered in combination with oral contraceptives. Thus in a further aspect of the invention there is provided a pharmaceutical product comprising a Via antagonist and an oral contraceptive as a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhea. Pharmaceutical products in which the compounds of the invention may be administered in combination with PDE5 inhibitors. Thus in a further aspect of the invention there is provided a pharmaceutical product comprising a Via antagonist and a PDE5 inhibitor as a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhea.

PDEV inhibitors that may be used in combination with Via antagonists include (but are not limited to):

(i) In International Patent Application Publication Nos. WO 03/000691; WO 02/64590; WO 02/28865; WO 02/28859; WO 02/38563; WO 02/36593; /00656, the PDE5 inhibitors mentioned in WO 02/10166; WO 02/00658; WO 01/94347; WO 01/94345; WO 00/15639 and WO 00/15228;

(ii) PDE5 inhibitors mentioned in US Patent Nos. 6,143,746; 6,143,747 and 6,043,252;

(iii) pyrazolo[4,3-d]pyrimidin-7-ones disclosed in EP-A-0463756; pyrazolo[4,3-d]pyrimidines disclosed in EP-A-0526004- 7-ketones; pyrazolo[4,3-d]pyrimidin-7-ones disclosed in published international patent application WO 93/06104; isomers disclosed in published international patent application WO 93/07149 Pyrazolo[3,4-d]pyrimidin-4-ones; quinazolin-4-ones disclosed in published international patent application WO 93/12095; disclosed in published international patent application WO 94/05661 Pyrido[3,2-d]pyrimidin-4-ones; Purin-6-ones disclosed in published international patent application WO 94/00453; disclosed in published international patent application WO 98/49166 pyrazolo[4,3-d]pyrimidin-7-ones; the pyrazolo[4,3-d]pyrimidin-7-ones disclosed in published international patent application WO 99/54333; disclosed in Pyrazolo[4,3-d]pyrimidin-4-ones in EP-A-0995751; Pyrazolo[4,3-d]pyrimidin-7 disclosed in published international patent application WO 00/24745 - Ketones; pyrazolo[4,3-d]pyrimidin-4-ones disclosed in EP-A-0995750; hexahydropyrazino[2 ',1': 6,1]pyrido[3,4-b]indole-1,4-diones; pyrazolo[4,3-d]pyrimidine-4 disclosed in WO 00/27848 - Ketones; imidazo[5,1-f][1,2,4]triazine-ketones disclosed in EP-A-1092719 and published international patent application WO 99/24433 and disclosed in published international patent application WO 99/24433 Bicyclic compounds in patent application WO 93/07124; pyrazolo[4,3-d]pyrimidin-7-ones disclosed in published international patent application WO 01/27112; disclosed in published international patent application WO 01/27112; Pyrazolo[4,3-d]pyrimidin-7-ones of 01/27113; compounds disclosed in EP-A-1092718 and compounds disclosed in EP-A-1092719; disclosed in EP-A- Tricyclic compounds in 1241170; Alkylsulfone compounds disclosed in published international patent application WO 02/074774; Compounds disclosed in published international patent application WO 02/072586; Compounds disclosed in published international patent application WO 02/072586 079203 and compounds disclosed in WO 02/074312.

销售)，也被称为1-[[3-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3-d]嘧啶-5-基)-4-乙氧基苯基]磺酰基]-4-甲基哌嗪(参见EP-A-0463756)；5-(2-乙氧基-5-吗啉基乙酰基苯基)-1-甲基-3-正-丙基-1，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮(参见EP-A-0526004)；3-乙基-5-[5-(4-乙基哌嗪-1-基磺酰基)-2-正-丙氧基苯基]-2-(吡啶-2-基)甲基-2，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮(参见WO98/49166)；3-乙基-5-[5-(4-乙基哌嗪-1-基磺酰基)-2-(2-甲氧基乙氧基)吡啶-3-基]-2-(吡啶-2-基)甲基-2，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮(参见WO 99/54333)；(+)-3-乙基-5-[5-(4-乙基哌嗪-1-基磺酰基)-2-(2-甲氧基-1(R)-甲基乙氧基)吡啶-3-基]-2-甲基-2，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮，也被称为3-乙基-5-{5-[4-乙基哌嗪-1-基磺酰基]-2-([(1R)-2-甲氧基-1-甲基乙基]氧基)吡啶-3-基}-2-甲基-2，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮(参见WO 99/54333)；5-[2-乙氧基-5-(4-乙基哌嗪-1-基磺酰基)吡啶-3-基]-3-乙基-2-[2-甲氧基乙基]-2，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮，也被称为1-{6-乙氧基-5-[3-乙基-6，7-二氢-2-(2-甲氧基乙基)-7-氧代-2H-吡唑并[4，3-d]嘧啶-5-基]-3-吡啶基磺酰基}-4-乙基哌嗪(参见WO 01/27113，实施例8)；5-[2-异-丁氧基-5-(4-乙基哌嗪-1-基磺酰基)吡啶-3-基]-3-乙基-2-(1-甲基哌啶-4-基)-2，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮(参见WO01/27113，实施例15)；5-[2-乙氧基-5-(4-乙基哌嗪-1-基磺酰基)吡啶-3-基]-3-乙基-2-苯基-2，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮(参见WO01/27113，实施例66)；5-(5-乙酰基-2-丙氧基-3-吡啶基)-3-乙基-2-(1-异丙基-3-吖丁啶基)-2，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮(参见WO01/27112，实施例124)；5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-吖丁啶基)-2，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮(参见WO01/27112，实施例132)；(6R，12aR)-2，3，6，7，12，12a-六氢-2-甲基-6-(3，4-亚甲基二氧基苯基)吡嗪并[2′，1′∶6，1]吡啶并[3，4-b]吲哚-1，4-二酮(塔达拉非(tadalafil)，IC-351，犀利士(Cialis)

)，即公开的国际专利申请WO95/19978的实施例78和95的化合物，以及实施例1、3、7和8的化合物；2-[2-乙氧基-5-(4-乙基-哌嗪-1-基-1-磺酰基)-苯基]-5-甲基-7-丙基-3H-咪唑并[5，1-f][1，2，4]三嗪-4-酮(瓦地那非(vardenafil)，LEVITRA)也被称为1-[[3-(3，4-二氢-5-甲基-4-氧代-7-丙基咪唑并[5，1-f]-as-三嗪-2-基)-4-乙氧基苯基]磺酰基]-4-乙基哌嗪，即公开的国际专利申请WO 99/24433的实施例20、19、337和336的化合物；公开的国际专利申请WO 93/07124的实施例11的化合物(EISAI)；得自Rotella D P，J.Med.Chem.，2000，43，1257的化合物3和14；4-(4-氯苯甲基)氨基-6，7，8-三甲氧基喹唑啉：N-[[3-(4，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3-d]-嘧啶-5-基)-4-丙氧基苯基]磺酰基]-1-甲基2-吡咯烷丙酰胺[″DA-8159″(WO 00/27848的实施例68)]；和7，8-二氢-8-氧代-6-[2-丙氧苯基]-1H-咪唑并[4，5-g]喹唑啉和1-[3-[1-[(4-氟苯基)甲基]-7，8-二氢-8-氧代-1H-咪唑并[4，5-g]喹唑啉-6-基]-4-丙氧苯基]甲酰胺。(iv) preferably 5-[2-ethoxy-5-(4-methyl-1-piperazinesulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-di Hydrogen-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil, e.g. Viagra

sales), also known as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidine- 5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine (see EP-A-0463756); 5-(2-ethoxy-5-morpholinoacetylphenyl )-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see EP-A-0526004); Base-5-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-di Hydrogen-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO98/49166); 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulfonyl) -2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d ]pyrimidin-7-one (see WO 99/54333); (+)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-(2-methoxy Base-1(R)-methylethoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, Also known as 3-ethyl-5-{5-[4-ethylpiperazin-1-ylsulfonyl]-2-([(1R)-2-methoxy-1-methylethyl] Oxy)pyridin-3-yl}-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO 99/54333); 5-[ 2-Ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6- Dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, also known as 1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2 -(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazine ( See WO 01/27113, Example 8); 5-[2-iso-butoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl- 2-(1-methylpiperidin-4-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO01/27113, Example 15); 5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H -pyrazolo[4,3-d]pyrimidin-7-one (see WO01/27113, Example 66); 5-(5-acetyl-2-propoxy-3-pyridyl)-3-ethane Base-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d ] pyrimidin-7-one (see WO01/27112, Example 124); 5-(5-acetyl-2-butoxy-3-pyridyl)-3-ethyl-2-(1-ethyl- 3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO01/27112, Example 132); (6R,12aR)-2,3 , 6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2′,1′:6,1]pyrido[ 3,4-b]indole-1,4-dione (tadalafil (tadalafil), IC-351, Cialis (Cialis)

), the compounds of Examples 78 and 95 of published International Patent Application WO95/19978, and the compounds of Examples 1, 3, 7 and 8; 2-[2-ethoxy-5-(4-ethyl- Piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4- Ketones (vardenafil, LEVITRA ) is also known as 1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]-as-triazine-2- base)-4-ethoxyphenyl]sulfonyl]-4-ethylpiperazine, the compounds of Examples 20, 19, 337 and 336 of published international patent application WO 99/24433; published international patent application Compound of Example 11 of WO 93/07124 (EISAI); Compounds 3 and 14 from Rotella D P, J. Med. Chem., 2000, 43, 1257; 4-(4-Chlorobenzyl)amino-6 , 7,8-trimethoxyquinazoline: N-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3 -d]-pyrimidin-5-yl)-4-propoxyphenyl]sulfonyl]-1-methyl 2-pyrrolidinepropionamide ["DA-8159" (Example 68 of WO 00/27848)] and 7,8-dihydro-8-oxo-6-[2-propoxyphenyl]-1H-imidazo[4,5-g]quinazoline and 1-[3-[1-[( 4-fluorophenyl)methyl]-7,8-dihydro-8-oxo-1H-imidazo[4,5-g]quinazolin-6-yl]-4-propoxyphenyl]methyl amides.

(v) 4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)-propoxy]-3(2H)pyridazinone; 1-[4-[( 1,3-Benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]-4-piperidine-carboxylic acid, monosodium salt; (+)- cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-methyl-cyclopenta-4,5]imidazo[ 2,1-b]purin-4(3H)one; furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-eight Hydrocyclopenta[4,5]-imidazo[2,1-b]purin-4-one; 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxy ester; 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate; 4-bromo-5-(3-pyridylmethylamino)-6- (3-(4-chlorophenyl)propoxy)-3-(2H)pyridazinone; 1-methyl-5(5-morpholinoacetyl-2-n-propoxyphenyl)-3 -n-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; 1-[4-[(1,3-benzodioxole -5-ylmethyl)amino]-6-chloro-2-quinazolinyl]-4-piperidinecarboxylic acid, monosodium salt; Pharmaprojects No. 4516 (Glaxo Wellcome); Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. 5064 (KyowaHakko; see WO 96/26940); Pharmaprojects No. 5069 (ScheringPlough); GF-196960 (Glaxo Wellcome); E-8010 and E-4010 (Eisai); Bay-38-3045 & 38-9456 (Bayer); FR226807 (Fujisawa); and Sch-51866.

The contents of the published patent applications and journal articles and in particular the formulas of the claimed therapeutically active compounds and the compounds exemplified therein are incorporated herein by reference in their entirety.

Preferably the PDEV inhibitor is selected from the group consisting of sildenafil, tadalafil, vardenafil, DA-8159 and 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolyl[4,3-d]pyrimidin-7-one.

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

The compounds of the invention may be administered in combination with an NO donor. Thus in a further aspect of the present invention there is provided a pharmaceutical product comprising a Via antagonist and an NO donor as a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhea.

The compounds of the present invention may be administered in combination with L-arginine, or an arginine salt. Thus in a further aspect of the present invention there is provided a pharmaceutical product comprising a Via antagonist and L-arginine as a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhea.

The compounds of the invention may be administered in combination with COX inhibitors. Thus in a further aspect of the present invention there is provided a pharmaceutical product comprising a Via antagonist and a COX inhibitor as a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhea.

COX inhibitors that may be used in combination with the compounds of the present invention include, but are not limited to:

(i) Ibuprofen, Naproxen, Benoxaprofen, Flurbiprofen, Fenoprofen, Fenbufen, Ketoprofen, Indoprofen, Piprofen, Carprofen, Oxaprofen , prapoprofen (prapoprofen), miprofen, thioxaprofen, suprofen, aminprofen, tiaprofen acid, fluprofen, buchloric acid, indomethacin, sulindac, tolmetin , zomeacin, diclofenac, fenclofenac, aclofenac, ibufenac, isoket acid, furofenac, thiapine acid, zidomacin, acetylsalicylic acid, indomethacin, pyridoxine Roxicam, tenoxicam, furosemide, ketorolac, azapropazone, mefenamic acid, tolfenamic acid, diflunisal, podophyllotoxin derivatives, acemetacin, droxxicam , Flofenine, Hydroxybuzone, Benbutazolidone, Proglumetacin, Acemetacin, Fentic Acid, Cycloindacid, Oxipinac, Mefenamic Acid, Methoxyfenam acid, flufenamic acid, niflumic acid, flufensal, sudoxicam, etodolac, piprofen, salicylic acid, choline magnesium trisalicylate, salicylate, Benoy Esters, fentic acid, clopinac, feprazone, isoxicam, and 2-fluoro-a-methyl[1,1'-biphenyl]-4-acetic acid, 4-(nitrox base) butyl ester (see Wenk, et al., Europ. J. Pharmacol. 453:319-324 (2002));

(ii) meloxicam, (CA Reg. No. 71125-38-7: described in US Patent No. 4,233,299), or a pharmaceutically acceptable salt or prodrug thereof;

(iii) Substituted benzopyran derivatives described in US Pat. No. 6,271,253. Also benzopyran derivatives described in U.S. Patent Nos. 6,034,256 and 6,077,850 and International Publication Nos. WO 98/47890 and WO 00/23433;

(iv) the chromene COX2 selective inhibitors described in U.S. Patent No. 6,077,850 and U.S. Patent No. 6,034,256;

(v) Compounds described in International Patent Application Nos. WO 95/30656, WO 95/30652, WO 96/38418 and WO 96/38442, and compounds described in European Patent Application Publication No. 799823, and pharmaceutically acceptable thereof Derivatives;

(vi) Celecoxib (US Patent No. 5,466,823), Valdecoxib (US Patent No. 5,633,272), Deracoxib (US Patent No. 5,521,207), Rofecoxib (US Patent No. 5,474,995) . Etoricoxib (International Patent Application Publication No. WO98/03484), JTE-522 (Japanese Patent Application Publication No. 9052882), or a pharmaceutically acceptable salt or prodrug thereof;

(vii) Parecoxib (described in U.S. Patent No. 5,932,598), which is a therapeutically effective prodrug of the tricyclic Cox-2 selective inhibitor valdecoxib (described in U.S. Patent No. 5,633,272), in particular parecoxib Recoxib sodium;

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

(ix) Nimesulide (described in US Patent No. 3,840,597), fluxamide (discussed in J. Carter, Exp. Opin. Ther. Patents . 8 (1). 21-29 (1997)), NS-398 (disclosed in U.S. Patent No. 4,885,367), SD 8381 (described in U.S. Patent No. 6,034,256), BMS-347070 (described in U.S. Patent No. 6,180,651), S-2474 (described in European Patent Application Publication No. 595546) and MK-966 (described in U.S. Patent No. 5,968,974);

(x) Disclosed in US Patent No. 6,395,724, US Patent No. 6,077,868, US Patent No. 5,994,381, US Patent No. 6,362,209, US Patent No. 6,080,876, US Patent No. 6,133,292, US Patent No. 6,369,275, US Patent No. 6,127,545, U.S. Patent No. 6,130,334, U.S. Patent No. 6,204,387, U.S. Patent No. 6,071,936, U.S. Patent No. 6,001,843, U.S. Patent No. 6,040,450, International Patent Application Publication No. WO 96/03392, International Patent Application Publication No. WO96/ 24585, U.S. Patent No. 6,340,694, U.S. Patent No. 6,376,519, U.S. Patent No. 6,153,787, U.S. Patent No. 6,046,217, U.S. Patent No. 6,329,421, U.S. Patent No. 6,239,137, U.S. Patent No. 6,136,831, U.S. Patent No. 6,297,282, US Patent 6,239,173, US Patent 6,303,628, US Patent 6,310,079, US Patent 6,300,363, US Patent 6,077,869, US Patent 6,140,515, US Patent 5,994,379, US Patent 6,028,202, US Patent 6,040,320, US Patent 6,083,969, US Patent 6,306,890, US Patent 6,307,047, US Patent 6,004,948, US Patent 6,169,188, US Patent 6,020,343, US Patent 5,981,576, US Patent 6,222,048 No., US Patent No. 6,057,319, US Patent No. 6,046,236, US Patent No. 6,002,014, US Patent No. 5,945,539, US Patent No. 6,359,182, International Patent Application Publication No. WO 97/13755, International Patent Application Publication No. WO 96/ 25928, International Patent Application Publication No. WO96/374679, 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 96/03 387. U.S. Patent No. 5,344,991, 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. WO96/09304, International Patent Application Compounds and pharmaceutically acceptable derivatives of Publication No. WO 98/47890, and International Patent Application Publication No. WO 00/24719.

The content of any patent application and in particular the formulas of the claimed therapeutically active compounds and the compounds exemplified therein are hereby incorporated by reference in their entirety.

Detailed ways

The following preparations and examples illustrate the preparation of compounds of formula (I).

¹ H nuclear magnetic resonance (NMR) spectra were consistent with the proposed structures in all cases. Inherent chemical shifts (δ) are given in parts per million downfield from tetramethylsilane, using the conventional abbreviations for major peak names: e.g. s, singlet; d, doublet; t, triplet; q , quartet; m, multiplet; br, broad. Mass spectra (m/z) were recorded using electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). The following abbreviations have been used for common solvents: _CDCl3 , deuterochloroform; _D6 -DMSO, deuterodimethylsulfoxide; _CD3OD , deuteromethanol; THF, tetrahydrofuran. "Ammonia" refers to a concentrated solution of ammonia in water having a specific gravity of 0.88. Where thin layer chromatography (TLC) is used, which refers to silica gel TLC using silica gel 60 F254 plates, R _f is the distance traveled by the compound divided by the distance traveled by the solvent front on the TLC plate. When microwave radiation was used, the two microwaves used were Emrys generator (Creator) and Ernrys releaser (Liberator), both supplied by Personal Chemistry. The power range is 15-300W at 2.45GHz. The actual power supplied was varied during the reaction in order to maintain a fixed temperature.

Preparation 1: 4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester:

8.1 mL of dimethylformamide dimethyl acetal (55.4 mmol, 1.5 eq) was added to 9.0 g of tert-butyl 4-hydrazinecarbonyl-piperidine-1-carboxylate (see references WO 9703986A1 19970206 ) (37 mmol, 1 equiv) in 40 mL of THF. The reaction mixture was then stirred at 50°C under nitrogen for 4 hours. The solvent was removed under reduced pressure, the residue was dissolved in 40 ml of toluene and 400 mg of p-toluenesulfonic acid was added. The mixture was then heated at 100°C under nitrogen for 18 hours, the volatiles were removed under reduced pressure and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane/methanol (98:2 v/v to 95:5 v/v) as eluent to afford 8.07 g of the title Compound as a white solid (81%).

¹ H NMR (400MHz, CD ₃ OD): 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]; found; C, 58.26%; H, 7.96%; N, _15.78 %; ₃ Required values C, 58.41%, H, 7.92%, N, 15.72%.

Preparation 2a: 4-[4-(4-Chloro-phenyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-piperidine:

4.0 g of the compound of Preparation 1 (15 mmol, 1 equiv.) was dissolved in 100 mL of toluene. 2.1 g of p-chloroaniline (16.5 mmol, 1.1 equiv) was added followed by 2 mL of TFA. The solution was heated at 110°C for 16 hours, 2 mL of TFA was added and the solution was heated at 110°C for another 48 hours. The reaction mixture was then cooled, an aqueous solution of sodium bicarbonate was added and the organic phase was decanted. The aqueous phase was basified with potassium carbonate and extracted four times with dichloromethane (50 mL). The dichloromethane solution was dried over magnesium sulfate and the solvent was removed in vacuo to afford 2.90 g of the title compound as a white solid.

¹ H 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-Chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidine hydrochloride

Hydrochloric acid in dioxane (4M, 10 mL) was added to a cooled (5° C.) solution of the compound of Preparation 1 (1.32 g, 4.76 mmol) in methanol (30 mL), and the solution was allowed to warm to room temperature and stirred for another 90 minutes. Tlc analysis showed starting material remaining, so additional hydrochloric acid in dioxane (4M, 10 mL) was added and the reaction was stirred for another 4 hours. The mixture was concentrated under reduced pressure and the residue was azeotroped with toluene (3x) to afford the title compound, 1.4 g.

¹ H 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)-piperidine-4-carboxylic acid ethyl ester

A solution of ethyl 4-piperidinecarboxylate (ethyl isonipecotate) (27.6 g, 175 mmol) in dichloromethane (50 mL) was added dropwise to 3-chlorobenzoyl chloride (20 mL 160 mL) over 10 minutes. mol) and triethylamine (28 mL, 200 mmol) in dichloromethane (500 mL) cooled to a solution between 10 and 15°C. The reaction was then stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was diluted with ether, and the solution was washed with 1N hydrochloric acid, sodium carbonate solution (x3) and brine. It was then dried over _MgSO4 and evaporated under reduced pressure to yield the title compound as a solid, 44.4 g.

¹ H 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)-piperidine-4-carboxylic acid hydrazide

A mixture of the ester of Preparation 3 (44.4 g, 0.15 mol) and hydrazine hydrate (30 mL, 0.58 mol) in methanol (120 mL) was heated at reflux for 10 hours and then allowed to cool to room temperature. The mixture was concentrated under reduced pressure and the product was crystallized from ethyl acetate/ether to afford the title compound as a solid, 32.5 g.

¹ H 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)-piperidine-4-carboxylic acid N'-(2-chloro-acetyl)-hydrazide

Acetyl chloride (4.3 mL, 53 mmol) was added dropwise over 30 min to the hydrazide (10 g, 35.5 mmol) of Preparation 4 and N-methylmorpholine (5.4 g, 53 mmol) in dichloromethane (200 ml) in an ice-cooled solution so as to maintain the internal temperature below 10°C. The reaction mixture was then allowed to warm to room temperature and stirred for another 18 hours. The reaction was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, then brine. The solution was dried over _MgSO4 , concentrated under reduced pressure and the residue was triturated with diethyl ether to afford the title compound as a white solid, 10.2 g.

¹ H NMR (400MHz, CD ₃ OD): 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]oxadiazol-2-yl)-piperidin-1-yl]-(3-chloro-phenyl)-methanone

Trifluoroacetic anhydride (9.45 mL, 57 mmol) was added dropwise to the compound of Preparation 5 (10.2 g, 28.5 mmol) and pyridine (11.5 mL, 142.5 mmol) in dichloromethane (300 mL) over 30 minutes. in a cooled solution (0 to 5°C). Once the addition was complete, the resulting pink suspension was stirred at 10°C for another 90 minutes. The reaction mixture was carefully poured into saturated sodium bicarbonate solution (600 mL) and the layers were separated. The organic phase was washed with further saturated sodium bicarbonate solution (x2), dried over _MgSO4 , and treated with decolorizing charcoal. The mixture was then filtered and the filtrate evaporated under reduced pressure to afford the title compound, 13 g.

¹ H NMR (400MHz, CD ₃ OD): 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)-hydrazinecarbonyl]-piperidine-1-carboxylic acid tert-butyl ester

4-Hydrazinecarbonyl-piperidine-1-carboxylic acid tert-butyl ester (see reference WO 2000039125, Preparation 27) (25 g, 103 mmol) was dissolved in dichloromethane (300 mL) and then 4- Methylmorpholine (12.5 mL, 113 mmol). The mixture was cooled using an ice bath and chloroacetyl chloride (8.2 mL, 103 mmol) was added dropwise. The reaction was then allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was partitioned with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and the filtrate evaporated to give the title compound as an off-white solid (29.6 g).

LRMS m/z APCl ^- -318[MH] ^-

Preparation 8: tert-butyl 4-(5-chloromethyl-[1,3,4]oxadiazolyl-2-yl)-piperidine-1-carboxylate

The hydrazide of Preparation 7 (5.0 g, 15.6 mmol) was suspended in dichloromethane (200 mL) and pyridine (6.4 mL, 78 mmol) was then added before cooling the mixture to 10°C. Trifluoroacetic anhydride (6.6 mL, 39 mmol) was added dropwise over 15 minutes, and the mixture was stirred at room temperature for 3 hours. The reaction was then partitioned with water (50 mL), the organic layer was dried over magnesium sulfate, filtered and the filtrate evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane as eluent (2:98) to afford the title compound as a white solid (2.95 g).

¹ H NMR (400MHz, CD ₃ OD): 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]triazol-2-ylmethyl-[1,3,4]oxadiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl Esters and tert-butyl 4-(5-[1,2,3]triazol-1-ylmethyl-[1,3,4]oxadiazol-2-yl)-piperidine-1-carboxylate

Preparation of the compound of 8 (8 g, 26.5 mmol), triazole (3.7 g, 53 mmol) and potassium carbonate (5.2 g, 38 mmol) in N,N-dimethylformamide (60 mL) The mixture was stirred at room temperature for 18 hours. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and brine, the layers were separated and the organic solution was dried over _MgSO4 and concentrated under reduced pressure to provide a mixture of isomers of the title compound.

¹ H NMR (400MHz, CD ₃ OD): δ1.43(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), 8.18(s) total 2H].

Preparation 9b: 4-(5-[1,2,3]triazol-2-ylmethyl-[1,3,4]oxadiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester

Dichloromethane (500 mL) was added to a suspension of the hydrazide of Preparation 170 (132.3 g, 375 mmol) in 1-methylimidazole (120 mL), and the resulting solution was cooled in an ice/acetone bath. Trifluoromethanesulfonic anhydride (92 mL, 561 mmol) was added dropwise over 2.5 hours so as to maintain the reaction temperature below 0°C. Once the addition was complete, the reaction was stirred for another 20 minutes. Then 2M hydrochloric acid (350 mL) was added to quench the reaction. The phases were separated and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic solutions were washed with brine, dried over _MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane as eluent to afford the title compound as a viscous oil.

Preparation 10: (3-Chloro-phenyl)-[4-(5-[1,2,3]triazol-2-ylmethyl-[1,3,4]oxadiazol-2-yl)- piperidin-1-yl]-methanone

A mixture of the compound of Preparation 6 (2 g, 5.9 mmol), triazole (810 mg, 11.75 mmol) and potassium carbonate (1.2 g, 8.85 mmol) in acetonitrile (20 mL) was stirred at room temperature for 30 minutes, This was followed by another hour of stirring at 50°C. The reaction mixture was filtered, washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The residual brown oil was partitioned between ethyl acetate and water, the layers were separated and the organic phase was washed with additional water, then brine. The solution was dried over _MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol (100:0 to 95:5) to afford the title compound, (202 mg).

¹ H NMR (400MHz, CD ₃ OD): 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]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl ]-piperidine-1-carboxylic acid tert-butyl ester

Trifluoroacetic acid (1 mL, 13.2 mmol) was added to a solution of the compound of preparation 9a (8.8 g, 26.5 mmol) and 4-chloroaniline (5 g, 39.75 mmol) in toluene (200 mL) to neutralize The reaction mixture was stirred at reflux for 5 hours. The cooled mixture was diluted with dichloromethane, then washed with 1N sodium hydroxide solution and brine, and evaporated under reduced pressure. Purification by column chromatography on silica gel with an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) followed by ethyl acetate:methanol:0.88 ammonia (100:0 :0 to 90:10:1) Re-column analysis of the residual brown oil provided the title compound, (2.3 g).

¹ H NMR (400MHz, CD ₃ OD): 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]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl ]-piperidine-1-carboxylic acid tert-butyl ester

N-Methylimidazole (4.66 g, 56.75 mmol) and dichloromethane (20 mL) were added to bis-acylhydrazide (5.00 g, 14.19 mmol) from Preparation 170, and the resulting solution was cooled to -20°C. Trifluoromethanesulfonic anhydride (6.00 g, 21.28 mmol) was added keeping the temperature below 0°C. Once the addition was complete, the reaction was allowed to warm to room temperature and stir for 15 hours. The reaction was quenched with H2O (10 mL), the phases were separated and the aqueous layer re-extracted with dichloromethane (10 mL). The combined organic phases were dried over magnesium sulfate, filtered, and the dichloromethane was distilled under vacuum and replaced with toluene to yield a toluene solution of the intermediate oxadiazole (-20 mL volume). 4-Chloroaniline (1.90 g, 14.90 mmol) followed by trifluoroacetic acid (0.81 g, 7.09 mmol) was added to the toluene solution and the reaction was stirred at 85°C for 5.5 hours. The mixture was cooled to room temperature and stirred with 1.8N aqueous ammonia (14 mL) for 5 minutes. The phases were separated and the organic phase was diluted with tert-butylmethyl ether (20 mL) and stirred for 15 hours. The resulting solid precipitate was collected by filtration and washed with tert-butyl methyl ether (2 x 5 mL) to yield the title compound as a beige solid (2.72 g).

¹ H 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]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl ]-piperidine

4M hydrochloric acid in dioxane (10 mL) was added to a solution of the compound of preparation 11a (2.3 g, 5.2 mmol) in methanol (30 mL) and the reaction was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure, the residue was diluted with dichloromethane and basified to pH 10 with 1N sodium hydroxide solution, and the layers were separated. The aqueous phase was re-extracted with dichloromethane and the combined organic solutions were dried over _MgSO4 and concentrated under reduced pressure to afford the title compound as a foam, (1.65 g).

¹ H NMR (400MHz, CD ₃ OD): 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]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl ]-piperidine bis-p-toluenesulfonate

Ethyl acetate (30 mL) was added to a mixture of the compound from Preparation 11b (6.5 g, 14.6 mmol) and p-toluenesulfonic acid monohydrate (8.4 g, 44.2 mmol) and the reaction was stirred at room temperature 17 hours. The resulting solid precipitate was collected by filtration, washed with ethyl acetate (20 mL) to give the title compound as a white solid, (9.32 g).

¹ H 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-Tetrazol-1-yl acetate methyl ester

A mixture of tetrazol-1-ylacetic acid (5 g, 39 mmol) and 4M hydrochloric acid in dioxane (100 μl) in methanol (50 ml) was heated at reflux for 18 hours. The cooled mixture was evaporated under reduced pressure to afford the title compound.

¹ H 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-isoxazol-5-yl)-acetyl chloride

N,N-Dimethylformamide (a few drops), followed by oxalyl chloride (9.5 mL, 106 mmol) was added dropwise to (3-methyl-isoxazol-5-yl)-acetic acid (5 g , 35.4 mmol) in a cooled (10° C.) solution in dichloromethane (50 mL), and the solution was allowed to warm to room temperature. The reaction was stirred for another 3 hours, then concentrated under reduced pressure. The residue was azeotroped with toluene to provide the title compound.

¹ H NMR (400 MHz, CDCl ₃ ): δ 2.30 (s, 3H), 4.32 (s, 2H), 6.18 (s, 1H).

Preparation 15: Ethyl (2-Methyl-1H-imidazol-1-yl)acetate

Potassium carbonate (8.42 g, 61 mmol) was added to a solution of 2-methylimidazole (5 g, 61 mmol) in THF (100 mL) and the suspension was stirred for 30 minutes. Ethyl bromoacetate (6.75 mL, 61 mmol) was added and the reaction was stirred at room temperature for another 30 minutes. The mixture was filtered, washing with dichloromethane:methanol (90:10). The filtrate was evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (93:7:0.5) as eluent to afford the title compound as an oil, 5.28 g.

¹ H 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-Tetrazol-1-yl)acetohydrazide

Hydrazine hydrate (3.2 g, 63 mmol) was added to a solution of the ester of Preparation 13 (3 g, 21.1 mmol) in methanol (18 mL) and the mixture was heated at reflux for 18 hours. The cooled reaction was concentrated under reduced pressure and the residue was azeotroped with toluene to provide the title compound.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 5.18 (s, 2H), 9.38 (s, 1H). LCMS: m/z APCl ⁺ 143[MH] ⁺

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

1,2,3-Triazole (19.00 kg, 275 mol) was fed into a suspension of potassium carbonate (42.15 kg, 305 mol) in ethanol (80 liters) over 30 minutes, and was mixed with ethanol (2 liters) rinse. A solution of ethyl bromoacetate (45.8 kg, 274 mol) in ethanol (30 L) was added slowly and rinsed with ethanol (2 L). The reaction temperature was maintained at <20°C during this time. The reaction mixture was then allowed to warm to room temperature and stirred overnight. The suspension was filtered; the residue was washed with ethanol (25 L and 17 L) and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate (120 L) and the solution was washed with 1N hydrochloric acid (1×40 L, 7×20 L, 4×15 L). The aqueous washes were combined and extracted with ethyl acetate (3 x 21 L). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated to dryness to give a mixture of the title compounds (25 kg). ¹ H NMR spectroscopic analysis showed this to be a 6:5 mixture of N-2/N-1 isomers.

¹ H NMR (400MHz, CDCl ₃ ): δ1.25(m, 3H), 4.13(q, 2H, N-1 isomer), 4.25(q, 2H, N-2 isomer), 5.20(s , 2H, N-1 isomer), 5.22 (s, 2H, N-2 isomer), 7.70 (s, 2H, N-2 isomer), 7.77 (s, 2H, N-1 isomer body).

Preparation 18: [1,2,3]triazol-2-yl-acetic acid hydrazide

Hydrazine hydrate (8.65 kg, 270 mol) was added to a cooled (<10°C) solution of the ester mixture of Preparation 17 (19 kg) in ethanol (69 L), keeping the temperature below 20°C throughout the addition . The reaction mixture was stirred between 14 and 19°C for 3 hours, then more ethanol (25 L) was added and the product was collected by filtration, washing with ethanol (10 L). The crude solid was purified three times by recrystallization from ethanol (120 L) followed by methanol (150 L, 120 L and 90 L) to give the title compound (4.53 kg) after drying in vacuo.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 4.33 (s, 2H), 5.02 (s, 2H), 7.77 (s, 2H), 9.40 (s, 1H).

Preparation 19: 2-(2-Methyl-1H-imidazol-1-yl)acetylhydrazide

The title compound was obtained from the compound of Preparation 15 as a white solid following a procedure similar to that described for Preparation 16, except that 5 equivalents of hydrazine was used, and isopropanol was used as the reaction solvent.

¹ H NMR (400 MHz, CD ₃ OD): δ 2.35 (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-1,2,4-oxadiazolyl-5-yl)acetohydrazide

The title compound was prepared from 3-methyl 1,2,4-oxadiazol-5-yl-acetic acid methyl Ester (NL 7807076) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ): δ 2.42 (s, 3H), 3.86 (s, 2H), 6.89 (brs, 1H), 8.18 (brs, 1H).

Preparation 21: 2-(Pyrimidin-2-yloxy)acetylhydrazide

A mixture of ethyl 2-pyrimidinyloxyacetate (GB2373186, step i Example 368) (4.4 g, 24.15 mmol) and hydrazine hydrate (5 mL, 160 mmol) in isopropanol (30 mL) was Heat at reflux for 1 hour. The mixture was then cooled and concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (100:0:0 to 100:10:1) to afford the title compound, 600 mg .

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

Preparation 22: tert-Butyl 2-[(3-methylisoxazol-5-yl)acetyl]hydrazinecarboxylate

Triethylamine (24 mL, 17 mmol) was added slowly to a cooled (10 °C) solution of the acid chloride of Preparation 14 (5.64 g, 35.4 mmol) in dichloromethane (200 mL) followed by hydrazine tert-Butyl carbamate (5.6 g, 42.5 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction was diluted with ethyl acetate and the precipitate was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (50:50 to 100:0) to provide the title compound.

¹ H 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: tert-Butyl 2-[3-(3,5-Dimethylisoxazol-4-yl)propionyl]hydrazinecarboxylate

Oxalyl chloride (5.16 mL, 59.2 mmol) was added to β-(3,5-dimethyl-4-isoxazolyl)propionic acid (J.Org.Chem.59(10); 1994; 2882) ( 2.5 g, 14.8 mmol) in a solution in dichloromethane (50 mL) and N,N-dimethylformamide (1 drop), and the solution was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure and the residue was azeotroped with dichloromethane (5x) to afford a brown liquid. This liquid was dissolved in dichloromethane (25 mL) and tert-butyl carbazate (2.93 g, 22.2 mmol) was added portionwise. The mixture was further diluted with dichloromethane (23 mL) and the reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure, the residue was suspended in dichloromethane, the resulting precipitate was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (95:5:0.5 to 90:10:1) to afford the title compound as an oil, 3.08 g.

¹ H 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-(3-Methylisoxazol-5-yl)acetylhydrazide hydrochloride

A mixture of the compound of Preparation 22 (1.6 g, 6.3 mmol) in 4M hydrochloric acid in dioxane (20 mL) and methanol (60 mL) was stirred at room temperature for 3 hours. The solution was concentrated under reduced pressure to low volume and the resulting precipitate was filtered, washed with dichloromethane and dried to afford the title compound, 810 mg.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.20 (s, 3H), 3.86 (s, 2H), 6.24 (s, 1H). LCMS: m/z APCl ⁺ 156[MH] ⁺

Preparation 25: 3-(3,5-Dimethylisoxazol-4-yl)propanohydrazide hydrochloride

A solution of the compound of Preparation 23 (3.08 g, 10.87 mmol) in 2.2M methanolic hydrochloric acid (50 mL) was stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure and the residue was azeotroped with toluene. The crude product was triturated with pentane/ether then ether and the resulting solid was filtered to afford the title compound as a white solid, 1.39 g.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.22 (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: tert-Butyl 2-(hydrazinecarbonyl)morpholine-4-carboxylate

2,4-Morpholine carboxylic acid 4-(tert-butyl) 2-methyl ester (WO 03/018579, Example 1 part i) (2.03 g, 8.3 mmol), hydrazine hydrate (1.2 mL, 24 mmol) and methanol (50 mL) was heated at reflux for 4 days. The cooled mixture was evaporated under reduced pressure, the residue was partitioned between water and ethyl acetate, and the layers were separated. The organic phase was dried over _MgSO4 and evaporated under reduced pressure to afford the title compound, 1.92 g.

LCMS: m/z ES ⁺ 268[MNa] ⁺

Preparation 27: tert-Butyl 3-(hydrazinecarbonyl)piperidine-1-carboxylate

Hydrazine hydrate (75 mL, 1.5 mol) was added to 1 tert-butyl 3-ethyl piperidine-1-3-dicarboxylate (US 2002 0099035, Example 12) (72 g, 280 mmol) in A solution in ethanol (250 mL) was dissolved and the reaction was heated at reflux for 18 hours. The cooled mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane and water, and the layers were then separated. The aqueous phase was extracted with dichloromethane, and the combined organic solutions were dried over _MgSO4 and evaporated under reduced pressure. The product was azeotroped with diethyl ether to afford the title compound as a colorless gum, 59.8g.

¹ H 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: Ethyl 1-(4-chlorobenzoyl)piperidine-4-carboxylate

The title compound was obtained from ethyl 4-piperidinecarboxylate and 4-chlorobenzoyl chloride following a procedure similar to that described in Preparation 3 as a yellow oil.

¹ H 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-Chlorobenzoyl)piperidine-4-carbazide

A solution of the compound of Preparation 28 (148 g, 0.5 mol) in methanol (400 mL) was heated at 70°C for 30 min. Hydrazine hydrate (50 g, 1.0 mol) was then added, and the reaction was stirred at 60°C for an additional 3 hours. Tlc analysis showed starting material remaining, so additional hydrazine hydrate (50 mL, 1.0 mol) was added and the reaction was stirred at 75°C for another 48 hours. The cooled mixture was concentrated under reduced pressure, the residue was suspended in dichloromethane (1 L) and washed with water (2x). The organic solution was dried over _MgSO4 and evaporated under reduced pressure to afford the title compound as a white solid, 119 g.

¹ H 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-Chlorobenzoyl)-N′-(trifluoroacetyl)piperidine-4-carbazide

Trifluoroacetic anhydride (1.56 mL, 11.18 mmol) was added dropwise to the compound of Preparation 29 (3.0 g, 10.65 mmol) and N-methylmorpholine (1.29 mL, 11.7 mmol) in dichloromethane (50 mL ), and the reaction was stirred at room temperature for 18 hours. The resulting precipitate was filtered, washed with dichloromethane and dried to afford the title compound, 1.78 g.

¹ H 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-Chlorobenzoyl)-N′-(-ethoxyacetyl)piperidine-4-carbazide

N-Methylmorpholine (2.60 g, 26.6 mmol), then ethoxyacetyl chloride (WO01/46150, Example 33A) (1.09 g, 8.87 mmol) was added to the compound of Preparation 29 (2.5 g, 8.87 mmol) mol) in dichloromethane (70 mL), and the reaction was stirred at room temperature for 18 hours. The mixture was washed with water, then ammonium chloride solution and finally sodium carbonate solution. It was dried over _MgSO4 and evaporated under reduced pressure to afford the title compound.

¹ H 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 (s2H), 4.62 (m, 1H), 7.38 (m, 4H), 8.90 (d, 1H), 8.99 (d, 1H). LCMSm/z ES ⁺ 368, 370[MH] ⁺

Preparation 32: 1-(3-Chlorobenzoyl)-N′-(-ethoxyacetyl)piperidine-4-carbazide

The title compound was obtained from the compound of Preparation 4 and ethoxyacetyl chloride (WO 01/46150 Example 33A) in 91% yield following a procedure similar to that described for Preparation 31.

¹ H 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: tert-Butyl 4-{[(4-chlorophenyl)amino]carbonyl}piperidine-1-carboxylate

1-BOC-piperidine-4-carboxylic acid (100 g, 437 mmol), 4-chloroaniline (61.2 g, 480 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbon Diimine hydrochloride (100 g, 524 mmol) and triethylamine (182.6 mL, 1.31 mol) were dissolved in cold (10°C) acetonitrile (1.75 L). The reaction mixture was stirred at room temperature for 54 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and partitioned with 2N hydrochloric acid. The resulting precipitate was filtered, re-dissolved in dichloromethane, the solution was dried over _MgSO4 and evaporated under reduced pressure. The residue was triturated with diethyl ether to afford the desired compound as a white solid. The filtrate was separated, and the organic layer was washed with 2N hydrochloric acid (2x), dried over _MgSO4 and evaporated under reduced pressure. The solid was triturated with diethyl ether to provide the further compound as a white solid, combined yield 99.4 g.

¹ H 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: tert-Butyl 4-{[(4-chlorophenyl)amino]carbonothioyl}piperidine-1-carboxylate

A solution of the compound of Preparation 33 (99.4 g, 294 mmol) and Lawesson's reagent (30 g, 74.3 mmol) in toluene (1 L) was heated at reflux for 1 hour and then stirred at room temperature for a further 18 hours. Tlc analysis showed starting material remaining, so additional Lawesson's reagent (11.1 mmol) was added and the reaction was heated at reflux for another hour. The cooled mixture was concentrated under reduced pressure and the residue was azeotroped with ethyl acetate. The crude product was triturated with hot ethyl acetate and the resulting solid was filtered and dried to afford the title compound as a white solid, 53 g.

LCMS: m/z APCl ^- -353[MH] ^-

Preparation 35: Ethyl 1-{[(4-chlorophenyl)amino]thiocarbonyl}piperidine-4-carboxylate

A mixture of 4-chlorophenyl isothiocyanate (3.5 g, 20.7 mmol) and ethyl 4-piperidinecarboxylate (3.19 mL, 20.7 mmol) in dichloromethane (30 mL) was stirred at room temperature for 1 Hour. The mixture was concentrated under reduced pressure, the residue was triturated with diethyl ether, and the resulting solid was filtered and dried to afford the title compound as a white solid, 6.27 g.

¹ H 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-Chlorophenyl)-3-methylpiperazine-1-carbothioamide (carbothioamide)

A solution of 4-chlorophenylisothiocyanate (8.0 g, 47.17 mmol) in dichloromethane (250 mL) was added dropwise to 2-methylpiperazine (9.45 g, 94.33 mmol) over 30 minutes in Ice-cooled solution in dichloromethane (250 mL). Once the addition was complete, the reaction was stirred at room temperature for one hour. The reaction was then washed with water (3x), dried over _MgSO4 and concentrated under reduced pressure to give the title compound as a white solid, 11.8 g.

¹ H 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-Chlorophenyl)-4-(2,2-dimethylpropionyl)-3-methylpiperazine-1 thiocarboxamide

Di-tert-butyl bicarbonate (9.30 g, 42.6 mmol) was added to a solution of the compound of preparation 36 (11.5 g, 42.6 mmol) in dichloromethane (300 mL) and dioxane (100 mL) , and the reaction was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and the product was recrystallized from methanol. The resulting solid was filtered off, and the filtrate was evaporated under reduced pressure. The residue was again recrystallized from methanol to afford the title compound, 9.64 g.

¹ H 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-Chlorophenyl)-4-(2,2-dimethylpropionyl)-2-methylpiperazine-1-carbothioamide

A solution of 4-chlorophenylthiocyanate (5.1 g, 30 mmol) and 4-N-BOC-2-methylpiperazine (6.0 g, 30 mmol) in dichloromethane (250 ml) was Stir at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure to afford the title compound as a white foam.

LCMS: m/z APCl ⁺ 370[MH] ⁺

Preparation 39: 1-{[(4-Chlorophenyl)amino]thiocarbonyl}-4-methylpiperazine-4-carboxylic acid ethyl ester

4-chlorophenyl isothiocyanate (2.36 g, 13.98 mmol), and ethyl 4-methylpiperazine-4-carboxylate (US 2002/0086887, Example 532C) (2.17 g, 12.71 mmol) The mixture in dichloromethane (50 mL) was stirred at room temperature for 30 minutes. The mixture was partitioned between dichloromethane and brine, and the layers were separated. The organic phase was dried over _MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:ethyl acetate (100:0 to 90:10) to afford the title compound as a white solid, 3.46 g.

¹ H 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-Chlorophenyl)-4-cyano-4-phenylpiperidine-1-carbothioamide

Triethylamine (1.4 mL, 10 mmol) was added to 4-chlorophenyl isothiocyanate (1.69 g, 10 mmol) and 4-cyano-4-phenylpiperidine hydrochloride (2.22 g, 10 mmol) in dichloromethane (100 mL), and the reaction was then stirred at room temperature for 20 minutes. The mixture was washed with 2N hydrochloric acid, then brine, which was dried over _MgSO4 and evaporated under reduced pressure to afford the title compound as a white solid, 3.62 g.

¹ H NMR (400 MHz, CDCl ₃ ): δ 2.18 (m, 4H), 3.50 (m, 2H), 4.78 (m, 2H), 7.08 (d, 2H), 7.27-7.48 (m, 7H).

Preparations 41 to 44:

A mixture of 4-chlorophenylisothiocyanate (1 eq) and the appropriate amine (1 eq) in ethanol (0.8-1.28 mL mmol ^-1 ) was stirred at room temperature for 30 min. The reaction mixture was then evaporated under reduced pressure to afford the title compound as a white solid.

Preparation 45: 4-{[(4-Chlorophenyl)amino]thiocarbonyl}-1,4-diazepane-1-carboxylic acid tert-butyl ester

A mixture of 4-chlorophenylisothiocyanate (5.0 g, 29.95 mmol), and BOC-homopiperazine (6.0 g, 29.95 mmol) in ethanol (50 mL) was stirred at room temperature for 2 hours . The mixture was evaporated under reduced pressure, the residue was partitioned between ethyl acetate and water and the layers were separated. The organic phase was dried over _MgSO4 and evaporated under reduced pressure to yield the title compound as a white foam.

¹ H NMR (400MHz, CD ₃ OD): 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: tert-Butyl 4-[(Z)-[(4-chlorophenyl)imino](methylthio)methyl]piperidine-1-carboxylate

Potassium tert-butoxide (20.1 g, 0.18 mol) was added portionwise to a cooled (10°C) solution of the compound of Preparation 34 (53 g, 0.15 mol) in THF (1 L) so as to maintain the temperature at 10°C . Iodomethane (11.2 mL, 0.18 mol) was added dropwise so as to maintain the temperature at 10°C, and the reaction was then allowed to warm slowly to room temperature. The reaction was stirred for another 90 minutes, then water was added to quench the reaction. The reaction was diluted with ethyl acetate and washed with water. The phases were separated, the aqueous layer was extracted with additional ethyl acetate, and the combined organic solutions were dried over _MgSO4 and evaporated under reduced pressure. The residual oil was absorbed on silica gel and purified by column chromatography on silica gel using pentane:ethyl acetate (75:25) as eluent to afford the title compound as an oil which crystallized on standing.

¹ H 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: Ethyl 1-[(Z)-[(4-chlorophenyl)imino](methylthio)methyl]piperidine-4-carboxylate

Potassium tert-butoxide (2.58 g, 23.1 mmol) was added portionwise to a solution of the compound of Preparation 35 (6.27 g, 19.2 mmol) in tetrahydrofuran (100 mL) and the reaction was stirred for 10 minutes. Iodomethane (1.44 mL, 23.1 mmol) was added and the reaction was stirred at room temperature for another 30 minutes. The reaction was diluted with ether and washed with brine. The organic solution was evaporated under reduced pressure and the resulting orange solid was purified by column chromatography on silica gel using dichloromethane as eluent to afford the title compound as an oil, 3.6 g.

¹ H 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-Chlorophenyl)imino](methylthio)methyl]-4-methylpiperazine-4-carboxylic acid ethyl ester

The title compound was obtained from the compound of Preparation 39 and methyl iodide in 75% yield following a procedure similar to that described for Preparation 47, except that the product was not purified by column chromatography on silica gel.

¹ H 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] ⁺ .

To prepare 49 to 55:

Potassium tert-butoxide (1.1 eq) followed by methyl p-toluenesulfonate (1.1 eq) was added to a solution of a compound (1 eq) selected from Preparations 37, 38, 40-42 and 45 in THF and reacted Stir at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water, the layers were separated and the organic solution was washed with water ( _3x ), dried over MgSO4 and evaporated under reduced pressure to give the title compound.

A = The reaction was stirred at room temperature for 18 hours and the product was additionally purified by column chromatography on silica gel using dichloromethane:methanol as eluent.

Preparation 56: 4-[(tert-Butoxycarbonyl)amino-N-(4-chlorophenyl)piperidine-1-carbimidothioate methyl ester

Potassium tert-butoxide (12.8 g, 114 mmol) was added to a suspension of the compound of Preparation 44 (42.3 g, 114 mmol) in THF (400 mL) and the suspension was stirred at room temperature for 10 min. Methyl p-toluenesulfonate (21.29 g, 114 mmol) was added and the reaction was stirred for 10 minutes. Additional potassium tert-butoxide (641 mg, 5.7 mmol) and methyl p-toluenesulfonate (1.08 g, 5.7 mmol) were added and the reaction stirred for another 10 minutes. The mixture was diluted with ether, washed with water (200 mL) and brine, then dried over _MgSO4 and evaporated under reduced pressure to afford the title compound.

¹ H 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: tert-Butyl 4-[5-(methoxymethyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate

Potassium tert-butoxide (3.40 g, 30.3 mmol) was added to a solution of the compound of Preparation 8 (7.62 g, 25.25 mmol) in methanol (120 mL) and the reaction was stirred at room temperature for 18 hours. Tlc analysis showed starting material remaining so additional potassium tert-butoxide (1 g, 8.9 mmol) was added and the reaction was stirred at 50°C for 2 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and ammonium chloride solution. The layers were separated, the organic phase was dried over _MgSO4 and evaporated under reduced pressure to afford the title compound as a yellow oil, 7.30 g.

¹ H 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: tert-Butyl 4-{5-[(2,2,2-trifluoroethoxy)methyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate ester

Potassium tert-butoxide (1.8 g, 41.8 mmol) was added to a solution of 2,2,2-trifluoroethanol (4.64 g, 46.4 mmol) in THF (100 mL) and the solution was stirred at room temperature for 10 min . The compound of Preparation 8 (7.0 g, 23.2 mmol) was added and the mixture was heated at 50°C for 2 hours. The reaction was quenched with the addition of ammonium chloride solution, then the organic layer was decanted and evaporated under reduced pressure. The residue was re-dissolved in ethyl acetate, the solution was washed with brine, dried over _MgSO4 and evaporated under reduced pressure to afford the title compound as a yellow oil, 8.15 g.

¹ H 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: tert-Butyl 4-[5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate

Potassium acetate (5.2 g, 53.0 mmol) was added to a solution of the compound of Preparation 8 (8 g, 26.5 mmol) in acetonitrile (150 mL), and the reaction was heated at 80°C for 18 hours. The cooled mixture was concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate, and the layers were separated. The organic phase was washed with brine, dried over _MgSO4 and evaporated under reduced pressure. The residual oil was dissolved in methanol (120 mL), and sodium carbonate (5.6 g, 53.0 mmol) and water (1 mL) were added. The mixture was stirred at room temperature for 2 hours and then it was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over _MgSO4 and evaporated under reduced pressure to afford the title compound as a white solid, 7.16 g.

¹ H 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: tert-Butyl 4-[5-(morpholin-4-ylmethyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate

A mixture of the compound of Preparation 8 (10 g, 33.1 mmol), morpholine (4.3 mL, 49.7 mmol) and potassium carbonate (9.2 g, 66.2 mmol) in acetonitrile (300 mL) was stirred at 80°C for 4 hours. The cooled mixture was concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic phase was dried over _MgSO4 and evaporated under reduced pressure to afford the title compound as an orange oil, 12.06 g.

¹ H NMR (400MHz, CD ₃ OD): 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: tert-Butyl 4-{[2-(-Ethoxyacetyl)hydrazino]carbonyl}piperidine-1-carboxylate

tert-Butyl 4-hydrazinecarbonyl-piperidine-1-carboxylate (WO 2000039125, Preparation 27) (3 g, 12.33 mmol), ethoxyacetic acid (1.28 mL, 13.56 mmol), 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.6 g, 13.56 mmol), 1-hydroxybenzotriazole hydrate (1.83 g, 13.56 mmol) and triethylamine (2.1 mL, 14.8 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and aqueous sodium carbonate. The layers were separated, the organic phase was dried over _MgSO4 and evaporated under reduced pressure to afford the title compound as an oil which crystallized on standing.

¹ H 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: tert-Butyl 4-{[2-(3,3,3-trifluoropropionyl)hydrazino]carbonyl}piperidine-1-carboxylate

The title compound was obtained from tert-butyl 4-hydrazinecarbonyl-piperidine-1-carboxylate (WO 2000039125, Preparation 27) and 3,3,3-trifluoropropionic acid following a procedure similar to that described for Preparation 61.

¹ H NMR (400MHz, CD ₃ OD): 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[MH] ^- .

Preparation 63: tert-Butyl 4-[5-(-ethoxymethyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate

Pyridine (4 mL, 49.3 mmol) was added dropwise to an ice-cooled solution of the compound of Preparation 61 (4.06 g, 12.33 mmol) in dichloromethane (60 mL). Trifluoromethanesulfonic anhydride (4.2 mL, 24.6 mmol) was then added dropwise over 20 minutes and the solution was stirred at 0 °C for one hour. It was then stirred at room temperature for another hour. The mixture was basified to pH 4 using aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic extracts were dried over _MgSO4 , and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (97:3:0.3) to afford the title compound as a yellow oil, 1.25 g.

¹ H 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: tert-Butyl 4-[5-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate

The title compound was obtained from the compound of Preparation 62 following a procedure similar to that described for Preparation 63 as a light yellow solid.

¹ H 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-Chlorobenzoyl)-4-(1,3,4-oxadiazol-2-yl)piperidine

N,N-Dimethylformamide dimethyl acetal (5.71 g, 47.9 mmol) was added to the compound of Preparation 29 (9.0 g, 31.94 mmol) in N,N-dimethylformamide (100 mL) The solution in and the reaction was stirred at 50°C for 3 hours. The mixture was concentrated under reduced pressure and the residue was suspended in toluene (150 mL). p-Toluenesulfonic acid (1 g, 5.26 mmol) was added and the reaction was heated at 110 °C for 18 hours. The reaction was diluted with ethyl acetate (100 mL), washed with brine, water then brine again. The solution was dried over _MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography using a silica gel cartridge and dichloromethane:methanol (100:0 to 90:10) as eluent to afford the title compound as a white solid, 4.25 g.

LCMS: m/z APCl ⁺ 292[MH] ⁺

Preparation 66: 1-(3-Chlorobenzoyl)-4-(1,3,4-oxadiazol-2-yl)piperidine

N,N-Dimethylformamide dimethyl acetal (5.71 g, 47.9 mmol) was added to a solution of the compound (9.0 g, 31.94 mmol) of Preparation 4 in tetrahydrofuran (6 ml) and reacted in 50 °C and stirred for 3 hours. Tlc analysis showed starting material remaining, so additional N,N-dimethylformamide dimethyl acetal (15 mmol) was added and stirring continued for another 2 hours. The mixture was concentrated under reduced pressure and the residue was suspended in toluene (32 mL). p-Toluenesulfonic acid (1 g, 5.26 mmol) was added and the reaction was heated at 110°C for 18 hours. The reaction was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution (2x) and brine, then dried over _Na2SO4 and evaporated under reduced pressure _. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) to afford the title compound.

¹ H 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-Chlorobenzoyl)-4-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine

N,N-Dimethylformamide dimethyl acetal (6.38 g, 47.9 mmol) was added to the compound of Preparation 29 (9.0 g, 31.94 mmol) in N,N-dimethylformamide (20 mL) in solution, and the reaction was stirred at room temperature for 1 hour. It was then stirred at 40°C for another 2 hours. The mixture was diluted with toluene (150 mL), heated to 110°C, and p-toluenesulfonic acid (400 mg, 2.22 mmol) was added. The reaction was heated at 110°C for 18 hours, then cooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with ammonium chloride solution and brine, then it was dried over _MgSO4 and evaporated under reduced pressure to afford the title compound as an oil, 9.75 g.

¹ H 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-Chlorobenzoyl)-4-(5-ethyl-1,3,4-oxadiazol-2-yl)piperidine

Triethyl orthopropionate (1.63 g, 9.23 mmol) was added to a solution of the compound of Preparation 29 (2.0 g, 7.1 mmol) in N,N-dimethylformamide (10 mL), and in 60 °C and stirred for 3 hours. Tlc analysis showed starting material remaining, so additional triethyl orthopropionate (0.5 g, 2.83 mmol) was added and the reaction was stirred at 60°C for another 18 hours. The mixture was concentrated under reduced pressure, the residue was suspended in toluene (15 mL) and trifluoroacetic acid (5 drops) was added. The reaction was heated at reflux for 18 hours, then cooled and concentrated under reduced pressure. The crude product was purified by column chromatography using a silica gel cartridge and dichloromethane:methanol (100:0 to 95:5) as eluent to afford the title compound as an oil, 1.6 g.

¹ H 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-Chlorobenzoyl)-4-[5-(-ethoxymethyl)-1,3,4-oxadiazol-2-yl]piperidine

Pyridine (1.8 g, 22.84 mmol) and then trifluoromethanesulfonic anhydride (3.22 g, 11.42 mmol) were added to an ice-cooled solution of the compound of Preparation 32 (2.80 g, 7.61 mmol) in dichloromethane (50 mL). in solution. The reaction was then stirred at room temperature for 2 hours. The mixture was washed with ammonium chloride solution (3x), then saturated aqueous sodium carbonate, dried over _MgSO4 and treated with activated carbon. The mixture was then filtered and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography using a silica gel cartridge and an elution gradient of dichloromethane:methanol (100:0 to 95:5) to afford the title compound as a yellow oil, 566 mg.

¹ H 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-Chlorobenzoyl)-4-[5-(-ethoxymethyl)-1,3,4-oxadiazol-2-yl]piperidine

The title compound was obtained from the compound of Preparation 31 following a procedure similar to that described for Preparation 69 as a crystalline solid.

¹ H 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-Chlorobenzoyl)-4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]piperidine

Trifluoromethanesulfonic anhydride (1.98 mL, 11.7 mmol) was added to an ice-cooled solution of the compound of Preparation 30 (1.77 g, 4.69 mmol) and pyridine (1.53 mL, 18.74 mmol) in dichloromethane (40 mL). in solution. The mixture was then allowed to warm to room temperature and stirred for 18 hours. The reaction was diluted with dichloromethane, washed with 2N hydrochloric acid, then saturated aqueous sodium bicarbonate. It was dried over _MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (99:1 to 96:4) to afford the title compound as a brown oil, 620 mg.

¹ H 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:

Compounds with the following general structure are shown below:

Prepared following a procedure similar to that described for Preparation 67 from N,N-dimethylacetamide dimethyl acetal and the appropriate hydrazide.

A = tert-butyl 3-hydrazinecarbonyl-pyrrolidine-1-carboxylate (from CB Research and Development company) was used.

Preparation 75: 1-(3-Chlorobenzoyl)-4-[5-(1H-pyrazol-1-ylmethyl)-1,3,4-oxadiazol-2-yl]piperidine

Preparation of compound 6 (1 g, 2.94 mmol), pyrazole (400 mg, 5.9 mmol) and potassium carbonate (610 mg, 4.4 mmol) in acetonitrile (10 mL) and N,N-dimethylformamide (10 mL) was stirred at 100°C for 18 hours. The cooled mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water (2x), and brine. It was then dried over _MgSO4 . The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (100:0:0 to 95:5:0.5) to afford the title compound, 550 mg.

¹ H NMR (400MHz, CD ₃ OD): 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-Chlorophenyl)-5-(2-morpholin-4-ylethyl)-4H-1,2,4-triazol-3-yl]piperidine-1 - tert-butyl carboxylate

Trifluoroacetic acid (0.35 ml, 4.3 mmol) was added to 4-morpholine propionic acid hydrazide (Comptes Rendus des Seances de I'acadamie des Sciences, Serie C; Sciences Chimiques 1976; 282 (17 ); 857-60) (1.5 g, 8.7 mmol) and the compound of preparation 46 (2.7 g, 7.25 mmol), and the reaction was heated at reflux for 8 hours. The cooled mixture was diluted with dichloromethane, washed with 1N sodium hydroxide solution, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 10:10:1) to give the title compound, 2.2 g.

¹ H 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] ⁺ .

To prepare 77 to 87:

Compounds with the following general structures:

Prepared from the compound of Preparation 46 and the appropriate hydrazide following a procedure similar to that described for Preparation 76.

Preparation number data 77 X = 2-oxo-1-pyrrolidinylmethyl ¹ H 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] ^{+ 78A} X = imidazol-1-ylmethyl ¹ H 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/zAPCl ⁺ 443[MH] ^{+ 79B} X = 2-methyl-1H-imidazol-1-ylmethyl ¹ H 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-ylmethyl ¹ H 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 = tetrazol-1-ylmethyl ¹ H 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] ^{+ 82C} X = 3-methylisoxazol-5-ylmethyl ¹ H 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 X = 3-methyl-1,2,4-oxadiazol-5-ylmethyl ¹ H 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 = pyrimidin-2-yloxymethyl ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.41 (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-ylethyl ¹ H 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] ^{+ 86C} X=2-pyridin-2-ylethyl ¹ H 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-Dimethylisoxazol-4-yl)ethyl ¹ H 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 = using 1-imidazol-1-ylacetic acid hydrazide; prepared as described in BOll. Chim Farm. 114(2); 70-72; 1975.

B = The reaction was stirred at reflux for 18 hours.

C = 1 equivalent of hydrazide was used.

Preparation 88: tert-Butyl {1-[4-(4-Chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidin-4-yl}carbamate

Acetohydrazide (16.9 g, 228 mmol) followed by trifluoroacetic acid (4.4 mL, 57.1 mmol) was added to a solution of the compound of Preparation 56 (43.6 g, 114 mmol) in THF (250 mL) and the mixture was refluxed. Lower heat for 7 hours. The cooled mixture was then washed with dilute ammonia solution, the layers were separated and the aqueous phase was further extracted with ethyl acetate. The combined organic solutions were dried over _MgSO4 and evaporated under reduced pressure. The residue was triturated with diethyl ether (100 mL) and the resulting crystals were removed by filtration and dried in vacuo to afford the title compound, 32.4 g.

¹ H 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-Chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-1,4-diazepine-1-carboxylic acid tert -Butyl ester

The title compound was obtained from the compound of Preparation 55 and acetylhydrazide in 75% yield following a procedure similar to that described for Preparation 88, except that 2 equivalents of acetylhydrazide were used.

¹ H 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: Ethyl 1-[4-(4-chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidine-4-carboxylate

Trifluoroacetic acid (0.84 mL, 10.85 mmol) followed by acetylhydrazide (2.41 g, 32.6 mmol) was added to a solution of the compound of Preparation 47 (7.38 g, 21.7 mmol) in THF (100 mL) and the mixture was refluxed. Lower the heat for 3 hours. The cooled mixture was partitioned between ethyl acetate and ammonia and the layers were separated. The organic phase was washed with brine, dried over _MgSO4 and evaporated under reduced pressure. The crude product was triturated with diethyl ether to afford the title compound as a white solid, 5.04 g.

¹ H 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-Chlorophenyl)-5-(2H-1,2,3-triazol-2-ylmethyl)-4H-1,2,4-triazole-3- Ethyl]piperidine-4-carboxylate

Trifluoroacetic acid (0.41 mL, 5.3 mmol) was added to a solution of the hydrazide of Preparation 18 (3.6 g, 10.6 mmol) and the compound of Preparation 47 (2.24 g, 15.9 mmol) in THF (50 mL), And the reaction was heated at reflux for 15 hours. The cooled mixture was partitioned between ethyl acetate and brine and the layers were separated. The organic phase was filtered, dried over _MgSO4 and evaporated under reduced pressure to afford the title compound as a gum.

¹ H 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-Chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-4-methylpiperidine-4-carboxylic acid ethyl ester

The title compound was obtained from the compound of Preparation 48 and acetylhydrazide following a procedure similar to that described for Preparation 91 in 86% yield as a clear oil.

¹ H 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-Chlorophenyl)-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl]-2-methylpiperazine-1 - tert-butyl carboxylate

Methoxyacetylhydrazide (1.95 g, 18.75 mmol) was added to a solution of the compound of Preparation 49 (4.80 g, 12.50 mmol) in THF (200 mL) and the solution was stirred for 10 minutes. Trifluoroacetic acid (710 mg, 6.25 mmol) was added, and the reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the crude product was purified by repeated column chromatography using a silica gel cartridge and dichloromethane:methanol (100:0 to 90:10) as eluent, and ethyl acetate as eluent to obtain Provided the title compound as a foam, 1.84 g.

¹ H 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-Chlorophenyl)-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl]-3-methylpiperazine-1 - tert-butyl carboxylate

The title compound was obtained from the compound of Preparation 50 in 67% yield following a procedure similar to that described for Preparation 93, except that the reaction was heated at reflux.

LCMS: m/z APCl ⁺ 363[MH] ⁺

Preparation 95: tert-Butyl 4-[4-(4-chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]piperazine-1-carboxylate

Acetohydrazide (6.51 g, 88 mmol) was added to a solution of the compound of Preparation 52 (32.46 g, 88 mmol) in n-butanol (250 mL) and the reaction was heated at reflux for 18 hours. The reaction was heated at reflux for another 5 days and additional acetylhydrazide (36.5 g total) was added periodically. The cooled mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) to afford the title compound as a white foam.

¹ H 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-Chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-4-phenylpiperidine-4-carbonitrile

Acetohydrazide (1.65 g, 22.3 mmol) was added to a solution of the compound of Preparation 51 (3.3 g, 8.93 mmol) in n-butanol (5 mL) and the reaction was heated at reflux for 2 days. The cooled mixture was concentrated under reduced pressure and the residue was preattached to silica gel. It was then purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5), and the product was triturated with ethyl acetate to afford the title compound as a solid.

¹ H 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-Chlorophenyl)-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylic acid tert- Butyl ester

Trifluoroacetic acid (2.14 g, 18.83 mmol) was added to a solution of the compound of Preparation 57 (7.0 g, 23.54 mmol) and 4-chloroaniline (3.60 g, 28.24 mmol) in toluene (50 mL) and reacted The mixture was heated at reflux for 18 hours. The cooled solution was concentrated under reduced pressure and the residue was purified by column chromatography using a silica gel cartridge and an elution gradient of dichloromethane:methanol (100:0 to 90:10) to afford the title compound as an oil, 4.25 g.

¹ H NMR (400MHz, CD ₃ OD): 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: tert-Butyl 4-[4-(4-chlorophenyl)-5-(hydroxymethyl)-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylate

A mixture of compound 59 (6.8 g, 24 mmol), 4-chloroaniline (4.3 g, 33.7 mmol) and trifluoroacetic acid (0.9 ml, 12 mmol) in toluene (40 ml) was prepared at 100° C. Stir for 18 hours. The cooled mixture was evaporated under reduced pressure and the residue was dissolved in dichloromethane and washed with 2M sodium hydroxide solution. The organic solution was dried over _MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate:methanol:0.88 ammonia (95:5:0.5 to 90:10:1) to afford the title compound as a white solid, 7.1 g.

¹ H 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:

Compounds showing the general structure are as follows:

Prepared following a procedure similar to that described for Preparation 98 from the appropriate compound selected from Preparations 60, 63 and 64 and 4-chloroaniline.

Preparation number data ^99A X=Ethoxymethyl ¹ H 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] ^{+ 100A} X=2,2,2-trifluoroethyl ¹ H 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] ^{+ 101B} X = morpholin-4-ylmethyl ¹ H 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 = Use 0.8 equivalents of trifluoroacetic acid.

B = 1 equivalent of trifluoroacetic acid was used.

Preparation 102: tert-Butyl 2-[4-(4-chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]morpholine-4-carboxylate

The title compound was obtained from the compound of Preparation 72 and 4-chloroaniline following a procedure similar to that described for Preparation 98, except that 1 equivalent of trifluoroacetic acid and 2 equivalents of 4-chloroaniline were used in 75% yield as an oil.

LCMS: m/z APCl ⁺ 393[MH] ⁺

Preparation 103: 3-[4-(4-Chloro-2-methylphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylic acid tert- Butyl ester

4-Chloro-2-methylaniline (3.78 g, 26.3 mmol) and p-toluenesulfonic acid (50 mg) were added to the oxadiazole (2.33 g, 8.9 mmol) of Preparation 73 in xylene (10 mL) In solution and the reaction was heated at reflux for 24 hours. The cooled reaction was directly purified by column chromatography on silica gel using ethyl acetate:methanol:dichloromethane (100:0:0 to 0:5:95). The product was azeotroped with dichloromethane to afford the title compound as a purple crystalline solid.

¹ H 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-methylphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]pyrrolidine-1-carboxylic acid tert- Butyl ester

A mixture of compound 74 (1.50 g, 5.92 mmol), trifluoroacetic acid (528 μl, 7.1 mmol) and 4-chloroaniline (1.68 g, 11.8 mmol) in toluene (20 ml) was prepared at 110° C. Under heating for 18 hours. The cooled mixture was concentrated under reduced pressure and chromatographed by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:triethylamine (98:1.5:0.5 to 90:10:1 to 80:20:1) Purification of the residue afforded the title compound, 810 mg.

¹ H 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-methoxyphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylic acid tert -Butyl ester

The compound of Preparation 1 (2 g, 7.5 mmol), 4-chloro-2-methoxyaniline (Bioorganic and Medicinal Chemistry Letters, 1999; 9(19); 2805-2810) (1.77 g, 11.2 mmol) and three A mixture of fluoroacetic acid (0.29 mL, 3.7 mmol) in toluene (20 mL) was stirred at 85°C for 5 hours. The cooled mixture was diluted with ethyl acetate and washed with 2M sodium hydroxide solution. The aqueous solution was extracted with dichloromethane (2x) and the combined organic solutions were dried over _Na2SO4 and concentrated under reduced pressure _. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) to afford the title compound, 2 g.

¹ H NMR (400MHz, CD ₃ OD): 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: tert-Butyl 4-[4-(2,4-Dichlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylate

The title compound was prepared from the oxadiazole and 2,4-dichloroaniline of Preparation 1 following a procedure similar to that described for Preparation 105, except that 2 equivalents of aniline were used.

¹ H 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:

The appropriate aniline (Y'Y-PhNH ₂ ) (1-1.1 equiv) followed by trifluoroacetic acid (0.5 equiv) was added to a solution of the compound of Preparation 9 (1 equiv) in toluene (1.6 mL mmol ^-1 ) and in The reaction mixture was heated at reflux. The reaction was monitored by tlc and once complete (45 min to 9 hrs) the mixture was allowed to cool. The reaction was washed with dilute ammonia solution and brine, then dried over _MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol (95:5) as eluent to afford the title compound.

Preparation number data 107 Y=H; Y'=H; ¹ H 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; ¹ H 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; ¹ H 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] ^{+ 110A} Y=4-Br; Y'=H; ¹ H 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; ¹ H 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; ¹ H 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; ¹ H 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] ⁺

^114A Y=4-Cl; Y'=2-CH ₃ ; ¹ H 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; ¹ H 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; ¹ H 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] ⁺

A = 1.5 equivalents of aniline were used in the reaction.

Preparation 117: 4-[4-(4-Chlorophenyl)-5-({[(methylthio)carbonyl]oxy}methyl)-4H-1,2,4-triazole-3- Base]piperidine-1-carboxylate tert-butyl ester

Sodium hydride (60% dispersion in mineral oil, 112 mg, 2.8 mmol) was added to an ice-cooled solution of the compound of Preparation 98 (1 g, 2.55 mmol) in THF (20 mL) and the solution was Stir at room temperature for one hour. Carbon disulfide (230 μL, 3.83 mmol) was added followed by iodomethane (238 μL, 3.83 mmol), and the reaction was stirred at room temperature for another 2 hours. Water (1 mL) was added, the mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phase was dried over _MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (97:3:0.3 to 95:5:0.5) to afford the title compound as a pale yellow solid, 460 mg.

¹ H 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 dioxane (8 to 30 equivalents) was added to the appropriate protected piperidine (1 equivalent) selected from Preparations 76, 77, 80 to 85 and 105 to 116 in methanol (9 to 22.5 mL The solution neutralization reaction in -1) was stirred at room temperature between 1.5 and 3 hours. The mixture was concentrated under reduced pressure, the residue was partitioned between dichloromethane and 1M sodium hydroxide solution and the layers were separated. The organic solution was dried over _MgSO4 and evaporated under reduced pressure to afford the title compound.

Preparation number data ^118A Y=4-Cl; Y'=2-Cl; X=CH ₃ ¹ H NMR (400MHz, CD ₃ OD): 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/zAPCl ⁺ 311[MH] ^{+ 119A} Y=4-Cl; Y'=2-OCH ₃ ; X=CH ₃ ¹ H NMR (400MHz, CD ₃ OD): 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-pyrrolidinylmethyl ¹ H 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/zAPCl ⁺ 360[MH] ⁺

121 Y=4-Cl; Y'=H; X=1,2,4-triazol-1-ylmethyl ¹ H 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-triazol-2-ylmethyl ¹ H NMR (400MHz, CD ₃ OD): 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-triazol-2-ylmethyl ¹ H 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-triazol-2-ylmethyl ¹ H 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-triazol-2-ylmethyl ¹ H 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/ zES ⁺ 362[MH] ⁺ 126 Y=4-Cl; Y'=3-Cl; X=1,2,3-triazol-2-ylmethyl ¹ H 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-triazol-2-ylmethyl ¹ H 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-triazol-2-ylmethyl ¹ H 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-triazol-2-ylmethyl ¹ H 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-triazol-2-ylmethyl ¹ H NMR (400MHz, CD ³ OD): 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-triazol-2-ylmethyl ¹ H 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] ⁺

^132A Y=4-Cl; Y'=H; X=tetrazol-1-ylmethyl ¹ H 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] ^{+ 133A} Y=4-Cl; Y'=H; X=3-methylisoxazol-5-ylmethyl ¹ H NMR (400MHz, CD ₃ OD): 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] ⁺ 134A Y=4-Cl; Y'=H; X=3-methyl-1,2,4-oxadiazol-5-ylmethyl ¹ H NMR (400MHz, CD ₃ OD): 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/zAPCl ⁺ 359[MH] ⁺ 135 Y=4-Cl; Y'=H; X=pyrimidin-2-yloxymethyl ¹ H 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-ylethyl ¹ H 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=morpholin-4-ylethyl ¹ H 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] ⁺

A = The reaction mixture was evaporated under reduced pressure and then worked up to isolate the hydrochloride salt of the title compound.

Preparation 138 to 141:

A solution of the appropriate protected piperidine (1 equiv) selected from Preparations 78 to 79 and 86 to 87 in 2.2M methanolic hydrochloric acid (13 mL mmol ^-1 ) was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue was azeotroped with toluene. The crude product was partitioned between dichloromethane and 1M sodium hydroxide solution and the layers were separated. The organic solution was dried over _MgSO4 and evaporated under reduced pressure to afford the title compound.

A = The reaction mixture was evaporated under reduced pressure and azeotroped with toluene. The product was triturated with ethyl acetate, filtered and dried to yield the hydrochloride salt of the title compound.

Preparation 142: 4-[4-(4-Chlorophenyl)-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl 4-[]piperidine

4M hydrochloric acid in dioxane (60 mL) was added to a solution of the compound of Preparation 97 (3.75 g, 9.22 mmol) in dioxane (50 mL) and the reaction was stirred at room temperature for 3 hours. The mixture was evaporated under reduced pressure and the residue was re-dissolved in dichloromethane and washed with ammonia, then brine. The organic solution was dried over _MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography using a silica gel cartridge and dichloromethane:methanol:0.88 ammonia (90:10:1 ) as eluent to afford the title compound, 1.99 g.

¹ H 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-Chlorophenyl)-5-(-ethoxymethyl)-4H-1,2,4-triazol-3-yl]piperidine hydrochloride

4M hydrochloric acid in dioxane (20 mL) was added to a solution of the compound of Preparation 99 (990 mg, 2.35 mmol) in dioxane (20 mL) and the reaction was stirred at room temperature for 18 hours. The mixture was evaporated under reduced pressure and the residue was azeotroped with dichloromethane to afford the title compound, 910 mg.

¹ H NMR (400MHz, CD ₃ OD): 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-Chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]piperazine dihydrochloride

4M hydrochloric acid in dioxane (13.75 mL) was added to a solution of the compound of Preparation 95 (4.12 g, 110 mmol) in dichloromethane (50 mL) and the reaction was stirred at room temperature for 30 minutes. The mixture was evaporated under reduced pressure and dried in vacuo to afford the title compound as a white solid, 3.8 g.

¹ H NMR (400 MHz, CDCl ₃ ): δ 2.23 (s, 3H), 2.80 (m, 4H), 3.05 (m, 4H), 7.25 (d, 2H), 7.50 (d, 2H).

Preparation 145: 1-[4-(4-Chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidin-4-amine dihydrochloride

A suspension of the compound of Preparation 88 (32.3 g, 82.5 mmol) in methanol (250 mL) and 4N hydrochloric acid in dioxane (40 mL) was warmed to 50°C for 3 hours. The mixture was concentrated under reduced pressure and the residue was slurried in THF (50 mL). The resulting solid was filtered and dried in vacuo to provide the title compound.

¹ H NMR (400MHz, CD ₃ OD): 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-methylphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidine

4M hydrochloric acid (5 mL) was added to a solution of the compound of preparation 103 (846 mg, 2.16 mmol) in dioxane (10 mL) and the reaction was stirred at room temperature for 18 hours. Tlc analysis showed starting material remaining, so additional 4M hydrochloric acid in dioxane (5 mL) was added and the reaction was stirred at room temperature for another hour. The reaction mixture was then concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (90:10:1). The product was azeotroped with dichloromethane and diethyl ether to afford the title compound as an off-white foam.

¹ H 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-methylphenyl)-3-methyl-5-pyrrolidin-3-yl-4H-1,2,4-triazole

A solution of the compound of Preparation 104 in 4M hydrochloric acid in dioxane (20 mL) was stirred at room temperature for 4 hours. The mixture was partitioned between ethyl acetate and 2N sodium hydroxide solution, and the layers were separated. The organic solution was dried over _MgSO4 and evaporated under reduced pressure to afford the title compound.

¹ H 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-Chlorophenyl)-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl]-1,4-diazepine

4M hydrochloric acid (30 mL) in dioxane (25 mL) was added to a solution of the compound of Preparation 89 (5.45 g, 12.93 mmol) in dioxane (30 mL) and the reaction was stirred at room temperature for 18 hours . The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and ether. The layers were then separated, the aqueous phase was basified using sodium hydroxide and the solution was extracted with dichloromethane (3x). The combined organic extracts were dried over _MgSO4 to afford the title compound as a foam, 3.84 g.

¹ H NMR (400MHz, CD ₃ OD): 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-Chlorophenyl)-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl]-2-methylpiperazine

The title compound was obtained from the compound of Preparation 94 in 95% yield as a yellow oil following the procedure described for Preparation 148.

¹ H 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-Chlorophenyl)-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl]-3-methylpiperazine

Trifluoroacetic acid (25 mL) was added to an ice-cooled solution of the compound of Preparation 93 (2.80 g, 6.63 mmol) in dichloromethane (25 mL) and the solution was stirred at room temperature for one hour. The mixture was concentrated under reduced pressure and the residue was redissolved in ethyl acetate, then washed with 1N sodium hydroxide solution. The organic solution was dried over _MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography using a silica gel cartridge and an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) to afford the title compound as an oil, 780 mg.

¹ H 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-methylphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidine

Compound of Preparation 1 (3 g, 11.2 mmol), 4-chloro-2-methylaniline (2.4 g, 16.8 mmol) and trifluoroacetic acid (0.8 mL, 11.2 mmol) in toluene (30 mL) The mixture was stirred at room temperature at 110°C for 18 hours. The cooled mixture was concentrated under reduced pressure, 2M sodium hydroxide solution (10 mL) was added and the mixture was azeotroped with toluene. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5 to 80:20:3) to afford the title compound as a pale foam, 1.45 g.

¹ H NMR (400MHz, CD ³ OD): 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-triazol-3-yl]piperidine ditrifluoroacetate

The compound of preparation 1 (900 mg, 3.4 mmol), 4-chloro-2-fluoroaniline (109.1 mg, 0.75 mmol) and trifluoroacetic acid (288 μl, 3.74 mmol) in toluene (8 ml) The mixture was stirred at 110°C for 72 hours. The cooled mixture was concentrated under reduced pressure, 0.88 ammonia was added and the mixture was concentrated under reduced pressure. The residue was azeotroped with toluene and purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (90:10:1 to 80:20:3) to afford the title compound White foam, 985 mg.

¹ H 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-Chlorophenyl)-5-[(2,2,2-trifluoroethoxy)methyl]-4H-1,2,4-triazol-3-yl }piperidine

Trifluoroacetic acid (2.49 g, 21.8 mmol) was added to a solution of 4-chloroaniline (3.63 g, 28.4 mmol) and the compound of preparation 58 (8.0 g, 21.9 mmol) in toluene (50 mL), and The reaction was heated at reflux for 48 hours. Tlc analysis showed starting material remaining, so additional trifluoroacetic acid (8 mL) was added and the reaction was heated at reflux for another 4 hours. The cooled mixture was extracted with water, the aqueous solution was basified with potassium hydroxide and extracted with dichloromethane (4 x 100 mL). The combined organic extracts were dried over _MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography using a silica gel cartridge and an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 85:15:1.5) to yield the title compound, 4.34 g.

¹ H 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-Chlorophenyl)-5-[(trifluoromethoxy)methyl]-4H-1,2,4-triazol-3-yl}piperidine

Hydrogen fluoride-pyridine (0.35 mL, 13.2 mmol), followed by a solution of the compound of preparation 117 (160 mg, 0.33 mmol) in dichloromethane (1 mL) was added to 1,3-dichloromethane at -78°C. A solution of bromo-2,4-dimethylhydantoin (283 mg, 1.0 mmol) in dichloromethane (5 mL) was. The reaction was allowed to warm to room temperature over 30 minutes then stirred for another hour. The mixture was washed with 1N sodium hydroxide solution, dried over _MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (90:10:1 ) as eluent to afford the title compound as a yellow oil, 45 mg.

LCMS: m/z APCl ⁺ 361[MH] ⁺

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

Trifluoroacetic acid (600 μl, 8.1 mmol) was added to 4-chloroaniline (2.1 g, 16.2 mmol) and 4-(5-methyl-1,3,4-oxadiazol-2-yl)benzene A suspension of carbonitrile (Journal für Praktische Chemie, 1994; 336(8):678-85) (3.0 g, 16.2 mmol) in tetrahydrofuran (50 mL) was neutralized and the reaction was heated at reflux for 22 hours. The cooled mixture was partitioned between ethyl acetate (300 mL) and 20% 0.88 ammonia (120 mL) and the layers were separated. The organic phase was dried over _MgSO4 and evaporated under reduced pressure. The residue was triturated with diethyl ether and a minimum volume of ethyl acetate to afford the title compound as a white crystalline solid, 2.82 g.

¹ H 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-Chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]benzoic acid

A solution of potassium hydroxide (2.6 g, 46.0 mmol) in water (10 mL) was added to a solution of the compound of preparation 155 (2.7 g, 9.2 mmol) in ethylene glycol dimethyl ether (40 mL) and The reaction was heated at reflux for 18 hours. Ethanol (50 mL) was added and the reaction was heated at reflux for another 72 hours. The cooled mixture was acidified to pH 6 and concentrated under reduced pressure. The residue was extracted with dichloromethane:methanol:0.88 ammonia (84:14:2), then the suspension was filtered and the filtrate was evaporated under reduced pressure. The product was triturated with diethyl ether, filtered and dried to afford the title compound as a white solid.

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

Preparation 157: 4-[4-(4-Chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]benzoyl chloride

Oxalyl chloride (3 mL, 32 mmol) followed by N,N-dimethylformamide (5 drops) was added to the acid of Preparation 156 (2 g, 6.4 mmol) in dichloromethane (200 mL) solution, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, the filtrate was evaporated under reduced pressure, and the residue was azeotroped with dichloromethane (3 x 200 mL) to afford the title compound as an orange oil, 2.01 g.

¹ H NMR (400 MHz, CDCl ₃ ): δ 2.78 (s, 3H), 7.58 (d, 2H), 7.63 (d, 2H), 7.74 (m, 2H), 8.06 (d, 2H).

Preparation 158: 1-[4-(4-Chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidine-4-carboxylic acid

A solution of the ester of 90 (4 g, 10.4 mmol) and 4N sodium hydroxide (13 mL, 52 mmol) in dioxane (20 mL) was stirred at room temperature for 2 hours. The mixture was partitioned between water and ethyl acetate and the phases were separated. The aqueous layer was acidified to pH 4 using 2N hydrochloric acid, and the resulting precipitate was filtered and washed with water. The solid was triturated with diethyl ether, filtered and dried in vacuo to afford the title compound as a white solid.

¹ H NMR (400MHz, CD ₃ OD): 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-Chlorophenyl)-5-(2H-1,2,3-triazol-2-ylmethyl)-4H-1,2,4-triazole-3- Base]piperidine-4-carboxylic acid

The title compound was obtained from the ester of Preparation 91 as a white solid following a procedure similar to that described for Preparation 158, except that 10 equivalents of sodium hydroxide was used in the reaction.

¹ H NMR (400MHz, CD ₃ OD): 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-Chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-4-methylpiperidine-4-carboxylic acid

A mixture of the ester of Preparation 92 (1.45 g, 4.0 mmol) and 4N sodium hydroxide solution (5 mL, 20 mmol) in dioxane (50 mL) was stirred at reflux for 16 hours. Tlc analysis showed starting material remaining, so additional sodium hydroxide (4N, 5 mL, 20 mmol) was added, and the reaction was heated at reflux for another 18 hours. The cooled mixture was partitioned between ethyl acetate and water, and the layers were separated. The aqueous phase was acidified to pH 3.5 using 2N hydrochloric acid and extracted with ethyl acetate (2x). The combined organic extracts were dried over MgSO ₄ and evaporated under reduced pressure. The product was triturated with ethyl acetate. The resulting solid was filtered and dried to afford the title compound as a white solid, 800 mg.

¹ H NMR (400MHz, CD ₃ OD): 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-Chlorophenyl)-2-(2H-1,2,3-triazol-2-ylacetyl)hydrazinethiocarboxamide

4-Chlorophenylisothiocyanate (8.58 g, 50.6 mmol) was added portionwise to a suspension of hydrazide (7.0 g, 50.6 mmol) of Preparation 18 in ethanol (200 mL) and the mixture was incubated at room temperature. Stir for 72 hours. The resulting precipitate was filtered, washed with ether and dried to afford the title compound as a white solid, 14.5 g.

¹ H NMR (400 MHz, CD ₃ OD): δ 5.30 (s, 2H), 7.36 (d, 2H), 7.44 (d, 2H), 7.78 (s, 2H).

Preparation 162: 4-(4-Chlorophenyl)-5-(2H-1,2,3-triazol-2-ylmethyl)-2,4-dihydro-3H-1,2,4-tris Azole-3-thione

A solution of the compound of Preparation 161 (14.5 g, 46.5 mmol) and 2M sodium hydroxide solution (232 mL, 465 mmol) in ethanol (36 mL) was stirred at 80°C for 18 hours. The cooled mixture was acidified to pH 9 using concentrated hydrochloric acid, then it was extracted with dichloromethane (6 x 250 mL). The combined organic solutions were evaporated under reduced pressure to afford the title compound as a white solid, 7.5 g.

¹ H NMR (400 MHz, CDCl ₃ ): δ 5.54 (s, 2H), 7.05 (d, 2H), 7.42 (d, 2H), 7.58 (s, 2H).

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

Potassium tert-butoxide (2.9 g, 25.6 mmol) was added to a solution of the compound of Preparation 162 (7.5 g, 25.6 mmol) in tetrahydrofuran (250 mL) and the suspension was stirred at room temperature for 30 minutes. Methyl p-toluenesulfonate (4.8 g, 25.7 mmol) was added and the mixture was heated at reflux for 45 minutes and then at room temperature for a further 2 hours. The mixture was diluted with dichloromethane (1000 mL), washed with saturated ammonium chloride solution (300 mL) and brine (300 mL), which was then dried over MgSO ₄ and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel using dichloromethane:methanol (85:15) as eluent to afford the title compound, 4.9 g.

¹ H NMR (400 MHz, CDCl ₃ ): δ 2.70 (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-Chlorophenyl)-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]methyl}-2H-1,2 , 3-triazole

m-Chloroperbenzoic acid (3.4 g, 19.56 mmol) was added to a solution of the compound of preparation 163 (1.5 g, 4.90 mmol) in dichloromethane (60 mL) and the reaction was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane, then washed with saturated sodium bicarbonate solution (300 mL) and brine (200 mL). The organic solution was dried over _Na2SO4 and concentrated _under reduced pressure. The residual solid was washed with ethanol, then dried in vacuo to afford the title compound as a white solid, 1.40 g.

¹ H 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-ethoxynitrobenzene

Sodium ethoxide (21% in ethanol, 8.6 mL, 26 mmol) was added dropwise to a solution of 4-chloro-2-fluoronitrobenzene (3 g, 17.1 mmol) in ethanol (20 mL), And once the addition was complete the reaction was stirred for another hour. The mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and the solution was washed with water (x2), then brine. The solution was dried over _MgSO4 and evaporated under reduced pressure to afford the title compound as a solid, 3.45 g.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.49 (t, 3H), 4.19 (q, 2H), 7.00 (d, 1H), 7.05 (s, 1H), 7.81 (d, 11H).

Preparation 166: 4-Chloro-2-ethoxyaniline

Preparation of nitro compound of 165 (3.30 g, 16.4 mmol), iron powder (2.7 g, 49 mmol) and calcium chloride (810 mg, 7.4 mmol) in water (5 mL) and ethanol (30 mL) The mixture was heated at reflux for 3.5 hours. through Celite The cooled mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate, the layers were separated, and the organic phase was further washed with brine. The solution was dried over _MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate (100:0 to 0:100) to afford the title compound as an oil, 2.4 g.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.42 (t, 3H), 402 (q, 2H), 6.61 (d, 1H), 6.76 (m, 2H).

Preparation 167: 1-(5-Chloro-2-nitrobenzyl)pyrrolidine

Pyrrolidine (4 mL, 48.5 mmol) was added to a solution of 5-chloro-2-nitrobenzaldehyde (6 g, 32.2 mmol) in dichloromethane (150 mL) and the solution was stirred at room temperature for 30 minutes . The solution was then cooled in ice, and sodium triacetoxyborohydride (10.3 g, 48.5 mmol) was added portionwise. Once the addition was complete, the reaction was stirred at room temperature for 4 hours. The reaction was washed with sodium carbonate solution, dried over _MgSO4 and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using ethyl acetate:pentane (86:14) to afford the title compound as a light yellow solid, 6.3 g.

¹ H 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-ylmethyl)aniline

镍(400毫克)在乙醇(200毫升)中的混合物在40psi和室温下氢化2小时。混合物经过Arbocel过滤及在减压下蒸发滤液。通过在硅胶上使用二氯甲烷∶甲醇∶0.88氨(95∶5∶0.5到90∶10∶1)的洗脱梯度的柱色谱法纯化残余物以提供标题化合物的固体，3.95克。Compound 167 (6.2 g, 25.8 mmol) and Rene

A mixture of nickel (400 mg) in ethanol (200 mL) was hydrogenated at 40 psi at room temperature for 2 hours. The mixture was passed through Arbocel Filter and evaporate the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (95:5:0.5 to 90:10:1) to afford the title compound as a solid, 3.95 g.

¹ H 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-Chlorophenyl)-5-piperidin-4-yl-4H-1,2,4-triazol-3-yl]methyl}morpholine

A solution of the compound of Preparation 101 (8.6 g, 18.6 mmol) in dioxane (50 mL) and 4M hydrochloric acid in dioxane (30 mL) was stirred at room temperature for 18 hours. The solution was evaporated under reduced pressure and the residue was partitioned between 2N sodium hydroxide solution and ethyl acetate. The resulting solid was filtered and dried to afford the title compound as a white solid, 1.2 g. The filtrate was separated, the aqueous layer was extracted with dichloromethane, and the combined organic solutions were dried over MgS0 ₄ and evaporated under reduced pressure to afford additional product, 1.11 g.

LCMS: m/z APCl ⁺ 362 [MH] ⁺ .

Preparation 170: tert-Butyl 4-{[2-(2H-1,2,3-triazol-2-ylacetyl)hydrazino]carbonyl}piperidine-1-carboxylate

A suspension of N-BOc-4-piperidinecarboxylic acid (isonipecotic acid) (30.0 g, 130.8 mmol) and the hydrazide of Preparation 18 (18.5 g, 130.8 mmol) in dichloromethane (150 ml) was dissolved in N ₂ Cool in an ice bath. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25.6 g, 133.5 mmol) was added via the addition funnel and the funnel was washed with additional dichloromethane (10 mL). The resulting solution was warmed to room temperature. Once the reaction was complete, isopropanol (150 mL) was added and the homogeneous solution was concentrated in vacuo to about 165 mL, heated to about 70°C, and allowed to cool to room temperature with stirring. The resulting thick white slurry was filtered in vacuo, washed with isopropanol (15 mL and 30 mL) and dried in vacuo at 50°C to give the title compound as a white solid, 25.3 g (55%). The liquid from the filtration was concentrated to low volume under reduced pressure and the resulting syrup was treated with water (50 mL) and stirred vigorously to produce a thick slurry within two minutes. After overnight granulation, the slurry was filtered (snap-filtered), the residue was washed with water (2 x 10 mL) and dried in vacuo at 50°C to yield additional product, 8.5 g (18%).

¹ H 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).

Examples 1 to 162:

Examples 1 to 162 described below were synthesized as a library. Use the following solutions:

Carboxylic acid, _ZCO2H , was dissolved in dimethylacetamide (anhydrous) plus 3.75% triethylamine, 0.2M concentration.

The amine of preparation 2a was dissolved in DMA (anhydrous) plus 3.75% triethylamine, 0.2M concentration.

HBTU was dissolved in DMA (anhydrous), 0.2M concentration.

(N.B. Mild sonication in a warm water bath (temperature < 40°C) for dissolving monomers, where required).

Experimental steps:

The reaction scale was between 20 and 30 micromolar per well (experimental details shown for 20 micromolar reactions, scale can therefore be adjusted within this range). Reactions were performed in polypropylene 96-well plates.

a) Amine solution (0.1 mL, 20 micromoles, 1 equiv) was added to the well

b) Carboxylic acid solution (0.15 mL, 30 micromol, 1.5 equiv) was added to the well

c) HBTU solution (0.15ml, 30μmol, 1.5eq) was added to each well

d) Polypropylene 96-well plates are sealed with PTFE and rubber seals and sandwiched between a pair of metal plates.

e) Plates were heated in the oven at 60°C for 6 hours and then left to cool in the oven overnight.

f) When cooled, the plates were not clamped and placed in a Genevac to remove solvent.

g) The sample was re-dissolved in DMSO/water (9:1) (500 microliters) and filtered to remove any particulate matter.

h) Purification by RP-HPLC.

HPLC purification conditions:

Column: Phenomenex Luna C18, 10 micron, 150 x 10 mm id

Temperature: room temperature

Eluent A: 0.05% diethylamine in water

Eluent B: Acetonitrile

Samples were dissolved in: 90% dimethyl sulfoxide in water.

Samples loaded using a Gilson autosampler with an injection volume of 550 microliters

Gilson LC pump initial conditions:

solvent

A% 80.0

B% 20.0

Flow rate (ml/min) 8.000

Gilson LC pump gradient schedule:

Time A% B% Flow Rate (ml/min)

0.00 80.0 20.0 8.000

0.20 80.0 20.0 8.000

7.00 5.0 95.0 8.000

9.00 5.0 95.0 8.000

9.10 80.0 20.0 8.000

10.50 80.0 20.0 8.000

Gilson 119 uv detector monitoring at 254 nm:

Collector set at 225 nm

Double Sensitivity 200

Peak Sensitivity 80

The peak width is 0.3 minutes.

HPLC analysis conditions and mass spectrometry details:

Column: Phenomenex Luna C18, 5 micron, 30 x 4.6 mm id.

Eluent A: 0.05% diethylamine in water

Eluent B: Acetonitrile

Sample dissolved in: 90% DMSO in water

Samples loaded using a Gilson Quad Z with an injection volume of 5 microliters

Waters 1525 binary LC pump initial conditions:

solvent

A% 95.0

B% 5.0

Flow rate (ml/min) 2.5 (each channel)

Temperature (℃) Room temperature

LC pump gradient schedule:

The gradient timetable contains 4 records which are:

time A% B% flow rate

0.00 95.0 5.0 2.500

3.00 5.0 95.0 2.500

3.50 95.0 5.0 2.500

Total runtime 4.50 minutes

Detection:

Waters 2488 Dual Wavelength Detector

UV1(nanometer) 225

UV2(nanometer) 255

and

ELSD: PolymerLabs, temperature: 75 °C, gas flow rate: 1.2 bar

Mass spectrometer:

Waters ZQ 2000 4 way MUX,

ES+ cone voltage: 26v Capillary: 3.85 kV

ES-Cone Voltage: -30v Capillary: -3.00 kV

Desolvent gas: 800 l/min

Source temperature: 300°C.

Scanning range 160-1000Da

implementation number Z The found value of the mass ion of the product HPLC retention time (minutes) 1 2-methoxy-pyridin-3-yl 412.15 1.55 2 3-Trifluoromethyl-phenyl 449.13 2 3 2-methoxy-phenyl 411.15 1.35 4 2-Methanesulfonyl-phenyl 459.12 1.6 5 3-Methanesulfonyl-phenyl 459.12 1.55 6 Phenyl 381.14 1.72 7 3-methoxy-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-Methanesulfonyl-phenyl 459.12 1.49 12 2,4-Dichloro-phenyl 449.06 1.99 13 3,4-Dichloro-phenyl 449.06 2.04 14 2,5-Dichloro-phenyl 449.06 1.99 15 4-Ethoxy-phenyl 425.17 1.77 16 4-Methylthio-phenyl 427.13 1.85 17 4-Chloro-2-methoxy-phenyl 445.11 1.89 18 2-Ethoxy-phenyl 425.17 1.84 19 Isoquinolin-1-yl 432.15 1.6 20 2,6-Dimethyl-phenyl 409.17 1.82

twenty one Quinolin-2-yl 432.15 1.74 twenty two Quinolin-4-yl 432.15 1.6 twenty three Quinolin-3-yl 432.15 1.57 twenty four 2-Chloro-6-fluoro-phenyl 433.09 1.54 25 2,3-Dichloro-phenyl 449.06 1.95

26 2,5-Difluoro-phenyl 417.12 1.82 27 2,5-Dimethoxy-phenyl 441.16 1.55 28 2,3-Difluoro-phenyl 417.12 1.8 29 2,4-Difluoro-phenyl 417.12 1.8 30 3,4-Difluoro-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-naphthalen-1-yl 449.15 2 34 3,5-difluoro-phenyl 417.12 1.87 35 3-Aminosulfonyl-4-chloro-phenyl 494.07 1.5 36 1H-benzimidazol-5-yl 421.15 1.37 37 2-Chloro-4-fluoro-phenyl 433.09 1.85 38 4-Trifluoromethoxy-phenyl 465.12 2.07 39 1H-Benzotriazol-5-yl 422.14 1.34 40 4-methoxy-quinolin-2-yl 462.16 1.82 41 2-fluoro-4-trifluoromethyl-phenyl 467.12 2.04 42 2,3,6-Trifluoro-phenyl 435.11 1.87 43 2-Methyl-pyridin-3-yl 396.15 1.32

44 2,4,5-Trifluoro-phenyl 435.11 1.85 45 4-Propyl-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-dichloro-5-fluoro-phenyl 467.05 2.05 49 3-fluoro-4-methoxy-phenyl 429.14 1.8 50 4-Isopropoxy-phenyl 439.18 1.89 51 4-propoxy-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-Difluoromethoxy-phenyl 447.13 1.79 57 Biphenyl-2-yl 457.17 2.02 58 4-Aminosulfonyl-phenyl 460.11 1.45 59 3-Chloro-phenyl 415.1 1.9 60 4-cyano-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-methoxy-4-methyl-phenyl 425.17 1.9

67 Naphthalene-1-yl 431.16 1.95 68 Pyridin-3-yl 382.14 1.3 69 Pyridin-2-yl 382.14 1.42 70 6-Methyl-pyridin-2-yl 396.15 1.52 71 m-tolyl 395.16 1.85 72 p-Tolyl 395.16 1.74 73 4-fluoro-3-methoxy-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-pyridin-3-yl 474.16 1.82 79 2-Trifluoromethoxy-phenyl 465.12 1.99 80 3-Ethoxy-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-methoxy-phenyl 495.21 2 86 4-methoxy-3-propoxy-phenyl 469.19 1.89 87 3-Isopropoxy-4-methoxy-phenyl 469.19 1.85 88 3-Butoxy-4-methoxy-phenyl 483.21 1.95 89 4-Trifluoromethyl-pyridin-3-yl 450.12 1.65

90 6-(2,2,2-Trifluoro-ethoxy)-pyridin-3-yl 480.13 1.95 91 2-(4-fluoro-phenoxy)-pyridin-3-yl 492.15 1.9 92 2-Chloro-3-trifluoromethyl-phenyl 483.09 1.97 93 2-Difluoromethoxy-phenyl 447.13 1.82 94 3-Difluoromethoxy-phenyl 447.13 1.89 95 6-Trifluoromethyl-pyridin-3-yl 450.12 1.84 96 2-Methyl-[1,8]naphthyridin-3-yl 447.16 1.32 97 2-Methyl-[1,6]naphthyridin-3-yl 447.16 1.42 98 2,3-Dihydro-benzofuran-7-yl 423.15 1.57 99 2-Chloro-3-methyl-phenyl 429.12 1.92 100 4-methoxy-3-methyl-phenyl 425.17 1.92 101 2-Ethoxy-pyridin-3-yl 426.16 1.6 102 2-Ethoxy-naphthalen-1-yl 475.18 2.02 103 3-(Dimethylamino)sulfonyl-phenyl 488.14 1.72 104 2-propoxy-pyridin-3-yl 440.18 1.84 105 2-(4-Chloro-phenoxy)-pyridin-3-yl 508.12 1.93 106 2-Methyl-1H-benzimidazol-5-yl 435.16 1.4 107 6-Hydroxy-pyridin-2-yl 398.13 1.32 108 2-(5-Methyl-[1,2,4]oxadiazole-3- 464.15 1.45

Base)-pyridin-4-yl 109 4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl 463.16 1.67

110 4-(5-Ethyl-[1,2,4]oxadiazol-3-yl)-phenyl 477.17 1.92 111 3-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl 463.16 1.68 112 3-(5-Ethyl-[1,2,4]oxadiazol-3-yl)-phenyl 477.17 1.9 113 2-Hydroxy-pyridin-4-yl 398.13 1.25 114 2-Benzyl-phenyl 471.19 2.17 115 3,5-dichloro-phenyl 449.06 2 116 3-Chloro-2-methyl-phenyl 429.12 1.93 117 2,3-Dihydro-benzofuran-5-yl 423.15 1.74 118 2-(3-Methyl-[1,2,4]oxadiazol-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-methoxy-2-methyl-phenyl 425.17 1.82 122 3-methoxy-2-methyl-phenyl 425.17 1.82 123 2-Hydroxy-5-methyl-phenyl 411.15 1.68 124 3,5-dichloro-4-hydroxy-phenyl 465.06 1.57 125 2-Hydroxy-3-isopropyl-phenyl 439.18 2.93 126 1H-indol-6-yl 420.15 1.75 127 3-Hydroxy-phenyl 397.14 1.6 128 3-methoxy-naphthalen-2-yl 461.17 1.9 129 3-Hydroxy-4-methoxy-phenyl 427.15 1.54 130 4-Chloro-2-hydroxy-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-quinolin-2-yl 462.16 1.82 136 Quinoxalin-6-yl 433.15 1.42 137 1,2-Dimethyl-1H-benzimidazol-5-yl 449.18 1.49 138 1H-indol-5-yl 420.15 1.7 139 2-(3,5-Dimethyl-1H-pyrazol-4-yl)-5-methoxy-phenyl 505.2 1.6 140 8-methyl-2-oxo-1,2-dihydroquinolin-6-yl 462.16 1.45 141 3-Aminosulfonyl-phenyl 460.11 1.5 142 4-(3-Methyl-6-oxo-3-piperidinyl)-phenyl 492.21 1.54 143 2-(2-Methoxy-ethoxy)-phenyl 455.18 1.62 144 2-Hydroxy-4-methyl-phenyl 411.15 1.68 145 3-Chloro-4-hydroxy-phenyl 431.1 1.64 146 3-Hydroxy-4-methyl-phenyl 411.15 1.75 147 3-Methoxy-5-(methylsulfonyl)amino-phenyl 504.14 1.57 148 2-{[(2,2-Dimethylpropyl)amino]carbonyl}-phenyl 494.22 1.85 149 5-Acetyl-2-ethoxypyridin-3-yl 468.17 1.7 150 2-(2-Methoxy-ethoxy)-pyridin-3-yl 456.17 1.62

151 Isoquinolin-4-yl 432.15 1.52

152 2-Ethoxy-3-methoxy-phenyl 455.18 1.8 153 4-[(1R)-1-(acetylamino)ethyl]-phenyl 466.19 1.47 154 4-pyrimidin-4-yl-phenyl 459.16 1.6 155 3-Methyl-2-propoxy-phenyl 453.2 2 156 4-Ethoxy-pyridin-3-yl 426.16 1.5 157 2-Chloro-4-methylsulfonylamino-phenyl 508.09 1.64 158 2-Ethoxy-5-methanesulfonyl-phenyl 503.14 1.68 159 4-Hydroxy-2-(2,2,2-trifluoro-ethoxy)-phenyl 495.13 1.65 160 4-Hydroxy-2-methoxy-phenyl 427.15 1.52 161 4-cyano-pyridin-2-yl 407.13 1.55 162 2-pyridin-4-yl-3H-benzimidazol-5-yl 498.17 1.5

Example 163: (3-Chloro-phenyl)-{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1 ,2,4]triazol-3-yl]-piperidin-1-yl}-methanone

A mixture of the compound from Preparation 10 (202 mg, 0.54 mmol), 4-chloroaniline (140 mg, 1.1 mmol) and trifluoroacetic acid (42 μl, 0.54 mmol) in toluene (2 mL) was Heated at 170° C. for 20 minutes under microwave irradiation. The cooled mixture was diluted with ethyl acetate, washed with 1N sodium hydroxide solution and brine, then dried over _Na2SO4 and concentrated under reduced pressure _. The product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) to afford the title compound, (234 mg).

¹ H NMR (400MHz, CD ₃ OD): 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] ⁺ .

Example 164: (4-Chloro-phenyl)-{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1 ,2,4]triazol-3-yl]-piperidin-1-yl}-methanone

4-Chlorobenzoyl chloride (49 μl, 0.38 mmol) was added to the compound obtained from Preparation 12a (120 mg, 0.35 mmol) and N-methylmorpholine (77 μl, 0.70 mmol) in dichloro methane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane, washed with 1N sodium hydroxide solution and the water wash was re-extracted with dichloromethane. The combined organic solutions were evaporated under reduced pressure to yield an oil. The oil was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (90:10:1) to afford the title compound as a white solid, (160 mg).

¹ H 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 ] ⁺ .

Example 165a: {4-[4-(4-Chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazole-3 -yl]-piperidin-1-yl}-(3,5-difluoro-phenyl)-methanone

The title compound was obtained from the compound from Preparation 12a and 2,4-difluorobenzoyl chloride following the procedure described in Example 164 in 92% yield.

¹ H NMR (400MHz, CD ₃ OD): 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] ⁺ .

Example 165b: {4-[4-(4-Chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazole-3 -yl]-piperidin-1-yl}-(3,5-difluoro-phenyl)-methanone

Triethylamine (3.2 mL, 23.0 mmol) was added to a slurry of the double salt from Preparation 12b (4.89 g, 7.12 mmol) in dichloromethane (25 mL), resulting in a pale yellow solution. The solution was cooled in an ice bath, then 3,5-difluorobenzoyl chloride (0.95 mL, 8.09 mmol) was added. The reaction was stirred for 30 minutes, then water (20 mL) was added. After stirring for another 20 minutes, the phases were separated and the organic phase was washed successively with aqueous citric acid, water, aqueous sodium bicarbonate and half-saturated brine. The clear dichloromethane solution was then dried over magnesium sulfate and concentrated to yield a white foam. Recrystallization from ethyl acetate gave the title compound as a white solid, (2.69 g), the same material as prepared as described in Example 165a.

Examples 166 to 167:

The appropriate acid chloride (1.2 equiv) was added to a solution of the amine of Preparation 2 (1 equiv) and N-methylmorpholine (1.5 equiv) in dichloromethane (5.5 mL mmol ^-1 ) and the reaction was neutralized at room temperature Stir for 4 hours. Tris-(2-aminoethyl)amine polystyrene (3.85 mmol/g) was added and the reaction was stirred for another hour. Saturated ammonium chloride solution was added, then the mixture was stirred for 20 minutes and the layers were separated using a hydrophobic membrane. The organic phase was washed with saturated sodium bicarbonate solution, the layers were separated and the organic solution was evaporated under reduced pressure to provide the title compound.

Example number Z Yield(%) data 166 neopentyl 39 ¹ H 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/zAPCl ⁺ 375[MH] ⁺ 167 Cyclopropyl 39 ¹ H 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] ⁺

Examples 168 to 173:

Suitable amines, or amine salts, selected from Preparations 12a, 100, 118, 119, 143, and 152 (1 equivalent), appropriate acid chlorides (W-PhCOCl) (1.2 to 1.4 equivalents) and N-ethyl diiso A mixture of propylamine (4 equiv) in dichloromethane (16 mL mmol ^-1 ) was stirred at room temperature for 2 hours. Tris-(2-aminoethyl)amine polystyrene was then added and the mixture was stirred for another hour. The mixture was then washed with 1 N sodium hydroxide solution, the aqueous solution was extracted with dichloromethane (2x) and the combined organic solutions were concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate:methanol:0.88 ammonia (90:10:1 ) as eluent to afford the title compound.

Example number data 168 W=3-F, 4-CH ₃ ; Y=4-Cl; Y'=2-Cl; X=CH ₃ ¹ H 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] ^{+ 169A} W=3-F, 4-CH ₃ ; Y=4-Cl; Y'=2-F; X=CH ₃ ¹ H 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 ¹ H NMR (400MHz, CD ₃ OD): 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] ^{+ 171A} W=2-F, 3-Cl; Y=4-Cl; Y'=H; X=CH ₂ OCH ₂ CH ₃ ; ¹ H 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] ^{+ 172A} W=4-Cl; Y=4-Cl; Y'=H; X=CH ₂ CF ₃ ; ¹ H 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] ⁺

^173B W=2-OCF ₃ ; Y=4-Cl; Y'=H; X=[1,2,3]-triazol-2-ylmethyl ¹ H 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 = Using 4 equivalents of triethylamine, the crude product was not treated with polymer supported amine.

B = 10 equivalents of polymer supported N-ethyldiisopropylamine was used instead of N-ethyldiisopropylamine.

Examples 174 to 187:

Appropriate acid chloride (W-PhCOCl) (1.0 to 1.5 equivalents) is added to appropriate amine hydrochloride, or amine, selected from preparations 120 to 121, 132, 134 to 135, 137, 139 to 142, 151, 153 to A solution of 154 and 169 (1 equiv) and triethylamine (1.2 to 5 equiv) in dichloromethane (10 to 25 mL mmol ^-1 ). The reaction was stirred at room temperature for 18 hours. The mixture was then diluted with dichloromethane, which was washed with saturated sodium carbonate solution, followed by ammonium chloride solution, and then it was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol (100:0 to 90:10) as eluent to afford the title compound.

Example number data ^174A W=3-Cl; Y=4-Cl; Y'=2-CH ₃ ; X=CH ₃ ¹ H 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] ^{+ 175B} W=3,5-di-Cl; Y=4-Cl; Y'=H; X=CH ₂ OCH ₃ ¹ H NMR (400MHz, CD ₃ OD): 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] ^{+ 176A} W=4-Cl; Y=4-Cl; Y'=H; X=CH ₂ OCF ₃ ¹ H 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] ^{+ 177B} W=3,5-di-F; Y=4-Cl; Y'=H; X=CH ₂ OCH ₂ CF ₃ ¹ H NMR (400 MHz, 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-oxopyrrolidin-1-yl)methyl; ¹ H 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] ^{+ 179A} W=3,5-di-Cl; Y=4-Cl; Y'=H;X=morpholin-4-ylmethyl; ¹ H 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-tetrazol-1-ylmethyl; ¹ H 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-imidazol-3-ylmethyl; ¹ H 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]oxadiazol-5-ylmethyl ¹ H NMR (400 MHz, 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-methyl ¹ H 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/z APCl ⁺ 484, 486[MH] ^{+ 184B} W=2-F, 3-Cl; Y=4-Cl; Y'=H; X=pyrimidin-2-yloxymethyl ¹ H 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-pyridin-2-yl-ethyl ¹ H 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-morpholin-4-ylethyl; ¹ H 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-isoxazol-4-yl)-ethyl; ¹ H 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 = Ethyl acetate:methanol:0.88 ammonia was used as column eluent.

B = Using 2 equivalents of N-methylmorpholine instead of triethylamine.

C = Using 3 equivalents of N-methylmorpholine instead of triethylamine.

Example 188: 4-[4-(4-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-4H-1,2,4-triazol-3-yl]-1-( 3,3-Dimethylbutyryl)piperidine

The title compound was obtained from the compound of Preparation 138 and isovaleryl chloride following the procedure described in Examples 174 to 187.

¹ H 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] ⁺ .

Examples 189 to 198:

The appropriate acid chloride, ZCOCl, (1.0 eq) was added to a solution of the appropriate amine (1 eq) selected from Preparations 122 to 131 and triethylamine (1.1 eq) in dichloromethane (4 mL mmol ^-1 ) . The reaction was stirred at room temperature for 1 hour. It was then diluted with water, stirred for 5 minutes, then filtered through a phase separation cartridge. The organic solution was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel using ethyl acetate:dichloromethane:methanol (100:0:0 to 0:95:5) as eluent. The product was azeotroped with diethyl ether to afford the title compound as a white foam.

Examples 199 to 201:

The appropriate acid, ZCO ₂ H (1.2 equiv), 1-hydroxybenzotriazole hydrate (1.2 equiv), triethylamine (2 to 4 equiv), and 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride (1.2 equiv) and the appropriate amine selected from Preparations 2 and 143, or a mixture of amine hydrochloride (1 equiv) in dichloromethane (26 mL mmol-1) at room temperature Stirring was continued for 24 hours. The reaction was then washed with 2N sodium hydroxide solution and the organic solution was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:methanol:0.88 ammonia (100:0:0 to 95:5:0.5) to afford the title compound.

Example number data 199 Z = cyclopropylmethyl; X = CH ₂ OCH ₂ CH ₃ ¹ H NMR (400 MHz, CDCl ₃ ): δ 0.18 (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] ^{+ 200A} Z=5-trifluoromethylpyridin-2-yl; X=CH ₂ OCH ₂ CH ₃ ¹ H 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] ^{+ 201B} Z=1H-indazol-3-yl; Y=4-Cl; Y'=H; X=CH ₃ ¹ H 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/zAPCl ⁺ 421[MH] ⁺

A = 5-(trifluoromethyl)-2-pyridinecarboxylic acid was used and it can be prepared as described in J. Org. Chem. (Europe) 2003; (8); 1559-1568.

B = The reaction was carried out in the absence of 1-hydroxybenzotriazole hydrate and triethylamine.

Examples 202 to 204:

Appropriate acid, ZCO ₂ H, (1.5 equivalents), O-benzotriazol-1-yl-N, N, N', N'-tetramethylurea cation hexafluorophosphate (2 equivalents), N- A solution of methylmorpholine (5 equiv) and the hydrochloride salt of the appropriate amine selected from Preparations 2 and 133 (1 equiv) in dichloromethane (8 mL mmol ^-1 ) was stirred at room temperature for 24 hours. The reaction was then washed with sodium hydroxide solution and the organic solution was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) to afford the title compound.

Example number data 202 Z=4-chloro-3-fluorophenyl; X=CH ₃ ; ¹ H NMR (400MHz, CD ₃ OD): 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=CH ₃ ; ¹ H NMR (400MHz, CD ₃ OD): 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-indazol-3-yl; X=3-methyl-isoxazol-5-ylmethyl; ¹ H 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 ] ⁺

Examples 205 to 207:

Appropriate acid, ZCO ₂ H, (1.2 equivalents), O-benzotriazol-1-yl-N, N, N', N'-tetramethylurea cation hexafluorophosphate (1.2 equivalents), N- A solution of methylmorpholine (1.4 equiv) and the appropriate amine selected from Preparations 2 and 136 (1 equiv) in dichloromethane (7 to 10 mL mmol ^-1 ) was stirred at room temperature for 24 hours. The reaction was then partitioned between sodium hydroxide solution and dichloromethane, and the layers were separated. The organic solution was washed with ammonium chloride solution, dried over _MgSO4 and then evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) to afford the title compound.

Example number data ^205A Z=3-difluoromethyl-phenyl; X=[1,2,3]-triazol-2-ylmethyl ¹ H 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] ⁺

206B ^,C Z = 4-difluoromethyl-phenyl; X = [1,2,3]-triazol-2-ylmethyl ¹ H NMR (400 MHz, 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-indazol-3-yl; X=2-piperidin-1-yl-ethyl; ¹ H 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 = Use of 3-difluoromethylbenzoic acid. It can be prepared according to Tetrahedron 31; 1977; 391-410.

B = 4-difluoromethylbenzoic acid was used. It can be prepared according to Tetrahedron 31; 1977; 391-410.

C = additional crystallization of the product from isopropanol, and 2.8 equivalents of N-methylmorpholine were used.

Examples 208 to 210:

The appropriate oxadiazole (1 equivalent) from Preparations 66 and 67, the appropriate aniline from Preparations 166 and 168 or the commercial 4-chloro-2-(trifluoromethoxy)aniline (1.5 to 2.0 equivalents) and trifluoro A mixture of acetic acid (0.5 to 1.0 equiv) in toluene (2.5 to 9.5 mL mmol-1) was heated at 110°C for 18 hours. The cooled mixture was partitioned between dichloromethane and sodium carbonate solution, and the layers were then separated. The organic phase was dried over _MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) as eluent to afford the title compound.

Example number data 208 Z=3-chlorophenyl; Y=4-Cl; Y'=2-OCH ₂ CH ₃ ; X=H; ¹ H NMR (400MHz, CD ₃ OD); 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-chlorophenyl; Y=4-Cl; Y'=2-OCF ₃ ; X=H; ¹ H NMR (400MHz, CD ₃ OD): 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 Z=4-chlorophenyl; Y=4-Cl; Y'=2-pyrrolidin-1-ylmethyl; X=CH ₃ ; ¹ H 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] ⁺

Examples 211 to 216:

The appropriate oxadiazole (1 equiv), aniline (1.5 to 2.0 equiv) and trifluoroacetic acid (0.5 to 1.0 equiv) selected from Preparations 66 to 69, 71 and 75 in toluene (1.0 to 2.5 mL mmol-1) The mixture was heated at 170 to 185° C. for 20 minutes under microwave irradiation. The crude solution was purified by column chromatography on a silica gel cartridge using dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) as eluent to afford the title compound.

Example number data 211 Z=3-chlorophenyl; Y=4-Cl; Y'=2-OCH ₂ CF ₃ ; X=H; ¹ H 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] ^{+ 212A} Z=4-chlorophenyl; Y=4-Cl; Y'=H; X=CF ₃ ; ¹ H 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 Z=3-chlorophenyl; Y=4-Cl; Y'=H; X=CH ₂ OCH ₂ CH ₃ ; ¹ H 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 Z=4-chlorophenyl; Y=4-CH ₃ ; Y'=2-CH ₃ ; X=CH ₃ ; ¹ H 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 Z=4-chlorophenyl; Y=4-Cl; Y'=2-CH ₃ ; X=CH ₂ CH ₃ ; ¹ H 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 Z=3-chlorophenyl; Y=4-Cl; Y'=H;X=pyrazol-1-ylmethyl; ¹ H NMR (400MHz, CD ₃ OD): 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] ⁺

A = The crude reaction mixture was partitioned between ethyl acetate and 2N hydrochloric acid, then the organic solution was washed with saturated sodium bicarbonate solution and evaporated under reduced pressure.

Examples 217 to 222:

The appropriate acid (1 equiv), 1-hydroxybenzotriazole hydrate (1.5 equiv), triethylamine (4 equiv) and 1-(3-dimethylaminopropyl)-3- ^A solution ^of ethylcarbodiimide hydrochloride (1.5 equiv) in dichloromethane (3.5 ^mL mol ^-1 ) in the solution and stirred at room temperature for 24 hours. The reaction was then washed with ammonium chloride solution and the organic solution was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 95:5:0.5) to afford the title compound.

Example number data ^217A R ⁴ =H; R ⁵ =bicyclo[1.1.1]pent-1-yl; X=CH ₃ ; ¹ H 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]-triazol-2-ylmethyl ¹ H 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 ⁴ R ⁵ = azetidin-1-yl; X = [1,2,3]-triazol-2-ylmethyl ¹ H NMR (400 MHz, 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 ⁴ R ⁵ = pyrrolidin-1-yl; X = [1,2,3]-triazol-2-ylmethyl ¹ H NMR (400MHz, CDCl ₃ ): δ1.59-1.76 (m, 4H) , 1.82(m, 2H), 1.95(m, 2H), 2.41(m, 1H), 2.g2(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 ⁴ R ⁵ =morpholin-4-yl; X=[1,2,3]-triazol-2-ylmethyl ¹ H 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]-triazol-2-ylmethyl ¹ H 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-bicyclo[1.1.1]pentylamine hydrochloride (see references J.O.C. 2001; 66(19); 6282-6285).

Example 223: 1-[4-(4-Chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-N-isopropyl-4-methylpiperidine -4-formamide

Oxalyl chloride (0.04 mL, 0.55 mmol) was added to a solution of the acid of Preparation 160 (50 mg, 0.15 mmol) in dichloromethane (50 mL), and the solution was stirred at room temperature for 20 minutes. Additional oxalyl chloride (0.02 mL, 0.27 mmol) was added and the solution was stirred for another 10 minutes. The solution was then evaporated under reduced pressure and the residue was azeotroped with dichloromethane (3x). The oily residue was dissolved in dichloromethane (10 mL). Isopropylamine (0.19 mL, 2.25 mmol) was added to the solution and the mixture was then stirred at room temperature for 18 hours. The reaction was then washed with ammonium chloride solution, dried over _MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (95:5:1) as eluent. The product was triturated with ether to afford the title compound as a solid, 30mg.

¹ H 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] ⁺ .

Example 224: N-{1-[4-(4-Chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidin-4-yl}benzamide

Triethylamine (105 μl, 0.75 mmol) followed by benzoyl chloride (79.6 μl, 0.69 mmol) was added to the amine of preparation 145 (200 mg, 0.69 mmol) in dichloromethane (5 mL) solution, and the reaction was stirred at room temperature for 5 minutes. Water (5 mL) was added and the mixture was stirred vigorously for 5 minutes. The mixture was then filtered using a phase separation cartridge and the organic layer was concentrated under reduced pressure. The residue was then azeotroped with diethyl ether to afford the title compound as a white solid, 278 mg.

¹ H NMR (400MHz, CD ₃ OD): 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] ⁺ .

Example 225: 1-Benzoyl-4-[4-(4-chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]piperazine

1-Hydroxybenzotriazole hydrate (150 mg, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (225 mg, 1.17 mmol), Triethylamine (0.4 mL, 2.7 mmol) and the amine of preparation 144 (250 mg, 0.9 mmol) were added sequentially to a solution of benzoic acid (110 mg, 0.9 mmol) in dichloromethane (10 mL) . The reaction was then stirred at room temperature for 18 hours. The mixture was partitioned between 2M sodium hydroxide solution and dichloromethane and the phases were separated. The aqueous layer was further extracted with dichloromethane, and the combined organic solutions were evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 95:5:0.5) to afford the title compound as a white foam, 182 mg.

¹ H 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 found: C, 61.66; H, _5.32 ; _{N , 17.42} . , 5.19; N, 17.79%.

Example 226: 4-Benzoyl-1-[4-(4-chlorophenyl)-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl]-2 -Methylpiperazine

Triethylamine (100 μl, 0.71 mmol) and then benzoyl chloride (82 μl, 0.71 mmol) were added to the compound of preparation 149 (150 mg, 0.47 mmol) in dichloromethane (10 ml). solution, and the reaction was then stirred at room temperature for 18 hours. The mixture was washed with sodium bicarbonate solution, the layers were separated and the organic solution was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate:methanol:0.88 ammonia (95:5:0.5) as eluent to afford the title compound as a white solid, 120 mg.

¹ H 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/zAPCl ⁺ 426[MH] ⁺ .

Example 227: 1-(4-Chlorobenzoyl)-4-[4-(4-chlorophenyl)-5-(methoxymethyl)-4H-1,2,4-triazole-3 -yl]-2-methylpiperazine

The title compound was prepared according to the procedure described in Example 226 from the compound of Preparation 150 and 4-chlorobenzoyl chloride in 37% yield.

¹ H 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/zAPCl ⁺ 460[M] ⁺ .

Example 228: 1-[4-(4-Chlorophenyl)-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl]-4-(3-fluorobenzene Formyl)-1,4-diazepine

The title compound was prepared according to the procedure described in Example 224 from the compound of Preparation 148 and 3-fluorobenzoyl chloride in 84% yield.

¹ H 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 ( LCMS : m/z APCl ⁺ 444[M] ⁺ .

Example 229: 4-(2-Chlorobenzoyl)-2-[4-(4-chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]morpholine

Trifluoroacetic acid (5 mL) was added to a cooled (5° C.) solution of the compound of Preparation 102 (1.3 g, 3.43 mmol) in dichloromethane (5 mL), and the solution was then stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, then triethylamine (450 mg, 4.47 mmol) and dichloromethane (30 mL) were added. A portion of this solution (10 mL) was treated with 2-benzoyl chloride (1.26 mmol) and then stirred at room temperature for 2 hours. Tris-(2-aminoethyl)amine polystyrene (500 mg) was added and the mixture was stirred for another 24 hours. The mixture was then diluted with aqueous ammonium chloride, the layers were separated using a hydrophobic membrane and the organic solution was directly purified using a silica gel cartridge and dichloromethane:methanol (100:0 to 95:5) as eluent to provide the title compound.

¹ H NMR (400MHz, CDCl ₃ ) (rotamer): δ2.23, 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] ⁺ .

Example 230: 1-(2-Chlorobenzoyl)-3-[4-(4-chloro-2-methylphenyl)-5-methyl-4H-1,2,4-triazol-3-yl ]piperidine

Triethylamine (79 μl, 0.57 mmol) followed by 2-benzoyl chloride (66 μl, 0.52 mmol) was added to the compound of preparation 146 (150 mg, 0.52 mmol) in dichloromethane (5 ml ) in the solution. The mixture was then stirred at room temperature for 18 hours. After this time the reaction was diluted with water (5 mL), and the mixture was stirred rapidly for 30 minutes. The layers were then separated, the organic solution was evaporated under reduced pressure, and the product was azeotroped from diethyl ether to afford the title compound as a white foam, 193 mg.

¹ H 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] ⁺ .

Example 231: 3-[1-(2-Chlorobenzoyl)pyrrolidin-3-yl]-4-(4-chloro-2-methylphenyl)-5-methyl-4H-1,2,4 -triazole

Compound 147 (97 mg, 0.35 mmol), 2-chlorobenzoyl chloride (40.4 μl, 0.32 mmol) and N-methylmorpholine (58 μl, 0.53 mmol) were prepared in dichloromethane (5 mL) was stirred at room temperature for 18 hours. The reaction was then diluted with dichloromethane (20 mL), washed with 2N hydrochloric acid (20 mL) and saturated sodium bicarbonate solution (20 mL). The organic solution was then dried over _MgSO4 and concentrated under reduced pressure. The residual oil was triturated with ether and the resulting solid was filtered and dried to afford the title compound, 55 mg.

¹ H NMR (400MHz, CDCl ₃ ) (rotamers): δ1.84-2.62(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] ⁺ .

Example 232: N-{1-[4-(4-Chlorophenyl)-5-(2H-1,2,3-triazol-2-ylmethyl)-4H-1,2,4-tris Azol-3-yl]pyrrolidin-3-yl}-N-methylacetamide

The title compound was obtained from the compound of Preparations 54 and 18 following the procedure described for Preparation 93 in 50% yield.

¹ H NMR (400MHz, CDCl ₃ ) (rotamer): δ1.78-1.90 (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] ⁺ .

Example 233: 1-[4-(4-Chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-4-phenylpiperidine-4-carboxamide

Sulfuric acid (930 mg, 95%, 9.5 mmol) was added to a solution of the compound of Preparation 96 (700 mg, 1.9 mmol) in acetic acid (1.5 mL), and the reaction was then heated at 100°C for 3 days. The cooled mixture was quenched by careful addition of 0.88 g of ammonia and extracted with dichloromethane (4x). The combined organic layers were washed with brine, then dried over _MgSO4 and evaporated under reduced pressure. The product was crystallized from ethyl acetate to afford the title compound, 282 mg.

¹ H 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] ⁺ .

Example 234: 4-{[4-(4-Chlorophenyl)-5-(2H-1,2,3-triazol-2-ylmethyl)-4H-1,2,4-triazole- 3-yl]oxy}piperidine-1-carboxylic acid tert-butyl ester

Tetrahydrofuran (2 mL) was added to sodium hydride (24 mg, 60% in mineral oil), which had been prewashed with pentane (2 mL), and the suspension was stirred at room temperature. Then tert-butyl 4-hydroxy-1-piperidinecarboxylate (119 mg, 0.6 mmol) was added and the mixture was stirred at room temperature for another 30 minutes. The compound of preparation 164 (100 mg, 0.3 mmol) was added and the reaction was stirred at room temperature for another 18 hours. The reaction was then partitioned between dichloromethane (20 mL) and brine (20 mL), the layers were separated and the organic phase was evaporated under reduced pressure. The residue was dissolved in dichloromethane (6 mL), PS-DIEA (Argonaut Technologies) (638 mg) and triethylamine (0.5 mL, 3.6 mmol) were added. The mixture was then stirred for 18 hours. The mixture was filtered, washed with saturated aqueous potassium carbonate and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol (99:1 ) as eluent. The product was further purified by HPLC using a Phenomenex Luna C18 column and 0.1% aqueous formic acid:acetonitrile/0.1% formic acid (80:20 to 5:95) to afford the title compound, 34 mg.

¹ H NMR (400MHz, CD ₃ OD): 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).

Example 235: N-(tert-Butyl)-4-[4-(4-chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]benzamide

tert-Butylamine hydrochloride (223 mg, 2.0 mmol) followed by a solution of the acid chloride of Preparation 157 (150 mg, 0.4 mmol) in dichloromethane (3 mL) was added to triethylamine (300 μL, 2.0 mmol) in dichloromethane (2 mL) and the reaction was stirred at room temperature for one hour. The mixture was then partitioned between dichloromethane and aqueous citric acid and the phases were separated. The aqueous layer was further extracted with dichloromethane (2 x 25 mL) and the combined organic solutions were dried over _MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (93:7:1) as eluent to afford the title compound, 122 mg.

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

Examples 236 to 395:

Appropriate acid, ZCO ₂ H, (0.25 mL, 0.2 M solution in N,N-dimethylformamide, 50 µM) and, if necessary, triethylamine (7 µL, 50 µM per salt equivalent) mol) and then O-(7-azabenzotriazole-yl)-N,N,N',N'-tetramethyluronium cation hexafluorophosphate solution (0.1 ml, 0.525M, 52.5 micro Mole) processing. The solution was then prepared in a 96 deep-well polypropylene microtiter plate with triethylamine (28 μl, 0.20 mmol) and the amine of preparation 12 (0.25 ml, a 0.2M solution in N,N-dimethylformamide, 50 micromole) treatment. The plate was closed and agitated at 40°C for 16 hours. The reaction mixture was then evaporated under reduced pressure and the residue was purified by HPLC using a Watera XTerra MS C18 column, and acetonitrile:10 mM ammonium bicarbonate (adjusted to pH 10 with ammonium hydroxide) (5:95 to 98:2) to Provide the desired compound.

Example number Z MS[MH] ⁺ Retention time (minutes) 236 5-Methyl-1-phenyl-1H-pyrazol-4-yl 529 2.26 237 5-methyl-1H-indol-2-yl 502 2.56 238 3-(1H-indol-3-yl)propyl 530 2.17 239 1-Benzyl-1H-pyrazol-4-yl 529 2 240 3-(2-fluorophenyl)-1H-pyrazol-5-yl 533 2.08 241 3-(4-methylphenyl)-1H-pyrazol-5-yl 529 2.17 242 2-(phenylmethyl)thiazol-4-yl 546 2.26 243 5-Methyl-1H-indazol-3-yl 503 2.04

244 (2,5,7-trimethyl-1H-indol-3-yl)methyl 544 2.3 245 4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl 507 1.95 246 1H-Indazol-1-ylmethyl 503 1.95 247 3-(2,5-Dimethylphenyl)propyl 519 2.47

248 (1S)-1-(dimethylamino)-2-phenylethyl 520 2.04 249 (2,5-Dimethyl-1,3-thiazol-4-yl)methyl 498 1.87 250 (4-methoxyphenyl)-5-methyl-1H-pyrazol-4-yl] 559 2.04 251 1-(1-cyclopenten-1-yl)butyl 495 2.47 252 Cyclohex-3-en-1-yl 453 2.04 253 (1,3-Dimethyl-1H-thieno[2,3-c]pyrazol-5-yl) 523 1.91 254 (2S)-1-(tert-butoxycarbonyl)piperidin-2-yl 556 2.3 255 Benzo[b]thiophen-3-yl 505 2.21 256 4-(5-oxazolyl)phenyl 516 1.87 257 3-(2-Methyl-4-thiazolyl)phenyl 546 2.13 258 2-phenoxypyridin-5-yl 542 2.21 259 2-Methyl-4-phenylpyrimidin-5-yl 541 1.95 260 5-methoxy-indol-2-yl 518 2.13 261 4-Chlorobenzyl 497 2.43 262 1-Phenylcyclopentyl 517 2.69 263 3-(4-fluorophenyl)-3-oxopropyl 523 2.03 264 1,2,3,4-tetrahydronaphthalene-2-yl 503 2.23

265 Cyclopentyl(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-1-phenylbutyl 519 2.49 270 (1-Naphthyloxy)methyl 529 2.13 271 (2,3-Dimethylphenoxy)methyl 507 2.2 272 3-(4-Methylphenyl)propyl 505 2.18 273 1H-Indol-1-ylethyl 516 2.12

274 (Phenylthio)methyl 495 2.08 275 1-(4-Chlorophenyl)ethyl 511 2.27 276 2,3-Dihydro-1H-inden-2-ylmethyl 503 2.23 277 2-[(4-Chlorophenyl)thio]propyl 558 2.47 278 2-Chloro-4-fluorobenzyl 515 2.13 279 (1R)-1-phenyl-propyl 491 2.22 280 3-Methoxycyclohexyl 485 1.81 281 1-Benzyl-2,2-dimethylpropyl 533 2.52 282 1-methyl-2-phenylethyl 491 2.15 283 (Benzyloxy)methyl 493 1.96 284 3-(4-Chlorophenyl)-3-oxopropyl 539 2.17 285 [(4-Chlorophenyl)thio]methyl 529 2.27 286 (Benzylthio)methyl 509 2.12 287 3-Chlorobenzyl 497 2.1

288 1,1-Diphenylethyl 553 2.5 289 2,2-Diphenylethyl 553 2.39 290 (2,3-Dichlorophenoxy)methyl 291 4-Fluorobenzyl 548 2.29 292 2-Methoxybenzyl 481 1.98 293 2-(2-Methoxyphenyl)ethyl 493 1.91 294 2,8-Dimethylquinolin-4-yl 507 2.16 295 (2-Naphthyloxy)methyl 528 2.21 296 2-Naphthylmethyl 529 2.29 297 2-Phenoxyethyl 513 2.26 298 1-(2-Fluorophenyl)cyclopentyl 493 2.11 299 5-methoxy-1-oxoindan-2-ylmethyl 535 2.36 300 (3-Methylbenzoyl)aminomethyl 520 1.89

301 trans-4-methylcyclohexyl 469 2.26 302 3-phenyl 3-oxo-1 methylpropyl 519 2.09 303 2-(2-Methylphenyl)ethyl 491 2.21 304 1-Methyl-indol-3-ylmethyl 516 2.14 305 Diphenylmethyl 539 2.38 306 1-(4-Chlorophenyl)-1-methylethyl 525 2.41 307 1-methyl-1-phenylethyl 491 2.26 308 1-vinyloxy-1-phenylmethyl 521 2.01 309 Cyclohex-1-en-1-ylmethyl 467 2.12

310 (2R)-2-Phenylpropyl 491 2.19 311 [(4-Fluorophenyl)thio]methyl 513 2.14 312 (2R)-1-(tert-butoxycarbonyl)piperidin-2-yl 556 2.26 313 3-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl 549 2.14 314 6-Chloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl 568 2.11 315 2-(4-fluorophenoxy)ethyl 511 2.16 316 2-Hydroxyquinoxalin-3-yl 517 1.57 317 5-methyl-3-phenylisoxazol-4-yl 530 2.07 318 Isoquinolin-1-yl 500 1.87 319 2-Phenoxyphenyl 541 2.29 320 Quinolin-2-yl 500 1.97 321 Quinolin-4-yl 500 1.8 322 Quinolin-3-yl 500 1.87 323 2-Naphthyl 499 2.21 324 5-Butylpyridin-2-yl 506 2.22 325 3-Benzoylphenyl 553 2.21 326 1H-benzimidazol-6-yl 489 1.55

327 9-oxo-9H-fluoren-1-yl 551 2.16 328 4-methoxyquinolin-2-yl 530 2.07 329 1-benzofuran-2-yl 489 2.16 330 2-(4-Methylbenzoyl)phenyl 567 2.31 331 7-methoxy-1-benzofuran-2-yl 519 2.17

332 2,6-Dimethoxypyridin-3-yl 510 2.3 333 2,5-Dimethyl-3-furyl 467 2.26 334 Biphenyl-2-yl 525 2.52 335 5-methyl-2-thienyl 469 2.3 336 2-phenoxypyridin-3-yl 542 2.17 337 1,3-Benzothiazol-6-yl 506 2.08 338 3-Phenylcinnolin-4-yl 577 1.76 339 3-tert-butyl-1-methyl-1H-pyrazol-5-yl 509 2.26 340 2,1,3-Benzoxadiazol-5-yl 491 2.26 341 5-bromo-2,3-dihydro-1-benzofuran-7-yl 570 2.43 342 1-(4-Chlorophenyl)cyclopropyl 523 2.27 343 5-isobutylisoxazol-3-yl 496 2.23 344 3-(1H-pyrazol-1-yl)phenyl 515 1.91 345 3,5-Dimethylindol-2-yl 516 2.32 346 4-(tert-butoxycarbonyl)morpholin-3-ylmethyl 572 1.98 347 3-isobutyl-1H-pyrazol-5-yl 495 1.96 348 5-Propylisoxazol-3-yl 482 2.1 349 2,4-Dimethyl-1,3-thiazol-5-yl 498 1.61 350 2-Methylquinolin-4-yl 514 1.81 351 6-Chloro-imidazo[1,2-a]pyridin-2-yl 523 1.71 352 3-Phenyl-1H-pyrazol-5-yl 515 1.96 353 3-Isopropyl-1H-pyrazol-5-yl 481 1.66 354 4,5,6,7-tetrahydro-2-indazol-3-yl 493 1.81

355 2,3-Dimethyl-1H-indol-5-yl 516 2.05 356 3,5-Dimethyl-1H-pyrrol-2-yl 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′-Fluorobiphenyl-4-yl 543 2.37 360 4-Phenyl-1,3-thiazol-2-yl 546 2.17 361 4-(1H-pyrazol-1-yl)phenyl 515 1.9 362 5,7-Dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl 518 1.76 363 3-Phenylisoxazol-5-yl 516 2.2 364 2,3-Dihydro-1-benzofuran-2-yl 491 2 365 1H-benzimidazol-1-ylmethyl 503 1.73 366 5-(4-Methoxyphenyl)-2-furyl 545 2.25 367 1,3-Benzothiazol-2-ylethyl 534 2.03 368 2-Methyl-5-propylpyrazol-3-yl 495 1.96 369 1-Benzyl-2-oxo-1,2-dihydropyridin-3-yl 556 1.85 370 1-Benzyl-6-oxo-1,6-dihydropyridin-3-yl 556 1.75 371 2-Phenyl-1,3-thiazol-4-yl 532 2.22 372 4-Methyl-2-phenyl-1,3-thiazol-5-yl 546 2.18 373 8-methoxy-2H-chromen-3-yl 533 2.02 374 2H-chromen-3-yl 503 2.12 375 6-methoxy-2H-chromen-3-yl 533 2.1

376 4-(tert-butoxycarbonyl)morpholin-3-yl 558 1.95 377 4-methoxy-3-thienyl 485 1.85

378 4-(1H-imidazol-1-yl)phenyl 515 1.68 379 2-Methyl-1H-benzimidazol-5-yl 503 1.51 380 2,3-Dihydro-1H-inden-2-yl 489 2.15 381 trans-2-phenylcyclopropan-1-yl 489 2.15 382 1-methyl-1H-indol-2-yl 502 2.18 383 1-methyl-1H-indol-3-yl 502 2.02 384 5-fluoro-1H-indol-2-yl 506 2.13 385 6-Methyl-4-oxo-4H-chromen-2-yl 531 2.02 ^386A 3-isopropyl-1-methylpyrazol-5-yl 495 1.95 387 ^B 5-Bromo-2-methoxypyridin-3-yl 559 2.03 ^388C 5-methyl-2-phenyl-1H-imidazol-4-yl 529 1.95 ^389D 3-(1-oxo-1,3-dihydro)-2H-isoindol-2-yl)propyl 532 1.82 ^390E 1-Ethylpiperidin-2-yl 484 1.91 ^391F 3-[(pyrimidin-2-ylthio)methyl]phenyl 573 2.08 ^392G 4-[(pyridin-2-ylthio)methyl]phenyl 572 2.17 393 ^H 6-cyclohexyl-2-oxo-1,2,3,6-tetrahydropyrimidin-4-yl 551 2.04 394 ^I 5-oxo-1-propylpyrrolidin-3-yl 498 1.74 ^395J 5-Propylisoxazol-4-yl 482 2

A = Use 3-isopropyl-1-methyl-1H-pyrazole-5-carboxylic acid; see DE 3029281.

B = Use of 5-bromo-2-methoxynicotinic acid, see EP 306251, Preparation 1.

C = use of 5-methyl-2-phenyl-1H-imidazole-4-carboxylic acid, see J. Chem Soc. 1948; 1969.

D = 3-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)propanoic acid, see J.Med.Chem.83;26(2);243.

E = use of 1-ethylpiperidine-2-carboxylic acid, see Journal of Inorganic and Nuclear medicine; 1978; 40(6); 1103-6.

F = Using 3-[(pyrimidin-2-ylthio)methyl]benzoic acid, see J. Indian Chem. Soc. (97); 74(7); 575.

G = Use 4-[(pyridin-2-ylthio)methyl]benzoic acid, see US 4325959, Example 2.

H = Use 6-cyclohexyl-2-oxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid, see J.O.C. 2000; 65(20); 6777.

I = use of 5-oxo-1-propylpyrrolidine-3-carboxylic acid, see WO 200202614.

J = Use of 5-propylisoxazole-4-carboxylic acid, see J. Het. Chem. 1991; 28(2) 453.

Examples 396 to 403:

Appropriate amine (1 eq), appropriate acid chloride (1.2 to 1.4 eq) and polymer-supported N-ethyldiisopropylamine (10 eq) from Preparation 12a in dichloromethane (16 mL mmol ^-1 ) The mixture in was stirred at room temperature for 2 hours. Tris-(2-aminoethyl)amine polystyrene was added and the mixture was stirred for one hour. It was then washed with 1N sodium hydroxide solution. The aqueous solution was extracted with dichloromethane (2x) and the combined organic solutions were concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate:methanol:0.88 ammonia (90:10:1 ) as eluent to provide the title compound.

Example number data 396 W=2-CF ₃ ; ¹ H 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/zAPCl ⁺ 516[MH] ⁺ 397 W=3-CF ₃ ; ¹ H 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 ; ¹ H NMR (400MHz, CD ₃ OD): 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] ^{+ 399A} W=2-F, 5-Cl; ¹ H 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] ^{+ 400B} W=3-F ¹ H 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] ^{+ 401B} W=2,3-di-F ¹ H 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] ^{+ 402B} W=2-F, 3-Cl ¹ H 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] ^{+ 403B} W=4-F, 3-Cl; ¹ H 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/zAPCl ⁺ 500[MH] ⁺

A = 2.5 equivalents of triethylamine was used instead of polymer supported N-ethyldiisopropylamine.

B = Using 2 equivalents of N-methylmorpholine instead of N-ethyldiisopropylamine on polymer support.

Examples 404 to 405:

Appropriate acid, ZCO ₂ H (1.2 equiv), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium cation hexafluorophosphate (1.2 equiv), N-formazol A solution of the morpholine (1.4 equiv) and the amine from Preparation 12a (1 equiv) in dichloromethane (7-10 mL mmol ^-1 ) was stirred at room temperature for 24 hours. The reaction was partitioned between sodium hydroxide solution and dichloromethane, and the layers were then separated. The organic solution was washed with ammonium chloride solution, dried over _MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) to afford the title compound.

Example number data 404 Z=3-fluoro-5-chlorophenyl; ¹ H 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 = indazol-3-yl; ¹ H 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[MH] ^-

All of the above exemplified compounds showed Ki values of less than 500 nM when tested in Screen 1.0 (V _1A filter binding assay) as described above.

Examples of special compounds are illustrated below:

Example number Ki(nM) 165 2.98 206 2.43 399 1.99 405 1.11

Claims (15)

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: X represents -[CH ₂ ] _a -R or -[CH ₂ ] _a -O-[CH ₂ ] _b -R; a represents a number selected from 0 to 6; b represents a number selected from 0 to 6; R represents H, CF ₃ or Het; Het represents a 5- or 6-membered saturated, partially saturated or aromatic heterocycle containing (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, optionally substituted by one or more groups independently selected from W; Y and Y' independently represent one or more substituents independently selected from -[O] _c -[CH ₂ ] _d -R ¹ , which may be the same or different for each occurrence; each occurrence of c independently represents a number selected from 0 or 1; each occurrence of d independently represents a number selected from 0 to 6; Each occurrence of R ¹ independently represents H, halo, CF ₃ , CN or Het ¹ ; Each occurrence of Het ¹ independently represents a 5- or 6-membered unsaturated heterocycle containing (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atoms or 1 sulfur atom and 1 or 2 nitrogen atoms; V means direct key or -O-; Ring A represents a 5- to 7-membered saturated heterocyclic ring containing (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom And 1 or 2 nitrogen atoms; Ring A is optionally substituted by one or more groups selected from C _1-6 alkyl, phenyl or hydroxyl; Q means direct bond or -N(R ² )-; R ² represents hydrogen or C _1-6 alkyl; Z represents -[O] _e- [ _CH2 ] _f - ^R3 ; a phenyl ring, which is optionally fused to a benzene ring or ^Het2 , and the group as a whole is optionally selected from one or more independently selected from W or Het ³ , which is optionally fused to a benzene ring or Het ⁴ , and the group as a whole is optionally substituted by one or more groups independently selected from W; R ³ represents C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl optionally substituted by one or more groups independently selected from W, optionally substituted by one or more Phenyl substituted by a group independently selected from W, Het ⁵ or NR ⁴ R ⁵ ; e represents a number selected from 0 or 1; f represents a number selected from 0 to 6; Het ² and Het ⁵ independently represent a 5- or 6-membered saturated, partially saturated or aromatic heterocyclic ring comprising (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or ( c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, optionally substituted by one or more groups selected from W; Het ³ represents a 4 to 6-membered saturated, partially saturated or aromatic heterocyclic ring containing (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom Or 1 sulfur atom and 1 or 2 nitrogen atoms, optionally substituted by one or more groups selected from W; Het ⁴ represents a 6-membered aromatic heterocycle containing (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 Or 2 nitrogen atoms, optionally substituted by one or more groups selected from W; R ⁴ and R ⁵ independently represent hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _{3-8 cycloalkyl optionally fused to C 3-8 cycloalkyl} , or Het ⁶ ; R ⁴ and R ⁵ are optionally independently replaced by one or more C 3-8 cycloalkane selected from C _1-6 alkyl, _{C 1-6} alkoxy, optionally fused to C _3-8 cycloalkyl radical or phenyl group substitution; Het ⁶ represents a 5- or 6-membered saturated, partially saturated or aromatic heterocycle containing (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, optionally substituted by one or more groups selected from W; Each occurrence of W independently represents halo, [O] _g R ⁶ , SO ₂ R ⁶ , SR ⁶ , SO ₂ NR ⁶ R ⁷ , [O] _h [CH ₂ ] _i CF ₃ , [O] _j CHF ₂ , phenyl optionally substituted by halogen, C _1-6 alkyl or C _1-6 alkoxy, CN, phenoxy optionally substituted by halogen, OH, benzyl, NR ⁶ R ⁷ , NCOR ^6. Benzyloxy, oxo, CONHR ⁶ , NSO ₂ R ⁶ R ⁷ , COR ⁶ , C _1-6 alkylene-NCOR ⁷ , Het ⁷ ; R ⁶ represents hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl or C _1-6 alkylene-OC _1-6 alkyl; R ⁷ represents hydrogen or C _1-6 alkyl; i represents a number selected from 0 to 6 h represents a number selected from 0 or 1; g represents a number selected from 0 or 1; j represents a number selected from 0 or 1; Het ⁷ represents a 5- or 6-membered saturated, partially saturated or aromatic heterocycle containing (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, optionally substituted by R ⁶ and/or R ⁷ and/or bridged oxo. 2. Compounds according to claim 1, wherein X represents -[ _CH2 ] _a -R. 3. Compounds according to claim 2, wherein R represents Het. 4. Compounds according to any one of claims 1 to 3, wherein Y represents halo. 5. Compounds according to any one of claims 1 to 3, wherein V represents a direct bond. 6. Compounds according to any one of claims 1 to 3, wherein Q represents a direct bond. 7. The compound according to any one of claims 1 to 3, wherein ring A represents a six-membered ring. 8. Compounds according to any one of claims 1 to 3, wherein Z represents phenyl. 9. The compound according to any one of claims 1 to 3, wherein Z is substituted by halogen. 10. A compound according to claim 1 selected from the group consisting of (3-chloro-phenyl)-{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4 ]triazol-3-yl]-piperidin-1-yl}-methanone; (4-chloro-phenyl)-{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4 ]triazol-3-yl]-piperidin-1-yl}-methanone; (5-chloro-2-fluoro-phenyl)-{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1 , 2,4] Triazol-3-yl]-piperidin-1-yl}-methanone; {4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]- Piperidin-1-yl}-(3,5-difluoro-phenyl)-methanone; {4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]- Piperidin-1-yl}-(3-fluoro-phenyl)-methanone; {4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]- Piperidin-1-yl}-(2,3-difluoro-phenyl)-methanone; (3-chloro-2-fluoro-phenyl)-{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1 , 2,4] Triazol-3-yl]-piperidin-1-yl}-methanone; (3-chloro-4-fluoro-phenyl)-{4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1 , 2,4] Triazol-3-yl]-piperidin-1-yl}-methanone; {4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]- Piperidin-1-yl}-(4-trifluoromethyl-phenyl)-methanone; {4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]- Piperidin-1-yl}-(3-trifluoromethyl-phenyl)-methanone; {4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]- Piperidin-1-yl}-(2-trifluoromethyl-phenyl)-methanone; {4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]- Piperidin-1-yl}-(4-difluoromethyl-phenyl)-methanone; {4-[4-(4-chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]- Piperidin-1-yl}-(1H-indazol-3-yl)-methanone; and pharmaceutically acceptable salts thereof. 11. Use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment of a disorder for which a Via antagonist is indicated. 12. Compounds according to any one of claims 1 to 10 for use in the manufacture of anxiety, cardiovascular diseases including angina pectoris, atherosclerosis, hypertension, heart failure, edema and hypernatremia, primary Sexual and secondary dysmenorrhea, endometriosis, vomiting including motion sickness, intrauterine growth retardation, inflammation including rheumatoid arthritis, intermenstrual pain, preeclampsia, premature ejaculation, preterm labor Or use in medicines for pre-term childbirth or Raynaud's disease. 13. Use according to claim 11 or claim 12, wherein the disorder is primary or secondary dysmenorrhea. 14. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 10, together with a pharmaceutically acceptable excipient, diluent or carrier. 15. Compounds of formula (I'):

or a pharmaceutically acceptable salt thereof, wherein: X represents -[CH ₂ ] _a -R or -[CH ₂ ] _a -O-[CH ₂ ] _b -R; a represents a number selected from 0 to 6; b represents a number selected from 0 to 6; R represents H, CF ₃ or Het; Het represents a 5- or 6-membered heterocycle containing (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms; Y represents -[O] _c -[CH ₂ ] _d -R ¹ ; Y' represents -[O] _c' -[CH ₂ ] _d' -R ¹ '; c and c' independently represent a number selected from 0 or 1; d and d' independently represent a number selected from 0 to 6; R ¹ and R ¹ ' independently represent H, halo, CF ₃ or Het ¹ ; Het ¹ represents a 5- or 6-membered unsaturated heterocycle containing (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom atom and 1 or 2 nitrogen atoms; Ring A represents a 5- or 6-membered saturated heterocyclic ring comprising at least one nitrogen atom; Z represents -[O] _e- [ _CH2 ] _f - ^R2 ; a phenyl ring optionally fused to a phenyl ring or a 5- or 6-membered saturated, partially unsaturated or aromatic heterocycle, and /or optionally substituted by one or more groups independently selected from W; or a 6-membered aromatic heterocycle optionally fused to a phenyl ring or a 6-membered aromatic heterocycle, and/or any is optionally substituted by one or more groups independently selected from W; R ² represents C _1-6 alkyl or C _3-6 cycloalkyl; e represents a number selected from 0 or 1; f represents a number selected from 0 to 6; W represents halo, [O] _g R ³ , SO ₂ R ³ , SR ³ , SO ₂ NR ³ R ⁴ , [O] _h [CH ₂ ] _i CF ₃ , OCHF ₂ , phenyl, CN, optionally Halogen-substituted phenoxy, OH, benzyl, NCOR ³ , benzyloxy, oxy, CONHR ³ , NSO ₂ R ³ R ⁴ , COR ³ , C _1-6 alkylene-NCOR ³ , Het ² ; ^R represents hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 alkylene-OC _1-6 alkyl: R ⁴ represents hydrogen or C _1-6 alkyl; i represents a number selected from 0 to 6; h represents a number selected from 0 or 1; g represents a number selected from 0 or 1; Het ² represents a 5- or 6-membered saturated, partially unsaturated or aromatic heterocyclic group comprising (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 Oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, heterocyclic group is optionally substituted by R ³ and/or R ⁴ and/or bridged oxo.