NL1027833C2 - Compounds useful in therapy. - Google Patents

Description

5 CONNECTIONS AVAILABLE AT THERAPY

•. ·. · "I

This invention relates to triazole derivatives and to processes for the preparation of intermediates used in the preparation of such derivatives, compositions which. these and their applications.

The triazole derivatives of the present invention are vasopressin antagonists. In particular, they are antagonists of the V1a receptor and. They have a number of applications, particularly in the treatment of dysmenorrhea (primary and secondary).

There is a large unmet need in the field of menstrual disorders and it is estimated that this affects up to 90% of all menstruating women to some extent. Up to 42% of women are missing at work or other activity, due to menstrual pain and it is estimated that as a result around 600 million working hours per year in the US are lost {Coco, A.S. (1999). Primary dysmenorrhoea. [Review] [30 ref.]. American Family Physician, 60, 489-96}.

Menstrual pain in the lower abdomen is caused by hyperactivity of the myometrium and decreased blood flow in the womb. These pathophysiological changes result in abdominal pain, which radiates to the back and legs. This can result in women feeling nauseous, having a headache and suffering from insomnia. This condition is called dysmenorrhea and can be classified as either primary or secondary dysmenorrhea.

1027833 2

Primary dysmenorrhea is diagnosed when no abnormality that causes the condition is identified. This affects up to 50% of the female population {Coco, A.S. (1999). Primary dysménorrhoea. [Review] [30 5 ref.] American Family Physician, 60, 489-96 / Schroeder, B. & Sanflippo, J.S. (1999). Dysmenorrhoea and pelvic pain in adolescents. [Review] [78 ref.]. Pediatrics Clinics of North America, 46, 555-71}. When an underlying gynecological disorder is present, secondary dysmenorrhea will be diagnosed. Secondary dysmenorrhea is diagnosed in only about 25% of women suffering from dysmenorrhea. Dysmenorrhea can occur in conjunction with menorrhagia, which makes up around 12% of the references to outpatient gynecology departments.

3.5

Currently, women suffering from primary dysmenorrhea are being treated with non-steroidal anti-inflammatory drugs (NSAIDs) or the oral contraceptive pill. In cases of secondary dysmenorrhea, surgery can be performed to remedy the underlying gynecological disorder.

Women suffering from dysmenorrhea have circulating vasopressin concentrations that are higher than those observed in healthy women at the same time of the menstrual cycle. Inhibition of the pharmacological actions of vasopressin at the level of the vasopressin receptor in the uterus can prevent dysmenorrhea.

The compounds of the present invention are therefore potentially useful in the treatment of a wide range of disorders, in particular aggression, Alzheimer's disease, anorexia nervosa, anxiety, anxiety disorders, asthma, atherosclerosis, autism, cardiovascular disease (including angina, atherosclerosis, hypertension, cardiac insufficiency, edema, hypematemia), cataract, central nervous system disease, cerebrovascular ischemia, cirrhosis, cognitive impairment, Cushing's disease, depression, diabetes mellitus, dysmenorrhea ( primary and secondary), emesis / vomiting (including movement sickness), endometriosis, gastrointestinal disease, glaucoma, gynecological disease, heart disease, intrauterie growth retardation, inflammation (including rheumatoid arthritis), ischemia, ischemic. . heart disease, lung tumor, disturbed urine, "little schmerz", neoplasm, nephrotoxicity, non-insulin-dependent diabetes, obesity, obsessive / compulsive disorder, ocular hypertension, pre-eclampsia, premature ejaculation, premature contractions, pulmonary disease , Raynaud's disease, kidney disease, renal failure, male or female sexual dysfunction, septic shock, sleep disorder, spinal cord injury, thrombosis, urogenital tract infection or urolithiasis.

Of particular interest are the following diseases or disorders: anxiety, cardiovascular disease (including angina, atheros-clerosis, hypertension, cardiac insufficiency, edema, hypernatraemia), dysmenorrhea (primary and secondary), endometrial, emesis / vomiting (including movement sickness), intrauterine growth retardation, inflammation (including rheumatoid arthritis), "mittleschmerz", pre-eclampsia, premature ejaculation, premature labor and Raynaud's disease.

The compounds of the invention and their pharmaceutically acceptable salts and solvates have the advantage that they are selective inhibitors of the V1a receptor (and thus probably have reduced side effects), that they have a faster onset of action, that they are more potent that they can work longer, that they have a greater bioavailability or that they have other more desirable properties than the compounds of the prior art.

1027833 4

According to the present invention there is provided a compound of formula (I): "fr · -

Y

(0 10 or a pharmaceutically acceptable derivative thereof, wherein: X represents - [CH 2] a R or - [CH 2] a-0- [CH 2] b R; a represents a number selected from 0-6; b represents a number selected from 0-6; R represents H, CF 3 or Het;

It represents a 5 or 6 membered, saturated, partially saturated or aromatic heterocyclic ring with either (a) 1-4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom 20 and 1 or 2 nitrogen atoms, optionally substituted with one or more groups independently selected from W; Y represents one or more substituents independently selected from -O] c- [CH 2] a -R 1, which may be the same or different at each occurrence; c for each occurrence independently represents a number selected from 0 or 1; d for each occurrence independently represents a 30 number selected from Ö - 6; R 1 represents, for each occurrence, independently H, a halogen atom, CP3, CN or Het1;

Het1 independently represents a 5- or 6-membered unsaturated heterocyclic ring, which comprises either (a) 1-4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 includes nitrogen atoms; 1027833 r 5 V represents a direct bond or -0-;

Ring A represents a 5- to 7-membered saturated heterocyclic ring, which either (a) 1-4 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 includes; wherein ring A is optionally substituted with one or more groups selected from C 1-8 alkyl, phenyl or hydroxyl; Q represents a direct bond or -N (R2) -; R2 represents hydrogen or C1-6 alkyl; Z represents - [O] e- [CH 2] f -R 3, a phenyl ring (optionally condensed to a benzene ring or Het 2 and wherein the group as a whole is optionally substituted with one or more groups independently selected from W ), or Het 3 (optionally condensed on a benzene ring or Het 4 and wherein the group as a whole is optionally substituted with one or more groups independently selected from W); R 3 represents C 1-6 alkyl (optionally substituted with one or more groups independently selected from W), C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl (optionally substituted with one or more groups that become independent 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 0-6;

Het2 and Het5 independently represent a 5- or 6-30 membered, saturated or partially saturated or aromatic heterocyclic ring, which either (a) 1-4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom or (c) 1 oxygen atom or 1 comprises a sulfur atom and 1 or 2 nitrogen atoms, optionally substituted with one or groups selected from W; Het3 represents a 4- to 6-membered, saturated, partially saturated or aromatic heterocyclic ring, which either (a) 1-4 nitrogen atoms, (b) 1 oxygen 1027833 6 atom or 1 sulfur atom or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, optionally substituted with one or more groups selected from W;

Het 4 represents a 6-membered aromatic heterocyclic ring comprising either (a) 1-4 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 with one or more groups selected from W; R 4 and R 5 independently represent hydrogen, C 1-10 alkyl, C 3-10 alkoxy, C 3-8 cycloalkyl (optionally condensed with C 3-8 cycloalkyl) or Het 6; wherein R 4 and R 5 are optionally independently substituted with one or more groups selected from C 1-6 alkyl, C 1-6 alkyloxy, C 3-8 cycloalkyl (optionally condensed with C 3-8 cycloalkyl) or phenyl;

Het 6 represents a 5- or 6-membered, saturated, partially saturated or aromatic heterocyclic ring, which either (a) 1-4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom or (c) 1 oxygen atom or 1 sulfur atom 20 and 1 or 2 nitrogen atoms, optionally substituted with one or more groups selected from W; W represents, for each occurrence, independently a halogen atom, [0] g R 6, SO 2, R 6, SR 6, SO 2 NR 6 R 7, [1] h [CH 2] 4 P 10 [Ol 2 CHF 3] a phenyl group (optionally substituted with halogen, 0-8 alkyl (C 1-6 alkyloxy), CN, phenoxy (optionally substituted with halogen), OH, benzyl, NR 6 R 7, NCRO 6, benzyloxy, oxo, CONHR 6, NS 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-O-C 1-6 alkyl; R 7 represents hydrogen or C 1-6 alkyl; i represents a number selected from 0-6;

h represents a number selected from 0 or 1; g represents a number selected from 0 or 1; J stands for a number selected from 0 or 1;

Het 7 represents a 5 or 6 membered, saturated, partially saturated or aromatic heterocyclic ring 1027833 7, which either (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 with R 6 and / or R 7 and / or an oxo group.

: -5-

In an alternative embodiment, a compound of formula (I #) is provided: Λ! rx 10

. 0 o Y

(0.

Or a pharmaceutically acceptable derivative thereof, wherein: X represents - [CH 2] a-R or - [CH 2] a-0- [CH 3 Jb-R; a represents a number selected from 0 to 6; B represents a number selected from 0-6; R represents H, CF 3 or Het;

It represents a 5- or 6-membered heterocyclic ring comprising either (a) 1-4 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 - [ojc- [CHjla -R1; Y 'stands for - [0] c. - [CH 3] -1 -R 1; c and c 'independently represent a number selected from 0 or 1; .

d and d 'independently represent a number selected from 0-6; R1 and R1 'independently represent H, halogen, CF3 or Het1; Het1 represents a 5- or 6-membered unsaturated heterocyclic ring, which either (a) 1-4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 includes nitrogen atoms;

Ring A represents a 5 or 6 membered saturated heterocyclic ring comprising at least one nitrogen atom; Z represents [0] e- [CH 3] f -R 2, a phenyl ring (optionally fused to a phenyl ring or a 5 or 6 membered saturated, partially unsaturated or aromatic heterocyclic ring, and / or optionally substituted with one or more groups independently selected from W), or a 6-membered aromatic heterocyclic ring (optionally fused to a phenyl ring or a 6-membered aromatic heterocyclic ring, and / or optionally substituted with 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; 20 W represents halogen, [0] gR 3, SO 2 R 3, SR 3, SO 2 NR 3 R 4, [0] h [CH 2] 1 CF 3, OCHF 3, phenyl, CN, phenoxy (optionally substituted with halogen), OH, benzyl, NCOR 3, benzyloxy, oxy, CONHR3, NS02R3R4 ,. COR3, C1-4 alkylene NCOR3, Het2; R 3 represents hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkylene-O-C 1-6 alkyl; R 4 represents hydrogen or C 3-6 alkyl; i represents a number selected from 0-6; h represents a number selected from 0 or 1; 30 g stands for a number selected from 0 or 1;

Het 2 represents a 5 or 6 membered saturated, partially unsaturated or aromatic heterocyclic ring, which either (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom or (c) 1 oxygen atom or 1 sulfur-35 atom and 1 or 2 nitrogen atoms, optionally substituted with R 3 and / or R 4 and / or an oxy group.

1027833 9

In the above definitions, halogen means fluoro,. chlorine, bromine or iodine. Alkyl groupefi, alkylene groups and alkoxy groups containing the required number of carbon atoms can be unbranched or branched. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, and t-butoxy. Examples of alkylene include methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, and 2,2-propylene. It represents a heterocyclic group and examples thereof include tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperaziny1,1 1,4-diazathianyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2,3,4-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl , pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 20-oxa-2,3-diazolyl, 1-oxa 2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1. 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl.

A preferred compound is one in which X represents CH 2OGH 3. More preferred has a connection where X stands for - [CH2] aR.

A preferred compound is one in which a represents a number selected from 0-5. More preferred is a compound in which a represents a number selected from 0-4. Even more preferred is a compound in which a represents a number selected from 0 to 3. Even more preferred is a compound in which a represents a number selected from 0 to 2. Most preferred is a compound in which a represents the number 1 .

1027833 10

A preferred compound is one in which R stands for H. A more preferred compound is one in which R stands for Het. Even more preferred is a compound in which R represents triazolyl.

5

A preferred compound is one in which Y represents one or two substituents. A more preferred compound is one in which Y represents a single substituent.

A preferred compound is one in which Y represents halogen. A connection with more preferred is one in which. Y stands for chlorine and / or fluorine.

A preferred compound is one in which V stands for a direct bond. A preferred compound is one in which Q is a direct bond. A more preferred compound is one in which both V and Q represent a direct bond.

There is a preferred connection. one in which Ring λ contains 2 nitrogen-20 dust atoms. A more preferred compound is one in which Ring A contains 1 nitrogen atom *

A preferred compound is one in which; Ring A represents a 5-membered ring. A more preferred compound is one in which Ring A represents a 6-membered ring. An even more preferred compound is one in which Ring A stands for piperidinylene.

A preferred compound is one in which Ring A is attached to V 30 via a nitrogen atom. A more preferred compound is one in which Ring A is attached to Q via a nitrogen atom. A preferred compound is one in which Ring A is attached to both Q and V via a nitrogen atom.

A preferred compound is one in which Z represents Het 3. Het 3 may represent an optionally substituted group selected from indazolyl, indolyl, indenyl, pyrazolyl, piperidin, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, benzothienyl, benzothiazolyl; quinolinyl, benzoxazinyl, isoxazolyl, imidazolyl, furyl., benzofuryl, cinnolinyl, morpholinyl, chromenyl or derivatives thereof. A more preferred compound is one in which Z represents phenyl.

A preferred compound is one in which Z is mono- or di-substituted. A more preferred compound is one in which Z is mono-substituted.

10

A preferred compound is one in which Z is substituted with trifluoromethyl. A more preferred compound is one in which Z is substituted with halogen. A more preferred compound is one in which Z is substituted with chlorine and / or fluorine.

Specific preferred compounds of the invention are those listed in the Examples section below, and the pharmaceutically acceptable salts thereof. In particular: (3-Chlorophenyl) - {4- [4- (4-chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazole- 3-yl) -piperidin-1-yl} -methanone; (4-Chlorophenyl) - {4- [4- (4-chlorophenyl) -5- [1,2,3] -25 triazol-2-ylmethyl-4 H- [1,2,4] triazol-3-yl] -piperidin-1-yl} -methanone; (5-Chloro-2-fluorophenyl) - {4- [4- (4-chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4-triazol-3 -yl] -piperidin-1-yl} -methanone; {4-4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazole-3-l-piperidin-1-yl } - (3,5-difluoro-phenyl) -methanone; {4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-1] piperidin-1-yl } - [3-fluorophenyl) methanone; 1027833 12 {4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazole-3-1] piperidine-1 -yl} - (2,3-difluoro-phenyl) -methanone; (3-Chloro-2-fluorophenyl) - {4- [4- (4-chlorophenyl) -5-5 [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazole-3 -yl] Tpiperidin-1-yl} methanone; (3-Chloro-4-fluorophenyl) - {4- [4- (4-chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4-triazole-3- yl] -piperidin-1-yl} -methanol; 10 {4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl } - (4-trifluoromethylphenyl) methanone; {4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl } - (3-trifluoro-methylphenyl) -methanone; {4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl3-piperidin-1-yl} - (2-trifluoromethylphenyl) methanone; (3-Chloro-5-fluorophenyl) - {4- [4- (4-chlorophenyl) -5-20 [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazole-3 -yl] -piperidin-1-yl} -methanone; {4 - [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl } - (4-difluoro-methylphenyl) methanone; {4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidine-1- yl} - (1H-inda-sol-3-yl) -methanone; and pharmaceutically acceptable derivatives thereof.

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

The pharmaceutically acceptable salts of the compounds of formula (1) include the acid addition and base salts thereof.

Suitable acid addition salts are formed with acids that form non-toxic salts. Examples include salts. Such as the acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate; borate, camsylate, citrate, edisylate, esylate, formate, fumarate, glucate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, palmoate, phosphate, hydrogen phosphate, dihydrogen phosphate, saccharate, stearate, succihate, sulfate, D- and L-trate , tosylate and trifluoroacetate. A particularly suitable salt is the besylate derivative of the compounds of the present invention.

Suitable base salts are formed from bases that form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

30 For an overview of suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties,

Selection and Use, Wiley-VCH, Weinheim, Germany (2002). A pharmaceutically acceptable salt of a compound of formula (I) can be easily prepared by mixing solutions of the compound of formula (I) and the desired acid or base, as appropriate. The salt can precipitate out of the solution and be collected by filtration 1027833 14 and it can be recovered by evaporation of the solvent. The degree of ionization of the salt can vary from completely ionized to almost non-ionized.

5

The compounds of the invention can exist in both unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex with the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term "hydrate" is used when the solvent is water.

Within the scope of the invention are complexes such as clathrates, drug-host-inclusion complexes in which, unlike the aforementioned solvates, the drug and the host are present in a stoichiometric amount. Also included are drug complexes containing two or more organic and / or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized or unionized. For an overview of such complexes, see J. Pharm. Sci. 64 (8), 1269-1288 from Halebli-25 ari (August 1975).

All references to. compounds of formula (I) and pharmaceutically acceptable salts references to salts, solvates and complexes thereof and. to 30 solvates and complexes of salts thereof.

The compounds of the invention include compounds of formula (I) as hereinbefore defined, polymorphic compounds, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as defined below and isotope-labeled compounds of formula (I) · 1027833

As stated, the invention encompasses all polymorphic states of the compounds of formula (I) as defined above.

Also included within the scope of the invention are so-called "prodrugs" of the compounds of formula (I). For example, certain derivatives of compounds of formula (I) which themselves have little or no pharmacological activity when administered in or on the body can be converted into compounds of formula (I) with the desired activity, for example by hydrolytic cleavage. Such derivatives are called "prodrugs". Further information on the use of prodrugs can be found in "Pro-drugs such as Novel Delivery Systems, Volume 14, 15 ACS Symposium Series (T. Higuchi and W. Stella) and" Biodiversable Carriers in Drug Design, "Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can be produced, for example, by replacing suitable functionalities present in the compounds of formula (I) with certain residues known to those skilled in the art as "precursor residues" as described, for example, in "Design of Prodrugs" from H. 25 Bundgaard (Elsevier, 1985).

Some examples of drugs in accordance with the invention include: (i) when the compound of formula (I) contains a carboxylic acid function (-COOH), an ester thereof, e.g. replacement of the hydrogen atom with C 1-4 alkyl; (ii) when the compound of formula (I) contains an alcohol function (-OH), an ether thereof, for example replacement of the hydrogen atom with C 1-6 alkanoyloxymethyl; and 1027033 16 (iii) when the compound of formula (I) has a primary or secondary amino function (-NHa or -NHR, wherein R is H), an amide thereof, e.g. replacement of one or both of the hydrogen atoms with C 1-6 alkanoyl. .

Further examples of replacement groups in accordance with the previous examples and examples of other types of prodrugs can be found in the above references.

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

15

Also within the scope of the invention are the 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. When a compound of formula (I) contains an alkenyl or alkenylene group, geometric ci / trane (or Z / E) isomers are possible, and when the compound contains, for example, a keto or oxime group or an aromatic radical, tautomeric isomerism ("tautomerization") occur. It will be appreciated that a single compound may exhibit more than one type of isomerism.

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 are included within the scope of the present invention. Also included are acid addition and base salts in which the counter ion is optically active, for example D-lactate or L-lysine, or racemically, for example DL-tartrate or. DL arginine.

1027833 17

C18 / tran8 isomers can be separated by conventional techniques well known to those skilled in the art, for example by fractional crystallization and chromatography.

5

Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or separation of the racemate (or the racemate of a salt or derivative) using, for example, chiral HPLC.

Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, for example an alcohol or, in the case that the compounds of formula (I) contain an acid or basic radical, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization and either or both diastereomers can be converted into the corresponding pure enantiomer / enantiomers with agents well known to those skilled in the art. .

Chiral compounds of the invention (and chiral precursors thereof) can be obtained in an enantiomerically enriched form by means of chromatography, generally HPLC, on an asymmetric mobile phase resin consisting of a hydrocarbon, generally heptaari or hexane, with 0 - 50% isopropanol, generally between 2 and 20%, and 0 - 50% of an alkylamine, generally 0.1% diethylamine. Concentration of the eluate yields the enriched mixture.

Stereoisomeric conglomerates can be separated by conventional techniques well known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E.L. El iel (Wiley, New York, 1994).

1027833 18

The present invention also encompasses all pharmaceutically acceptable isotope variations of a compound of formula (I) in which one or more atoms are replaced by atoms with the same atomic number, but an atomic mass or mass number other than the atomic mass or atomic number usually found in nature .

Examples of isotopes suitable for incorporation into the compounds of the invention include isotopes of hydrogen such as 3 H and 3 H, of carbon such as 11 C, 13 C and 14 C, of nitrogen such as 13 N and 15 N, of oxygen such as 150, 170 and 18, of phosphorus such as 3aP, of sulfur such as 35 S, of fluorine such as 18 F, of iodine such as 123 I and 15 I and of chlorine such as 36 Cl.

15

Certain isotope-labeled compounds of formula (I), for example those into which a radioactive isotope is incorporated, are useful in tissue distribution studies of drugs and / or substrates. The radioactive isotope tritium, i.e., 3H, and carbon-14, i.e., 14C, are particularly useful for this purpose in view of the ease of their incorporation and easy method of detection.

Substitution with heavier isotopes such as deuterium, i.e., 3 H, may provide certain therapeutic benefits that result from greater metabolic stability, e.g., increased in vivo half-life, or reduced dosage requirements, and therefore may be preferred in certain circumstances.

30

Substitution with positron-emitting isotopes, such as 11 C, 18 F, 150 and 13 N, may be useful in studies with Positron Emission Topography (PET) to investigate receptor occupancy with substrate.

35

Isotope-labeled compounds of formula (I) can generally be prepared by conventional techniques well known to those skilled in the art, or by methods analogous to those described in the accompanying Examples and Preparations using suitable isotope-labeled reagents in place of the previously used unlabeled reagent.

Pharmaceutically acceptable solvates in accordance with the invention include those in which the crystallization solvent may be substituted with an isotope, e.g., D 2 O, d 6 acetone and de-DMSO.

The compounds of the invention are useful in therapies. Therefore, a further aspect of the invention is the use of a compound of formula (I) or a pharmaceutical salt or solvate thereof as a medicament.

The compounds of the invention exhibit activity as Vla antagonists. In particular, they are useful in the treatment of a number of disorders including aggression, Alzheimer's disease, anorexia nervosa, anxiety, anxiety disorders, asthma, atherosclerosis, autism, cardiovascular disease (including angina, atherosclerosis, hypertenesis, cardiac insufficiency, edema) , hypernatremia), cataracts, central nervous system disease, cerebrovascular disease. ischemia, cirrhosis, cognitive, disorder, Cushing's disease, depression, diabetes mellitus, dysmenorrhea (primary and secondary), emesis / vomiting (including movement sickness), endometriosis, gastrointestinal disease, glaucoma, gynecological disease, heart disease, intrauterine growth retardation, 30 inflammation (including rheumatoid arthritis), ischemia, ischemic heart disease, lung tumor, disturbed urine, "mittleschmerz", neoplasm, nephrotoxicity, non-insulin-dependent diabetes, obesity, obsessive / compulsive disorder, ocular hypertension, pre-eclampsia, premature ejjac premature (premature) contractions, lung disease, Raynaud's disease, kidney disease, renal failure, male or female sexual dysfunction, septic shock, 1027833 2Ó sleep disorder, spinal cord injury, thrombosis, urogennal canal infection or urolithiasis. Of special interest is dysmenorrhea (primary or secondary), more particularly primary dysmenorrhea.

5

Therefore, a further aspect of the finding is the treatment method for a mammal, including a human being, to treat a disorder for which a V 1a antagonist is indicated, which comprises administering a therapeutically effective amount of a compound with formula (I) or a pharmaceutically acceptable salt or solvate thereof to the mammal. In particular, the compounds of formula (I) are useful in treating anxiety, cardiovascular disease (including angina, atheros-clerosis, hypertension, cardiac insufficiency, edema (hypernatremia), dysmenorrhea (primary and secondary), endometriotic , emesis (including motion sickness), intrauterine growth retardation, inflammation (including rheumatoid arthritis), mittleschmerz, pre-eclampsia, premature ejaculation, premature (premature) contractions or Raynaud's disease. treating dysmenorrhea (primary or secondary).

A further aspect of the present invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the production of a medicament for the treatment of a disorder for which a V 1a receptor antagonist is indicated.

All compounds of formula (I) can be prepared by the methods described in the general methods presented below, or by the specific methods described in the Examples section and the Preparations section, or with routine modifications thereof. The present invention also includes any or one or more of these processes for preparing the compounds of formula (I), in addition to any of the novel intermediates used therein.

Unless otherwise stated herein: 5 WSCDI means 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride, DCC means N, N'-dicyclohexyl carbodiimide, HOAT means 1-hydroxy-7-azabenzotriazole and HOBT means 1-hydroxybenzotriazole hydrate;

PyBOP® means Benzotriazole-1-yloxytris (pyrroli-10 dino) phosphonium hexafluorophosphate, PyBrOP® means bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate and HBTÜ means O-benzotriazole-1-yl-Ν, onor-heon-heor-ium, phosphorium, mCPBA means meta-chloroperbenzoic acid, AcOH means acetic acid, HCl means hydrochloric acid, TPA means trifluoroacetic acid and p-TSA means p-toluenesulfonic acid;

Et 3 N means triethylamine and NMM means N-metyl-morphine; K 2 CO 3 means potassium carbonate and KO-t-Bu means potassium tert-butoxide;

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

Boe means tert-butoxycarbonyl and CBz means benzyloxycarbonyl; PTFE means polytetrafluoroethane;

Mei means methyl iodide;

Metosylate means methyl p-toluene sulfonate;

MeOH means methanol, EtOH means ethanol and n-BuOH means n-butyl alcohol; EtOAc means ethyl acetate, MeCN means acetonitrile, THF means tetrahydrofuran, DMSO means dimethyl sulfoxide, DCM means dichloromethane, DMP means Ν, Ν-dimethylformamide, NMP means 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 catalytic.

1027833 22

In the following general methods, R, R1, Ra, R3, ring A, V, X, Q, Z, Y, Y ', Het, Het1 and Het2 are as previously defined for a compound of formula (I) unless otherwise specified indicated. When Q stands for NR 2, or Q stands for a direct bond attached to a nitrogen atom in ring A, then the compounds of formula (I) can be prepared according to Scheme 1.

/ * vx

XNHi V

0 ») K 0 (HO PG-Q (iv). N-" fr ^ 0 X ^ ·

Z 0) Y

PG represents a suitable N-protecting group, generally a benzyl group, BOC or CB2 group and preferably BOC.

25 Schedule 1

Compounds of formula (II) can be obtained as described in WO 9703986 A1 19970206, or by reaction of the corresponding lower alkyl ester (e.g. methyl or ethyl) with hydrazine under standard conditions, 30 of which are given in the preparations below.

Step (a): Compounds of formula (III) can be prepared by reacting hydrazine (II) with a suitable acetal (e.g. Ν, Ν-dimethylacetamide-dimethyl-acetal) in a suitable solvent such as THF or DMF, at a temperature between room temperature and about 60 ° C, for up to. 18 hours. The resulting intermediate can then be treated under acid catalysis (e.g. with p-TSA or TFA) iii a high-boiling solvent (e.g. toluene or xylene) for about 18 hours, with formation of the compound of formula (III). Preferred conditions: 1.5 - 2.0 eq. of an acetal (e.g., N, N-dimethylacetamide-dimethyl-acetal, triethyl orthopropionate), in THF or DMF at room temperature - 60 ° C for about 18 hours, followed pTSA or TFA (cat), in toluene under reflux for 18 hours.

10

Step (b): Formation of triazole (IV) can be achieved by reacting compound (III) with a suitable aniline, in the presence of a suitable acid catalyst, such as TFA or p-TSA, in a suitable high-boiling solvent (e.g. toluene or xylene), at a high temperature.

Preferred conditions: 0.5 - 1.0 eq. TFA, 1.0-2.0 eq. aniline in toluene at approximately reflux temperature for up to 18 hours.

Step (c): Removal of the protecting group from compound (IV) is done using. of standard methodology, as described in "Protecting Groups in Organic Synthesis" of T.W. Greene and P. Wutz. When PG stands for BOC, the preferred conditions are: 4 M HCl in dioxane in MeOH, dioxane or DCM at a temperature between room temperature and about 50 ° C for a maximum of 18 1 hour;

Or, 2.2 M HCl in MeOH for up to 18 hours at room temperature; Or, TFA in DCM at room temperature for about 1 hour.

Alternatively, when PG stands for BOC, compound (V) can be prepared directly from compound (III) by treatment with an excess of TFA, generally 1.1 - 1.5 eq.) And the appropriate aniline in toluene, at the reflux temperature of the reaction mixture, for a maximum of 4 days.

10 V 8 33. 24

Step (d): Compounds of formula (I) can be prepared by reacting amine (V) with a suitable acid or acid. Chloride (z T, wherein T represents OH or Cl). The coupling can be carried out using either: (i) an acyl chloride 2 '', +ι + amine (V) with an excess acid base in a suitable solvent; or (ii) an acid ZCO2 H with a conventional coupling agent + amine (V), optionally in the presence of a catalyst, with an excess of base in a suitable solvent.

In general, the circumstances are as follows:. . (I) acyl chloride 2-amino-amine 00 (optionally with an excess of 3 ° amine such as Et 3 N, Hünig's base or NMM) in DCM or THF, without heating for 1-24 hours; or (ii) acid ZCOaH, WSCDI / DCC and HOBT / HOAT, amine, excess NMM, Et3 N or Hünig's base, in THF, DCM, DMA or EtOAc, at room temperature for 4 - 48 hours; or acid ZCO 2 H, PYB0P® / PyBr0P® / O-benzotriazol-1-yl-Ν, Ν, Ν ', N'-tetramethyluronium hexafluorophosphate, excess amine, excess NMM, Et3N or Hünig's base, in THF, DCM, DMA or EtOAc , at room temperature for 4-24 hours. Preferred conditions are: 30 1 eq. amine (V), 1.0 - 1.5 eq. 2> ^ CI * 1.5-5 eq. NMM, Et3 N or Hünig's base in DCM at room temperature for up to 18 hours; 35 Or, 1 eq. amine (V), 1.2 eq. ZO 2 H, 1.2 - 1.5 eq. HOBT, 1.2 - 1.5 eq. WSCDI, 2-4 eq. Et 3 N, in DCM at room temperature for 24 hours; 1027833 25

Or, i eq. amine (V), 1.2 - 1.5 eq. ZCO, H, 1.2 - 2.0 eq. HBTXJ, 5 eq. Et 3 N or NMM in DMA or DCM, at a temperature between room temperature and 60 ° C for 24 hours.

Compounds of formula (IV) wherein Q represents NR a or Q represents a direct bond attached to a nitrogen atom in ring A, which in turn is attached to the triazole ring via a nitrogen atom, can alternatively be prepared as described in Scheme 2 below and 10 are shown as (IVA).

15 ° (3ύ

0 A— A

Y ^ «yU ® yQ

T V

w. (VWA). (KA) 20 / yx ^.

jA, Q (IVA) Y 25

Schedule 2.

30

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

(VI), in EtOH or DCM, at room temperature for 0.5-2 hours.

1027833 26

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

5

Step (f): Compounds of formula (IXA) can be prepared by methylation of thiourea (VIIIA) using a suitable raethylating agent (e.g. Mei or MeTosylate) in the presence of a suitable base (e.g. KO * - Bu) in a suitable solvent (e.g. THF or ether) at a temperature between 0 ° C and the reflux temperature of the reaction mixture, for about 18 hours. Preferred conditions: 1 eq. (VIIIA), 1 - 1.2 eq. KOfc-Bu, 1 - 1.2 eq. May or MeTosylate, in THF, at a temperature between 10 ° C 15 and room temperature for a maximum of 18 hours.

Step (g): Compounds of formula (IVA) can be prepared by reacting compounds (IXA) with a suitable hydrazide (XCONHNH2), optionally under acid catalysis (e.g., TFA or p-TSA) in a suitable solvent (e.g. THF or n-BuOH), at a temperature between room temperature and the reflux temperature of the reaction mixture. Preferred conditions: 0.5 eq. TFA, excess hydrazide (XCONHNH) in THF under reflux for up to 18 hours.

25

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

35 1027833 27 A> A-L ΜΤ) Α ΛΛ J - '^ ^ Υ (VI) (XI) (V1UA) 10 Scheme 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 isothiocyanate (VI) and amine (X) analogous to the methods previously described for Step (e) above.

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

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

35 1027833. 28 5 O -V Q "'° Or V = f = / ^ Y w. PG \ = {= / ^ Y Γλ ^ Υ Y (XIV) Y« (XIII)' wv '

Schedule 4.

10

Step (i) Compounds of formula (XIV) can be prepared by coupling aniline (XIII) with acid (XII) analogously to the methods previously described in Step (d). Preferred conditions: 1 "eq. Acid (XII), 1.1 eq. Amine (XIII), 1.2 eq. WSCDI, 3 eq. Et 3 N in MeCN at room temperature for about 3 days.

Step (j): The compound of formula (VIIIB) is prepared by thionation of compound (XIV) by treatment with a suitable thioning agent, such as Lawesson's reagent, in a high-boiling solvent (e.g. toluene) at a temperature between room temperature and the reflux temperature of the reaction mixture. Preferred conditions: 1 eq. (XIV), 0.5 eq. Lawesson's reagent in toluene at a temperature between room temperature and reflux temperature, for up to 18 hours.

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

35 1027833 29 • s * Η *: ΝΗί Os = ("Ν <ν ° 5 (k) \ Yv, w (^ a)

pg ^ q Q

PG. PO U

(«) (XV) P) 10 Scheme 5.

Step (s) Di-acyl hydrazides (XV) can be prepared by coupling hydrazides (II) with an acid or acid chloride (where T represents OH or Cl) analogous to the processes described earlier in Step (d). Preferred conditions: 1 eq. hydrazide (II), 1.1 eq. XCO 2 H, 1.1 eq.

WSCDI, 1.1 eq. HOBT, 1.2 eq. Et 3 N, in DMP at room temperature for 18 hours.

Step (1): Oxadiazole (III) can be prepared by cyclizing compound (XV), generally under acid catalysis e.g. with polyphosphoric acid, POCl 3, triflic anhydride / pyridirie, or 1-methyl imidazole), optionally in a suitable solvent (e.g. DCM), between 0 ° C and the reflux temperature of the reaction mixture. Preferred conditions: 1 eq.

(XV), excess pyridine or 1-methyl imidazole, 1.5-2 eq. triflic anhydride, in DCM, at a temperature between 30 ° C and. room temperature for up to 3 hours.

Compounds of formula (XV) can alternatively be prepared by coupling acid (XII) with a suitable hydrazide (XCONYNHa) analogous to the methods previously described in Step (d) .35. Preferred conditions: 1 eq. acid (XII), 1. eq. hydrazide, 1.02 eq. WSCDI, in DCM at. a temperature between 0 ° C and room temperature.

1027833 30

Compounds of formula (III) wherein X is CHaN-linked-Het can alternatively be prepared as shown in Scheme 6.

V CW β O N <y ° Νγ °

Y ΓίΓ Q "cd" (S VQ

pg "q i T 1

pg pg ^ q i JL

PG PG "PG

Μ (XVI) (XVII) (III)

Schedule 6.

Step (xn) s The compounds of formula (XVI) can be prepared by reacting hydrazide (II) with chloroacetyl chloride in the presence of a suitable 3 ° amine base (e.g. Et 3 N or NMM) in a suitable solvent (e.g. EtOAc or DCM) at a temperature between 0 ° C and room temperature, for approximately 18 hours. Preferred conditions: 1 eq. (II), 1 eg, acetyl chloride, 1.1 eq. NMM in DCM, at 10 ° C to room temperature, for up to 18 hours.

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

Step (s): Compounds of formula (III) can be prepared by reacting compound (XVII) with a suitable Het compound (containing a reactive N atom), in the presence of a suitable base (e.g. Et3 N or KaCO 3), in a suitable solvent (e.g. DMF or MeCN), at a temperature between room temperature and the reflux temperature of the reaction mixture for about 18 hours. Preferred 35 conditions: 1 eq. (XVII), 1.4 eq. KjCO3, 2 eq. It, in DMF at room temperature for 18 hours.

1027833 31

Compounds of formula (I) wherein Q is NR 2 or Q is a direct bond attached to a nitrogen atom in ring A may alternatively be prepared as shown in Scheme 7.

Y * Y “^

CO (o) * (p) ”φ (K)" CO

10. ®. 0 = <0 0 = ^ ° o_X «N

1 * i.

/ V * CXVB1) (XDO (XX) (XXI) Vj / -νζΚ. (Β ™: "R 20 Ra represents a C 1-6 alkyl group or a benzyl group and is preferably Me or Et.

Schedule 7.

Step (o). The compound of formula (XIX) can be prepared by reacting amine (XVIII) with a suitable acid or acid chloride.

S

(i, wherein T represents OH or Cl) analogous to the methods previously described in Step (d). Preferred conditions: 1 eq. (XVIII), 0.9 eq. ZCOCl, 1.1 eq. Et 3 N, in DCM, at a temperature between 10 ° C and room temperature, for approximately 3 hours.

Step (p): The hydrazide of formula (XX) can be prepared by treating ester (XIX) with an excess. hydrazine in a suitable solvent (e.g. EtOH or MeOH). 1 2/8 33: 32 at the reflux temperature of the reaction mixture for a maximum of 18 hours. Preferred conditions: 1 eq. (XIX), 2 -4 eq. hydrazine, in MeOH under reflux for between 10 and 48 hours; 5

Compounds of formula (XXI) can be prepared by

X

reaction of hydrazide (XX) with ζ · τ, using the methods previously described in Step (k).

Compounds of formula (XXII) can be prepared by cyclization of compound (XXI) using the methods described earlier in Step (1).

15

Compounds of formula (I) can be prepared from oxadiazole (XXII) with a suitable aniline as previously described in Step (b).

Alternatively, compounds of formula (XXII) can be prepared directly from compound (XX) by reaction with a suitable acetal (e.g. triethyl orthopropionate, N / N-dimethylacetamide-dimethyl-acetal) analogous to the previously described in Step (a) methods.

25

Compounds of formula (XXII) wherein X represents CHα-linked-Het can alternatively be prepared as shown in Scheme 8.

XCI y - Cl X

t <t <O Ny ° N Y ° <m) (0 r CAj (") r

o ^ Q T \ I

Y v ° ° γ ° γ ° 35 z 2 2 poo (xxiii) pöav) (xxii)

Scheme 8 1027833 33

Compounds of formula (XXIII) can be prepared by reacting hydrazide (XX) with chloroacetyl chloride analogously to the methods previously described in Step (m).

Oxadiazole (XXIV) can be prepared by cyclization of compound (XXIII) analogously to the methods previously described in Step (1).

Compound (XXII) can be prepared by reacting compound (XXIV) with a suitable Het (containing a reactive N atom), as previously described in Step (n).

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

^ (xxvi) 25 S®

z (D

30

Schedule 9

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

1027833 34

Compounds of formula (XXVI) can be prepared by reacting compound (XXV) with a suitable isothiocyanate (VI) analogous to the methods previously described in Step (e).

5

The compound of formula (XXVII) can be prepared by alkylating compound (XXVI) analogously to the methods previously described in Step (f).

The compound of formula (I) can be prepared by reacting compound (XXVII) with a suitable hydrazide as previously described in Step (g).

Compounds of formula (I) wherein Q stands for a direct bond attached to a carbon atom in ring A, which in turn is attached to the triazole ring via a nitrogen atom in ring A, and Z stands for NR 4 R 5, can be prepared as shown in Scheme 10.

RaO

_ Λ V RaO, V XJZ) V0 Γ> ° <«v * (7) Λτλ Q" .ry '"25 (vu pornq Y γ ·' '

RaQ

V V> .py Srr.

r (I) (XXXII) (XXXI) 35 Ra represents a C 1-4 alkyl group or a benzyl group and is preferably Me or Et.

Scheme 10 1027833 35

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

5

Compounds of formula (XXIX) can be prepared by reacting compound (XXIX) with a suitable isothiocyanate (VI) analogous to the methods previously described in Step (e).

1 °

The compound of formula (XXX) can be prepared by alkylating compound (XXIX) analogously to the methods previously described in Step (f).

The compound of formula (XXXI) can be prepared by reacting compound (XXX) with a suitable hydrazide as previously described in Step (g).

Step (q): Hydrolysis of ester (XXX) using a suitable acid or base as a catalyst, preferably an alkali metal base (e.g. NaOH, KOH or LiOH) in a suitable aqueous solvent (e.g. dioxane or MeOH) at a temperature between room temperature and the reflux temperature of the reaction mixture, for between 2 and 48 hours. In front of- . 25 test conditions: 1 eq. (XXXI), 5? 10 eq. NaOH solution, in dioxane, between room temperature and reflux, for 2 to 16 hours.

Compounds of formula (I) can be prepared by reacting Z-H (with a reactive N atom) with acid (XXXII) analogous to the methods previously described in Step (d). Preferred conditions: 1 eq. acid (XXXII), 1.5 eq. amine (ZH), 4 eq. Et3 N, 1.5 eq. WSCDI, 1.5 eq. HOBT, in DCM at room temperature for 24 hours.

35

Compounds of formula. (XXXII) may alternatively be prepared by hydrolysis of the corresponding nitrile compound (XXXIII) under standard conditions (e.g. 5 eq. KOH, 1 eq. Nitrile (XXXIII), in ethanol / ethylene glycol dimethyl ester under reflux).

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

'L (b> -y |; P.

(XXXIII)

Schedule 11 15

Compounds of formula (XXXIII) wherein Q is a direct bond and ring λ is attached to the triazole ring via a nitrogen atom, can be prepared from the appropriate isothiocyanate (VI) and an A ring with a nitrile group, analogous to the one in Scheme 9 described methods. N == ·

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

30 35 1027833 37 •: ύ ': ·· 6 · .γ r \ (XXXVI) (XXXVII) \ (h)

(VI) poow) I

Al «Λψ-Λ γβτ A <2 ^ Q: Z (XXXDQ Y r m (XXXVW) 15 h

Schedule 12

Step (r): The compound of formula (XXXV) can be prepared by reacting hydrazide (XCONHNH 3) with isothiocyanate (VI) analogous to the one previously described in Step (e). methods. Preferred conditions: 1 eq. isothiocyanate, 1 eq. hydrazide, in EtOH at room temperature for 72 hours.

Step (s): Compounds of formula (XXXVI) can be prepared by cyclization of compound (XXXV) under acidic or basic conditions, preferably basic catalysis (e.g. with an alkali metal hydroxide) in an aqueous solvent (e.g. water / EtOH), at an elevated temperature, for about 24 hours. Preferred conditions: 1 eq. (XXXV), 10 eq. NaOH (aq., In EtOH at 80 ° C for 18 hours.

Step (t): Alkylation of compound (XXXVI) to provide compound 35 (XXXVII) can be accomplished with a suitable alkylating agent (e.g. Mei or Me-Tosylate) analogous to the methods previously described in Step (f).

1027833 38

Preferred conditions: 1 eq. (XXXVI), 1 eq. KO-t-Bu, 1 eq. Me-Tosylate, in THF at a temperature between room temperature and the reflux temperature for 3 hours.

Step (u): Compounds of formula (XXXVIII) can be obtained by. oxidation of compound (XXXVII) by treatment with a suitable oxidizing agent (e.g. mCPBA or hydrogen peroxide) in a suitable solvent (e.g. DCM) at room temperature for about 18 hours. 10 Preferred conditions: 1 eq. (XXXVII), 4 eq. mCPBA, in DCM at room temperature for 18 hours.

Step (v): Compounds of formula (I) can be prepared by reacting sulfoxide (XXXVIII) with an excess of alcohol (XXXIX) in the presence of a. suitable base (e.g., NaH or KO-t-Bu) in a suitable solvent (e.g., THF or ether) at a temperature between 0 ° C and room temperature for up to 18. hours. Preferred conditions: 1 eq. (XXXVIII), 2 eq. NaH, 2 eq. alcohol (XXXIX), in THF for 18 hours at room temperature.

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

Certain compounds of the formulas (I) / (III), (IV), (V), (XXII) and (XXXI) may undergo conversions of functional groups (e.g., alkylation or hydrolysis) to form alternative compounds with, respectively, the formulas (I), (III), (IV), (V), (XXII) or (XXXI).

Compounds of the invention intended for pharmaceutical use can be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by processes such as precipitation, crystallization, freeze drying, spray drying, or drying under evaporation. Microwave or radio frequency drying can be used for this purpose.

5

They can 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 as any combination thereof). In general they will be. Administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any component other than the compound (s) of the invention. The choice of excipient will largely depend on factors such as the particular administration method, the effect of the excipient on solubility and stability, and the nature of the dosage form.

A further aspect of the invention is a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, diluent or carrier. In a further embodiment, a pharmaceutical formulation is provided for either prophylactic administration or when pain occurs.

Pharmaceutical compositions suitable for the release of the compounds of the present invention and methods of their preparation will be readily understood by 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 Cómpany, 1995).

The compounds of the invention can be administered orally. Oral administration may include ingestion such that. the compound enters the gastrointestinal tract, or administration -1027 8 33 40 can be applied via the cheek or under the tongue, whereby the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid formulations such as tablets, capsules with solid particles, liquids or powder, lozenges (including filled with a liquid), chewable tablets, multi or nanoparticles, gels, solid solutions, liposomes, films, globules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules and generally comprise a carrier, for example water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil, and one or more emulsifying agents. and / or suspending agents. Liquid formulations can also be prepared by redissolving a solid, for example from a bag.

The compounds of the invention can also be used in rapidly dissolving, rapidly disintegrating dosage forms, such as those described in Expert Opinión 25 in Therapetic Patents, 11 (6), 981-986, from Liang and Chen (2001).

i. ! For dosage forms, depending on the dose, the drug may comprise between 1% and 80% by weight of the dosage form, more generally between 5% and 60% by weight of the dosage form. Next . the drug tablets generally contain a disintegrant.

Examples of disintegrating agents include sodium starch glycolate> sodium carboxymethylcellulose, calcium carboxymethylcellulose, crosslinked sodium carmellose, crosslinked povidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, substituted hydroxypropyl cellulose starch, starched starch, sodium propyl cellulose, sodium starch. In general, the disintegrant will comprise between 1% by weight and 25% by weight, preferably between 5% by weight and 20% by weight of the dosage form.

5

Binders are generally used to impart adhesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pre-gelled starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may optionally contain surfactants such as sodium lauryl sulfate and polysorbate 60, and lubricants such as silica and talc. If present, surfactants may comprise between 0.2% and 5% by weight of the tablet and lubricants may comprise between 0.2% and 1% by weight of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise from 0.25% to 10% by weight, preferably between 0.5% and 3.30% by weight of the tablet.

Other possible ingredients include antioxidants, colorants, flavors, preservatives, and taste masking agents.

Examples of tablets contain up to about 80% drug, between about 10% by weight and about 90% by weight binder, between about 0% by weight and about 85% by weight of diluent, between about 2% by weight. % and about 10% by weight of disintegrant and between about 0.25% by weight and about 10% by weight of lubricant.

5

Tablet mixtures can be compressed directly or with one. roller to form tablets. Tablet blends or portions of blends may alternatively be granulated wet, dry or melted, molten thickened or extruded prior to tableting. The final formulation can include one or more layers and can be coated or uncoated; it may even be encapsulated.

The formulation of tablets is discussed in Pharmaceutical Dosaae Porms; Tablets. part 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

Edible oral films for human or veterinary use are generally foldable water-soluble or water-swellable thin film-shaped dosage forms that rapidly dissolve or stick to the mucous membranes, and generally include a compound of formula (I), a film-forming polymer , a binder, a solvent, a wetting agent, a plasticizer, a stabilizing agent or an emulsifier, a viscosity modifying agent and a solvent. Some components of the formulation may perform more than one function.

The compound of formula (I) can be water-soluble or insoluble. A water-soluble compound generally comprises 1 wt% - 80 wt%, more typically 20 wt% - 50 wt% of the solutions. Less soluble compounds may comprise a larger portion of the compound, generally up to 88% by weight of the solutions.

Alternatively, the compound of formula (I) may be in the form of beads consisting of a plurality of particles.

...

1027833 43

The filtering polymer can be selected from natural polysaccharides, proteins or synthetic hydrocolloids and is generally present in the range of 0.01 - 99% by weight, more typically in the range of 30-80% by weight.

5

Other possible ingredients include antioxidants, colorants, flavorings and flavor enhancers, preservatives, saliva enhancers, coolants, co-solvents (including oils), emollients, fillers, foam inhibitors, surfactants, and taste masking agents.

Films in accordance with the invention are generally prepared by drying thin aqueous films, which form a coating on a peelable support or paper, under evaporation. This can be done in a drying oven or tunnel, generally a combined coating-drying device or by freeze-drying or vacuum-drawing.

Solid formulations for oral administration can be formulated such that they are a direct and / or modified release. show. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

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

35

The compounds of the invention may also be added directly into the bloodstream, into the muscles, or into an internal organ 1027833 44.

become servant. Suitable means of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intrauretral, intrasteral, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle injecters (including those with a micro needle), no-needle injectors, and infusion techniques.

Parenteral formulations are generally aqueous solutions that may contain excipients such as salts, hydrocarbons and buffering agents (preferably up to a pH of 3 - 9), but for some applications they may be more suitably formulated as a sterile non-aqueous solution or in dried form in combination with a suitable carrier such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions such as, for example, by freeze drying can be easily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compound of formula (I) used in the preparation of parenteral solutions can be increased by using the appropriate formulation techniques, such as incorporating solubility enhancing agents.

Formulations for parenteral administration can be formulated such that they exhibit a direct and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release. Compounds of the invention can thus be formulated as a solid, a semi-solid or a thixotropic liquid for administration as an implanted depot that provides for modified release of the active compound.

102/833 45

Examples of such formulations include drug-coated stents and microspheres of poly (dl-lactic acid-coglycolic acid) (PGLA). The compounds of the invention can also be administered topically to the skin or mucous membranes, i.e., dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, fine powders, wound dressings, foams, films, skin patches, waffles, implants, sponges, fibers, dressings and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petroleum jelly, white petroleum jelly, glycerin, polyethylene glycol, and propylene glycol. Means that increase penetration can be incorporated - see, for example, J Pharm Sci, 83 (10), 955 - 958, by Finnin and Morgan (October 1999).

Other means for topical administration include the delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and injection with micronaids or needle-free injection (e.g., Powderject1 ", Bioject" *, etc.).

Formulations for topical administration can be formulated such that they exhibit a direct and / or a modified release. Modified release formulation: Gene includes delayed, sustained, pulsed, controlled, targeted and programmed release.

The compounds of the invention can also be administered intranasally or via inhalation, generally in the form. of a dry powder (either separately, as a mixture for example in a mixed form with lactose, or as a particle with mixed constituents, for example mixed with phospholipids such as phosphatidylcholine), from a powder inhalation device or as one. aerosol spray from a container, a pump, a spray, an atomizer (preferably an atomizer employing electro-hydrodymamics to produce a fine mist) that is under pressure or a nebulizer with or without the use of a suitable propellant such as 1,1,1,2-tetraflu-5 orethane or 1,1,1,2,3,3> 3-heptafluoropropane. For intranasal use, the powder may comprise a biological adhesive, for example, chitosan or cyclodextrin.

The pressurized container, pump, spray, sprayer or nebulizer 10 contains a solution or suspension of the compounds of the invention, which include, for example, ethanol, aqueous ethanol or a suitable alternative means for dispersing, dissolving or sustained release of the active substance, a propellant gas (es) as a solvent and optionally a surfactant, such as sorbitan trioleate, oleic acid or an oligamic acid

Prior to use in a dry powder or dry suspension formulation, the drug product is micronized to a format suitable for delivery by inhalation (generally less than 5 microns). This is possible. can be achieved by any suitable pulverizing method, such as with a spiral spray mill, liquid bed spray mill, machining in a supercritical fluid to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (made for example from gelatin or hydroxypropyl methylcellulose), blister packs, and cassettes 30 for use in an inhalation device or a powder blower. may be formulated to contain a powder mixture of the compound of the invention, a suitable powder raw material such as lactose or starch, and a performance modifier such as L-leucine, mannitol or magnesium stearate. The lactose can be anhydrous or in the form of monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

A suitable solution formulation for use in a.

The atomizer, which uses electrohydro dynamics to produce a fine mist, can contain 1 μg - 20 mg of the compound of the invention per drive and the drive volume can vary from 1 μΐ -100 μΐ. A typical formulation may contain a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

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

20

Formulations for inhalation and intranasal administration may be formulated such that they exhibit a direct and / or modified release, for example by means of PGLA. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

In the case of a dry powder and aerosol inhaler, the dosage unit is determined by means of a valve 30 which supplies a metered amount. The entire daily dose will generally be in the range of 0.01 μg - 15 mg and can be administered in a single dose or, more commonly, in doses throughout the day.

35. The compounds of the invention can be administered rectally or vaginally * for example in the form of a suppository, pessary or enema. Cocoa butter is a traditional 1027831 48 raw material for a suppository, but various alternatives can be used suitably.

Formulations for rectal / vaginal administration can be formulated such that they exhibit a direct and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

The compounds of the invention can also be administered directly to the eye or ear, generally in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline solution. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g., soluble gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, waffles, lenses, and particulate or vesicle-shaped systems, such as niosomes or liposomes. A polymer such as a cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example hydroxypropyl methylcellulose, hydroxyethylcellulose or methylcellulose or a heteropolysaccharide polymer, for example, can be incorporated simultaneously with a preservative such as benzalkonium chloride. Such formulations can also be used. supplied by iontophoresis.

Formulations for ocular / aural administration can be formulated such that they exhibit a direct and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

The compounds of the invention can be combined with soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability to promote use in any of the aforementioned modes of administration.

5

For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiliary additive, i.e. as a carrier, diluent or solubilizer. The most commonly used for this purpose are alpha, beta and gamma cyclodextrins, examples of which can be found in International Patent Applications WO 91/11172, WO 94/02518 and WO. 98/55148.

To the extent that 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 present invention that two or more pharmaceutical compositions, at least one of which containing a compound according to the invention, can be suitably combined in the form of a kit suitable for co-administration of the compositions.

. The kit of the invention thus comprises two or more separate pharmaceutical preparations, at least one of which contains a compound of formula (1) according to the invention, and means for separately containing these preparations, such as a container, separate bottle or separately foil packet. An example of such a kit is the usual blister pack used for packaging tablets, capsules and the like.

1027833 50

The kit of the invention is particularly suitable for administering different dosage forms, for example orally and parenterally, for administering individual preparations at different dosage intervals, or for titrating the individual preparations against each other. To help with compliance, the kit generally contains instructions for administration and can be provided with a so-called reminder.

For administration to human patients, the total daily dose of the compounds of the invention is generally in the range of 0.01 mg to 15 mg, of course depending on the mode of administration. The total daily dose may be administered in a single dose or in divided doses, and may, in the physician's opinion, fall outside the general range given herein.

These dosages are based on an average human patient with a weight of approximately 60 kg - 70 kg. The physician will be able to easily determine doses for patients whose weight falls outside this range, such as young children and the elderly.

For the avoidance of doubt, references to "treatment" include references to healing, analgesic, and prophylactic treatment.

The compounds of the present invention can be tested in the screenings as set out below.

1.0 V1F1 Filter Bindina Assay 1.1 Membrane Preparation Receptor binding assays were performed on cell membranes prepared from CHO cells that stably expressed the human v1 receptor (CHO-hV ^). The 1 ° 27β33 51 cell line CHO-hV1A was kindly provided under license agreement by Mare Thibonnier, Dept. of Medicine, Case Western Reserve University School of Medicine, Cleve Country, Ohio. CHO-hV1A cells were routinely maintained at 37 ° C in a humid atmosphere with 5% CO 2 in DMEM / Hams F12 nutrient mix supplemented with 10% fetal bovine serum, 2 mM. L-glutamine, 15 mM HEPES and 400 Mg / ml G418. For mass production of cell pellets, adherent CHO-hV ^ cells were grown to 90-100% confluence in 850 cm 2 roller bottles with a medium of DMEM / Hams F12 Food mix supplemented with 10% fetal, bovine serum, 2 mM L-glutamine and 15 mM HEPES. Confluent CHO-hV1A ellenes were washed with phosphate buffered saline (PBS), harvested in ice-cold PBS and centrifuged at 1,000 rpm. Cell pellets were stored at -80 ° C until use. The cell pellets were thawed on ice and homogenized in. membrane preparation buffer consisting of 50 rnM Tris-HCl, pH 7.4, 5 mM MgCl 3 and supplemented with a protease inhibitor cocktail (Roche). The cell homogenate was centrifuged at 1000 rpm, 10 minutes, 4 ° C, and the supernatant was removed and stored on ice. The remaining pellet was homogenized and centrifuged as before. The supernatants were pooled and centrifuged at 25,000 x g for 30 minutes at 4 ° C. The pellet was resuspended in freeze-buffer, consisting of 50 mM Tris-HCl, pH 7.4, 5 mM MgCl 3 and 20% glycerol, and stored in small portions at -80 ° C until used. The protein concentration was determined using Bradford reagent and BSA as standard.

1.2 V, filter bindina

Protein linearity followed by saturation binding studies were performed on each new batch of the membranes. A membrane concentration was selected that gave specific binding to the linear portion of the curve. Saturation binding studies were then performed using various concentrations of [3 H] arginine vaso? 0 2 7 8 J3 52 pressin, 13 H] -AVP (0.05 nM - 100 nM) and the Kd and were determined.

The compounds were tested for their effects on the binding of (¾] -AVP to CH0-hV1A membranes (3H-AVP; specific activity 65.5 Ci / mmol; NEN Life Sciences) .The compounds were dissolved in dimethyl sulfoxide (DMSO ) and diluted to the working concentration in 10% DMSO with assay buffer containing 50 mM Tris-HCl, pH 7.4, 5 mM MgCla and 0.05% BSA, 25 μΐ compound and 25 μΐ [3H] -AVP (final concentration on 10 or below the K, j determined for each batch of membranes, generally 0.5 nM - 0.6 nM) were added to a 96 well, round bottomed polypropylene plate, and the binding reaction was initiated by the addition of 200 μΐ membrane and the plates were gently shaken for 60 minutes at room temperature.The reaction was terminated by rapid filtration using a Filtermate Cell Harvester (Packard Instruments) through a 96 well GF / B UniFilter Plate, which was previously soaked in 0.5% polyethyleneimine to void peptides come. The filters were washed three times with 1 ml of ice-cold wash buffer containing 50 mM Tris-HCl, pH 7.4, and 5 mM MgCl 2. The plates were dried and 50 μΐ Microscint-0 (Packard Instruments) was added to each well. The plates were covered and counted in a TopCount 25 Microplate Scintillation Counter (Packard Instruments). The non-specific binding (NSB) was determined using 1 μΜ unlabelled d (CH2) 5 Tyr (Me) AVP ([/ 3-mercapto- / 3, β-cyclopentamethylenepropionyl, 0-MeTyra, Arg8] -vasopressin) (0MCPVP ), (Sigma). The data from the binding of the radioactive ligand was analyzed using a four-parameter logistic comparison with the minimum forced to 0%. The slope was allowed to fit fairly appropriately and it fell between -0.75 and -1.25 for validated curves. The specific binding was calculated by subtracting the mean cpm for the NSB from the mean total cpm. For the test compounds, the amount of ligand bound to the receptor was expressed in% bound = (cpm sample 1027833. 53.

- mean cpm NSB / cpm specific binding x 100. The% bound was plotted against the concentration of the test compound and a sigmoid curve was drawn. The inhibitory dissociation constant (¾) was calculated with the Cheng-Prusoff equation: ¾ = ICS0 / (1+ (L] / M), where [L] is the concentration L present in the well and JC ^ is the dissociation constant of the radioactive ligand obtained from Scatchard plot anisysis.

10 2.0 Functional VIA determination; Inhibition of by AVP /

Vn-R caused Ca 2+ mobilization with PLIPR (Fluorescent Imaging Plate Reader) (Molecular Devices) Intracellular calcium release was measured in CHO-hV ^ cells. FLIPR, which allows the rapid detection of calcium after receptor activation. The CHO-hV cell line was kindly provided under license agreement by Mare Thibonnier, Dept. of Medicine, Case 20 Western Reserve University School of Medicine, Cleveland, Ohio. The CHO-V1A cells were routinely maintained at 37 ° C in a humid atmosphere with 5% CO 2 in DMEM / Hams F12 food mix supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 15 mM HEPES and 400 Mg / ml G418 . The afternoon before the assay, the cells were plated at a density of 20,000 cells per well in black, 96-well, sterile, clear-bottomed plates to view the cells and allow fluorescence measurements from the bottom of each well. Wash buffer containing Dulbecco's phosphate buffered saline (DPBS) and 2.5 mM probenicid, and loading dye consisting of cell culture medium with 4 μΜ Fluo-3-AM (dissolved in DMSO. And pluronic acid) (Molecular Probes) and 2.5 mM probenecid was freshly prepared on the day of the determination. The compounds were dissolved in DMSO and diluted in assay buffer consisting of DPBS with 1% DMSO, 0.1% BSA and 2.5 mM probenecid. The cells were incubated with 100 μΐ loading dye per well for 1 hour at 37 ° C in a humid atmosphere with 5% CO 2. After loading with dye, the cells were washed three times in 100 μΐ wash buffer using a Denley plate washer. 100 μΐ were left in each well. The intracellular fluorescence was measured by FLIPR. Fluorescence readings were obtained at 2 second intervals, with 50 μΐ of the test compound added after 30 seconds. A further 155 measurements at 2 second intervals were then made to detect every 10 agonistic activity of the compound. Then 50 μΐ of arginine vasopressin (AVP) was added such that the final determination volume was 200 μΐ. Further fluorescence readings were collected at 1 second intervals for 120 seconds. Responses were measured as the peak in fluorescence intensity (FI). For pharmacological characterization, a basic FI was subtracted from each fluorescence reaction. For AVP dose-response curves, each response was expressed as a% of the response to the highest concentration of AVP in that row. For the determination of the IC 50, each reaction was expressed as a% of the response to AVP. IC50 values were converted to a modified Kb value using the Cheng-Prusoff equation, taking into account the agonist concentration [A], the agonist ECS0 and the slope: K * * ICgo / (· + [A] / Ago ") 1 / n - 1, where [A] is the concentration of AVP, A50 is the EC50 of AVP from the dos is response curve and n = the healing of the AVP dose response curve .

The compounds of the invention can 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 as any combination thereof). The compounds of the present invention can be administered in combination with an oral contraceptive. Thus, in a further aspect of the invention, there is provided a pharmaceutical product comprising a Vla antagonist and an oral contraceptive, as a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhea.

The compounds of the present invention can be administered in combination with a PDE5 inhibitor. Thus, in a further aspect, a pharmaceutical product is provided which contains a V1a antagonist and a PDEV inhibitor, as a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhea.

PDEV inhibitors useful for combining with V1a antagonists include, but are not limited to:

(i) The PDE5 inhibitors as stated in International Patent Applications WO 03/000691; WO 15 02/64590; WO 02/28865; WO. 02/28859; "WO

02/38563; WO 02/36593; WO 02/28858; WO

02/00657; WO 02/00656; WO 02/10166; WO

02/00658; WO 01/94347; WO 01/94345; WO

00/15639 and WO 00/15228; (Ii) The PDE5 inhibitors as disclosed in U.S. Patent Nos. 6,143,746; 6,143,747 and 6,043,252; (iii) the pyrazolo [4,3-d] pyrimidine-7-ones described in EP-A-0463756; the pyrazo-25 [4,3-d] pyrimidine-7-ones described in EP-A-0526004; the pyrazolo [4,3-d] pyrimidine-7-ones described in published international patent application WO 93/06104; the isomeric pyrazolo [3,4-30 d] pyrimidine-4-ones described in published international patent application WO 93/07149; the quinazoline-4-ones described in published international patent application WO 93/12095; the pyri-35 do [3,2-d] pyrimidine-4-ones described in published international patent application WO 94/05661; the purine-6-ones 1027833 56 described in published international patent application WO 94/00453; the pyrazolo [4,3-d] pyrimidine-7-ones described in published international patent application WO 98/49166; the pyrazolo [4,3-d] pyrimidine-7-ones described in published international patent application WO 99/54333; the pyrazolo [4,3-d] pyrimidine-4-ones described in EP-A-0995751; the pyrazolo [4,3-d] pyrimidin-7-ones described in published international patent application WO 00/24745; the pyrazolo [4,3-d] pyrimidine-4-ones described in EP-A-0995750; the hexahy-15 dropyrazino [2 ', 1': 6.1] pyrido [3,4-b] indole-1,4-dione described in published international patent application WO 95/19978; the pyrazolo [4,3-d] pyrimidine-4-ones described in WO 00/27848; the imidazo [5,1-f] [1,2,4] triazinones that be

are described in EP-A-1092719 and in published international application WO

99/24433, and the bicyclic compounds described in published international application WO 93/07124; the pyrazo

lo [4, 3-d] pyrimidine-7-ones described in published international application WO 01/27112; the pyrazolo [4,3-d] pyrimidine-7-ones described in published international application WO

01/27113; the compounds described in EP-A 1092718, and the compounds described in EP-A 1092719; the tricyclic compounds described in EP-A-1241170; the alkyl sulfone compounds described in published international application WO 02/074774; the 1027833 57 compounds described in published international application WO 02/072586; the compounds described in published international application WO 02/079203; and the compounds described in WO 02/074312.

(iv) Preferably 5- (2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7 H -pyrazolo [4,3- d] pyri-10 midin-7-one (sildenafil, e.g. as sold. as Viagra®), also known as 1 - [[3- (6,7-dihydro-1-methyl-7-oxo-3) -propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl) -4-ethoxyphenylsulfonyl] -4-methylpiperazine (see EP-A-0463756); 5- (2-ethoxy-5- morpholinoacetylphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7 H -pyrazolo [4,3-d] pyrimidine-7-one (see EP-A-0526004); 3-ethyl-5 - [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxyphenyl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo-

[4,3-d] pyrimidin-7-one (see WO 98/49166); 3-ethyl-5- [5- (4-ethyl-piperazine-1-ylsulphonyl) -2- (2-methoxyethoxy) -pyridin-3-yl] -2- (pyridine-2-yl) methyl 1 - 2,6-dihydro-7 Hr pyra-25-zolo [4,3-d] pyrimidin-7-one (see WO

99/54333); (+) - 3-ethyl-5- [5- (4-ethyl piperazin-1-ylsulphonyl) -2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl] -2- methyl 2,6-dihydro-7 H -pyrazolo [4,3-d) pyrimidin-7-one, also known as 3-ethyl-5- {5- [4-ethyl piperazine-1-ylsulfonyl] - 2- ([(IR) -2-methoxy-1-methyl ethyl] oxy) pyridin-3-yl} -2-methyl-2,6-dihydro-7 H -pyrazolo [4,3-d] pyrimidine-7- on (see WO 99/54333); 5- [2-ethoxy-5- (4- ethylpiperazine-1-ylsulphonyl) pyridin-3-yl] -3.-ethyl-2- [methoxyethyl] -2,6-dihydro-7 H -pyrazolo [4.3 -d] pyrimidin-7-one, also known as 1027833 58 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 5); 5- [2-iso-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- (1-methylpiperidin-4-yl) -2, 6-dihydro-7 H -pyrazolo [4,3-d] pyrimidin-7-one (see WO 01/27113, Example 15); 5- [2-ethoxy-5- (4-10 ethyl-piperazine-1-ylsulphonyl) -pyridin-3-yl] -3-ethyl-2-phenyl-2,6-dihydro-7 H -pyrazolo [4.3 pyrimidine-7-one (see WO 01/27113, Example 66); 5- (5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (lisopropyl-3-azeti-15-vinyl) -2,6-dihydro-7 H -pyrazolo [4,3-d] pyrimidinine 7-one (see WO 01/27112, Example 124); 5- (5-acetyl-2-butoxy-3-piridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7 H -pyrazolo [4,3-d] pyrimidine- 7-one (see WO 20.01 / 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, IC-351, Cialis®), ie the compound of examples 78 and 95 of published international application WO 95/19978, as well as the compound of examples 1, 3 , 7 and 8; 2-1,2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulfonyl) phenyl] -5-30 methyl-7-propyl-3 H -imidazo [5,1-f] [1,2, 4] - triazine-4-one (vardenafil, LEVITRA®), also known as 1 - [[3- (3,4-dihydro-5-methyl-4-oxo-7-propylimidazo [5,1-f] -as-triazin-2-yl) -4-ethoxyphenyl] sulfonyl] -4-ethylpiper-azine, ie the compound of Examples 20, 19, 337 and 336 of published international application WO 99/24433; the 1-0 27 8 3 3 59 compound of Example 11 of published international application WO 93/07124 (EISAI); the compounds 3 and 14 of Rotel-la, D. P., J. Med. Chem. 2000, 43, 1257; 4-5 (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-pyrrolidinepropanamide "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-tl- [(4-fluorophenyl) methyl] -7,8-dihydro-8-oxo-1H-imidazo [4,3-g] quinazoline-6- yl] -4-propoxyphenyl] carboxamide.

(v) 4-Bromo-5- (pyridylraethylatino) -6- [3- (4-chlorophenyl) propoxy] -3 (2H) -pyridazinone; 1- [4 - [(1,3-benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinozolinyl] -4-piperidine-carboxylic acid, monosodium salt; (+) - cis-5.6a, 7.9.9.9a-hexahydro-2- [4- (trifluoromethyl) -phenylmethyl-5-methylcyclopent-4,5] -imidazo [2,1b] purine- 4 (3 H) -one; furazlocil line; cis - 2-hexyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydrocyclopent [4,5] imidazo [2,1-b] purine-4-one; 3-acetyl-1- (2-chlorobenzyl) -2-propylindole-6-carboxylate; 3-acetyl-1- (2-chlorobenzyl) -2-propylindole-6-carboxylate; 4-bromo-5- (3-pyridylmethyl-amino) -6- (3- (4-chlorophenyl) propoxy) -3 (2H) -pyridazinone; 1-methyl-5- (5-morpholinoacetyl-2-n-propoxyphenyl) -3-n-propyl-1,6-dihydro-7 H -pyrazolo (4,3-d] pyrimidine-7-one; 1- [4 - [(1,3-benzodioxol-5-ylmethyl) amino] -6-pyra-35-zolo [4,3-d] pyrimidin-7-one; [4 - [(1,3-benzodioxol-5-ylmethyl)] ) amino] -6-chloro-2-quinazolinyl] -4-piperidinecarboxylic acid, mono-1027833 60 sodium salt; Pharmaprojects No. 4516 (Glaxo Wellcome); Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. 5064 (Kyowa Hakko; see WO 96/26940); Pharmaprojects No. 5069 (Schering Plow); GF-196960 (Glaxo Well come); E-8010 and E-4010 (Eisai); Bay-38-3045 & 38-9456 (Bayer); FR229924 and FR226807 (Fujisawa); and Sch-51866.

10 The content of the published patent applications and journal articles and in the. in particular the general formulas of the therapeutically active compounds of the claims and exemplary compounds therein are incorporated herein in their entirety by reference thereto.

15

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

20

Most preferably, the PDE5 inhibitor is sildenafil and pharmaceutically acceptable salts thereof. Sildenafilcitrate is the preferred salt.

The compounds of the present invention can be administered in combination with an NO donor. In a further aspect of the invention, therefore, there is provided a pharmaceutical product containing a V1a antagonist and an NO donor, as a combined preparation for simultaneous time. individual, or sequential use in the treatment of dysmenorrhea.

The compounds of the present invention can be administered in combination with L-arginine or as an arginate salt. Thus, in a further aspect of the invention, a pharmaceutical product is provided containing a V1a antagonist and L-arginine, as a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhea.

The compounds of the present invention can be administered in combination with a COX inhibitor. Thus, in a further aspect of the invention, a pharmaceutical product is provided which contains a V1a antagonist and a COX inhibitor, as a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhea.

COX inhibitors useful for combining with the compounds of the present invention include, but are not limited to: (i) ibuprofen, naproxen, benoxaprofen, flurbiprofofen, phenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen , oxaprözin, prapoprofen, microprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetine, summer pirac, diclofenac, fenclofenec, alclofenac, ibufenac, isoxofox, eroxenof, pacanac, tenox, fox, fox, fox, fox -rolac, azapropazone, mefenamic acid, tolfenaminic acid, diflunisal, podophyllotoxin derivatives, acemetacin, droxicam, floctaphenin, oxyphenbutazone, phenylbutazone, proglume tacin ,. acemetacin, fentiazac, clidanac,. oxipinac, mefenamic acid, meclofenamic acid, fluphenamic acid, niflumic acid, fluphenisal, sudoxicam, etodolac, piprofen, salicylic acid, cholinagnesium trisalicylate, salicylate, benoorylate, fentiazac, clopinac, feprazone-isox-35-fluor thyl [1,1'-biphenyl] -4-acetic acid, 4- (nitrooxy) butyl ester (see Wenk et al., Eur. J. Pharmacol. 453: 319-324 (2002); 1027833 62 (ii) meloxicam (CAS registration number 71125-38-7; described in U.S. Patent No. 4,233,299)> or a pharmaceutically acceptable salt or prodrug thereof; (iii) Substituted benzopyrant derivatives described in U.S. Patent No. 6,271,253. Also benzopyrant derivatives described in the U.S. Pat. U.S. Pat. Nos. 6,034,256 and 6,077,850 at the same time as International Publications WO 98/47890 and WO 00/23433 (iv) Selective C0X2 inhibitors based on chromes as described in U.S. Pat. No. 6,077,850 and U.S. Pat. Patent 6,034,256; (v) The compounds which b are described in International Patent Applications WO 95/30656, WO 95/30652, WO 96/38418 and WO 96/38442, and the compounds described in European Patent Application 799823, together with the pharmaceutically acceptable derivatives thereof; (vi) celecoxib (U.S. Patent No. 5,466,823), valdecoxib (U.S. Patent No. 25

No. 5,633,272), deracoxib (U.S. Patent No. 5,521,207), rofecoxib (U.S. Patent No. 5,474,995), etori-coxib (International Patent Application WO

98/03484), JTE-522 (Japanese Patent Application 30 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 selective COX2 inhibitor valdecoxib (described in U.S. Patent No. 0vv 33 33, 5,633,272), in particular sodium paroxoxib; (iii) ABT-963 (described in International Patent Application WO 00/24719); 5 (ix) Nimesulide (described in U.S. Pat. No. 3,840,597), flosulide (discussed in J. Carter, Exp. Ooin. Ther. Patents 8 (1), 21-29 (1997)), NS-398 (described in U.S. Patent No. 4,885,367), SD 10. 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 No. 595546) and MK-966 (described in U.S. Patent No. 5,968,974); (x) The compounds and pharmaceutically acceptable derivatives described in U.S. Pat. No. 6,395,724, U.S. Pat. No. 6,077,868, U.S. Pat. No. 5,994,381, U.S. Pat. No. 6,362,209, U.S. Pat. No. 6,080,876, U.S. Pat. No. 6,133,292 U.S. Patent No. 6,369,275, U.S. 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 WO 96/03392, International Patent Application WO 96/24585, U.S. Pat. No. 6,340,694, U.S. Pat. No. 6,376,519, U.S. Pat. No. 6,153,787, U.S. Pat. No. 6,046,217, U.S. Pat. No. 6,329,421, U.S. Pat. - f ° 27 8 35 64, 6,239,137, U.S. Patent 6,136,831, U.S. Patent 6,297,282, U.S. Pat. No. 6,239,173, U.S. Patent No. 6,303,628, U.S. Patent No. 6,310,079, U.S. Patent No. 6,300,363, U.S. Patent No. 6,077,869, U.S. Patent No. 6,140,515, U.S. Patent No. 5,994,379, U.S. Patent No. 6,028 .202, U.S. Pat. No. 6,040,320, U.S. Pat. No. 6,083,969, U.S. Pat. No. 6,306,890, U.S. Pat. No. 6,307,047, U.S. Pat. No. 6,004,948, U.S. Pat. No. 6,169,188, U.S. Pat. No. 6,020,343, U.S. Pat. 5,981,576, U.S. Pat. No. 6,222,048, U.S. Pat. No. 6,057,319, U.S. Pat. No. 6,046,236, U.S. Pat.

Patent No. 6,002,014, U.S. Patent No. 5,945,539, U.S. Patent No. 6,359,182, International Patent Application WO 97/13755, International Patent Application WO 96/25928, International Patent Application WO 96/374679, International Patent Application WO 95/15316, Internatio -30 International Patent Application WO 95/15315, International Patent Application WO 96/03385, International Patent Application WO 95/00501,

International Patent Application WO 94/15932, International Patent Application WO 95/00501, 35 International Patent Application WO 94/27980,

International Patent Application WO 96/25405, International Patent Application WO 96/03388, 1027833 65

International Patent Application WO 96/03387, U.S. Patent 5,344,991, International Patent Application WO 95/00501, International Patent Application WO 96/16934, International Patent Application WO 03392,

International Patent Application WO 96/47890 and International Patent Application WO 00/24719.

The contents of each of the patent applications and in particular the general formulas of the therapeutically active compounds of the claims and exemplary compounds therein are incorporated herein by reference in their entirety.

• 15

The following Preparations and Examples illustrate the preparation of compounds of formula (I).

Nuclear Magnetic Resonance (NMR) spectra were consistent with the proposed structures in all cases. Typical chemical shifts (δ) are given in parts-per-million downstream of tetramethylsilane, where use. is made of the usual abbreviations for the indication of important peaks: eg s, singlet; d, doublet, t, triplet; q, quartet; m, multiplet; br, wide. The mass spectra (m / z) were recorded with either electrospray ionization (ESI) or chemical ionization under atmospheric pressure (APCI). The following abbreviations have been used for common solvents: CDCl3, deuterochloro-form, De-DMS0, deuterodimethyl sulfoxide; CD3OD, deuteromethanol; THF, tetrahydrofuran. "Ammonia" refers to a concentrated aqueous ammonia solution with a specific gravity of 0.88. When thin layer chromatography (TLC): is used, this refers to TLC on silica gel using silica gel 60 F254 plates; Rf is the distance traveled by a compound, divided by the distance traveled by the solvent front on a TLC plate. When microwave irradiation is used, the two microwave devices used are the Emrys Creator and the Emrys Liberator, both supplied by Personal Chemis-try Ltd. The energy range is 15 - 300 W at 2.45 GHz. The energy actually supplied varies during the course of the reaction in order to maintain a constant temperature.

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

10

KMX

15

To a solution of 9.0 g of 4-hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (see reference WO 9703986 A1 19970206) (37 mmol, 1 eq.) In 40 ml of THF was added 8.1 ml of dimethyl formamide. dimethyl acetal (55.4 mmol, 1.5 eq.) was added. The reaction mixture was then stirred under nitrogen at 50 ° C for 4 hours. The solvent was removed under reduced pressure, the residue was dissolved in 40 ml of toluene and 400 mg of para-toluenesulfonic acid was added. The mixture was then heated to 100 ° C under nitrogen for 18 hours, the volatiles removed under reduced pressure and the residue partitioned between methylene chloride and an aqueous solution of 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 methylene chloride / methanol as eluant (98: 2 v / v to 95: 5 v / v) to yield 8.07 g of the title compound as a white solid (81%).

35 X H NMR (400 MHz, CD3 OD): δ 1.42 (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); LRMS: m / z APCI \ 269 [ΜΗ] \ · Found: C, 58.26%; H, 1 0 2 7833 67 7.96%; N, 15.78%; C 13 H 31 N 3 O 3 requires C, 58.14%, H, 7.92, N, 15.72.

Preparation 2a: 4- [4- (4-Chlorophenyl) -5-methyl-4H- [1,2,4] tria-5-zol-3-yl] -piperidine: 10 4.0 g of the compound of preparation 1 (15 mmol, 1 eg.) was dissolved in 100 ml of toluene. 2.1 g of para-chloroaniline (16.5 mmol, 1.1 eq.) Was added thereto, 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 a further 48 hours. The reaction mixture was then peeled off, an aqueous solution of sodium bicarbonate was added and the organic phase was decanted. The aqueous phase was made basic with potassium carbonate and extracted four times with methylene chloride (50 ml). The methylene chloride solution was dried over magnesium sulfate and the solvent was removed in vacuo to give 2.90 g of the title compound as a white solid.

25? -NMR (400 MHz, CDCl 3): δ 1.60 - 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); LRMS: m / z APCI +, 277 [MH) +.

Preparation 2b: 4- [4- (4-Chlorophenyl) -5-methyl-4 H -1,2,4-triazol-3-yl] piperidine hydrochloride 1027833 68

Hydrochloric acid in dioxane (4M, 10 ml) was added to a cooled (5 ° C) solution of compound 1 of preparation (1.32 g, 4.76 mmol) in methanol (30 ml) and the solution was allowed to warm to room temperature with stirring for another. 90 minutes. TLC analysis showed that starting material was still present, so that additional hydrochloric acid in dioxane (4M, 10 ml) was added and the reaction mixture was stirred for another 4 hours. The mixture was concentrated under reduced pressure and the residue was separated (3x) as azeotrope with toluene to form the title compound, 1.4 g.

^ -NMR (400 MHz, DMSO-d 6): δ 1.86 (m, 4 H), 2.25 (m, 3 H), 2.80 - 2.97 (m, 3 H), 3.22 (m, 2 H), 7.64 (m, 2 H), 7.77 (d, 2 H).

15

Preparation 3: 1- (3-Chlorobenzoyl) -piperidine-4-carboxylic acid ethyl ester 20 c | -y ch, o

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

^ -NMR (400 MHz, CDCl 3): δ 1.24 (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, 3 H). LRMS: m / z APCI * 296 [MH] +.

1027833 69

Preparation .4: 1 (3-Chlorobenzoyl) -piperidine-4-carboxylic acid hydrazide 5

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

^ -NMR (400 MHz, CDCl 3): δ 1.62 - 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 APCI + .282 [MH] *.

Preparation 5: 1- (3-Chlorobenzoyl) -piperidine-4-carboxylic acid. 20 N '- (2-chloro-acetyl) -hydrazide 0 25 ^ 25

Acetyl chloride (4.3 ml, 53 mmol) was added dropwise over 30 minutes to an ice-cooled solution of the hydrazide from Preparation 4 (10 g, 35.5 mmol) and N-methyl morpholine (5.4 g, 53 mmol) in dichloromethane (200 ml) to keep the internal temperature below 10 ° C. The reaction mixture was then allowed to warm to room temperature and it still became. stirred for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with a saturated sodium bicarbonate solution and then with brine. The solution was dried over MgSO 4, concentrated under reduced pressure, and the residue was triturated with ether to form the title compound as a white solid, 10.2 g.

1 H NMR (400 MHz, CD 3 OD): δ 1.66 - 1.84 (m, 3H), 1.98 (m, 1H), 2.61 (m, 1H), 2.99 (mi, 1H) ), 3.19 (m, 1H), 3.74 (m, 1H), 5.14 (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-chlorophenyl) -methanone Trifluoroacetic anhydride (9.45 ml, 57 mmol) ) was added dropwise over 30 minutes to a cooled solution (0-5 ° C) of the compound from preparation 5 (10.2 g, 28.5 mmol) and pyridine (11.5 ml, 142.5 mmol) in dichloro -thane (300 ml). After completion of the addition, the resulting pink suspension was stirred for an additional 90 minutes at 10 ° C. The reaction mixture was carefully poured into a saturated sodium bicarbonate solution (600 ml) and the layers were separated. The organic phase was washed with a further saturated sodium bicarbonate solution (x 2), dried over MgSO 4 and treated with decolorizing carbon. The mixture was then filtered and the filtrate was evaporated under reduced pressure to form the. title compound, 13 g.

X H NMR (400 MHZ, CD.3OD): δ 1.80 - 1.97 (m, 2H), 2.08 (m, 30.1 H), 2.22 (m, 1 H), 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] + 1 0 27 8 33.

71

Preparation 7: 4- [α '- (2-Chloroacetyl) -hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester 10-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (see reference WO 2000039125, prep 27) ( 25 g, 103 mmol) was dissolved dichloromethane (300 ml) and 4-methyl morpholine (12.5 ml, 113 mmol) was added. The mixture was cooled using an ice bath and chloroacetyl chloride (8.2 ml, 103 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was partitioned with an aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered and the filtrate was evaporated to form the title compound as an off-white solid (29.6%) · LRMS m / z APCI-318 [MH] - Preparation 8: 4 - (5-Chloromethyl- [1,3,4] oxadiazol-2-yl) -piperidine-1-carboxylic acid tert-butyl ester

The hydrazide from preparation 7 (5.0 g, 15.6 mmol) was suspended in dichloromethane (200 ml) and then pyridine (6.4 ml, 78 mmol) was added before the mixture was cooled to 10 ° C. Trifluoroacetic anhydride (6.6 ml, 39 mmol) was added dropwise over 15 minutes and then the mixture was added. Stirred 3 hours 1027833 72 at room temperature. The reaction mixture was partitioned with water (50 ml), the organic layer was dried over magnesium sulfate, filtered and the filtrate was evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane as eluent (2:98) to form the title compound as a white solid (2.95 g).

1 H NMR (400 MHz, CD 3 OD): δ 1.45 (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] oxadazol-2-yl) -piperidine-1-carboxylic acid tert-butyl ester and 4-15 (5 [1,2,3] Triazol-1-ylmethyl- [1,3,4] oxadiazol-2-yl) -piperidin-1-carboxylic acid tert-butyl ester 20 I Cs

A mixture of the compound from preparation 8 (8 g, 26.5 in mol), triazole (3.7 g, 53 mmol) and potassium carbonate (5.2 g, 38 mmol) in N, N-dimethylformamide (60 ml) was Stirred for 18 hours at room temperature. 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 MgSO 4 and concentrated under reduced pressure to form the title compounds as a mixture of isomers.

1 H NMR (400 MHz, CD 3 OD): 6 1.43. (s, 9Ή), 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) 35 total 2H].

1027833 I 73

Preparation 9b: 4- (5- [1,2,3] Triazol-2-ylmethyl- [1,3,4] oxadazol-2-yl) -piperidine-1-carboxylic acid tert-butyl ester Dichloromethane (500 ml ) was added to a suspension of the hydrazide from preparation 170 (132.3 g, 375 nunol) in 5 I-methyl imidazole (120 ml) and the resulting solution was cooled in an ice / acetone bath. Triflic anhydride (92 ml, 561 mmol) was added dropwise over 2.5 hours to keep the reaction temperature below 0 ° C. After completion of the addition, the reaction mixture was stirred for a further 10 minutes. The reaction mixture was then quenched by the addition of 2 M hydrochloric acid (350 ml). The phases were separated and the aqueous layer was extracted with dichloromethane (200 ml). The combined organic solutions were washed with brine, dried over MgSO 4 and thinned under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane as an eluent to form the title compound as a viscous oil.

20

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

A mixture of the compound from Preparation 6 (2 g, 5.9 mmol), triazole (810 g, 11.75 mmol) and potassium carbonate (1.2 g, 8.85 mmol) in acetonitrile (20 mL) was Stirred for 30 minutes at room temperature, followed by another one hour at 5 ° C. The reaction mixture was filtered, washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The remaining brown oil was partitioned between ethyl acetate and water, the layers were separated and the organic phase was washed with additional water and then with brine. The solution was dried 10 27 8 5, 3.74 over MgSO 4 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 form the title compound (202 mg).

5-NMR (400 MHz, CD 3 OD): δ 1.76 - 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] + 10 Preparation 11a: 4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H -. 4] triazol-3-yl] -piperidine-1-carboxylic acid. tert-butyl ester

Hfi CH.O b

Trifluoroacetic acid (1 ml, 13.2 mmol) was added to a solution of the compounds from preparation 9a (8.8 g, 26.5 mmol) and 4-chloroaniline (5 g, 39.75 mmol) in toluene (200 ml) and the reaction mixture was stirred under 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. The remaining brown oil 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) and then passed over the column again using ethyl acetate: methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) to form the title compound (2.3 g). X H NMR (400 MHz, CD 3 OD): δ 1.42 (m, 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 (APCI +) 444 35 [MH] + tÖ27833 75

Preparation 11b: 4- [4- (4-Chlorophenyl) -5- [1,2,3) triazol-2-ylmethyl-4H- [1,2,4] triazole-3-yl-piperidirie-1-carboxylic acid - tert-butyl ester 5 N-Methylimidazole (4.66 g> 56.75 mmol) and dichloromethane (20 ml) were added to the bis-acyl hydrazine from preparation 170 (5.00 g, 14.19 inmol) and the resulting solution was cooled to -20 ° C. Trifluoromethanesulfonic acid anhydride (6.00 g, 21.28 mmol) was added, keeping the temperature below 0 ° C. After completion of the addition, the reaction mixture was heated to ambient temperature and stirred for 15 hours. The reaction was quenched with H 2 O (10 mL), the phases were separated, and the aqueous layer was re-extracted with dichloromethane (10 mL). The combined organic phases were dried over magnesium sulfate, filtered and the dichloromethane was distilled and replaced with toluene in vacuo to form a toluene solution of the oxadiazole intermediate (volume - 20 ml). 4-Chloroaniline (1.90 g, 14.90 mmol) was added to the toluene solution, followed by trifluoroacetic acid (0.81 g, 7.09 mmol) and the reaction mixture was stirred at 85 ° C for 5.5 hours. The mixture was cooled to ambient temperature and stirred for 5 minutes with 1.8 N aqueous ammonia (14 ml). The phases were separated, the organic phase was diluted with tert-butyl methyl ether (20 ml) and then stirred for 15 hours. The resulting solid precipitate was collected by filtration and washing with tert-butyl methyl ether (2 x 5 ml) to form the title compound as a beige-colored solid (2.72 g). Ή NMR (400 MHz, CDCl 3): δ 1.43 (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) .

1 027 8 33 35 76

Preparation 12a: 4- [4- (4-Chloro-enyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidine 5 ^ 4M Hydrochloric acid in dioxane (10 ml) was added to a solution of the compound from Preparation 11a (2.3 g, 5.2 mmol) in methanol (30 ml) and the reaction mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure, the residue was diluted with dichloromethane and basified with 1 N sodium hydroxide solution to pH 10 and the layers were separated. The aqueous phase was re-extracted with dichloromethane and the combined organic solutions were dried over MgSO 4 and concentrated under reduced pressure to form the title compound as a foam (1.65 g).

Ή NMR (400 MHz, CD 3 OD): δ 1.79 (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] * 25

Preparation 12b: 4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3ryl] -piperidine bis-toluene sulfonate salt 30

/ 2 TsOH

(HCl 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 mixture was stirred at room temperature for 17 hours.

} 02 7-833 · 77

The solid precipitate was collected by filtration and washing with ethyl acetate to form the title compound as a white solid (9.32 g).

^ -NMR (400 MHz, DMS0-d6): δ 1.85 (m, 4H), 2.26 (s, 6H), 5.82 (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: Methyl lff-tetrazol-1-ylacetate fi A mixture of tetrazol-1-yl-acetic acid (5 g, 39 mmol) and 4M hydrochloric acid in dioxane (100 µl) in methanol (50 ml) was heated for 18 hours under reflux. The cooled mixture was evaporated under reduced pressure to form the title compound.

20 H-NMR (400 MHz, DMSO-d 9): δ 3.74 (s, 3 H), 5.58 (s, 2 H), 9.39 (s, 1 H); LCMS: m / z APC1 + 143 [MH] *

Preparation 14: (3-Methyl-isoxazol-5-yl) -acetoyl chloride N, N-Dimethylformamide (a few drops), followed by oxalyl chloride (9.5 ml, 106 mmol) were added dropwise to a cooled (10 ° C) solution of (3-methyl-isoxazol-5-yl) -acetic acid (5 g, 35.4 mmol) in dichloromethane (50 mL) and the solution was allowed to warm to room temperature. The reaction mixture was stirred for a further 3 hours and then concentrated under reduced pressure. The residue .35 was separated as azeotrope with toluene to form the title compound.

1027833 78

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-1 H -imidazol-1-yl) acetate 5

Potassium carbonate (8.42 g, 61 mmol) was added to a solution of 2-methyl imidazole (5 g, 61 mmol) in tetrahydrofuran (100 mL), and the suspension was stirred for 30 minutes. Ethyl bromoacetate (6.75 ml, 61 mmol) was added and the reaction mixture was stirred for another 30 minutes at room temperature. The mixture was filtered and washed 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 form the title compound as an oil, 5.28 g.

1 H NMR (400 MHz, CDCl 3): δ 1.26 (t, 3H), 2.35 (s, 3H), 4.22 (q, 2H), 4.58 (s, 2H), 6.81 (s, 1H), 6.94 (s, 1H). LRMS: m / z APCI + 169 [MH] +.

Preparation 16: 2- (ΙΗ-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 under reflux for 18 hours. The cooled reaction mixture was concentrated under reduced pressure and the residue was separated off as azeotrope with toluene to form the title compound.

1027833 79 1 H NMR (400 MHz, DMSO-d 6): δ 5.18 (s, 2 H), 9.38 (s, 1 H).

LCMS: m / z APCI + 143 [MH] + 5 Preparation 17: [1,2,3-Triazol-1-yl-acetic acid ethyl ester and [1,2,3] triazol-2-yl-acetic acid ethyl ester JLO JC10 10.1, 2,3-Triazole (19.00 kg, 275 mol) was charged over 30 minutes in a suspension of potassium carbonate (42.15 kg, 305 mmol) in ethanol (80 liters) and rinsed with. ethanol (2 liters). A solution of ethyl bromoacetate (45.8 kg, 274 mmol) in ethanol (30 liters) was added slowly and the whole was rinsed with ethanol (2 liters). The reaction temperature was kept <20 ° C during this time. The reaction mixture was then warmed to room temperature and stirred overnight. The suspension was filtered, the residue was washed with ethanol (25 liters and 17 liters) and then the filtrate was concentrated under reduced pressure. The concentrate. was dissolved in ethyl acetate (120 liters) and the solution was washed with 1 N hydrochloric acid (1 x 40 1, 7 x 20 1, 4 x 15 1). The aqueous washings were combined and extracted with ethyl acetate (3 x 21 liters). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated to dryness to form a mixture of the title compounds (25 kg). ^ NMR spectroscopic analysis indicated that this was a 6: 5 mixture of N-2 / N-1 isomers. 1 H-NMR (400 MHz, CDCl 3.): δ 1.25 (m, 3H), 4.13 (q, 2H, N1 isomer), 425 (1, 2H, N-2 isomer), 5.20 (s (2H, N1 isomer), 5.22 (s, 2H, N-2 isomer), 7> 70 (s, 2H, N-2 somer), 7.77 (s, .2H, N1 isomer) ).

1027833 80

Preparation 18 * H, 2,3-Triazol-2-yl-acetic acid hydrazide

* sXD

Η N

Hydrazine hydrate (8.65 kg, 270 mol) was added to a cooled (<10 ° C) solution of the mixture of the ester of preparation 17 (19 kg) in ethanol (69 liters), the temperature during the whole addition was kept below 20 ° C. The reaction mixture was added at a temperature between 14 and 19 ° C for 3 hours and then more ethanol (25 liters) was added and the product was collected by filtration and washed with ethanol (10 liters). The crude solid was purified by recrystallization from ethanol (120 liters) followed by three recrystallizations from methanol (105 l, 120 l and 90 l) to form the title compound (4.53 kg) after drying under vacuum.

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-1 H -imidazol-1-yl) acetohydrazide hnn tl 25 The title compound was obtained as a white solid from the compounds of preparation 15 and hydrazine, using a method similar to that described is before preparation 16, except that 5 equivalents of hydrazine were used and isopropanol was used as the solvent in the reaction.

^ -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 APCI * 155 [MH] +

Preparation 20: 2- (3-Methyl-1,2,4-oxadiazol-5-yl) acetohydrazole. yy p - N

1 0 2 7 8 3 3 81

The title compound was obtained from 3-methyl-1,2,4-oxadiazol-5-yl acetic acid methyl ester (NL 7807076) and hydrazine; following a method similar to that described for preparation 16, except that 58 equivalents of hydrazine were used, and isopropanol was used as the solvent in the reaction.

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

Preparation 21: 2- (Pyrimidine-2-yloxy) acetohydrazide 1. \ j

A mixture of ethyl 2-pyrimidinyloxyacetate (GB 2373186, step i, e.g. 368) (4.4 g, 24.15 mmol) and hydrazine hydrate (5 ml, 160 mmol) in isopropanol (30 ml). Heated under 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 form the title compound, 600 mg.

^ -NMR (400 MHz, CDCl 3): δ 4.98 (s, 3H), 7.04 (m, 1H), 8.58 (d, 2H). LCMS: m / z APCI * 169 [MH] + 25

Preparation 22: tert-Butyl-2 - [(3-methyl-isoxazol-5-yl) -acetyl-hydraz inecari-oxyl]

Triethylamine (24 ml, 17 mmol) was slowly added to a cooled (10 ° C) solution of the acid chloride from preparation 14 (5.64 g, 35.4 mmol) in dichloromethane (200 ml), followed by tert-butyl carbazate (5.6 g, 42.5 mmol) and. the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off. 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 form the title compound.

1 H NMR (400 MHz, CDCl 3): δ 1.47 (s, 9H), 2.30 (s, 3H), 3.77 (s, 2H), 6.15 (s, 1H), 6, 45 (br s, 1 H), 7.59 (br s, 1 H).

Preparation 23s tert-Butyl-2- [3- (3,5-dimethylisoxazol-4-yl) propanoyl] hydrazine carboxylate hcS / 0 "" 9 "Ί

O H, C

Oxalyl chloride (5.16 ml, 59.2 mmol) was added to a solution of β- (3,5-dimethyl-4-isoxazolyl) propionic acid (J. Org. Chem. 59 (10); 1994; 2882) (2 , 5 g, 14.8 mmol) in dichloromethane (50 ml) and Ν, Ν-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 separated (5x) as azeotrope with dichloromethane to form a brown liquid. This was dissolved in dichloromethane (25 ml) and tert-butyl carbazate (2.93 g, 22.2 mmol) was added in portions. The mixture was further diluted with dichloromethane (23. ml) and the reaction mixture 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 off 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 form the title compound as a oil, 3.08 g · 1027833 83 1 H NMR (400 MHz, CDCl 3): δ 1.45 (s, 9H), 2.21 (s, 3H), 2.36 (τη, 4H), 2.45 (τη, 1 H), 2.60 - 2.73 (m, 2 H), 6.48 (br s, 1 H), 7.42 (br s, 1 H). LCMS: m / z ES + 306 [MNa] + 5 Preparation 24: 2- (3-Methylisoxazol-5-yl) acetohydrazide hydrochloride γΛ-Ο-,

10

A mixture of the compound of preparation 22 (1.6 g, 6.3 in mol) in 4 M 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 a small volume, the resulting precipitate was filtered off, washed with dichloromethane and dried to give the title compound, 810 mg.

^ -NMR (400 MHz, DMSO-d 6): δ 2.20 (s, 3H), 3.86 (s, 2H), 6.24 (s, 1H). LCMS: m / z APCI * 156 [MH] + 20

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

H »C

A solution of the compound of preparation 23 (3.08 g, 10.87 mmol) in 2.2 M hydrochloric acid in methanol (50 ml) was stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure and the residue was separated with toluene as azeotrope. The crude product was triturated with pentane / ether and then ether and the resulting solid was filtered to form the title compound as an off-white solid, 1.39 g.

1 0 2 7 8 3 84 "H-NMR (400 MHz, DMSO-d 6): d 2.22 (s, 3H), 2.27 (s, 2H), 3.35 (S, 3H), 2, 66 (t, 2H), 6.75 (br s, 1H) LCMS: m / z APCI4 184 [MH] 4 Preparation 26: tert-Butyl 2- (hydrazinocarbonyl) morpholine-4-carboxylate o, -v vVÖ

HSC - ^ - O

h3c h2n-n 10

A mixture of 4- (tert-butyl) -2-methyl-2,4-morpholine carboxylate (WO 03/018576, e.g. 1 part i) (2.03 g, 8.3 mmol), hydrazine hydrate ( 1.2 ml, 24 mmol) and methanol (50 ml) was heated under 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 MgSO 4 and evaporated under reduced pressure to form the title compound, 1.92 g.

LCMS: m / z ES4 268 [MNa] *

Preparation 27: tert-Butyl-3- (hydrazinocarbonyl) piperidine-1-carboxylate "Λ-Κ-)"

HSC O

H? N - N 2 H

Hydrazine hydrate (75 ml, 1.5 mol) was added to a solution of piperidine-1,3-dicarboxylic acid 1-tert-butyl-3-ethyl ester (US 2002 0099035, e.g. 12) (72 g, 280 mmol) in ethanol (250 ml) and the reaction mixture was heated under 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 MgSO 4 and evaporated under reduced pressure. The product was separated as ether azeotrope to form the title compound as a colorless gum, 59.8. g ·.

1 H-NMR (400 MHz, CDCl 3): δ 1.40 - 1.50 (m, 11 H), 1.63 (m, 1 H), 1.83 (m, 2 H), 2.25 (m (1 H), 2.97 (m, 1 H), 3.16 (m, 1 H), 3.78 - 3.98 (m, 3 H), 7.40 - 7.60 (br s, 1 H).

Preparation 28: Ethyl 1- (4-chlorobenzoyl) piperidine-4-carboxylate o '15

The title compound was obtained as a yellow oil from ethylisonipecotate and 4-chlorobenzoyl chloride, following a method similar to that described for Preparation 3.

20 NM NMR (400 MHz, CDCl 3): δ 1.24 (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 APCIV296 [MH] * Preparation 29: 1- (4-Chlorobenzoyl) piperidine-4-carbohydrate ci ff Y) rYn - "*"

O

30

A solution of the compound of preparation 28. (148 g, 0.5 mol) in methanol (400 ml) was heated at 70 ° C for 30 minutes. Hydrazine hydrate (50 g, 1.0 mol) was then added and the reaction mixture was stirred for an additional 3 hours at 60 ° C. TLC analysis showed that starting material was left and therefore additional hydrazine hydrate (50 ml, 1.0 mol) was added and the reaction mixture 1027833 86 was stirred for another 48 hours at 75 ° C. The cooled mixture was concentrated under reduced pressure, the residue was suspended in dichloromethane (1 liter) and washed with water (2x). The organic solution was dried over MgSO 4 and evaporated under reduced pressure to form the title compound as a white solid, 119 g.

X H NMR (400 MHz, CDCl 3): δ 1.65 - 1.94 (m, 4 H), 2.35 (m, 1 H), 2.80 - 3.06 (m, 2 H), 3.79 ( m, 1 H), 4.65 (m, 1 H), 7.10 (s, 1 H), 7.38 (m, 4 H). LCMS: m / z APCI + 282 [MH] +

Preparation 30: 1- (4-Chlorobenzoyl) -N '- (trifluoroacety-piperidin-carbohydrazide)

O

Trifluoroacetic anhydride (1.56 ml, 11 # 18 mmol) was added dropwise to an ice-cooled solution of 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 mixture was stirred at room temperature for 18 hours. The resulting precipitate was filtered off, washed with dichloromethane and dried to give the title compound, 1.78 g.

1 H NMR (400 MHz, DMSO-d 6): δ 1.56 (m> 2H), 1.64 - 1.84 (m, 2H), 2.56 (m, 1H), 2.85 (m 1 H), 3.08 (m, 1 H), 3.58 (m, 1 H), 4.40 (m, 1 H), 7.40 (d, 2 H), 7.50 (d, 2 H), 10 , 20 (s, 1H), 11.15 (br s, 1H).

30

Preparation 31: 1- (4-Chlorobenzoyl) -N '- (ethoxyacetylpiperidine-4-carbohydrazide) N-methylmorpholine (2.60 g, 26.6 mmol) and then ethoxyacetyl chloride (WO 01/46150, e.g. 33A) (1.09 g, 8.87 mmol) were added to a solution of the compound of preparation 29 (2.5 g, 8.87 mmol) in dichloromethane (70 mL) 5 and the reaction mixture was stirred at room temperature for 18 hours, the mixture was washed with water, then with ammonium chloride solution and finally with sodium carbonate solution, dried over MgSO4 and evaporated under reduced pressure to form the title compound. .

1 H NMR (400 MHz, CDCl 3): δ 1.22 (t, 3H), 1.72 - 1.99 (m, 4H), 2.56 (m, 1H), 2.86 - 3.06 ( m, 2H), 3.60 (q, 2H), 3.80 (m, 1H), 4.04 (s, 2H), 4.62 (m, 1H), 7.38 (m, 4H), 8.90 (d, 1H), 8.99 (d, 1H). LCMS: m / z ES * 368, 370 [MH] + 15

Preparation 32: 1- (3-Chlorobenzoyl) -N '- (ethoxyacetyl) piperidine-4-carbohydrazide

The title compound was obtained in 91% yield from the compound of preparation 4 and ethoxyacetyl chloride (WO 01/46150, e.g. 33A), following the method described for preparation 31.

: X H NMR (400 MHz, CDCl 3): δ 1.22 (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, 3 H), 8.61 (d, 1 H), 8.75 (d, 1 H). LCMS: m / z APCI + 368, 370 [MH] * 02783j 88

Preparation 33: tert-Butyl-4 - {[(4-chlorophenyl) amino] carbonyl} piperidine-1-carboxylate 5; 1-BO-piperidine-4-carboxylic acid (100 g, 437 mmol), 4-chloro-aniline (61.2 g, 480 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (100 g, 524 mmol) and 10 triethylamine (182.6 ml, 1.31 mol) were dissolved in cold (10 ° C) acetonitrile (1.75 liters). 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 then partitioned with 2N hydrochloric acid. The resulting precipitate was filtered off, redissolved in dichloromethane, the solution was dried over MgSO 4 and evaporated under reduced pressure. The residue was triturated with ether to form the desired compound as a white solid.

The filtrate was separated and the organic layer was washed with 2N hydrochloric acid (2x), dried over MgSQ, and evaporated under reduced pressure. The solid was triturated with ether to form more of the compound as a white solid, with a combined yield of 99.4 g.

1 H NMR (400 MHz, CDCl 3): δ 1.46 (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 (8, 1H), 7.26 (d, 2H), 7.46 (d, 2H). LCMS: m / z APCI + 339 [MH] + 30

Preparation. 34: tert-Butyl-4- {t (4-chlorophenyl) amino] carbonyl} 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 liter) was heated under reflux for 1 hour and then stirred for a further 18 hours at room temperature . TLC-5 analysis showed that starting material remained and therefore Lawesson's reagent (11.1 mmol) was added and the reaction mixture was heated under reflux for an additional one hour. The cooled mixture. was concentrated under reduced pressure and the residue was separated as azeotrope with ethyl acetate. The crude product was triturated with hot ethyl acetate and the resulting solid was filtered off and dried to form the title compound as a white solid, 53 g.

LCMS: m / z APCI * 353 [MH] +.

15

Preparation 35s Ethyl 1- {[(4-chlorophenyl) amino] carbonothiyl} piperidine-4-carboxylate vKKo ·

A mixture of 4-chlorophenyl isothiocyanate (3.5 g, 20.7 mmol) and ethylisison isecotate (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 ether and the resulting solid was filtered off and dried to form the title compound as a white solid, 6.27 g.

1 H NMR (400 MHz, CDCl 3): δ 1.24 (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 (br S, 1H), 7.30 (d, 2H).

LCMS: m / z APCI + 327 [MH] + 35 1027833 90

Preparation 36: N- (4-Chlorophenyl) -3-methylpiperazine-1-carbothioamide η /

c / 'jf-V J-V

5 hsc H

A solution of 4-chlorophenyl isothiocyanate (8.0 g, 47.17 mmol) in dichloromethane (250 ml) was added dropwise over 30 minutes to an ice-cooled solution of 2-methylpiperazine (9.45 g, 94.33 mmol) in dichloromethane (250 ml). Once the addition was complete, the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was then washed with water (3x), dried over MgSO 4 and concentrated under reduced pressure to form the title compound as a white solid, 11 , 8 g.

1 H-NMR (400 MHz, CDCl 3): δ 1.08 (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] + 20

Preparation 37: N- (4-Chlorophenyl) -4- (2,2-dimethylpropanoyl) -3-methyl-piperazine-1-carbothioamide has 25

H, C

Di-tert-butyl dicarbonate (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 mixture 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 recrystallized from methanol to give the title compound, 9.64 g.

? 027aj3 91: ^ -NMR (400 MHz, DMSO-dj): δ 1.05 (d, 3H), 1.39 (s, 9H), 3.17-3.36 (τη, 2H), 3, 58 (m, 1H), 3.77 (m, 1H), 4.14 (m, 1H), 4.04 (m, 2H), 7.32 (m, 4H), 9.36 (s, 1H) ). LCMS: m / z APCr 370 [MH] 5

Preparation 38: N- (4-Chlorophenyl) -4- (2,2-dimethylpropanoyl) -2-methylpiperazine-1-carbothioamide CH

A solution of 4-chlorophenyl isothiocyanate (5.1 g, 30 mmol) and 4-N-BOC-2-methylpiperazine (6.0 g, 30 mmol) in dichloromethane (250 ml) was stirred at room tenqpe-15 for 2 hours nature. The reaction mixture was evaporated under reduced pressure to form the title compound as a white foam.

LCMS: rn / z APCr 370 [MH] + Preparation 39: Ethyl 1 - {[(4-chlorophenyl) amino3 carbothioyl} -4-methylpiperidine-4-carboxylate

^ r * ~ 0 / · ".S

25

A mixture of 4-chlorophenyl isothiocyanate (2.36 g, 13.98 mmol) and ethyl 4-methylpiperidine-4-carboxylate (US

2002/0086887, example 532C) (2.17 g, 12.71 mmol) in dichloromethane (50 ml) was stirred for 30 minutes at room temperature. The mixture was partitioned between dichloromethane and brine and the layers were separated. The organic phase was dried over MgSO 4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane; Thane:. ethyl acetate (100: 0 to 90:10) to form the title compound as a white solid, 3.46 g.

1027833 92 1 H NMR (400 MHz, CDCl 3); δ 1.22 (m, 6H), 1.58 (m, 2H), 2.18 (m, 4H), 3.30 (ra, 2H), 4.19 (q, 2H), 4.24. (τη, 1H), 7.09 (d, 2H), 7.28 (d, 2H); LCMS: fli / z APCI + 341 [MH] + 5 Preparation 40: N- (4-Chlorophenyl) -4-cyano-4-phenylpiperidine-1-carbothioamide 10

Triethylamine (1.4 ml, 10 mmol) was added to a suspension of 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 mixture was then stirred for 20 minutes at room temperature. The mixture was washed with 2N hydrochloric acid, then brine, dried over MgSO 4 and evaporated under reduced pressure to give 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 41-44:

A mixture of 4-chlorophenyl isothiocyanate (1 eq.) And a suitable amine (1 eq.) In ethanol (0.8 - 1.28 ml / mmol) was stirred at room temperature for 30 minutes. The reaction mixture was then evaporated under reduced pressure to form the title compounds as a white solid.

1027833 93

Ber. / TV Data

Nr. "VW

41 1 H NMR (400 MHz, CDCl 3): δ CH, 1.45 * S, 9H, 3, 50 (m, 4H), 3.80 (tn, 4H), 7.10 (d, 2H), H'C O 7.25 (d, 2H), 7.80 (s, 1H).

LCMS: m / z APCr 356 [MH] * 42 · "H-NMR (400 MHz, CDCl3): δ HC / ^ Vr 2.10 (S, 3H), 3.60 (m, 2H), 8.3, 78 (m, 4H), 4.02 (m, 2H), ° 7.14 (d, 2H), 7.30 (d, 2H).

LCMS: m / z APCI + 298 [MH] + 5 43. 1 H-NMR (400 MHz, CDCl 3): δ «2.04 - 2.24 (m, 4H), 2.85 (m, Γ 1H), 2.94 (s, 3H), 3.62 (m, · Η O m 3 CH, 2 H), 3.95 (m, 2 H), 5.25 (m, 1 H), 6.60 (θ, 1 H), 7.30 (s, 4 H). LCMS: m / z APCI4 312 [MH], + 44 X H NMR (400 MHz, CDCl3): δ 0, - 1.29 - 1.54 <m, 11 H), 2.01 y (m, 2 H) , 3.20 (ra, 2H), 3.74 Hc (br s, 1H), 4.35 - 4.55 (ra, 9H), 7.09 (d, 2H), 7.17 (br S 1 H), 7.32 (d, 2 H).

Preparation 45; tert-Butyl-4 - {. [(4-chlorophenyl) amino] carbonothioyl} -1,4-diazepane-1-carboxylate

^ VO ^ rCT

A mixture of 4-chlorophenyl isothiocyanate (5.0 g, 29.95 mmol) and BOC homopipera: zine (6.0 g, 29.95 mmol) in ethanol (50 mL) was stirred at room temperature for 2 hours . The 1027833 94 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 MgSO 4 and evaporated under reduced pressure to form the title compound as a white foam.

^ -NMR (400 MHz, CD3OD): δ 1.45 (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 APCI + 370 [MH] + 10 Preparation 46: tert-Butyl-4 - ((Z) - [(4-chlorophenyl) imino] (methyl thio) methyl] piperidine-1-carboxylate o. ~ \ S — CH, h, c - ^ - o '-' α

15 HjC

Potassium tert-butoxide (20.1 g, 0.18 mol) was added in portions to a cooled (10 ° C) solution of the compound of preparation 34 (53 g, 0.15 mol) in tetrahydrofuran 20 (1 liter ) to keep the temperature at 1 ° C. Methyl iodide (11.2 ml, 0.18 mol) was added dropwise to keep the temperature at 10 ° C and then the reaction mixture was allowed to warm slowly to room temperature. The reaction mixture was stirred for another 10 minutes and then it was quenched by the addition of water. The reaction mixture was diluted with ethyl acetate and washed with water. The phases were separated, the aqueous layer was further extracted with ethyl acetate and the combined organic solutions were dried over MgSO 4 and evaporated under reduced pressure. The residual oil was adsorbed on silica gel and purified by column chromatography on silica gel using pentane: ethyl acetate (75:25) as eluent to form the title compound as an oil which crystallized on standing.

* 1 H NMR (400 MHz, CDCl 3): δ 1.43 (s, 9H), 1.57 - 1.82 (m, 5H), 2.35 (S, 3H), 2.42 - 2, 62 (m, 1H), 2.78 (m, 1H),. 4.16 1 ° Z7833 95 (m, 2H), 6.65 (d, 2H), .27.26 (d, 2H). LCMS: m / z ES * 391 [MNa] +

Preparation 471 Ethyl 1 - [(Z) - [(4-chlorophenyl) imino] (methyl-5-thio) methyl] piperidine-4-carboxylate α / - \ s-ch, Cl 10 Potassium tert-butoxide (2.58 g, 23.1 in mol) was added in portions to a solution of the compound of preparation 35 (8.27 g, 19.2 mmol) in tetrahydrofuran (100 ml) and the reaction mixture was stirred for 10 minutes. Methyl iodide (1.44 ml, 23.1 mmol) was added and the reaction mixture was stirred for another 30 minutes at room temperature. The reaction mixture 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 form the title compound as an oil, 3.6 g. 1 H-NMR (400 MHz, CDCl 3): δ 1.25 (t, 3H), 1.78 (m, 2H), 1.98 (m, 2H), 2.04 (s, 3H), 2.56 (m, 1 H), 3.01 (m, 2 H), 4.12 -4.23 (m, 4 H), 6.80 (d, 2 H), 7.20 (d, 2 H); LCMS: m / z ES * 341 25 [MH] *

Preparation 48: Ethyl 1 - [(Z) - [(4-chlorophenyl) imino] (methylthio) methyl] -4-methylpiperidine-4-carboxylate o / -.

30 'H / == V

"-" 0 HjC '' N_ ^ U 01

The title compound was obtained as an oil with a yield of 75% from the compound of preparation 39 and methyl iodide, following a method similar to that described for preparation 47, except that the product was not purified by column chromatography on silica gel.

1 H NMR (400 MHz, CDCl 3): δ 1.25 (m, 6H), 1.50 (m, 2H), 2.04 (s, 3H), 2.18 (τη, 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] +

Preparations 49-55: R * \ Λ / ^ 1 \ v 01 1 °

Potassium tert-butoxide (1.1 eq.) Followed by methyl p-toluenesulfonate (1.1 eq.) Was added to a solution of a compound selected from preparations 37, 38, 40 - 42 and 45 (1 eq.) In tetrahydrofuran and the reaction mixture was stirred for 2 hours at room temperature. 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 MgSO 4 and evaporated under reduced pressure to form the title compound. things.

fgsssssasa j ’^^ gaaaassssssssssssB I asssssBssssssssssaassassasssasBBBSssrg ^^ BBaBsaa—

Ber. χ Data

Nr.

-, -! ----- 49 ^ -NMR (400 MHz, CDCl 3): δ ^ C ^ 0str ^ JT 1.20 <d '3H>' ^ 44 <s' 9H), 2.00 ( s, 3 H), 2.99 (m, 1 H),

H.C

3.19 (m, 2H), 3.88 (m, 1H), 4.16 (m, 1H), 4.20 - 4.36 (m, 2H), 6.83 (m, 2H), 7 , 21 (m, 2 H). LCMS: m / z APCI + 384 [MH] + ^ 0 27 8 33 97 50 ^ NMR (400 MHz, CDCl 3): δ - & jT ^ 1 T 1.21 (d '3H), 1.42 (S' 9H) 'HSC V "N" ", H 2.00 (s, 3H), 2.80 - 3.30 (m, 3H), 3.80 - 4.18 (τη, 3H), 4.54 (m, 1 H), 6.80 (τη, 2 H), 7.20 (m, 2 H) LCMS: m / z APCI + 384 [MH] * 51 X H NMR (400 MHz, CDCl3): δ ph 2.06 (s 3 H), 2.17 (m, 2 H), 3.38 - 3.52 (m, 4 H), 4.50 (m, N "2 H), 6.83 (d, 2 H), 7.22 (d, 2H), 7.38 (τη, 1H), 7.52 (d, 2H).

52 X H NMR (400 MHz, CDCl 3): δ éKCr. 1.46 (s, 9H), 2.02 (s, 3H), HSC q> V / 3.48 (m, 4H), 3.58 (m, 4H), 6.80 (d, 2H), 7.20 (d, 2H).

53 Ή NMR (400 MHz, CDCl 3): δ 2.01 (s, 3H), 2.10 (s, 3H),

HgC {3.48-3.76 (ra, 8H), 6.80 (d, ° 2H), 7.19 (d, 2H). LCMS: m / z APCI * 312 [MH] * 5 54 α H NMR (400 MHz, CDCl 3): δ 1.98 (s' 3H), '2'09 (s' 3H), £ 2.84 (ra 1 H), 2.90 (s, 3 H), 3.38 (m, 1 H), 3.46 (m, 1 H), 3.77 (m, 2 H), 5.22 (m, 1 H), 6.82 (d, 2H), 7.19 (d, 2H). LCMS: m / z APCI * 326 [MH] * 55A. Hi-NMR (400 MHz, CD3OD): δ H3c4-P / 1.45 (2xs, 9H), 1.90 (ra, 5H), H3C JS- / 3.44 (ra, 2H), 3.60 (m, 2H), 3.76 (ra, 2H), 2.80 (ra, 2H), 6.85 (d, 2H), 7, 20 (d, 2H).

1027833 98 A * = the reaction mixture was stirred at room temperature for 18 hours and the product was further purified by column chromatography on Bilicagel using dichloromethane: methanol as eluent.

5

Preparation 56: Methyl 4 - [(tert-butoxycarbonyl) amino] -N- (4-chlorophenyl} piperidine-1-carbimidothioate H C 9 H »O S" CH 1 v rvt XY °

io 0 fr \ y

Potassium tert-butoxide (12.8 g, 114 in mol) was added to a suspension of the compound of preparation 44 (42.3 g, 114 mmol) in tetrahydrofuran (400 ml) and the suspension was stirred for 10 minutes at room temperature . Methyl p-toluenesulfonate (21.29 g, 114 mmol) was added and the reaction mixture 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 mixture was stirred for a further 10 minutes. The mixture was diluted with ether, washed with water (200 ml) and brine, then dried over MgSO 4 and evaporated under reduced pressure to form the title compound. ^ -NMR (400 MHz, CDCl 3): δ 1.34 - 1.52 (m, 11 H), 2.00 (m, 2 H), 2.05 (s, 3 H), 3.04 (m, 2 H ), 3.68 (brs, 1 H), 4.19 (m, 2 H), 4.50 (br s, 1 H), 6.80 (d, 2 H), 7.20 (d, 2 H). LCMS: m / z ES + 384 [MH] +

Preparation 57: tert-Butyl-4- (5- (methoxymethyl) -1,3,4-oxadia-30-sol-2-yl) -piperidine-1-carboxylate

V rvO

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 it. reaction mixture 1027833 99 was stirred at room temperature for 18 hours. TLC analysis showed that there was still starting material, and therefore potassium tert-butoxide was added. (1 g, 8.9 mmol) was added and the reaction mixture was stirred at 50 ° C for 2 hours.

The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and an ammonium chloride solution. The layers were separated, the organic phase was dried over MgSO 4 and evaporated under reduced pressure to give the title compound as 10: a yellow oil, 7.30 g.

1 H-NMR (400 MHz, CDCl 3): δ 1.45 (s, 9H), 1.82 (m, 2H), 2.08 (m, 2H), 2.96 (m, 2H), 3.08 (m, 1 H), 3.44 (s, 3 H), 4.10 (m,. 2 H), 4.61 (s, 2 H). LCMS: m / z APCI + 298 [MH] * Preparation 58: tert-Butyl-4- {5 - [(2,2,2-trifluoroethoxy) methyl] -1,3,4-oxadiazol-2-yl} piperidine-1-carboxylate HSC / - / / / / / / / / / /;

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 tetrahydrofuran (100 mL) and the solution was Stirred at room temperature for 10 minutes. The compound of preparation 8 (7.0 g, 23.2 mmol) was added and the mixture was then heated at 50 ° C for 2 hours. The reaction was quenched by the addition of an ammonium chloride solution, then the organic layer was decanted and evaporated under reduced pressure. The residue was redissolved in ethyl acetate, the solution was washed with brine, dried over MgSO 4 and then evaporated under reduced pressure to give the title compound as a yellow oil, 8.15 g. -NMR (400 MHz, CDCl 3): δ 1.43 (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).

1027833 100

Preparation 59: tert-Butyl-4- [5- (hydroxymethyl) -1,3,4-oxadiazol-2-yl] piperidine-1-carboxylate

. h, c VA

=> O \ -oh

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 mixture was heated at 80 ° C for 18 hours . The cooled mixture was concentrated under reduced pressure and the residue 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 remaining oil was dissolved in methanol (120 ml) and sodium carbonate (5.6 g, 53.0 mmol) and water (1 ml) was added. The mixture was stirred at room temperature for 2 hours. then it was thinned 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 give the title compound as an off-white solid, 7.16 g.

X H NMR (400 MHz, CDCl 3): δ 1.45 (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 30 H C - Nv,

A mixture of the compound of preparation 8 (10 g, 33.1 35 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 partitioned between water and ethyl acetate. The organic phase was dried over MgSO 4 and evaporated under reduced pressure to form the title compound as an orange oil, 12.06 g.

^ -NMR (400 MHz, CD3OD): δ 1.45 (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] * 10

Preparation 61: tert-Butyl-4 - {[2- (ethoxy-acetyl) -hydrazino) -carbonyl] -piperidine-carboxylate o o

A mixture of 4-hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (WO 2000039125, preparation 27) (3 g, 12.33 mmol), ethoxyacetic acid (1.28 ml, 13.56 mmol), 1- (3-20 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 an aqueous hatrium carbonate solution. The layers were separated, the organic phase was dried over MgSO 4 and evaporated under reduced pressure to form the title compound as an oil, which crystallized on standing.

^ -NMR (400 MHz, CDCl 3): δ 1.24 (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 ε, 1H), 8.82 (br s, 1H). LCMS: m / z APCI * 330 [MH] * 35 • t. · <* J027g33 102

Preparation 62: tert-Butyl-4 - {[2- (3,3,3-trifluoropropanoyhydrazino) carbonyl} piperidine-1-carboxylate

The title compound was obtained from 4-hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (WO 2000039125, preparation 27) and 3,3,3-trifluoropropionic acid, following a method similar to that described for preparation 61.

^ -NMR (400 MHz, CD3OD): δ 1.44 (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 APCI * 352 [M-H] 3.5

Preparation 63: tert-Butyl ^ - [5- (ethoxymethyl) -1,3,4-oxadiazol-2-yl] piperidine-1-carboxylate h x "20 H, C", "X,". CH,

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). Thereafter triflic anhydride (4.2 ml, 24.6 mmol) was added dropwise over 20 minutes and the solution was stirred at 0 ° C for one hour. It was then stirred for another hour at room temperature. The mixture was made more basic to pH 4 using an aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic extracts were dried over MgSO 4 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 form the title compound as a yellow oil, 1.25 g.

1027833 103 1 H NMR (400 MHz, CDCl 3): δ 1.23 (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 APCI * 312 [MH] + 5 Preparation 64: tert-Butyl-4- [5- (2,2,2-trifluoroethyl) -1,4,4-oxadiazole-2-yi] piperidine-1-carboxylate 10

The title compound was obtained as a pale yellow solid from the compound of preparation 62, following a method similar to that described for preparation 63.

1 H NMR (400 MHz, CDCl 3): δ 1.42 (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 APCI * 358 [MNa] +

Preparation 65: 1- (4-Chlorobenzoyl) -4- (1,3,4-oxadiazol-2-yl) piperidine (25 N, N-Dimethylformamide-dimethyl acetal (5.71 g, 47.9 mmol) ) was added to a solution of the compound of preparation 29 (9.0 g, 31.94 mmol) in N, N-dimethylformamide (100 ml) and the reaction mixture was stirred at 50 ° C for 3 hours. reduced pressure and the residue was suspended in toluene (150 ml), p-toluenesulfonic acid (1 g, 5.26 mmol) was added and the reaction mixture was heated at 110 ° C for 18 hours. diluted with ethyl acetate (100 ml), washed with brine, water and then brine again The solution was dried over MgSO 4 and then evaporated under reduced pressure The crude product was purified by column chromatography using a silica gel pattern and 1027833 104 dichloromethane: methanol (100: 0 to 90:10) as an eluent to form the title compound as a white solid, 4, 25 g.

LCMS: m / z APCI + 292 [MH] + 5

Preparation 66: 1- (3-Chlorobenzoyl) -4 - (1,3,4-oxadiazol-2-yl) piperidine Ν, Ν-Dimethylformamide-dimethylacetal (5.71 g, 47.9 mmol) was added to a solution of the compound of preparation 4 (9.0 g, 31.94 mmol) in tetrahydrofuran (6 ml) and the reaction mixture was stirred at 50 ° C for 18 hours. TLC analysis showed that starting material was still present and, therefore, additional N, N-dimethyl-amamide-dimethylacetal (15 mmol) was added and stirring was continued for a further 2 hours. The mixture was concentrated under reduced pressure and the residue was suspended in j

toluene (32 ml). P-toluenesulfonic acid (1 g, 5.26 L) was added

mmol) was added and the reaction mixture was 18 hrs

heated to 110 ° C. The reaction mixture was diluted with J

Ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution (2x) and brine, then dried over Ma 2 SO 4 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 form the title compound.

1 H NMR (400 MHz, CDCl 3): δ 1.95 (m, 2H), 2.04 - 2.28 (m, 2H), 3.12 - 3.30 (m, 3H), 3.80 ( m, 1 H), 4.58 (m, 1 H), 7.28 (m, 2 H), 7.39 (m, 2 H), 8.40 (s, 1 H).

LCMS: m / z APCI + 292 [MH] * 1027033 105

Preparation 67: 1- (4-Chlorobenzoyl) -4- (5-methyl-1,3,4-oxadiazol-2-yl) piperidine: CH, N, N-dimethylacetamide-dimethylacetal (6.38 g, 47.9 mmol) was added to one. solution of the compound of preparation, 29 (9.0 g, 31.94 mmol) in N, N-dimethylformamide 10 (20 mL) and the reaction mixture was stirred at room temperature for 1 hour. It was then stirred for an additional 2 hours at 40 ° C. The mixture was diluted with toluene (150 ml), heated to 110 ° C, and then p-toluenesulfonic acid (400 mg, 2.22 mmol) was added. The reaction mixture was heated at 110 ° C for 18 hours, then cooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with an ammonium chloride solution and brine, then it was dried over MgSO 4 and evaporated under reduced pressure to form the title compound as an oil, 9.75 g.

^ -NMR (400 MHz, CDCl3): δ 1.81 - 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 APCI + 306 [MH] * Preparation 68: 1- (4 Chlorobenzoyl) -4- (5-ethyl-13,4-oxadiazol-2-yl) piperidine wKD-λ ·· 1 / ° Λ

30 / - I

cr h, c

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 stirred for 3 hours at 60 ° C. TLC analysis showed that starting material was still present and therefore additional triethyl orthopropionate (0.5 g, 2.83 mmol) was added 1027633 106 and the reaction mixture was stirred for another 18 hours at 60 ° C. The mixture was concentrated under reduced pressure, the residue was suspended in toluene (15 ml) and trifluoroacetic acid (5 drops) was added. The reaction mixture was heated under reflux for 18 hours, then cooled and concentrated under reduced pressure. The crude product was purified by column chromatography using a silica gel pattern and dichloromethane: methanol (100: 0 to 95: 5) as eluent to form the title compound as an oil, 1.6 g.

1-NMR (400 MHz, CDCl 3): δ 1.38 (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 q _ ^ _ '20

Pyridine (1.8 g, 22> 84 mmol) and then triflic 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). The reaction mixture was then made. Stirred at room temperature for 2 hours. The mixture was washed with an ammonium chloride solution (3x), then with. a saturated aqueous sodium carbonate solution, dried over MgSO 4 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 pattern and an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to form the title compound as a yellow oil, 566 mg.

.35 1 H NMR (400 MHz, CDCl 3): δ 1.23 (t, 3H), 1.83 - 2.24 (m, 3H), 3.14 - 3.26 (m, 4H), 3, 62 (q, 2H), 3.80 (m, 1H), 4.59 1027833 107 (m, 1H), 4.67 (s, 2H), 7.25 (m, 1H), 7.40 (m, 3 H). LCMS: m / z APCI * 350 [MH] *

Preparation 70s 1- (4-Chlorobenzoyl) -4- [5- (ethoxymethyl) -1,3,4-oxadiazol-2-yl] piperidin 10% The title compound was obtained as a crystalline solid from the compound of preparation 31, following a method similar to that described for preparation 69.

1 H NMR (400 MHz, CDCl 3): δ 1.23 (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, 4 H). LCMS: m / z APCI + 350 [MH] +

Preparation 71: 1- (4-Chlorobenzoyl) -4- [5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl] piperidine

Triflic 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, 1B, 74 mmol) ) in dichloromethane (40 ml). The mixture was then allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was diluted with dichloromethane, washed with 2N hydrochloric acid and then with saturated aqueous sodium bicarbonate solution. It was dried over MgSO 4 and evaporated under reduced pressure. The crude 35 product was purified by column chromatography on silica gel using an elution gradient of di 1 0 2 7 8 3 3 108 chloromethane: methanol (99: 1 to 96: 4) to form the title compound as a brown compound oil, 620 mg.

^ -NMR (400 MHz, CDCl3): δ 1.60 (m, 1H), 1.97 (m, 3H), 2.20 (m, 2H), 3.20 (m, 2H), 3.34 (m, 1 H), 7.39 (m, 4 H). LCMS: 5 m / z APCr 360 [MH] +

Preparations 72 - 74:

The compounds with the following general structure such as. pound below: 10 o were prepared from N, N-dimethylacetamide-dimethylacetal.

15 and the correct hydrazide, following a method similar to that described for preparation 67.

igZBaagnBBBSBga ^^^ Bgasgsssssssss .1 .ugagai 1 ·· - J · '- * · i ^ MaagsaBsaseaaaaaaBaaaa

Ber. data

Nr. ΔNJ 72 72 1 H NMR (400 MHz, CDCl 3): δ 1.46. (s, 9H), 2.58 (s, 3H), 3.15 (m, "-1H), 3.37 (m, 1H), 3.68 (m, 1H), 3.92 (m, 1 H), 4.00 (m, 1 H), 4.21 (m, 1 H), 4.70 (m, 1 H) LCMS: m / z APCI + 270 [MH] + 73 α H-NMR (400 MHz, DMS0 -d6): δ 'IJ 1.38 (m, 11H), 1.73 (m, 2H), 2.06 (d, 1H), 2.46 (s, 3H), 3.04 (m, 2H ), 3.63 (s, 1H), 3.95 (s, 1H).

74 * i—. 1 H NMR (4.00 MHz, CDCl 3): δ 1.44 (S, 9H), .2.19 - 2.38 (m, 2H), 2.54 (s, 3H), 3.44 (m, 1H ), 3.60 (m, 3 H), 3.80 (m, 1 H).

1 = 2 7 83 3 109 A. = 3-hydrazinocarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ester was used (obtained from CB Research and Development Ine.) Preparation .75: 1- (3-Chlorobenzoyl) -4- [5- (1H-pyrazol-1-ylmethyl) -1,3,4-oxadiazol-2-yl] piperidine JV * 1 10 Λ

A tangle of the compound of preparation 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 MgSO 4. 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 form the title compound, 550 mg. 1 H NMR (400 MHz, CD 3 OD): δ 1.76 - 1.92 (m, 3 H), 1.99 - 2.22 (m, 3 H), 3.18 (m, 1 H), 3.70 ( m, 1 H), 4.50 (m, 1 H), 5.63 (s, 2 H), 6.35 (d, 1 H), 6.38 (d, 1 H), 7.37 (d, 1 H), 7.44 (m, 2H), 7.52 (s, 1H), 7.80 (s, 1H). LCMS: m / z ES * 372 [MH] +

Preparation76: tert-Butyl-4- [4- (4-chlorophenyl) -5- (2-morpholin-4-ylethyl) -4H-1,2,4-triazol-3-yl] piperidine-1-carboxy -L-H-C, H, C, CH. Trifluoroacetic acid. (0.35 ml, 4.3 mmol) was added to 4-morpholine propanoic acid hydrazide (Comptes Rendus des. Seances de 1 Academy of Sciences, Series C; Sciences.

1 0 2 7 * 33 110

Chimique 1976; 282 (17); 857-60) (1.5 g, 8.7 tmmol) and the compound of preparation 46 (2.7 g, 7.25 mmol) in tetrahydrofuran (18 ml) and the reaction mixture was heated under reflux for 18 hours. The cooled mixture was diluted with dichloromethane, washed with 1 N 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 form the title compound, 2.2 g .

1 H-NMR (400 MHz, CDCl 3): δ 1.45 (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 APCI + 476, 478 [MH] ♦ ^ 15

Preparations 77 - 87:

The compounds of the general formula as shown below: 20 t / o W x no H, c CH, α 25 were prepared from the compound of preparation 46 and the appropriate hydrazide, following a method similar to that described for preparation 76.

Ber. Data 30 Nr.

77 Xe 2-oxo-1-pyrrolidinylmethyl 1 H-NMR (400 MHz, CDCl 3): δ 1.42 (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 APCI + 460 [MH] * 1027833 111 78 * X = imidazol-1-ylmethyl.

^ -NMR (400 MHz, CDCl 3): δ 1.41 (s, 9H), 1.70 (m, 2H), 1.83 (m, 2H), 2.55 (m, 1H), 2, 65 (m, 2H), 4.10 (m, 2H), 5.17 (s, 2H), 6.78 (s, 1H), 6.90 (d, 2H), 7.01 (s, 1H) ), 7.19 (s, 1H), 7.52 (d, 2H). LCMS: m / z APCI * 443 [MH] + 79® X - 2-methyl-1 H -imidazol-1-ylmethyl-NMR (400 MHz, CDCl3): δ 1.43 (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 APCI + 457 [MH] + 80 X = 1,2,4-triazol-1-ylmethyl X H NMR (400 MHz, CDCl 3): δ 1.42 (θ, 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, 2 H), 7.57 (d, 2 H), 7.82 (s, 1 H), 8.05 (s, 1 H).

LCMS: m / z APCI + 444 [MH] + 81 X = tetrazol-1-ylmethyl-NMR (400 MHz, CDCl 3): δ 1.43 (s, 9H), 1.63 - 1.95 (m, 4H), 2.58 - 2.75 (m, 3H), 4.11 (ra, 2H), 5.60 (S, 2H), 7.15 (d, 2H), 7.59 (d, 2H), 8 81 (s, 1H).

LCMS: m / z ES * 445 [MH] * 5 82c X = 3-methylisoxazol-5-ylmethyl-NMR (400 MHz, CDCl 3): δ 1.37 (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 APCI + 458 [MH] + 83 X = 3-methyl-1,2,4-oxadiazol-5-ylmethyl 1 H-NMR (400 MHz, CDCl3): δ 1.44 (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 APCI * 459 [MH] * 1 0 2 7 8 33 112 84 Xe pyrimidine-2-yloxymethyl X H NMR (400 MHz, CDCl 3): δ 1.41 (s, 9H), 1.59-1.76 (τη, 2H), 1.86 (τη, 2H), 2 , 58-2, 76 (τη, 3Η), 4.10 (m, 2Η), 5.39 (s, 2Η), 6.95 (τη, 1Η), 7.26 (d, 2Η), 7.43 (d, 2Η), 8.42 (s, 2Η) LCMS: m / z APCI + 471, 473 [ΜΗ] + 85 X β 2-piperidin-1-ylmethyl X H NMR (400 MHZ, CDCl 3) ): δ 1.39 - 1.78 (m, 19H), 1.78 - 1.86 (m, 2H), 2.28 - 3.04 (τη, 3Η), 2.56 - 2.82 ( τη, 6Η), 4.08 (m, 2Η), 7.19 (d, 2Η), 7.58 (d, 2Η) LCMS: m / z APCI * 474 [ΜΗ] 86c X = 2-pyridine-2-ylethyl X H NMR (400 MHZ, CDCl 3): δ 1.42 (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 (τη, 2H) , 7.03 (d, 2H), 7.12 (τη, 1H), 7.18 (d, 1H), 7.50 (d, 2H), 7.58 (τη, 1H), 8.42 ( d, 1 H).

LCMS: m / z APCI + 468 [MH] +.

87 X b 2- (3,5-dimethyl isoxazol-4-yl) ethyl X H NMR (400 MHz, CDCl 3): δ 1.42 (s, 9H), 1.70 (m, 2H), 1.79 - 1.93 (τη, 5H), 2.04 (s, 3H), 2.54 (m, 1H), 2.60 - 2.80 (τη, 4H), 4.10 (m, 2H), 5 , 32 (s, 2H), 6.90 (d, 2H), 7.56 (d, 2H). LCMS: m / z APCI + 486 [MH] * A-1-imidazol-1-yl-acetic acid hydrazide was used; prepared as described in Boll. Chim. Farm. 114 (2); 70-72; 1975.

β = the reaction mixture was stirred under reflux for 18 hours. 10 C = 1 eg. hydrazide was used.

15 1027833 113.

Preparation 88: tert-Butyl- {1- [4- (4-chlorophenyl) -5-methyl-4 H -1; 2,4-triazol-3-yl] piperidin-4-yl} carbamate H3 Cl

Acetic acid hydrazide (16.9 g, 228 tmmol) followed by triflu-10 oracetic acid (4.4 ml, 57.1 tmmol) were added to a solution of the compound of preparation 56 (43.6 g, 114 mmol in tetrahydrofuran (250 ml) and the mixture was heated under reflux for 7 hours The cooled mixture was then washed with a diluted ammonia solution, the layers were separated and the aqueous phase was further extracted with ethyl acetate.The combined organic solutions were dried over MgSO 4 and evaporated under reduced pressure The residue was triturated with ether (100 ml) and the resulting crystals were filtered off and dried under vacuum to form the title compound, 32.4 g.

X H NMR (400 MHz, CDCl 3): δ 1.32 (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, 1 H), 7.24 (d, 2 H), 7.51 (d, 2 H); LCMS: m / z APCI * 392 [MH] +

Preparation 89: tert-Butyl-4- [4- (4-chlorophenyl) -5-methyl-4 H -1,2,4-triazol-3-yl] -1,4-diazepane-1-carboxylate 35 The title compound was obtained with a yield of 75% from the compound of preparation 55 and acetic acid hydrazide, following a method similar to 1027833 114 to that described for preparation 88, except that 2 equivalents of acetic acid hydrazide were used.

"1 H NMR (400 MHz, CDCl 3): δ 1.41 (s, 9H), 1.58 <m, 1 H), 1.72 (m, 1 H>, 3.02 (τη, 1 H), 3, 20 (m, 1H), 3.24 - 3.44 (m, 5H), 5 3.52 (m, 2H), 4.24 (s, 2H), 7.38 (m, 2H), 7, 50 d, 2 H); LCMS: m / z APCI * 422 [MH] +

Preparation 90: Ethyl 1- [4- (4-chlorophenyl) -S-methyl-4 H -1-triazol-S-yl] piperidirte-4-carboxylate 10 V-ch, 0 α

Trifluoroacetic acid (0.84 ml, 10.85 tmol) followed by acetic acid hydrazide (2.41 g, 32.6 mmol) were added to a solution of the compound of preparation 47 (7.38 20 g, 21.7 mmol) in tetrahydrofuran. (100 ml) and the reaction mixture was stirred under reflux for 3 hours. The cooled mixture was partitioned between ethyl acetate and. aqueous ammonia and the layers were separated. The organic phase was washed with brine, dried over MgSO 4 and evaporated under reduced pressure. The crude product was triturated with ether to form the title compound as a white solid, 5.04 g.

X H NMR (400 MHz, CDCl 3): δ 1.22 (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 APCI * 349 [MH] * 35 1 0 27-8.3-3 115

Preparation, 91: Ethyl 1- [4- (4-chlorophenyl) -5- (2H-1,2,3-triazol-2-ylmethyl) ^ H-1 ^^ - triazobl-S-yl-piperidine-carboxylate

. 5 ^ VO

Trifluoroacetic acid (0.41 ral, 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 tetrahydrofuran (50 ml) and the reaction mixture was heated under 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 form the title compound as a gum.

^ -NMR (400 MHz, CDCl 3): δ 1.21 (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: Ethyl 1- [4- (4-chlorophenyl) -5-methyl-4H-1,2,4-25 triazol-3-yl] -4-methylpiperidine-4-carboxylate: h.

H.C.- / CH 2 ^ JU o Cl

The title compound was obtained as a clear oil with a yield of 86% from the compound of preparation 48 and acetic acid hydrazide, following the method described for preparation 91.

35 C-NMR (400 MHz> CDCl 3): δ 1.18 (s, 3H), 1.23 (t, 3H), 1.40 (m, 2H), 2.00 (m, 2Ή), 2, 23 (s, 3H), 2.90 (m, 2H), 3.18 (m, 1027833 116 2H), 4.14 (q, 2H), 7.26 (d, 2H), 7.57 (d , 2H); LCMS: m / z APCI + 363 [MH] *

Preparation 93: tert-Butyl-4- [4- (4-chlorophenyl) -5- (methoxymethyl) -4H-1,2,4-triazol-3-yl] -2-methylpiperazine-1-carboxy- leave m Λ / 0- ™ ·

o I A

μ '· ν Y \'. η · ° V ° "o

Methoxyacetic acid hydrazide (1.95 g, 18.75 mmol) was added to a solution of the compound of preparation 49 (4.80 g, 12.50 inmol) in tetrahydrofuran (200 ml) and the solution was stirred for 10 minutes. There. trifluoroacetic acid (710 mg, 6.25 mmol) was added and the reaction mixture was 18 hours. stirred at room temperature. The mixture was concentrated. under reduced pressure and the crude product was purified by column chromatography using a silica gel pattern and dichloromethane: methanol (100: 0 to 90:10) as eluent and repeated using ethyl acetate as eluent to form the title compound as a foam, 1.84 g.

25? -NMR (400 MHz, CDCl3): δ 0.98 (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, 2 H); LCMS: m / z APCI + 363 [MH] + 30 Preparation 94: tert-Butyl-4- [4- (4-chlorophenyl) -5- (methoxymethyl) -4H-1,2,4-triazole-3- yl] -3-methylpiperazine-1-carboxylate:

"Ly A

35 Ύ W

n * 0 ch3 0 α 1027833 117

The title compound was obtained in 67% yield from the compound of preparation 50, following a method similar to that described for preparation 93, except that the reaction mixture was heated under reflux.

LCMS: m / z APCI + 363 [MH] +

Preparation 95: tert-Butyl-4- [4- (4-chlorophenyl) -5-methyl-4 H -1,2,4-triazol-3-yl] piperazine-1-carboxylate IV, H »C CH 15

Acetic acid hydrazide (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 mixture was heated under reflux for 18 hours. The reaction mixture was heated under reflux for an additional 20 days, periodically adding additional acetic acid hydrazide (36.5 g in total). 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 form the title compound as a white foam . 1 H NMR (400 MHz, CDCl 3) s δ 1.42 (s, 9H), 2.24 (s, 3H), 3.01- (m, 4H), 3.38 (m, 4H), 7 , 25 (d, 2 »), 7.54 (d, 2 H). LCMS: m / z APCI + 378 [MH] * 30

Preparation 96: 1- [4- (4-Chlorophenyl) -S-methyl ^ H-1 ^^ - triazol-S-yl] -4-phenylpiperidine-4-carbonitrile 118

Acetic acid hydrazide (1.65 g, 22.3 nunol) 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 mixture was heated under 2 days reflux. The cooled mixture was concentrated under reduced pressure and the residue was pre-adsorbed on 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 form the title compound as a solid.

X H NMR (400 MHz, CDCl 3): δ 1.97 - 2.16 (m, 4 H), 2.24 (s, 3 H), 3.35 (m, 2 H), 3.42 (m, 2 H) , 7.22-7.45 (m, 7H), 7.56 (d, 2H); LCMS: m / z ES + 400 [MNa] + Preparation 97: tert-Butyl-4- [4- (4-chlorophenyl) -5- (methoxymethyl) -4H-1,2,4-triazole-3- yl] piperidine-1-carboxylate

20 V

n * C CH, ° Cl

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 the reaction mixture was heated under reflux for 18 hours. The cooled solution was concentrated under reduced pressure and the residue was purified by column chromatography using a silica gel pattern and an elution gradient of dichloromethane: methanol (100: 90 to 90:10) to form the title compound as an oil , 4.25 g.

1 H NMR (400 MHz, CD3 OD): δ 1.45 (s, 9H), 1.67 - 1.83 (m, 4H), 2.68 - 2.83 (m, 3H), 3.32 ( s, 3 H), 4.08 (m, 2 H), 4.39 (s, 2 H), 7.46 (d, 2 H), 7.63 (d, 2 H); LCMS: m / z APCI * 407 [MH] * 1027833

Preparation 98: tert-Butyl-4- [4- (4-chlorophenyl) -5- (hydroxymethyl) -4H-1,2,4-1riazol-3-yl] piperidine-1-carboxylate 119 iV "; 5

A mixture of the compound of preparation 59 (6.8 g, 24 mmol), 4-chloroaniline (4.3 g, 33.7 mmol) and trifluoroacetic acid (0.9 ml, 12 nimoles) in toluene (40 ml) was stirred for 18 hours at 100 ° C. The cooled mixture was evaporated under reduced pressure and the residue was dissolved in dichloromethane and washed with a 2M sodium hydroxide solution. The organic solution was dried over MgSO 4 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 form the title compound as an off-white solid , 7.1 g.

20 H-NMR (400 MHz, CDCl 3): δ 1.42 (s, 9H), 1.75 (m, 2H), 1.82 (m, 2H), 2.59 - 2.76 (m, 3H) ), 3.00 (br s, 1 H), 4.10 (m, 2 H), 4.58 (s, 2 H), 7.30 (d, 2 H), 7.58 (d, 2 H); LCMS: m / z APCI + 393 [MH] * 25 Preparations 99> 101:

The compounds of the general formula shown below: IV * 30% were prepared from a suitable compound selected from preparations 60, 63 and 64 and. 4-chloroaniline, following a method similar to that described for preparation 98.

1027833 120

Ber. data

Nr.

99 *. X cetboxymethyl / 1 H NMR (400 MHz, CDCl 3): δ 1.09 (t, 3H), 1.43 (s, 9H), 1.68 (m, 2H), 2.59 - 2.78 ( m, 3H), 3.42 (q, 2H), 4.14 (τη, 2H), 4.42 (s, 2H), 7.24 (d, 2H), 7.57 (d, 2H). LCMS: m / z APCI + 421 [MH] ♦ 100 * X = 2,2,2-trifluoroethyl X H NMR (400 MHz, CDCl3): δ 1.42 (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 ΆΡΟΓ 445 [MH] + 5 101B X = morpholin-4-ylmethyl-NMR (400 MHz, CDCl 3): δ 1.41 (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 APCI + 462 [MH] * A = 0.8 eg trifluoroacetic acid was used.

B - 1 eg. trifluoroacetic acid was used.

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

H »c“ 7 \ 0 kJ

HjC CH1

O

The title compound was obtained as an oil with a yield of 75% from the compound of preparation 72 and 4-chloroaniline, following a method similar to that described for preparation 98, except that 1 eq. trifluoroacetic acid and 2 eg. 4-chloroaniline were used; 1027833

Preparation 103: tert-Butyl-3- [4- (4-chloro-2-methylphenyl) -5-methyl-4 H -1,2,4-triazol-3-yl] piperidine-1-carboxylate 121 1! "LCMS: m / z APCI + 393 [MH] +"

h »c-7 \ 0 kJ

H.C. CH. J

I.

4-Chloro-2-methylaniline (3.78 g, 26.3 inmol) and p-toluene sulfonic acid (50 mg) were added to a solution of the oxadiazole of preparation 73 (2.33 g, 8.9 mmol) in 15 xylene (10 ml) and the reaction mixture was heated under reflux for 24 hours. The cooled reaction mixture was immediately purified by column chromatography on silica gel using ethyl acetate: methanol: dichloromethane (100: 0: 0 to 0: 5: 95). The product was separated as azeotrope with dichloromethane to form the title compound as a purple crystalline solid. ^ -NMR (400 MHz, CDCl 3): δ 1.39 (m, 10H), 1.6.9 (m, 1H), 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 APCI + 391 [MH] +

Preparation 104: tert-Butyl-3- [4- (4-chloro-2-methylphenyl) -5-methyl-4 H -1,2,4-triazol-3-yl] pyrrolidine-1-carboxylate cr;

A Q

HC-H 1 H, C CH 2 O 01 35 A mixture of the compound of preparation 74 (1.50 g, 5.92 mmol), trifluoroacetic acid (528 μΐ, 7.1 mmol) and 4-chloroaniline (1.68 g, 11.8 mmol). . in toluene (20 ml) was heated at 110 ° C for 18 hours. The cooled mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with. using an elution gradient of dichloromethane: methanol: triethylamine (98: 1: 0.5 to 90: 10: 1 to 80: 20: 1) to form the title compound, 810 mg.

^ -NMR (400 MHz, CDCl 3): δ 1.44 (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 APCI * 377 [MH] + 10

Preparation 105: tert-Butyl-4- [4- (4-chloro-2-methoxyphenyl) -5-methyl-4 H -1,2,4-triazol-3-yl] piperidine-1-carboxylate

H * CV ΊΓ V

Π »0 bH, 0 \

A mixture of 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 trifluoroacetic 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 a 2M sodium hydroxide solution. The aqueous solution was extracted with dichloromethane (2x) and the combined organic solutions were dried over Na 2 SO 4 and then 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 form the title compound. thing, 2 g.

1 H-NMR (400 MHz, CD3 OD): δ 1.46 (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, 2 H); LCMS: m / z APCI + 407 [MH] + 123 '

Preparation 106x tert-Butyl-4- [4- (2,4-dichlorophenyl) -5-methyl-4 H -1,2,4-triazol-3-yl] piperidine-1-carboxylate

«, C L o A

"Cl 10

The title compound was prepared from the oxadiazoil of preparation 1 and 2,4-dichloroaniline following a method similar to that described for preparation 105.

15 "1 H NMR (400 MHz, CDCl 3): δ 1.42 (s, 9H), 1.65-1.94 (m, 4H), 2.20 (s, 3h), 2.42 (m, 1 H), 2.61 - 2.78 (m, 2 H), 4.1 O (m, 2 H), 7.22 (d, 1 H), 7.46 (d, 1 H), 7.66 (S, 1 H ).

Preparations 107 - 116t

§-yOjX-Q

Y

25

A suitable aniline (ΥΎ-PKNHj) (1 - 1.1 eq.) Followed by trifluoroacetic acid (0.5 eq.) Was added to a solution of the compound of preparation 9 (1 eq.) In toluene (1.6 ml) / trunol) and the reaction mixture was heated under reflux. The reaction was monitored by TLC and on completion (45 minutes to 9 hours) the mixture was allowed to cool. The reaction mixture was washed with a diluted ammonia solution and brine, then dried over MgSO 4 and. evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol (95: 5) as eluent to form the title compounds.

1027833 124

Ber. Data no.

107 Y = H; Y 's H; ^ -NMR (400 MHz, CDCl3): δ 1.42 (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 (m, 5H). LCMS: m / z ES + 432 [MNa] * 108 Y and 4-OCH3 · Y '- H; "H-NMR. (400 MHz, CDCl 3): δ 1.42 (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] * 5 109 Y - 4-F; Y '- H; ^ -NMR (400 MHZ, CDCl 3): δ 1.42 (s, 9H), 1.72 (m, 2H), 1.89 (m, 2H), 2.56 (m, 1H), 2.65 (ra, 2H), 4.09 (m, 2H), 5.62 (s, 2H), 7.06 (d, 1H), 7.13 (ra, 2H), 7.48 (s, 2H). LCMS: m / z ES * 428 [MNa] * 110A Y - 4-Br; Y '= H? 1 H NMR (400 MHz, CDCl 3): δ 1.46 (s, 9H), 1.74 (m, 2H), 1.92 (ra, 2H), 2.59 (m, 1H), 2.68 (ra, 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-CF3} Y '> H1-NMR (400 MHz, CDCl3): δ 1.42 (s, 9H), 1.74 (m, 2H ), 1.90 (m, 2H), 2.54 (m, 1H), 2.65 (m, 2H), 4.10 (ra, 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-CH3; Y '= H; ^ -NMR (400 MHz, CDCl 3): δ 1.42 (s, 9H), 1.74 (m, 2H), 1.87 (m, 2H), 2.41 (s, 3H), 2.54 - 2, 73 (m, 3H), 4.07 (ra, 2H), 6.94 (d, 2H), 7.26 (d, 2H), 7.52 (s, 2H) LCMS: m / z ES * 446 [MNa] * 1027833 125 113 Y = 4-CN; Υ '= Η; * H-NMR (400 MHz, CDCl3): δ 1.42 (s, 9Η), 1.72 (m, 2Η), 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] 4 114A Y = 4-C1; Y '= H; ^ -NMR ( 400 MHz, CDCl 3): δ 1.45 (s, 9H), 1.62 - 1.78 (m, 3H), 1.86 (s, 3H), 2.00 (m, 1H), 2.41 (m, 1H), 2.67 (m, 2H), 4.01-1.18 (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 and 4-Cl ; Y 'b 3-F; 1 H NMR ( 400 MHz, CDCl 3): δ 1.44 (s, 9H), 1.73 (m, 2H), 1.89 (m, 2H), 2.57 (tn, 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 b 4-Cl; Y '= 3-C1; ^ -NMR (400 MHz, CDCl3): δ 1.42 (s, 9H), 1.73 (m, 2H), 1.88 (m, 2H), 2.55 (m, 1H), 2.70 (m, 2H), 4.08 (τη, 2H), 5.67 (s, 2H), 6.97 (d, 1H), 7.07 (d, 1H), 7.52 (s, 2H) , 7.55 (d, 1 H). LCMS: m / z ES * 478 [MH] * 5 A = 1.5 eg. aniline were used in the reaction.

Preparation 117: tert-Butyl-4- [4- (4-chlorophenyl) -5 - ({[(methylthio) carbonothioyl] oxy} methyl) -4H-1,2,4-triazole-3-10. yl] piperidine ^ 1-carboxylate • 6 T ”

15. cT

1027833 126

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 tetrahydrofuran (20 ml) and the solution was stirred for one hour at room temperature. Carbon disulfide (230 μΐ, 3.83 mmol) and then methyl iodide (238 μΐ, 3.83 mmol) were added and the reaction mixture was stirred for an additional 2 hours at room temperature. Water (1 ml) was added, the mixture was concentrated under reduced pressure, and the residue was partitioned between dichloromethane and an aqueous sodium bicarbonate solution. The organic phase was dried over MgSO 4 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 form the title liner as a light yellow solid, 460 mg. 1 H-NMR (400 MHz, CDCl 3: δ 1.42 (s, 9H), 1.77 (m, 2H), 1.90 (m, 2H), 2.54 (8, 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 APCI * 483 [MH] +

Preparations 118 - 137:

25 \ J

4M Hydrochloric acid in dioxane (8 - 30 eq.) Was added to a solution of the appropriately protected piperidine selected from preparations 76/77, 80 - 85 and 105 - 116 (1 eq.) In methanol (9 - 22.5 ml / mmol) and the reaction mixture was stirred at room temperature for 1.5 - 3 hours. The mixture was concentrated under reduced pressure, the residue was partitioned between dichloromethane and a 1M sodium hydroxide solution and the layers were separated.

1027833 127

The organic solution was dried over MgSO 4 and evaporated under reduced pressure to form the title compounds.

Ber. Data 5 nr.

118 * Y «= 4-C1; Y '= 2-Cl; X - CH3. ^ -NMR (400 MHz, CD3? D): δ 2.05 - 2.22 (τη, 4H), 2.58 (s, 3H), 3.10 (m, 3H), 3.45 (m, 2Η) , 7.78 (d, 1Η), 7.84 (m, 1H), 8.00 (s, 1H).

LCMS: m / z APCI + 311 [MH] *! ~ - 119 * Y - 4-Clf Y '= 2-OCH; X = CH 3 1 H-NMR (400 MHz, CD 3 OD): δ 2.00 - 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 / z 7 ^ PCI + 307 [MH] + 120 Y η 4-.Cl; Y '* »Η; X = 2-oxo-1-pyrrolidinylmethyl. ^ -NMR (400 MHz, CDCl 3): δ 1.70 - 1.90 (m, 4H), 1.98 (m, 2H), 2.21 (m, 2H), 2.58 (m, 3H) , 3.14 (m, 2H), 3.45 (t, 2H), 4.42 (s, 2H), 7.18 (d, 2H), 7.58 (d, 2H). LCMS: m / z APCI * 360 [MH] + 121 Y = 4-C1; Y '= Η; X e 1,2,4-triazol-1-ylmethyl-NMR (400 MHz, CDCl 3): δ 1.80 - 1.98 (τη, 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 1 H), 8.03 (S, 1 H). LCMS: m / z APCI + 344 [MH] + 10 122 Y s = H; Y '= H; X = 1,2,3-triazole-2-ylmethyl 1 H-NMR (400 MHz, CD 3 OD): δ 1> 83 - 1.96 (m, 4H), 2.65 - 2.85 (τη, 3H), 3.25 (d, 2H), 5.66 (s, 2H), 7.23 (d, 2H), 7.43-7.60 (m, 5H) LCMS: m / z ES * 310 [MH] +1027833 128 123 Y = 4-F; Υ '= Η; X 1,2,3-triazol-2-ylmethyl1 H NMR (400 MHz, CDCl3): δ 1.75 (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 b 4-Br; Y '= Η; X = 1,2,3-triazol-2-ylmethyl-NMR (400 MHz, CDCl3): δ 1.79 (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-tr ± azol-2-ylmethyl X H NMR (400 MHz, CDCl 3): δ 1.80 (m, 2H), 1.93 (m, 2H), 2.54 - 2.66 (m, 3H), 3.22 (d, 2H), 5.66 (s, 2H), 6.80-6.88 (m, 2H), 7.47 - 7.53 (m, 3H). LCMS: m / z ES + 362 [MH] + 126 Y b 4-C1; Y '= 3-C1; X = 1,2,3-triazol-2-ylmethyl-1 H-NMR (400 MHz, CDCl 3): δ 1.80 (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, 2 H), 7.54 (d, 1 H). LCMS: m / z ES + 378 [MH] + 5 127 Y b 4-CF 3; Y '= Ηι X = 1,2,3-triazol-2-ylmethyl X H NMR (400 MHz, CDCl3): δ 1.76 (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] * 10 2 7 8 33 129 · 128 Y 4-C1; Υ '2-CH 3; X => 1,2,3-triazol-2-ylmethyl-NMR (400 MHz, CDCl 3): δ.1.68 - 1.87 (τη, 5H),.

1.91 - 2.15 (m, 2Η), 2.45 (m, 1Η), 1.55 - 1.72 (m, 2H), 3.17 (d, 1H), 3.28 <d, 1 H), 5.47 (d, 1 H), 5.64 (d, 1 H), 6.84 (d, 1 H), 7.20 (d, 1 H), 7.31 (d, 1 H), 7, 46 (s, 2H). LCMS: ia / ζ ES * 358 [MH] * 129 Y 4-CH 3 Y 'b Η; X 1,2,3-triazol-2-ylmethyl Ή-ΝΜΗ (400 MHz, CDCl 3): δ 1.74 - 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 b 4-OCH; Y # = Η; X = 1,2,3-tr ± azol-2-ylmethyl-NMR (400 MHz, CD3 OD): δ 1.72 - 1.79 (m, 4H), 2.45 (m, 2H), 2.65 (m, 1 H), 3.00 (d, 2 H), 3.82 (S, 3 H), 5.62 (S, 2 H), 7.00 (d, 2 H), 7.11 (d (2 H), 7.57. (s, 2H). LCMS: m / z ES * 340 [MH] + 131 Y o 4-CN; Y '= Η; X »1,2,3-triazol-2-ylmethyl-NMR (400 MHz, CDCl3): δ 1.61 - 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] + 5 132A Y s 4-Clf Y # B Η; X = tetrazol-1-ylmethyl 1 H-NMR (400 MHz, DMSO-th): δ 1.80 - 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 Bi 1H), 9.18 (s, 1H). LCMS: m / z ES * 345, 347 [MH] *.

1 ° 27β3 130 133 * Y b 4-Cl; Y '= Η; X = 3-methyl-oxazol-5-yl-methyl-NMR (400 MHz, CD3 OD): 6 2.05 <m, 2H), 2.20 (m, 2H), 3.00 (m, 2H), 3 , 18 (m, 1H), 3.38 (τη, 2H), 3.54 (s, 3H), 4.25 (s, 2H), 7.48 (m, 2H), 7.58 (d, 2H). LCMS: m / z APCI + 358 [MH] 4 134 * Y = 4-Cl 3 Y '= Η; X = 3-methyl-1,2,4-oxadiazol-5-ylmethyl-NMR (400 MHz, CD3 OD): δ 2.12 (ra, 4H), 2.34 (s, 3H), 3.02 ( m, 2H), 3.15 (m, 1H), 3.43 (m, 2H), 3.64 (s, 2H), 7.57 (m, 2H), 7.68 (d, 2H). LCMS: m / z APCI4 359 [MH] + 135 Y = 4-Clj Y 'a Hj X = pyrimldin-2-yloxyxnethyl X H-NMR (400 MHz, CDCl3): Ö 2.05 (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 APCI + 371 '[MH] 4 136 Y «a 4-cl; Y'« Η; X - 2-piperidine-1-ylethyl1 H-NMR (400 MHz, CDCl3): δ 1.41 (m, 2H), 1.56 (m, 4H), 1.78 - 1.97 (m, 4H), 2 , 20 - 2.40 (ra, 6H), 2.60 - 2.78 (m, 5H)., 3.22 (m, 2H), 7.18 (d, 2H), 7.57 (d (2H) LCMS: m / z APCI4 374 [MH] 4 137 Y b 4-Cl; Y 'Η; X = 2-morpholine-4-ylethyl-NMR (400 MHz, CDCl 3): δ 1.70 - 1.90 (m, 4H), 2.38 (m, 4H), 2.58 (m, 3H), 2.70 (s, 4H), 3.14 (m, 2H), 3.61 (ra, 4H), 7.18 (d, 2H), 7.57 (d, 2H) .LCMS: m / z APCI4 376 [MH] 4 === ssssss = 3a ^ BK: ssaesasBSK = sesaasx83sssssBBBasssss ±. = sss = sssaBaaBBa SSgSSSssas5ssssss £ Sss ^ ssssasssS5SS £ A = The reaction mixture was evaporated under reduced pressure before isolation on the hydrochloride salt of the title compound.

10.

, 027833

133. " I

Preparations 138 - 141: o o.

tr \

A solution of the appropriately protected piperidine selected from preparations 78 to 79 and 86 to 87 (1 g.) In 2.2 M hydrochloric acid in methanol (13 ml / mmol) was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue was separated off as azeotope with toluene. The crude product was partitioned between dichloromethane and a 1M sodium hydroxide solution and the layers were separated. The organic solution was dried over MgSO 4 and evaporated under reduced pressure to form the. title connections.

RS = S ^^ SSaSBSSS = S = SSaaBSBSaSBSSSS = S = SS & SBSSBSSSSSSSSSSSSSSSSaSaSSaSSSSI ^ BSS = BaSaMBBSB8BBBaBBBBi

Ber. X Data

Nr.

138 ^ X H NMR (400 MHz, CDCl 3): δ 1.78 (m, A = N '2H), 1.80 - 1.98 (m, 2H), 2.56 (m, 3H), 3 , 16 (m, 2H), 5.12 (s, 2H), 6.75 (s, 1H), 6.84 (d, 2H), 7.00 (d, 2H), 7.50 (d, 2H). LCMS: m / z APCI + 343 [MH] + 20 139 1 H-NMR (400 MHz, CDCl 3): δ 1.74 - 1.97 (m, 4H), 2.04 (m, 3H), 2.48 - . . HSC 2.64 (m, 3.H), 3.19 (m, 2H), 5.00 (s, 2H), 6.46 (s, 1H), 6.82 (s, 2H), 6, 85 (d, 2H), 7.48 (d, 2H). .

LCMS: m / z APCI + 357 [MH] + 1 0 2 7 © 33 132 140A-NMR (400 MHz, CDCl 3): δ 2.06 - 2.19 (m, 4H), 3.03 (m, 2H ), 3.18 - 3.22 (m, 1H), 3.30 (m, 2H), 3.44 (m, 2H), 3.60 (m, 2H), 7.77 <s, 4H) , 7.98 (τη, 1H), 8.05 (d, 1H), 8.58 (m, 1H), 8.78 (d, 1H).

LCMS: m / z APCI * 368 [MH] + 141A. PH 3 1 H NMR (400 MHz, CD 3 OD): δ 1.99 (s, .3H), # 2.12 (m, 7H), 2.78 (t, 2H), X / 2.97 (t, 2 H), 3.00-3.18 (m, 3 H), H® C 3.43 (m, 2 H), 7.54 (d, 2 H), 7.78 (d, 2 H).

LCMS: m / z kPCV 386 [MH] * A = The reaction mixture was evaporated under reduced pressure and separated as azeotrope with toluene. The product was triturated with ethyl acetate, filtered and dried to form the hydrochloride salt of the title compound.

Preparation 142: 4- [4- (4-Chlorophenyl). 5- 5- (methoxymethyl) -4H-1,2,4-triazol-3-yl] -piperidine 15 C) -4M Hydrochloric acid in dioxane (60 ml) was added. added to a solution of the compound of preparation 97 (3.75 g, 9.22 mmol) in dioxane (50 ml) and the reaction mixture was stirred at room temperature for 3 hours. The mixture was evaporated under reduced pressure and the residue was redissolved in dichloromethane and washed with aqueous ammonia and then brine. The organic solution was dried over MgSO 4 and evaporated under reduced pressure. The crude product was purified by column chromatography using a silica gel cartridge of dichloromethane methanol: 0.88 ammonia (90: 10: 1) as eluent to form the title compound, 1.99 g.

X H NMR (400 MHz, CDCl 3): δ 1.80 - 1.98 (m, 4H), 2.57 - 2.70 5 (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 APCI + 307 [ΜΗΓ

Preparation 143: 4- [4- (4-Chlorophenyl) -5- (ethoxymethyl) -4 H -1,2,4 -1 -riazol-3-yl] piperidine hydrochloride 10%. 4 M 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 mixture was 18 stirred at room temperature for 1 hour, the mixture was evaporated under reduced pressure and the residue was separated off as azeotrope with dichloromethane to give the title compound, 910 mg.

NM NMR. (400 MHz, CD3OD): δ 1.02 (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 APCI + 321, [MH] +

Preparation 144: 1- [4- (4-Chlorophenyl) -5-methyl-4 H -1,2,4-triazol-3-yl] piperidine dihydrochloride 0 ° a

".2HCl

4M hydrochloric acid. dioxane (13.75 ml) was added to a solution of the compound of preparation 95 (4.12 g, 10 mmol). in dichloromethane (50 ml) and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was evaporated under reduced pressure and dried in vacuo to give the title compound as a white solid, 3.8 g, Ή 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 145s 1- [4- (4-Chlorophenyl) -5-methyl-4H-1,2,4-triazol-3-yl] piperidine-4-amine dihydrochloride ο γγ "cH" ίΌ b Η, Ν. 2HCI \

- Oh

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 heated at 50 ° C for 3 hours. The mixture was concentrated under reduced pressure and the residue was slurried in tetrahydrofuran (50 ml). The resulting solid was filtered off and dried in vacuo to form the title compound.

^ -NMR (400 MHz, CD3OD): δ 1.65 (m, 2H), 1.96 (m, 2H), 2.36 (s, 3H), 3.07 (m, 2H), 3.36 (m, 1 H), 3.47 (m, 2 H), 7.66 (d, 2 H), 7.75 (d, 2 H). LCMS: m / z APCI + 292 [MH] + 25

Preparation 146: 3- [4- (4-Chloro-2-methylphenyl) -5-methyl-4H- [1,2,4) triazol-3-yl] -piperidine

Q

4M hydrochloric acid (5 ml) was added to a solution of the compound from preparation 103 (846 mg, 2.16 mmol) in dioxane 35 (10 ml) and the reaction mixture was stirred at room temperature for 18 hours. TLC analysis showed that starting material remained, so additional 4M hydrochloric acid in 1027833 135 dioxane (5 ml) was added and the reaction mixture became another. stirred at room temperature for 1 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 separated as an azeotrope with dichloromethane and ether to form an off-white foam.

1 H NMR (400 MHz, CDCl 3): δ 1.49 (m, 1H), 1.68 - 1.93 (m, 3H), 1.97 (s, 3H), 2.16 (s, 3 H), 2.59 (m, 1 H), 2.80 (m, 1 H), 3.03 (m, 1 H), 3.16 (m, 1 H), 7.06 (2xd, 1 H), 7, 35 (2xm, 1H), 7.42 (2xd, 1H); LCMS: m / z APC1 * 291 (IMH) +

Preparation 147: 4- (4-Chloro-2-methylphenyl) -3-methyl-5-pyrrolidin-3-yl-4ff-1,2,4-triazole V 1 Pu, 20 K ci

A solution of the compound from preparation 104 in 4M hydrochloric acid in dioxane (20 ml) was stirred at room temperature for 4 hours. The mixture was partitioned between .25 ethyl acetate and a 2N sodium hydroxide solution and the layers were separated. The organic solution was dried over MgSO 4 and evaporated under reduced pressure to form the title compound.

1 H NMR (400 MHz, CDCl 3): δ 2.00 (m, 5H), 2.20 (m, 5M), 2.80 30 - 3.02 (m, 2H), 3.10 - 3, 27 (m, 1 H), 7.05 (d, 1 H), 7.38 (d, 1 H), 7.41 (s, 1 H); LCMS: m / z APCl + 277 [MH] + 35 1027833 136

Preparation 148: 1- [4- (4-Chlorophenyl) -5- (methoxymethyl-4 H -1,2,4-triazol-3-yl] -1,4-diazepane o-CH, 5 ft / o § 'c, 4M Hydrochloric acid in dioxane (25 ml) was added to a solution of the compound of preparation 89 (5.45 g, 12.93 10 mmol) in dioxane (30 ml) and the reaction mixture was stirred at room temperature for 18 hours. under reduced pressure and the residue was partitioned between water and ether, the layers were then separated, the aqueous phase was made basic with sodium hydroxide and the solution was extracted with dichloromethane (3x) .The combined extracts were dried over MgSO 4. forming the title compound as a foam, 3.84 g.

^ -NMR (400 MHz, CD 3 OD): δ 1.78 (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 APC1 + 322 [MHJ +

Preparation 149: 1- [4- (4-Chlorophenyl) -5- (methoxymethyl) -4-1,2,4-triazol-3-yl] -2-methylpiperazine 25 O-CH, <v 0¾ 30 ci

The title compound was obtained as a yellow oil with a yield of 95% of the compound from preparation 94, following the method described for preparation 148.

^ NMR (400 MHz, CDCl 3):. δ 1.14 (d, 3H), 2.10 (br s, 1H), 2.60 (m, 1H), 2.82 (m, 2H), 2.97 (m, 1H), 3.07 (m, 2H), 1027833 137 3.35 (s, 3H), 4.28 (d, 1H), 4.40 (d, 1H), 7.38 (d, 2H), 7.50 (d , 2H); LCMS: m / z APC1 + 322 [MH] 4

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 and then washed with 1 N sodium hydroxide solution. The organic solution was dried over MgSO * and evaporated under reduced pressure. The crude product was purified by column chromatography using a silica gel pattern and an elution gradient of dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) to form the title compound -thing as an oil, 780 mg.

M1 NMR (400 MHz, CDCl3): δ 1.19 (d, 3H), 2.98 (m, 2H), 3.02 25 - 3.23 (m, 5H) ·, 3.36 (s, 3 H), 4.34 (s, 2 H), 7.40 (d, 2 H), 7.52 (d, 2 H); LCMS: m / z APCl 4 322 [MH] 4

Preparation 151: 4- [4- (4-Chloro-2-methylphenyl) -5-methyl-4H-1,2,4-triazol-3-yl] piperidine A-0 '

Cftf A mixture of the 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) * 027833 138 was stirred at room temperature for 18 hours. The cooled mixture was concentrated under reduced pressure, 2M sodium hydroxide solution (10 ml) was added and the mixture was separated as azeotrope 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 form the title compound as an off-white foam , 1.45 g.

10? -NMR (400 MHz, CD3OD): δ 1.81 (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 APC1 + 291 [MH] * Preparation 152: 4- [4- (4-Chloro-2-fluorophenyl) -5-methyl-4H-1,2,4-triazol-3-yl] piperidine- ditrifluoroacetate ✓''W-ch,

20 \ J

H 2 CF, CO 3 H °

A mixture of the compound of preparation 1 (900 mg, 3.4 mmol), 4-chloro-2-fluoroaniline (109.1 mg, 0.75 mmol) and trifluoroacetic acid (288 μΐ, 3.74 mmol) in toluene ( 8 ml) 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 separated as azeotrope with toluene and the crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: 0.88 ammonia (90: 10: 1 to 80: 20: 3) under the formation of the title compound as an off-white foam, 985 mg.

"1 H NMR (400 MHz, CDCl 3): δ 2.02 - 2.30 (m, 7H), 2.80 (m,

35 1 H), 3.10 (m, 2 H), 3.59 (m, 2 H), 3.86 (m, 1 H), 7.26 (m, 1 H), 7.40 (m, 2 H), 9 34 (br s, 1 H), 10.10 (br s, 1 H); LCMS: m / z APCl * 295 [ΜΗ] V

ί0278YY

. 139

Preparation 153: 4- {4- (4-Chlorophenyl) -5- [(2,2,2-trifluoroethoxy) methyl] -4H-1,2,4-triazol-3-yl} piperidihe p Vf

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 mixture was heated under reflux for 48 hours. TIC art analysis showed that starting material remained, so additional trifluoroacetic acid (8 ml) was added and the reaction mixture was heated under reflux for a further 4 hours. The cooled mixture was extracted with water, the aqueous solution was made basic with potassium hydroxide and then extracted with dichloromethane (4 x 100 ml). The combined organic extracts were dried over MgSO 4 and thinned 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 form the title compound, 4.34 g.

25 1 H NMR (400 MHz, CDCl 3): 1.86 - 2.04 (m, 4H), 2.78 (m, 3H), 3.37. (m, 2H), 3.82 (q, 2H), 4.22 - 4.41 (br s, 1H), 4.58 (s, 2H), 7.22 (d, 2H), 7.58 (d, 2 H); LCMS: m / z ES + 375.1 [MH] * Preparation 154: 4- {4- (4-Chlorophenyl) -5 - [(trifluoromethoxy) methyl] -4H-1,2,4-triazol-3-yl } piperidine%>:. 0, v.

. α r 1027833 140

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 a solution of 1,3-dibromo -2,4-dimethylhydantoin 5 (283 mg, 1.0 mmol) in dichloromethane (5 ml) at -78 ° C. The reaction mixture was heated to room temperature over 30 minutes and then stirred for an additional one hour. with 1N sodium hydroxide solution, dried over MgSO 4 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 eluant under the formation of the title compound as a yellow oil, 45 mg.

LCMS: m / z APC1 + 361 [MH] * 15

Preparation 155: 4- [4- (4-Chlorophenyl) -5-methyl-4,111,4,4-triazol-3-yl] behzonitrile 20 \ NC Cl

Trifluoroacetic acid (600 μΐ, 8.1 mmol was added to a suspension of 4-chloroaniline (2.1 g, 16.2 mmol) and 4- (5-25 methyl-1,3,4-oxadiazol-2-yl) benzonitrile (Journal für

Practical Chemistry, 1994; 336 (8); 678-85) (3.0 g, 16.2 mmol) in tetrahydrofuran (50 ml) and the reaction mixture was heated under reflux for 22 hours. The cooled mixture was partitioned between ethyl acetate (300 ml) and 20% aqueous solution. 30 grams of 0.88 ammonia (120 ml) and then the layers were separated. The organic phase was dried over MgSO 4 and evaporated under reduced pressure. The residue was triturated with ether and a minimal volume of ethyl acetate to form the title compound as a white crystalline solid, 2.82 g.

1 H-NMR (400 MHz, CDCl 3): δ 2.38 (s, 3H), 7.19 (d, 2H), 7.55 (m, 4H), 7.60 (d, 2H); LCMS: m / z ES + 295 [MH] + 1027833 .. 141

Preparation 156: 4- [4- (4-Chlorophenyl) -5-methyl-4 H -1,2,4-triazol-3-yl] benzoic acid - 5 OH Cl

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 mixture was heated under reflux for 18 hours. Ethanol (50 ml) was added and the reaction mixture was heated under reflux for 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), the suspension was then filtered and the filtrate was evaporated under reduced pressure.

The product was triturated with ether, filtered off and dried to form the title compound as a white solid.

1 H NMR (400 MHz, CD 3 OD): <5 2.38 (s, 3H), 7.19 (m, 4H), 7.58 (d, 2H), 7.90 (d, 2H); LCMS: Sl / z ES "312 [M-H]" Preparation 157; 4- [4- (4-Chlorophenyl) -5-methyl-4 H -1,2,4-trazol-3-yl] benzoic acid 0¾ 30 0 = 5 / \ = - /

Cl Cl

Oxalyl chloride (3 ml, 32 mmol), followed by N, N-dimethylformamide (5 drops) were added to a solution of the acid of preparation 156 (2 g, 6.4 mmol) in dichloro-methane (200. ml) 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 give the title compound as an orange oil, 2.01 g.

-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-4I -1,2,4-tetrazole-3-yl] piperidine-4-carboxylic acid VCH * 10 Λ - * / OH Cl

A solution of the ester of preparation 90 (4 g, 10.4 mmole) 15 and 4 N 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 with 2 N hydrochloric acid, the resulting precipitate was filtered off and washed with water. The solid was triturated with ether, filtered and dried in vacuo to give the title compound as a white solid.

"1 H NMR (400 MHz, CD10D): δ 1.52 - 1.61 (m, 2H), 1.81 (m, 2H), 2.21 (s, 3H), 2.40 (m, 1 H), 2.81 (m, 2 H), 3.21 - 3.36 (m, 2 H), 7.47 (d, 2 H), 7.62 (d, 2 H).

Preparation 159: 1- [4- (4-Chlorophenyl) -5- (2H-1,2,3-trazol-2-ylmethyl) -4H-1,2,4-triazol-3-yl] piperidine-4-carboxylic acid 30 ^^ 35 c

The title compound was obtained as a white solid from the ester of preparation 91, following a procedure 1027833 143 similar to that described for preparation 158, except that 10 eq. sodium hydroxide was used in the reaction.

1 H NMR (400 MHz, CD3 OD): δ 1.48 - 1.60 (m, 2H), 1.81 (m, 5 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 APC1 * 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 a 4 N sodium hydroxide solution (5 mL, 20 mmol) in dioxane (50 mL) was stirred under reflux for 16 hours. TLC analysis showed that starting material remained, so additional sodium hydroxide (4N, 5 ml, 20 mmol) was added and the reaction mixture was heated under reflux for an additional 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). These 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 off and dried, yielding the title compound as a white solid, 800 mg.

. ^ -NMR (400 MHZ, CD 3 OD): δ 1.18 (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 APC1 + 335 [MH] * 35 1027833 144

Preparation 161: W- (4-Chlorophenyl) -2- (2H-1,2,3-triazol-2-ylacetyl) hydrazine carbothioamide 4-Chlorophenylisothiocyanate (8.58 g> 50.6 mmol) was added. portions were added to a suspension of the hydrazide from preparation 18 (7.0 g 50.6 mmol) in ethanol (200 ml) and the mixture was stirred at room temperature for 72 hours. The resulting precipitate was filtered off, washed with ether and dried to give 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-triazole-3-thione 20 JL /> JC> V>

Cl N = / A solution of the compound of preparation 161 (14.5 g, 46.5 mmol) and a 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 and then it was extracted with dichloromethane (6 x 250 ml). The conjugated organic solutions were evaporated under reduced pressure to form 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).

1027833 145

Preparation 163: 2- {[4- (4-Chlorophenyl) -5- (methylthio) -4 JK

1,2,4-triazol-3-yl] methyl} -2,7-1,2,3-triazole S'f% 5 Wv 0 cr n == /

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 30 stirred at room temperature for minutes. Methyl p-toluene sulfonate (4.8 g, 25.7 mmole). was added and the mixture was heated under reflux for 45 minutes and then at room temperature for a further 2 hours. The mixture was diluted with dichloromethane (1000 ml), washed with a saturated one. ammonium chloride solution (300 ml) and brine (300 ml), then it was dried over MgSO 4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol (85:15) as eluent to form the title compound, 4.9 g.

1 H NMR (400 MHz, CDCl 3): δ 2.70 (s, 3H), 5.64 (e, 2H), 7.02 (d, 2H), 7.41 (d, 2H), 7.54 (s, 2H). LCMS: m / z ES + 329! [MNa] * • 25

Preparation 164: 2- {[4- (4-Chlorophenyl) -5- (methylsulfonyl) -4H-1,2,4-triazol-3T-yl) methyl} -2Ji-1,2,3-triazole

HjC-.ς N

o "V> 30.

0 0 cr N— '

Meta-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 mixture was kept for 18 hours stirred at room temperature. The mixture was diluted with dichloromethane, then 1027833. Washed 146 with saturated sodium bicarbonate solution (300 ml) and brine (200 ml). The organic solution was dried over Na 2 SO 4 and concentrated under reduced pressure. The remaining solid was washed with ethanol, then dried under vacuum to form the title compound as a white solid, 1.40 g.

X H NMR (400 MHz, CDCl 3): δ 3.46 (s, 3H), 5.69 (s, 2H), 7.18 (d, 2H), 7.41 (d, 2H), 7.57 (s, 2H); LCMS: m / z ES + 361 [MNa] * 10

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 after completion of the addition The reaction mixture was stirred for an additional 20 hours. The mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate and the solution was washed with water (x2) and then with brine. The solution was dried over MgSO 4 and evaporated under reduced pressure to form 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, 1 H).

Preparation 166: 4-Chloro-2-ethoxyaniline 30

Cl '

A mixture of the nitro compound of preparation 165 (3.30 g, 16.4 mmol), iron powder (2.7 g, 49 mmol) and calcium chloride (810 g, 7.4 mmol) in water (5 mL) and ethanol (30 ml) was heated under reflux for 3.5 hours. The cooled 147 mixture was filtered through Celiet® 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 MgSO 4 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 form the title compound 10 as an oil, 2.4 g.

1 H-NMR (400 MHz, CDCl 3): 6 1.42 (t, 3H), 4.02 (q, 2H), 6.61 (d, 1H), 6.76 (m, 2H).

Preparation 167: 1- (5-Chloro-2-nitrobenzyl) pyrrolidine 15 V.

O 0 ^ 0

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 triacetoxy borohydride (10.3 g, 48.5 mmol) was added portionwise. After completion of the addition, the reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was washed with sodium carbonate solution, dried over MgSO * and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using ethyl acetate: pentane (86:14) below. formation of the title compound as a light yellow solid, 6.3 g.

1 H NMR (400 MHz, CDCl3): δ 1.82 (m, 4H), 2.58 (m, 2H), 3.98 (S, 2H), 7.37 (d, 1H), 7.80 (s, 1 H), 7.87 (d, 1 H). LCMS: 35 m / z APC14 241 [MH] 4,127,833 148

Preparation 168: 4-Chloro-2- (pyrrolidin-1-ylmethyl) aniline 5 Cl

A mixture of the compound of preparation 167 (6.2 g, 25.8 mmol) and Raney® Nickel (400 mg) in ethanol (200 ml) was hydrogenated under 40 psi and room temperature for 2 hours. The mixture was filtered through Arbocel® 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 form the title compound as a solid, 3.95 g.

15-NMR (400 MHz, CDCl 3): δ 1.78 (tri, 4H), 2.48 (m, 2H), 3.59 (S, 2H), 4.65 - 4.90 (br S, 2 H), 6.56 (d, 1 H), 6.98 (s, 1 H), 7.00 (d, 1 H). LCMS: m / z APCl * 211 [MH) +

Preparation 169: 4 - {[4- (4-Chlorophenyl) -5-piperidin-4-yl-4 H -20,2,2-trazol-3-yl] methyl} morpholine Cl

A solution of the compound of preparation 101 (8.6 g, 18.6 mmol) of dioxane (50 ml) and 4M hydrochloric acid. dioxane (30 ml) was stirred at room temperature for 18 hours. The solution was evaporated under reduced pressure and the residue was partitioned between a 2N sodium hydroxide solution and. ethyl acetate. The resulting solid was filtered off and dried to form the title compound as one. white solid 1.2 g. The filtrate was separated, the aqueous layer was extracted with dichloromethane and the combined organic solutions were dried over MgSO 4 and evaporated under reduced pressure to form additional product, 11.1 g.

1027833, 149 LCMS: m / z APC1 + 362 [MH] + ...

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

A suspension of N-Boc isonipecotinic acid (30.0 g, 130.8 nunol) and the hydrazine of preparation 18 (18.5 g, 130.8 mmol) in dichloromethane (150 ml) was cooled in an ice bath under After. 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (25.6 g, 133.5 mmol) was added via an addition funnel and the funnel was washed with additional dichloromethane (10 ml). The resulting solution was heated to ambient temperature. After completion of the reaction. 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 ambient temperature with stirring. After completion of the reaction, 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 ambient temperature with stirring. The resulting thick slurry was filtered under vacuum, washed with isopropanol (15 ml, and 30 ml) and dried under vacuum at 50 ° C to form the title compound as a white solid, 25.3 g (55%). The liquids from the filtration were concentrated under reduced pressure to a small volume, the resulting syrup was treated with water (50 ml) and stirred vigorously for two minutes to form a thick slurry. After cooling overnight, the slurry was filtered (rapid filtration), the residues were washed with water (2 x 10 ml) and dried under vacuum at 50 ° C to form additional product, 8.5 g (18%) ).

1027833 150 s-NMR (400 MHz, CDCl 3): 6 1.42 (s, 9H), 1.50 - 1.85 (m, 4H), 2.41) m, 1H), 2.73 (t (2H), 4.12 (d, 2H), 5.21 (e, 2H), 7.70 (S, 2H), 9.15 (d, 1H), 9.75 (d, 1H).

Examples 1 - 162:

Cj O m

Examples 1-166 illustrated below were synthesized as a library. The following solutions were used: carboxylic acid, ZCO3 H, was dissolved in dimethylacetamide (anhydrous) plus 0.75% triethylamine in a concentration of 0.2 M; the amine from preparation 2a was dissolved in DMA 20 (anhydrous) plus 3.75% triethylamine in a concentration of 0.2 M; HBTU was dissolved in DMA (anhydrous) in a concentration of 0.2 M.

(N.B. Quietly anonifying in a warm water bath (temp. <40 ° C) was used to dissolve the monomers, if necessary.)

Experimental method:

The reaction scale was between 20 and 30 micromoles per well 30 (experimental details are shown for a reaction with 20 / zmol, but the scale can be adjusted accordingly within this range).

Reactions were performed in a 96-well polypropylene plate.

35 a) Amine solutions (0.1 ml, 20 μτηοΐ, 1 eq.) Were added to the wells 2 / 83j 151 b) Carboxylic acid solutions (0.15 ml, 30 μΐ, 1> 5 eq.) Were added to the wells wells added c) HBTU solution (0.15 ml, 30 μπιοί, 1.5, eq.j was added to each well 5 d) The 96-well polypropylene plate was covered with a PTFE and rubber gasket and between a pair of metals plates clamped e) The plate was heated in an oven at 60 ° C for 6 hours and then allowed to cool in the oven overnight. f) When cooled, the plate was released from the clamps and placed in a Genevac to remove the solvent g) The samples were redissolved in DMSO / water (9: 1) (500 μΐ) and all particulate material was removed by filtration h) Purification was performed by RP-HPLC.

HPLC purification conditions:

Column: Phenomenex Luna C18, 10 μπι, 150 x 10 mm i.d. '

Temperature: ambient temperature Eluent A: 0.05% diethylamine in water

Eluent B: Acetonitrile

Samples dissolved in 90% dimethyl sulfoxide in water

Sample loaded using a Gilsoh Auto-30 sampler with an injection volume of 550 μΐ.

Gilson LC Pump Initial conditions:

Solvents.

A% 80.0. 35 B% 20.0

Flow rate (ml / min) 8,000 ° 2? 833 152

Timetable for the gradient in the Gilson LC Pump:

Time A% B% Flow rate (ml / min) 0.00 80.0 20.0 8.000 0.20 80.0 20.0 8.000 5 7.00 5.0 95.0 8.000 9.00 5, O 95.0 8.000 .

9.10 80.0 20.0 8.000 10.50 80.0 20.0 8.000 10 Gilson 119 UV detector analysis at 254 nm:

Collector set at 225 nm Dual sensitivity 20Ó Peak sensitivity 80 Peak width 0.3 min 15 HPLC analysis conditions and details Mass spectrometer:

Column: Phenomenex Luna C18, 5 μιη, 30 x 4.6 mm i.d. Eluent A: 0.05% Diethylamine in water Eluent B: Acetonitrile 20 Samples dissolved in: 90% Dimethyl sulfoxide in water

Sample loaded using Gilson Quad Z with an injection volume of 5 μΐ 25 Water 1525 binary LC pump

Solvents A% 95.0 B% 5.0

Flow rate (ml / min) 2.5 (per channel) 30 Temperature (° C) ambient temperature

Timetable for the gradient in the LC pump:

The Time table for the gradient comprises 4 entries, which are: 35 Time A% B% Flow rate 0.00 95.0 5.0 2.500 3.00 5.0 95.0 2.500! . . " . . 027833 153 3.50 95.0 5.0 2.500

Total run time 4.50 min

Detection: 5 Waters 2488 detector at two wavelengths UV1 (nm) 225 UV2 (nm) 255 and ELSD: PolymerLabs, Temperature: 75 ° C, Gas flow: 10 1.2 bar

Mass spectrometer:

Water ZQ 2000 4-way MUX

ES + Cone voltage: 26 v Capillary: 3.85 kv 15, ES- Cone voltage: -30 v Capillary :: -3.00 kv

Desolvation gas: 800 rpm.

Source temp .: 300 ° C Scan range: 160 - 1000 Da 1027833 154

Ex. Z Mass ion HPLC

Nr. of product retention time found (min) 1 2-methoxy-pyridin-3-yl 412.15 1.55 2 3-trifluoromethyl-phenyl 449.13 2 5 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 10 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 2.49 12 2,4-dichloro-phenyl 449.06 1.99 15 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- methylsulfanyl-phenyl 427.13 1.85 17 4-chloro-2-methoxy-phenyl 445.11 1.89 20 18 2-ethoxy-phenyl 425.17 1.84 19 isoquinoline-1-yl 432.15 1.6 2,6-dimethyl-phenyl 409.17 1.82 21 quinolin-2-yl 432.15 1.74 22 quinolin-4-yl 432.15 1.6 10 ^ 833 155 23 quinolin-3-yl 432, 15 1.57 24 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 5 27 2,5-dimethoxy-phenyl 441,16 1.55 28 2,3-difluoro-phenyl 417,11 1,8 29 2,4-difluoro-phenyl 417.12 1.8 30 3,4-difluoro-phenyl 417,11 1,85 31 4-isopropyl-phenyl 423,19 2 10 32 6-methyl-pyridin-3-yl 396.15 1.45 33 4- f-or-naphthalene-1-yl 449.15 2 34 3,5-difluoro-phenyl 417,11 1,87 35 3-aminosulfonyl-4-chloro-494,07 1,5 phenyl 36 1 H-benzoimidazole-5- yl 421.15 1.37 15 37 2-chloro-4-fluoro-phenyl 433.09 1.85 38 4-trifluoromethoxy-phenyl 465.12 2.07 39 1 H -benzotriazol-5-yl 422.14 1.34 40 4-methoxy-quinolin-2-yl 462.16 1.82 41 2-fluoro-4-trifluoromethyl-467.12 2.04 phenyl 20 42. 2,3,6-trifluorophenyl 235,11 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 trifluoro-phenyl 467.12 1.92 "Λ, · ·.

027 8 33 156 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 5 51 4-propoxy-phenyl, 439.18 2.02 52 3-chloro-4-fluoro-phenyl 443.09 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-467.12 2.09 phenyl 10 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 15 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-fluoromethyl-phenyl 413.15 1.8 65 3-fluorophenyl 399.13 1.75 20 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 25 71 m-tolyl 395.16 1.85 157 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 5 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 rows ifluoromethoxy-phenyl 465.12 1.99 80 3-ethoxy-phenyl 425.17 1.79 10 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 4.29.12 2.05 84 2-chloro-3,4-dimethoxy-phenyl 475.12 1.72 85 3-cyclopentyloxy-4-methoxy - 495.21 2 phenyl 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-pyridine-3 450,12 1.65 · 1 90 6- (2,2,2-trifluoro-ethoxy) - 4 * 80,13 1.95 pyridin-3-yl 91- (4-fluoro-phenoxy) -pyridine-492.15 1.9 3-yl 92 2-chloro-3-trifluoromethyl-483.09 1.97 phenyl 93 2-difluoromethoxy-phenyl 447.13 1 82 1027833 158 34 3-difluoromethoxy-phenyl 447.13 1.89 95 6-trifluoromethyl-pyridine-3 450,12 1.84 yi _____ 96 2-methyl- [1,8] naphthyridine-3,447,16 1.32 µl 97 2-methyl- [1,6] naphthyridine-3,447.16 1.42 y! 5 98 2,3-dichloro-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 92 101 2-ethoxy-pyridin-3-yl 426.16 1.6 102 2-ethoxy-naphthalene-1-yl 475.18 2.02 10 103 3- (dimethylamino) sulfonyl-488.14 1.72 phenyl 104 2-propoxy-pyridin-3-yl 440.18 1.84 105 2- (4-chlorophenoxy) -pyridine-508.12 1.93 3-yl 106-2-methyl-1H-benzoimidazole-435.16, 4 5-yl 107 6-hydroxy-pyridin-2-yl 398.13 1.32 15 108 2- (5-methyl- [1,2,4] oxadia-464,15 1,45 zol-3-yl) pyridin-4-yl 109 4- (5-methyl- [1,2,4] oxadia-463,16 1.67 zol-3-yl) -phenyl 110 4- (5-ethyl- [1,2,4 ] oxadia-477.17 1.92 zol-3-yl) -phenyl 111 3- (5-methyl- [1,2,4] oxadia-463,16 1.68 zol-3-yl) -phenyl 1027eJ3 159 .

112 3- (5-ethyl- [1,2,4] oxadia-477.17 1,9-z-3-yl) -phenyl 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 5 116 3-chloro-2-methyl-phenyl 429.12 1.93 1.93 117 2.3-dihydro-benzofuran-5-yl 423.15 1.74 118 2- (3-methyl- [1,2,4] oxadia-464,15 1/49 zol-5-yl) -pyridin-4-yl 119 3-hydroxy-2-methyl- phenyl 411.15 1/54 120 2-fluoro-5-trifluoromethyl-467.12 2.02 phenyl 10 121 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 15 126 1 H-indol-6-yl 420.15 1.75. 127 3-hydroxy-phenyl 397.14 1.6 128 3-methoxy-naphthalene-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 20 131 3,4-dimethoxy-2-methyl-phenyl 455, 18 1.79 132 6- (acetylamino) -pyridine-3- 439.16 1.35 yl 133 2,6-dimethoxy-4-methyl-phenyl 455.18 1.8 134 2-benzyloxy-phenyl 487.18 2 07 1027833 160 1 6-methoxy-quinolin-2-yl 462.16 1.82 136 quinoxalin-6-yl 433.15 1.42 137 1.2-dimethyl-1 H-benzoimida-449.18 1.49 zol-5-yl 138 1H -indol-5-yl 420.15 1.7 5 139 2- (3,5-dimethyl-1H-pyrazol-505.2 1,6-4-yl) -5-methoxy-phenyl 140 8-methyl-2- oxo-1,2-dihydro-462,16 1.45 quinolin-6-yl 141 3-aminosulfonyl-phenyl 460.11 1.5 142 4- (3-methyl-6-oxo-3-piperi 492.21 1.54 dinyl) phenyl 143 2- (2-methoxyethoxy) phenyl 455.18 1.62 10 144 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- (methylsulfo-504.14 1.57 nyl) amino-phenyl 148 2 - {[(2 (2-dimethylpropyl) amino-494.22 1.85 no] carbonyl} phenyl 149 5-acetyl-2-ethoxypyridine-3 468.17 1.7 yr; 150 2- (2-methoxyethoxy) -pyridin 456.17 1.62 ne-3-yl 151 isoquinolin-4-yl 432.15 1.52 152 2-ethoxy-3-methoxy-phenyl 455.18 1/8 153 4 - [(IR) -1- (acetylamino) -. 466.19 1.47 ethyl] -phenyl 161 154 4-pyrimidin-4-yl-phenyl 459.16 1.6 155 3-methyl-2-propoxy-phenyl 453.2 2 156 4-ethoxy-pyridine-3- yl 426.16 1.5 157 2-chloro-4-methylsulfonyl-508.09 1.64 mino-phenyl 5 158 2-ethoxy-5-methanesulfonyl-503.14 1.68 phenyl 159 4-hydroxy-2- ( 2,2,2-trifluoro-495,13 1.65 ethyl) -phenyl 160 4-hydroxy-2-methoxy-phenyl 427.15 1.52 1161 4-cyano-pyridin-2-yl 407.13 1.55 162 2-pyridin-4-yl-3 H-benzoimi- 498.17 1/5 dazol-5-yl 10 1027833 162

Example 163:. (3-chlorophenyl) - {4- [4- (4-chlorophenyl) -5- [1.2.3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] piperidin -l-yl} -methanol 5 er o α 10 A mixture of the compound of preparation 10 (202 mg, 0.54 mmol), 4-chloroaniline (140 mg, 1.1 nunol) and trifluoroacetic acid (42 μΐ, 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 1 N sodium hydroxide solution and brine, then dried over Na 2 SO 4 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 form the title compound (234 mg).

^ -NMR (400 MHz, CD3OD): δ 1.80 - 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).

LCMS: m / z APCI + 482 [MH] +

Example 164 »(4-Chlorophenyl) - {4- [4- (4-chlorophenyl) -5- [1.2.3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] - piperidin-1-yl} -methanone 30 α 4-chlorobenzoyl chloride (49 μΐ, 0.38 mmol) was added to a mixture of the compound of preparation 12a (120 1 0 2 7 8 3 3 '35 163 mg, 0 , Trahol) and N-methylmorpholine (77 μΐ, 0.70 mmol) in dichloromethane (2 ml) and then it became. stirred for 2 hours at room temperature. The reaction mixture was diluted with dichloromethane, washed with 1 N sodium-5 hydroxide solution and the aqueous wash fraction was re-extracted with dichloromethane. The combined organic solutions were evaporated under reduced pressure to form an oil. This was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (90: 10: 1) to form the title compound as a white solid (160 mg).

X H NMR (400 MHz, DMSO-d 6): δ 1.60 - 1.82 (m, 4 H), 2.70 - 3.04 (m, 3 H), 3.54 (m, 1 H), 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); LCMS :. m / z APCI * 482 [MH] ♦

Example 165a; {4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] piperidin-1-yl} - ( 3,5-20 difluorophenyl) methanone 25 cf

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

^ -NMR (400 MHz, CD3OD): δ 1.80 - 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). . LCMS: m / z APCI + 484 [MH] + 35 1 027 8.333 164

Example 165b: {4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmettiyl-4H- [1,2,4] triazol-3-yl] -piperidine-1- yl} - (3,5-difluorophenyl) -methanone Triethylamine (3.2 ml, 23.0 mmol) was added to a slurry of the bis salt from preparation 12b (4.89 g, 7.12 mmol) in dichloromethane (25 ml) to form a pale yellow solution. The solution was cooled in an ice bath and then 3,5-dichlorobenzoyl chloride (0.95 ml, 8.09 mmol) 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 hydrogencarbohate and semi-saturated brine. The clear dichloromethane solution was then dried over magnesium sulfate and concentrated to form a white foam. Recrystallization from ethyl acetate gave the title compound as a white solid (2.69 g), identical to the material prepared as described in Example 165a.

20

Examples 166 - 167:

fVcN

25 N-A f V

\

The appropriate acid chloride (1.2 eq.) Was added to a solution of the amine of preparation 2 (1 eq.) And N-methylmorpholine (1.5 eq.) In dichloromethane (5.5 ml / mmol) and the reaction mixture was stirred at room temperature for 4 hours. Tris (2-aminoethyl) amine polystyrene (3.85 mmol / g) was added and the reaction mixture was stirred for an additional hour. A saturated ammonium chloride solution was added and the mixture was then stirred for 20 minutes and the layers were separated using a hydrophobic membrane. The organic phase was washed with a saturated sodium bicarbonate solution, the layers were separated, and the organic solution was evaporated under reduced pressure to form the title compounds.

5 Ex. Z Opbr Data

Nr.

(%) 166 Neopentyl 39 / H NMR (400 MHz, CDCl 3): δ 1.00 (s, 9H), 1.71 (m, 2H), 1.82 (m, 1H), 1.98 ( m, 1H), 2.20 (s, 2H), 2.24 (s, 3H), 2.57 (m, 1H), 2.65 (m, 1H), 3.00 (m, 1H), 3.98 (m, 1H), 4.57 (m, 1H), 7.20 (d, 2H), 7.57 (d, 2H). LCMS: m / z APCI + 375 [MH] + 167 Cyclooro-39 "H-NMR (400 MHz, CDCl3): δ 0.73 pvl (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: in / z APCI * 347 [MH] * Example 168 - 173: 15 Vy

A mixture of the correct amine or amine salt, selected from preparations 12a, 100, 118, 119, 143 and 152 (1 eq.), The correct acid chloride (W-PhCOCl) (1.2 - 1.4 eq) .) And N-ethyl diisopropylamine (4 eq.) In dichloromethane (16 ml / mmol) was stirred at room temperature for 2 hours. Thereafter, tris (2-aminoethyl) amine polystyrene was 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 after-products were purified by column chromatography on silica gel using ethyl acetate: methanol: 0.88 ammonia (90: 10: 1) as eluent to form the 10. title connections.

isKssessssasssssasssss ^ sase ^ ssss ^ ssssssKsssssassesaiasBsssssss ^^ asnBasraBaBzs ^ aBnEa & ssssssasK

Ex. Data 168 W, 3-F, 4-CH 3; Y = 4-Cl; Y '= 2-Cl; X = CH3 - NMR (400 MHz, CDCl3): δ 1.77 - 1.99 (m, 4H), 2.19 (S, 3H), 2.26 (s, 3H), 2.59 (m (1 H), 2.84 - 3.02 (m, 2 H), 3.83 (m, 1 H), 4.55 (m, 1 H), 7.02 (m, 2 H), 7.18 - 7, 28 (m, 2H), 7.48 (m, 1H), 7.66 (s, 1H); LCMS: m / z APCI * 447 [MNa] * .169 * W = 3-F, 4-CH 3; Y = 4-Cl; Y '® 2-F; X = CH 3, 1 H NMR (400 MHz, CDCl 3): δ 1.75 - 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 APCI + 431 [MH] + 170 W = 3,5-di-Cl; Y = 4-Cl; Y '= 2-OCH 3; X = CH 3 1 H NMR (400 MHz, CD 3 OD): δ 1.70 - 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 (β, ΊΗ) »LCMS: m / z APCI * 480 [MH] + 15 171 * W = 2-F, 3-C1; Y = 4-Cl; Y '= Η; X δ CH 2 OCH 3 CH 3 / H NMR (400 MHz, CDCl 3): δ.1.08 (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.

APCI * 477 [M1 * ·.

1,027,833. . 167. .

172 * W = 4-Cl; Y = 4-Cl; Y '= Η; X = CH 2 CF 3 - NMR (400 MHz, CDCl 3): δ 1.81 (ra, 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, 2 H). LCMS: m / z APCI * 483 [M] * 173® W = 2-OCF3; Y = 4-C1; Y '= Η; X = [1,2,3] trio

zol-2-ylmethyl B

1 H NMR (400 MHz, CDCl 3): δ 1.76 (m, 1H), 1.79-1

2.02 (m, 3 H), 2.68 (m, 1 H), 2.82 - 3.02 (m, 2 H), |

3.58 (ra, 1H), 4.59 (m, 1H), 5.62 (s, 2H), 6.99 I

(m, 2H), 7.22-7.42 (ra, 6H), 7.5O (s, 2H).

LCMS: m / z APCI * 532 [MH] + A = 4 eg. triethylamine were used and the crude product was not treated with amine supported on polymer.

: B = 10 eq. polymer-supported N-ethyl diisopropylamine was used instead of N-ethyl diopropylamine.

Examples 174 - 187 $

10 K. ^ NV

\ y — x w o. 15 ·

The correct acid chloride (W-PhCOCl) (1.0 - 1.5 eq.) Was added to a solution of the correct amine hydrochloride or amine selected from the preparations 120-121, 132, 134-135, 137, 139 - 142, 151, 153 - 154, and 169 (1 eq.) And triethylamine (1.2 - 1.5 eq.) In dichloro-urethane (10-25 ml / mmol). The reaction mixture was stirred at room temperature for 18 hours. The mixture was then diluted with dichloromethane, washed with saturated sodium carbonate solution, followed by ammonium chloride solution and then concentrated 1027,833 m · 168 under reduced pressure. The crude products were purified by column chromatography on silica gel using dichloromethane: methanol (100: 0 to 90:10) as eluant to form the title compounds.

5 Ex. Data 174 * W = 3-Cl; Y = 4-Cl; Y '2-CH 3; X »CH3 - NMR (400 MHz, CDCl3): δ 1.65 - 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, 1 H). LCMS: m / z APCI * 451 [MNa] *! • - - - - - -: 175 * W - 3,5-di-Cl; Y "4 4-Cl; Y '- Η; X = CH 2 OCH 3 1 H-NMR (400 MHz, CD 3 OD): δ 1.81 - 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 APCI + 479, 481 (MH) 176 176A W = 4-Cl; Y = 4-Cl; Y '= Η; X = CH 2 OCF 3.

X H NMR (400 MHz, CDCl 3): δ 1.81 (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, 2 H). LCMS: m / z APCI * 499 [M] * 177® W = 3,5-di-P; Y = 4-Cl; Y '= Η; X = CH 2 OCH 2 CF 3 1 H-NMR (400 MHz, CDCl 3): δ 1.80 - 2.02 (m, 4 H), 2.79 (m, 1 H), (2.83 - 3.05 (m, 2 H), 3, 80 (m, 3H), 4.58 (m, 3H), 6.85 (m, 3H), 7.22 (d, 2H), 7.57 (d, 2H) LCMS: m / z APCI + 515 [MH] * 1027833 • *. 169 178 W = 3-Cl; Y = 4-Cl; Y '= Η; X = (2-oxopyrrolidin-n-1-yl) methyl; Ή NMR (400 MHz, CDCl 3) ): δ 1.78 - 2.00 (m, 6H), 2.22 (t, 2H), 2.75 (m, 1H), 2.97 (m, 2H), 3.48 (t, 2H) ), 3.80 (m, 1 H), 4.42 (s, 2 H), 4.58 (m, 1 H), 7.00 (d, 2 H), 7.23 (d, 1 H), 7.38 (m, 3H), 7.58 (d, 2H) LCMS: m / z APCI + 499, 501 [MH] * 179 * W = 3,5-di-Cl; Y = 4-Cl; Y '- Η ; X? = Morpholin-4-ylmethyl; - NMR (400 MHz, CDCl3): δ 1.78 - 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 APCI * 534 [M] + 180 W = 3-F; Y - 4-Cl; Y '= Η; X = 1H - tetrazol-1-ylmethyl; - NMR (400 MHz, CDCl 3): δ 1.60 - 1.83 (m, 4H), 2.60 - 2.78 (m, 2H), 3.00 (m 1 H), 3.90 (m, 1 H), 4.50 (m, 1 H), 5.58 (s, 2 H), 6.9 Δ (m, 2H), 7.50 (m, 2H), 7.29 (m, 1H), 7.60 (d, 2H), 8.79 (e, 1H). LCMS: m / z ES + 481, 4.83 [MH] + 181. W · 3-Cl; Y = 4-Cl; Y '; X = 2-methylimidazo-3-ylmethyl; ^ -NMR (400 MHz, CDCl 3): δ 1.77 - 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 APCI * 495, 497 [MH] + .1 0 2 7 8 3 3 • "" Λ. * 170 182 W = 3-Cl; Y = 4-Cl; Y '= H; X = 3-methyl- [1,2,4] oxadiazol-5-ylraethyl; ^ -NMR (400 MHz, CDCl 3): δ 1.80 (m, 2H), 1.98 (m, 2H), 2.30 (s, 3H), 2.76 (m, 1H), 2.95 (m, 2H), 3.80 (τη, 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 APCI * 497, 499 [MH] + - -: - -: - 183 W = 3.5-di-F; Y = 4-Cl; Y '= Η; X = [1,2,4] triazol-1-ylmethyl; ^ -NMR (400 MHz, CDCl3): δ 1.82 (τη, 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, 2 H), 7.82 (s, 1 H), 8.04 (s, 1 H). LCMS: m / z APCI + 484, 486 [MH] * 184 * W = 2-F, 3-Cl; Y = 4-Cl; Y '= Η; x'-pyrimidine-2-yloxymethyl; ^ -NMR (400 MHz, CDCl3): δ 1.75 (τη, 2H), 1.97 (m, 2H), 2.81 (m, 1H), 2.88 τ 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 (τη, 1 H), 7.36 (d, 2 H), 7.44 (m, 3 H), 8.44 (d, 2 H). LCMS: m / z APCI * 527 [M] * 185 W = 2-F, 3-Cl; Y = 4-Cl; Y '· - Η; X - 2-pyridine-2-ylethyl; ^ -NMR (400 MHz, CDCl 3): δ 1.58 - 1.98 (m, 4H)., 2.75 (m, 1H), 2.90 - 3.00 (τη, 2H), 3.04 - 3.18. (m, 2H), 3.42 (tn, 2H), 3.61 (m, 1H), 4.60 (m, 1H), 7.10 - 7.27 (m, 6H), 7.42 ( m, 1 H), 7.56 (d, 2 H), 7.82 (m, 1 H), 8.48 (s, 1 H). LCMS: m / z APCI * 524 [MH] * 1027833 171 186 W, = 3-Cl; Ύ =. 4-C1; Y '= Η; X * 2-Morpholine-4-ylethyl 1 H-NMR (400 MHz, CDCl 3): δ 1.80 (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 APCI * 514 [M] * 187 W + 5-Cl, 2-F; Y = 4-Cl; Y '= Η; X - 2- (3,5-dimethyl-isoxazol-4-yl) -ethyl; 1 H NMR (400 MHz, CDCl 3): δ 1.75 - 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 (τη, 1H), 6.75 (m, 2H), 7.01 (m, 1H), 7.37 (m , 2H), 7.57 (d, 2H), LCMS :. m / z APCI * 542, 544 [MH] * A = ethyl acetate: methanol: 0.88 ammonia was used as eluent for the column.

B = 2 eg. N-methyl morpholine was used in place of triethylamine.

C = 3 equivalents of N-methylmorpholine were used instead of triethylamine.

10

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

The title compound was obtained as a white solid from the compound of preparation 138 and isovaleryl chloride, following the method as described for Examples 174 - 187.

1027835 172 X H NMR (400 MHz, CDCl 3): δ 1.01 (s, 9H), 1.70-1.85 (m, 2H), 1.98 (m, 3H), 2.22 (m, 2 H), 2.55 - 2.66 (m, 2 H), 3.00 (m, 1 H), 4.00 (m, 1 H), 4.59 (m, 1 H), 5.18 (s, 2 H) ), 6.60 (s, 1H), 6.90 (m, 2H), 7.00 (s, 1H), 7.20 (s, 1H), 7.52 (m, 5 2H); LCMS: m / z APCI * 441 [MH] +

Examples 189 - 1981 10 γ

The appropriate acid chloride, ZCOCl, (1.0 eq.) Was added to a solution of the correct amine selected from preparations 122-131 (1 eq.), And triethylamine (1.1 eq.) In dichloromethane (4 ml / mmol). The reaction mixture was stirred at room temperature for 1 hour. It was then diluted with water, stirred for> 5 minutes, and 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 products were separated with ether as azeotrope to form the title compounds as a white foam.

rsgBSBgSBBS ^ BSSSBSSSS & SSSBS = S = SBSSSSSSBSSSSSSS = SBS ±., 1 "-I ..........,. 18ίΒ8ΤΒΒΜηη888ΒΒ3ΒΒΒ88

Ex. Data . . Nr. 189 Z = 3-chloro-2-fluorophenyl; Y = H; Y '= H; • NM NMR (400 MHz, CDCl 3): δ 1.68 - 2.07 (m, 4H), 2.75 (m, 1H), 2.92 (m, 1H), 3.01 (m, 1H ), 3.61 (m, 1H), 4.60 (m, 1H), 5.64 (s, 2H), 7.06 (d, 2H), 7.13 (t,; 1H), 7 , 38-7.57 (m, 7H). LCMS: m / z ES ♦ 488 [MNa] * 1 027 8 33 - k 173

190 Z = 3-chloro phenyl; Y = 4-OCH 3; Y # = Η; I

^ -NMR (400 MHz, CDCl 3): δ 1.75 - 2.20 (m, 4H), 2.79 (m, 1H), 2.93 (m, 2H) ,. 3.80 (m, 1H), 3.84 (S, 3H), 4.56 (m, 1), 5.66 (s, 2H), 6.94 (m, 2H), 7.01 (m (2H), 7.26 (m, 1H)., 7.28 - 7.40 (m, 3H), 7.51 (s, 2H). LCMS: m / z ES * 500 [MNa] * 191 Z = 3-chloro-2-fluorophenyl; Y = 4-F; Y '= H; X H NMR (400 MHz, CDCl 3): δ 1.72 - 2.07 (τη, 4H), 2.77 (m, 1H), 2.90 (m, 1H), 3.02 (m, 1H) , 3.62 (m, 1H), 4.61 (m, 1H), 5.64 (s, 2H), 7.05-7.19 (m, 6H), 7.41 (t, 1H), 7.49 (s, 2H). LCMS: m / z ES * 503 [MNa] * 192 Z = 3-chloro-2-fluorophenyl; Y = 4-F; Y '= H; 1 H NMR (400 MHz, CDCl 3): δ 1.71 - 2.06 (m, 4 H), 2.72 (m, 1 H), 2.94 (m, 1 H), 3.05 (m, 1 H ), 3.63 (m, 1H), 4.62 (m, 1fl), 5.65 (s, 2H), 6.95 (d, 2H), 7.14 (t, 1H), 7.27 (m, 1H), 7.43 (t, 1H), 7.49 (S, 2H), 7.60 (d, 2H). LCMS: m / z ES * 546 [MH] * 193 Z. = 3-chloro-2-fluorophenyl; Y = 4-CF 3; Y '- H; X H NMR (400 MHz, CDCl 3): δ 1.75 - 2.15 (m, 4H), 2.76 - 2.94 (m, 2H), 3.05 (m, 1H), 3.62 ( m, 1H), 4.67 (m, 1H), 5.76 (s, 2H), 7.14 (dd, 1H), 7.20 - 7.30 (m, 2H), 7.36 - 7 , 50 (m, 4H), 7.75 (d, 2H). LCMS: m / z ES * 556 [MNa] * 5 194 Z = 3-chlorophenyl; Y - 4-CH 3; Y '= H; 1 H NMR (400 MHz, CDCl 3): δ 1.88 (m, 2H), 2.06 (m, 2H), 2.42 (s, 3H), 2.79 - 3.00 (m, 3H ), 3.80 (m, 1H), 4.59 (m, 1H), 5.70 (s, 2H), 7.07 (d, 2H), 7.23 - 7.40 (m, 6H) , 7.53 (s, 2H). LCMS: m / z ES *. 484 [MNa] * 1027833 174 195 Z = 3-chloro-2-fluorophenyl; Y. = 4-CN; Y 'H; X H NMR (400 MHz, CDCl 3): δ 1.67 - 2.00 (m, 4H), 2.67 (tri, 1H), 2.80 - 3.08 (m, 2H),. 3.60 (m, 1 H), 4.58 (m, 1 H), 5.64 (s, 2 H), 7.11 <t, 1 H), 7.16 - 7.25 (m> 3 H), 7 , 41 (t, 1H), 7.46 (s, 2H), 7.75 (d, 2H). LCMS: m / z ES * 513 [MNa] * 196 Z = 3-chloro-2-fluorophenyl; Y = 4-Cl; Y '2-CH 3; * 1 H NMR (400 MHz, CDCl 3): δ 1.68 - 1.98 (m, 6H), 2.07 (m, 1H), 2.60 (m, 1H), 1.80 - 3.13 (τη, 2H), 3.60 (d, 1H), 4.60 (d, 1H), 5.55 (d, 1H), 5.67 (d, 1H), 6.86 - 7.50 ( m, 8 H). LCMS: m / z ES * 536 [MNa] * 197 Z = 3-chlorophenyl; Y = 4-C1; Y '= 3-F; ^ -NMR (400 MHz, CDCl 3): δ 1.84 (m, 2H), 2.00 (ra, 2H), 2.72 (τη, 1H), 2.94 (m, 2H), 3.83 (τη, 1H), 4.55 (m, 1H), 5.67 (S, 2H), 6.9 (d, 2H), 7.26 - 7.41 (m, 4H), 7.50 - 7.56 (m, 3 H). LCMS: m / z ES * 500 [MH] * 198 Z · 3-chloro-2-fluorophenyl; Y - 4-Cl; Y '= 3-Cl; ^ -NMR (400 MHz, CDCl 3): δ 1.80 (m, 1H), 1.86 - 2.05 (ra, 3H), 2.74 (m, 1H), 2.92 (m, 1H) , 3.04 (m, 1H), 3.61 (m, 1H), 4.61 (m, 1H), 5.70 (s, 2H), 7.05-7.16 (m, 3H), 7.27 (br s, 1 H), 7.40 (t, 1 H), 7.50 (S, 2 H>, 7.55 (d, 1 H). LCMS: m / z ES * 534 [MNa] * 5

Examples 199 - 201: 10 - or 2 Cl

A mixture of the appropriate acid, ZCO3 H, (1.2 eq.), 1-hydroxybenzotriazole hydrate (1.2 eq.), Triethylamine (2-4 1027833 • 175.

eq.) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1/2 eq.) and the appropriate amine or amine hydrochloride selected from Preparations 2 and 143 (1 eq.) in dichloromethane ( 26.ml / mmole) was stirred for 24 hours at room temperature. The reaction mixture was. then washed with a 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 form the title compounds.

| Bsssssss = ssss3assss = aBs = ss9BBsssBssBs; ^ anB8BaaaaBaaBBssaas |

Ex. data

Nr.

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 ( in, 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 APCI + 403 [MH] 4 15 200 * Z = 5-trifluoromethylpyridin-2-yl; X 2 = CH 3 OCH 2 CH 3 1 H-NMR (400 MHz, CDCl 3): δ 1.08 (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 APCI + 494 [MH] 4. 201 "Z = 1H-indazol-3-yl; Y = 4-C1; Y '- Η; X - CH3 - NMR (400 MHz, CDCl3): δ 1.65 - 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), 13.42 (s, 1H). LCMS: m / z APCI4 421 [MH] 4 1027833 176 A = 5- (trifluoromethyl) -2-pyridinecarboxylic acid was used and can be prepared as described in J. Org. Chem. (European) 2003; (8); 1559-1568.

B = the reaction was carried out in the absence of 1-5 hydroxybenzotriazole hydrate and triethylamine.

Examples 202 - 204: JO -: 2 Cl

A solution of the correct acid, ZCO, H, (1.5 eq.), 0-15 benzotriazol-1-yl-Ν, Ν, Ν ', N'-tetramethyluronium hexafluorophosphate (2 eq.j, N methyl morphoiine (5 eq.) and the appropriate amine hydrochloride selected from Preparations 2 and 133 (1 eq.) in dichloromethane (8 ml / mmol) was stirred at room temperature for 24 hours, and the reaction mixture 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 form the title compounds.

Ex. data

Nr.

202 Z = 4-chloro-3-fluorophenyl; X = CH 3> -NMR (400 MHz, CD 3 OD): δ 1.79 - 1.99 (m, 4H), 2.23 (s, 3H), 2.85 (m, 2H), 3.11 ( m, 1 H), 3.70 (m, 1 H), 4.58 (m, 1 H), 7.22 (d, 1 H), 7.37 (d, 1 H), 7.45 (d, 2 H), 7.58 (m, 1 H), 7.64 (d, 2 H). LCMS: m / z APCI + 433 [M] + 1027833 177 203 Z = 2,3,4-trifluorophenyl; X '- = CH3; ^ -NMR (400 MHz, CD3OD): δ 1.82 (ra, 3H), 1.98 (m, 1H), 2.22 (s, 3H), 2.89 (m, 2H)., 3, 15 (ra, 1H), 3.60 (m, 1H), 4.60 (m, 1H), 7.12 (m, 2H), 7.44 (m, 2H), 7.66 (m, 2H) ). LCMS: m / z APCI * 435 [M] + 204 Z = 1H-indazol-3-yl; X »3-methyl-isoxazol-5-ylmethyl; 1 H NMR (400 MHz, CDCl 3): δ 1.80 - 2.15 (ra, 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). LCMSi m / z ES + 500, 502 [M] +

Examples 205 - 207: 5 0 <N Λ 10

A solution of the correct acid, ZCOaH (1.2 eq.), O-benzptriazol-1-yl-N, N, N,, N'-tetramethyluronium hexafluorophosphate (1.2 eq.), N-methylmorpholine (1.4 eq.) And the appropriate amine selected from Preparations 12 and 136 (1 eq.) In dichloromethane (7-10 ml / mmol) was stirred for 24 hours at room temperature. The reaction mixture was then partitioned between a sodium hydroxide solution and dichloromethane and the layers were (separated. The organic solution was washed with an ammonium chloride solution, dried over MgSO 4 and then evaporated under reduced pressure. The crude product was purified by of column chromatography on silica gel using an elution gradient of dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) to form the title compounds.

1027833 178

Ex. data

Nr.

205 * Z = 3-difluoromethyl-phenyl: X »[1,2,3] triazol-2-ylmethyl X H NMR (400 MHz, CDCl3): δ 1.78 - 2.0.0.2 (m, 4H) 2.70 (ra, 1H), 2.95 (ra, 2H), 3.80 (τη, 1H), 4.58 (m, 1H), 5.63 (s, 2H), 6.50 - 6.80 (t, 1H), 7.01 (d, 1H), 7.42 - 7.58 (ra, 8H). LCMS: m / z APCI * 498, 500 [MH] * 206>, c Z * * 4-difluoromethyl-phenyl; X = [1,2,3] triazol-2-ylmethyl1 H NMR (400 MHz, CDCl3): b 1.78 (m, 2H), 1.97 (m, 2H), 2.66 (m, 1 H), 2.90 (m, 2 H), 3.78 (ra, 1 H), 4.58 (m, 1 H), 5.61 (s, 2 H), 6.46 - 6.78 (t, 1 H ), 6.98 (d, 2H), 7.22 (s, 2H), 7.39-7.57 (m, 8H).

LCMS: m / z APCI * 498, 500 [MH] + 5 207 Z = 1H-indazol-3-yl; X = 2-piperidin-1-yl-ethyl; 1 H-NMR (400 MHz, CDCl 3): δ 1.38 (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 (ra, 1H), 7.54 (m, 3H), 8.02 (d, 1H). LCMS: m / z APCI * 518 [M] + A = 3-difluoro-methyl-benzoic acid was used. This core is prepared according to Tetrahedron 31/1977; 391-401.

B = 4-difluoromethyl-benzoic acid was used. This can be prepared according to Tetrahedron 31/1977 / 391-401.

C = the product was further recrystallized from ieopropyl alcohol and 2.8 g. N-methyl morpholine used.

15 1 0 27 8 33 - 179

Examples 208 - 210t XV, '

5 fX

2 y V.

! A. mixture of the correct oxadiazole selected from preparations 66 and 67 (1 eg.) / the correct aniline of preparations 166 and 168 or commercially available 4-10 chloro-2- (trifluoromethoxy) phenylamine (1.5 - 2.0 eq.) And trifluoroacetic acid (0.5 - 1.0 eq.) In toluene (2.5 - 9.5 ml / mmol) was heated at 110 ° C for 18 hours. The cooled mixture was partitioned between dichloromethane and a sodium carbonate solution and the layers were then separated. The organic phase was dried over MgSO 4 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 an eluent to form the title compounds.

Ex. data

Nr.

208 Z + 3 - chloro phenyl; Y = 4-Cl; Y '= 2-OCH 2 CH 3; X = H; Ή-ΝΜΚ (400 MHz, CDCl 3): δ 1.23 (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, 3 H), 8.43 (s, 1 H). LCMS: m / z APCI * 445 [MH] + 209 Z = 3-chlorophenyl; Y = 4-Cl; Y '= 2-OCF 3; X = H; 1 H-NMR (400 MHz, CDCl 3): δ 1.80 - 1.98 (τη, 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 , 1 H), 8.62 (s, 1 H).

LCMS: m / z APCI + 485 (M) + 1027833 180 210 Z = 4-chlorophenyl; Y ≤ 4 Cl; Y '= 2-pyrrolidin-1-ylmethyl; X = CH 3; ^ -NMR (400 MHz, CDCl 3): δ 1.64 - 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, 1 H), 7.09 (m, 1 H), 7.30 - 7.44 (m, 5 H), 7.62 (s, 1 H). LCMS: m / z APCI * 498 [M] +

Examples 211 - 216: z Y '10 A mixture of the correct oxadiazole selected from the preparations 66 - 69, 71 and 75 (1 eg.), Aniline (1.5 - 2.0 eq.) And trifluoroacetic acid ( 0.5 - 1.0 eq. In toluene (1.0-2.5 ml / mmol) was heated to 170 - 185 ° C 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 an eluent to form the title compounds.

Ex. Data 20 Nr.

211 Z = 3-chloro phenyl; Y = 4-C1; Y '= 2-OCH 2 CH 3; X = H; 1 H NMR (400 MHz, CDCl 3): δ 1.78 - 2.02 (m, 4H), 2.80 (m, 1H), 2.95 - 3.06 (m, 2H), 3.81 ( m, 1 H), 4/40 (q, 2 H), 4.58 (m, 1 H), 7.17 (s, 1 H), 7.25 (m, 3 H), 7.38 (m, 3 H), 8.18 (s, 1H). LCMS: m / z APCI + 499 [M] * 1027833 181 212 * Z = 4-chlorophenyl; Y = 4-Cl; Y '= Η; X = CF 3; Ή NMR (400 MHz, CDCl 3): δ 1.82 (m, 2H), 2.00 (m, 2H), 2.76 (m, 1H), 2.83 - 3.02 (τη, 2H) , 3.83 (ra, 1H), 4.60 (m, 1H), 7.22 (d, 2H), 7.37 (d, 2H), 7.40 (d, 2H), 7.60 (d, 2H). LCMS: m / z APCI * 469 (M] * 213 Z-3-chlorophenyl; Y = 4-Cl; Y '= Η; X -CH2 OCH2 CH3; ^ -NMR (400 MHz, CDCl3): δ 1.08 (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 APCI + 459 [M] + j - - - ....... II .. ··· - 214 Z = 4-chlorophenyl; Y-4-CH 3, Y '= 2-CH 3, X = CH 3, 1 H-NMR (400 MHz, CDCl 3): δ 1.68 - 2.00 (m, 7H), 2.14 (s, 3 H), 2.40 (s, 3 H), 2.58 (ra, 1 H), 2.78 - 2.98 (m, 2 H), 3.78 (m, 1 H), 4.54 (m, 1 H ), 6.97 (m, 1H), 7.15 (m, 1H), 7.20 (s, 1H), 7.30 (d, 2H), 7.36 (d, 2H) .LCMS: m / z APCI * 409 [MH] * 215 Z = 4-chlorophenylY = 4-C1; Y '= 2-CH3; X = CH2 CH3; ^ -NMR (400 MHz, CDCl3): δ 1.20 (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, 1 H), 4.58 (m, 1 H), 7.04 (m, 1 H), 7.26 - 7.39 (m, 5 H), 7.41 (s, 1 H). m / z ES * 443, 446 [MH] + 5 216 Z = 3-chlorophenyl; Y = 4-C1; Y '= Η; X - pyrazoo 1-1-ylmethyl; 1 H-NMR (400 MHz; CDCl3): δ 1.80 - 1.97 (m, 4H), 2.82 (m, 2H), 3.06 (ra, 1H), 3.69 (m, 1H), 4.58 (m, 1 H), 5.41 (S, 2 H), 6.18 (s, 1 H), 7.20 (ra, 2 H), 7.30 (m, 2 H), 7.38 - 7.57 (τη, 5 H ). LCMS: m / z APCI + 481 [M] + Ί O-27'β 33 - 182 A = The crude reaction mixture was partitioned between ethyl acetate and a 2N hydrochloric acid and the organic solution was washed with a saturated sodium bicarbonate solution and evaporated under reduced pressure .

5

Examples 217 - 222: rJQ? 10 0 ^^ 4 \ r · 'R α

A solution of the correct acid selected from the preparations 158 and 159 (1 eq., 1-hydroxybenzotriazole hydrate (1.5 eq.), Triethylamine (4 eq.) And 1- (3-dimethylamine). laminopropyl) -3-ethylcarbodiimide hydrochloride (1.5 eq.) in dichloromethane (3.5 ml / mmol) was added to a solution of the appropriate amine (NHR 4 R 5) (1.5 eq.) in dichloromethane (2.5 ml / mmol) and the reaction mixture was stirred at room temperature for 24 hours.The reaction mixture was then washed with an ammonium chloride solution and the organic solution was evaporated under reduced pressure.The crude product was purified by column chromatography on silica gel using a elution gradient of dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 95: 5: 0.5) to form the title compounds.

Ex. Data "" Nr. .

217A R4 = H; R5 = bicyclo [1.1.1] pent-1-yl / X = CH3; 1 H-NMR (400 MHz, CDCl 3): δ 1.58 - 1.78 (m, 4H), 1.86 (tri, 3H), 2.02 (m, 5H)., 2.22 (θ, 3H ), 2.79 (m, 2H), 3.32 (m, 2H, 5.90 (s, 1H), 7.24 (d, 2H), 7.54 (d, 2H). m / z APCI + 486 [MH] + 1 0 27 8 33 183 218 R 4 = H; R 5 = t-butyl; X = [1,2,3] triazol-2-ylmethyl X H NMR (400 MHz, CDCl 3) δ 1.29 (β, 9H), 1.55 1.74 (m, 4H), 1.9 - 2.09 (m, 1H), 2.80 (ra, 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 APCI * 443 [MH] * 219 NR 4 R 5 = azetidin-1-yl; X = [1,2,3] triazol-2-ylmethyl; X H NMR (400 MHz, CDCl 3): δ 1 , 56 - 1.68 (m, 4H), 2.18 - 2.30 (m, 3H), 2.80 (ra, 2H), 3.37 (m, 2H), 3.98 (t, 2H), 4.16 (t, 2H), 5.59 (β, 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-ylraethyl; 1-NMR (400 MHz, CDCl 3): δ 1.59 - 1.76 (m, 4H), 1.82 (ra, 2H), 1.95 (m, 2H), 2.41 (m, 1H), 2.82 (m, 2H), 3.36 - 3.46 (ra, 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; X H NMR (400 MHz, CDCl 3): δ 1.58 - 1.78 (m, 4 H), 2.56 (m, 1 H), 2.82 (m, 2 H), 3.38 (m, 2 H) , 3.44 (τη, 2H), 3.60 (ra, 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] * 5 222 R 4 = H; R 5 = 2-phenylethyl; X = [1,2,3] triazol-2-ylmethyl; X H NMR (400 MHz, CDCl 3): δ 1.52 - 1.68 (m, 4 H), 2.04 (m, 1 H), 2.79 (m, 4 H), 3.36 (m, 2 H) , 3.47 (m, 2H), 5.40 (m, 1H), 5.59 (s, 2H), 7.10 (d, 2H), 7.17 (d, 2H), 7.20 - 7.36 (ra, 3H), 7.40 (d, 2H), 7.54 (s, 2H). LCMS: m / z ES * 491 [MH] * 1027833 184 A = 1-bicyclo [11.1] pentylamine hydrochloride (see ref. J.O.C. 2001; 66 (19); 6282-6285).

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

HC j CH ’L J

10. ch, α

Oxalyl chloride (0.04 ml, 0.55 mmol) was added to a solution of the acid from 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 a further 10 minutes. The solution was then evaporated under reduced pressure and the residue was separated off (3x) as azeotrope with dichloromethane. 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 mixture was then washed with an ammonium chloride solution, dried over MgSO 4 and then 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 form the title compound 30 as a solid, 30 mg.

X H NMR (400 MHz, CDCl 3): δ 1.15 (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 APCI4 376 [MH] + 35.

1Θ-2 7 8 3 5 ..

185

Example 224: N- {1- [4- (4-Chlorophenyl) -5-methyl-4 H -1,2,4-triazol-3-yl] -piperidine-4-yl} benzaniide, e.g.

a

Triethylamine (105 μΐ, 0.75 mmol) and then benzoyl chloride (79.6 μΐ, 0.69 mmol) were added to a solution of the amine. of preparation 145 (200 mg, 0.69 mmol) in dichloromethane (5 mL) and the reaction mixture 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 pattern and the organic layer was concentrated under reduced pressure. The residue was then separated as ether azeotrope to form the title compound as an off-white solid, 278 mg.

20 a H NMR (400 MHz, CD3 OD): δ 1.55 (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) β LCMS: m / z APCr 418 [MNa] + Example 225: 1-Benzoyl-4- [4- (4-chlorophenyl) -5-methyl-4H-1,2,4-triazole -3-yl] piperazine o / - <u. 30 /

Cl 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 left behind. 35 subsequently added to a solution of benzoic acid (110 mg> 0.9 mmol) in dichloromethane (10. ml). The reaction mixture was then stirred at room temperature for 18 hours.

1027833 186

The mixture was partitioned between a 2M sodium hydroxide solution and dichloromethane and then 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 form the title compound as a white foam, 182 mg. 10 * H-NMR (400 MHz, CDCl 3): δ 2.22 (s, 3H), 3.08 (m, 4H), 3.38 - 3.78 (m, 4H), 7.25 (d, 2 H), 7.39 (m, 4 H), 7.54 (d, 3 H). LCMS: m / z APCI * 382 [MH] *. Microanalysis found: C, 61.66; H, 5.32; N, 17.42. C 30 H 20 ClN 5 O; 0.14 CH 2 Cl 2 requires C, 61.43; H, 5.19; N, 17.79%.

3.5

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

Triethylamine (100 μΐ, 0.71 mmol) and then benzoyl chloride (82 μΐ, 0.71 mmol) were added to a solution of the compound of preparation 149 (150 mg, 0.47 mmol) in dichloromethane (10 ml) and the reaction mixture 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 form the title compound as a white solid, 120 mg.

1 H-NMR (400 MHz, CDCl 3): δ 1.01. - 1.16 (ra, 3H), 3.18 - 3.23 (τη> 3H), 3.30 (s, 3H), 3.39 - 3.48 (m, 3H), 3.83 (ra 1 H), 1027833 187 4.04 (πν 1Η), 4.28 (d, 1 H), 4.38 (d, 1 H), 7.39 (m, 7 H), 7.52 (d, 2 H); LCMS: m / z APCI + 426 [MH] 4

Example 227: 1- (4-Chlorobenzoyl) -4- [4- (4-chlorophenyl) -5-5 methoxymethyl) -4 H -1,2,4-triazol-3-yl] -2-methylpiperazine / = (Χ0Η ,

SJ

.10 ci /. α

The title compound was prepared from the compound of preparation 150 and 4-chlorobenzoyl chloride in 37% yield, following the method described for Example 226.

X H NMR (400 MHz, CDCl 3): δ 1.08 (d, 3H), 2.94 - 3.39 (m, 8H), 4.34 (s, 2H), 7.25 (d, 2H) , 7.39 (m, 4H), 7.54 (d, 2H); LCMS: m / z APCI * 460 [M] * Example 228: 1- [4- (4-Chlorophenyl) -5- (methoxymethyl) -4H-1,2,4-triazol-3-yl] -4- (3-fluorobenzoyl) -1,4-diazepane (/ -Λ ^ Λν'Λν0Η.

TV ό

Cl

The title compound was prepared from the compound of .30 preparation 148 and 3-fluorobenzoyl chloride in 84% yield, using the method described for Example 224. was followed.

1 H NMR (400 MHz, CDCl 3): δ 1.68 - 1.80 (m, 2H), 3.17 (m, 1H), 3.25 (s, 3H), 3.39 (m, 4H) ), 3.58 (m, 1H), 3.65 (m, 1H), 3.78 (m, 1H), 4.22 (d, 2H), 7.02 (d, 1H), 7> 10 (m, 2H), 7.22 - 7.42 (m, 3H), 7.49 (m, 2H); LCMS: m / z APCI * 444 [M] * 1 0 27 8 35. 188

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

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 for 2 hours at room temperature . The mixture was concentrated under reduced pressure and 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 for 2 hours at room temperature. Tris (2-aminoethyl) amino-poly-styrene (500 mg) was added and the mixture was stirred for an additional 20 hours. The mixture was then diluted with an aqueous ammonium chloride solution, the layers were separated with a hydrophobic membrane and the organic solution was immediately purified using a silica gel cartridge and dichloromethane: methanol (100: 0 to 95: 5) as eluent under the formation of the title compound.

X H NMR (400 MHz, CDCl 3) (rotamers): δ 2.23, 2.34 (2 x s, 3 H), 3.00 - 3.62 (m, 3 H), 3/64 - 4.00 (m (2 H), 4.11 - 4.40 (m, 1 H), 4.58, 4.90 (2 x m, 1 H), 7.17 - 7.40 (m, 6 H), 7.56 30 (m , 2H); L04S: 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 35 1027633 189 ·

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

^ -NMR (400 MHz, CDCl 3): δ 1.38 - 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, 7 H); LCMS: m / z ES * 451 [MNa] * 15. Example 231: 3- [1- (2-Chlorobenzpyl) pyrroidin-3-yl] -4- (4-chloro-2-methylphenyl) -5-methyl-4H-1,2,4-triazole

A mixture of the compound of preparation 147 (97 mg, 0.35 mmol), 2-chlorobenzoyl chloride (40.4 µl, 0.32 mmol). and N-methylmorpholine (58 μΐ, 0.53 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was then diluted with dichloromethane (20 ml), washed with 2N hydrochloric acid (20 ml) and one. saturated sodium bicarbonate solution (20 ml). The organic solution was. then dried over MgSO 4 and concentrated under reduced pressure. The remaining oil was triturated with ether, the resulting solid was filtered off. and then dried to form the title compound, 55 mg * 35. ^ -NMR (400 MHz, CDCl 3) (rotamers): δ 1.84 - 2.62 (m, 8H), 3.00 - 3.20 (m, 1H), 3.22 - 3.42 (m, 1 H), 3.44 - 3.79 (m, 10 2/6 33 190 2 H), 3.81 - 3.98 (m, 1 H), 7.20 - 7.50 (m, 7 H); LCMS: m / z AP CI + 415 [MH] *

Example 232: N- {1- [4- (4-Chlorophenyl) -5- (2H-1,2,3-triazol-2-ylmethyl) -4H-1,2,4-triazole-3- yl] pyrrolidin-3-yl} -N-methylacetamide JLn «* 0 Ί [T // * 10 xj Sa CT N - /

The title compound was obtained as a solid with a yield of 50% of the compounds of the preparations 54 and 18, following the method described for preparation 93. 1 H-NMR (400 MHz, CDCl 3) (rotamers): δ 1.78 - 1.90 (m, 2H), 2.04 (s, 3H), 2.74 (s, 1H), 2.80 (s, 3H), 2.98 (m (1 H), 3.04 - 3.18 (m, 2 H), 3.22 - 3.38 (τη, 2 H), 4.40, 5.21 (2 x m, 1 H), 5.55 (m, 2 H), 7.03 (d, 2 H), 7.38 (d, 2 H), 7.52 (s, 2 H); LCMS: m / z ES * 423 [MNa] *

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

On V '

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 mixture was then heated for 3 days at 100 ° C. The cooled mixture was gently quenched by the addition of 0.88 ammonia and then extracted with dichloromethane. (4 x).

-10 27 8 33 · **. * · _. . - 191.

The combined organic. layers were washed with brine, then dried over MgSO 4 and evaporated under reduced pressure. The product was crystallized from ethyl acetate to form the title compound, 5 282 g.

^ -NMR (400 MHz, CDCl 3): δ 2.06 (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: tert-Butyl-4 - {[4- (4-chlorophenyl) -5- (2H-1,2,3-triazol-2-ylmethyl) - 4H-1,2,4-triazol-3-yl] oxy} -piperidine-1-carboxylate Tetrahydrofuran (2 ml) was added to sodium hydride (24 mg, 60% in mineral oil), which was washed 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 for another 30 minutes at room temperature. The compound of preparation 164 (100 mg, 0.3 mmol) was added and the reaction mixture was stirred for a further 18 hours at room temperature. The reaction mixture 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) and 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, the filtrate was washed with a saturated aqueous potassium carbonate solution and evaporated under reduced pressure. The crude product 10 27 8 33 192 was purified by column chromatography on silica gel using dichloromethane: methanol (99: 1) as eluant. The product was further purified by HPLC using a Phenomenex Luna C1 8 column and 0.1% aqueous formic acid: acetonitrile / 0.1% formic acid (80:20 to 5:95) to form the title compound, 34 mg, .beta.-NMR (400 MHz, CD 3 OD): δ 1.40 (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) ,. 50 (m, 2 H).

Example 235: N- (tert-Butyl) -4- [4- (4-chlorophenyl) -5-methyl-4 H -1,2,4-triazol-3-yl] benzamide rV-CH. TX1 v M> c ch, α 20 tert-Butylamine hydrochloride (223 mg, 2.0 mmol), followed by a solution of the acid chloride from preparation 157 (150 mg, 0.4 mmol) in dichloromethane (3 ml) was added to a solution of triethylamine (300 μΐ, 2.0 mmol) in dichloromethane (2. ml) and the reaction mixture was stirred for 1 hour at room temperature. The mixture was then partitioned between dichloromethane and an aqueous citric acid solution 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 MgSO 4 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 form the title compound, 122 mg.

1021851 193 X H NMR (400 MHz, CDCl 3): δ 1.42 (s, 9H), 2.40 (θ, 3H), 5.98 (br s, 1H), 7.19 (d, 2H) ), 7.41 (d, 2H), 7.50 (d, 2H), 7.61 (d, 2H); LCMS: m / z ES * 391 [MNa] + 5 Examples 236 - 395: 10 ^

Cl '

The appropriate acid, ZCOaH, (0.25 ml, 0.2 M solution in N, N-dimethylformamide, 50 μχηοΐ) was neutralized with triethylamine (7 μl, 50 μϊαοί per salt equivalent) if necessary. ) and then heated with 0- (7-azabenzotriazol-yl) -N, N, N ', N' tetramethyluronium hexafluorophosphate solution (0.1 ml, 0.525 M, 52.5 phimol). The solution was then treated with triethylamine (28 μΐ, 0.20 mmol) and the amine of preparation 12 (0.25 ml, 0.2 M solution in N, N-dimethylformamide, 50 mol) in a polypropylene microtiter plate with 96 deep wells. The plate was covered and shaken at 40 ° C for 16 hours. The reaction mixtures were then evaporated under reduced pressure and the residues were purified by HPLC using a Waters XTerra MS C18 column and acetonitrile: 10. mM ammonium hydrogen carbonate (adjusted to pH 10 with sodium hydroxide) (5:95 to 98: 2) ) to provide the desired connections.

Ti-id »A% B% D

0 min 94 5 1 3.5 min 4.5 95 0.5 4.0 min 4.5 95 0.4

V

1027833 194

Vl>. Z MS Ret.

Nr. [MH] + time (min) 236 5-methyl-1-phenyl-1H-pyrazole-4-529 2.26 yi 237 5-methyl-1H-indol-2-yl 502 2.56 5 238 3- ( 1H-indol-3-yl) propyl 530 2.17 239 i-benzyl-1H-pyrazol-4-yl 529 2 240 3- (2-fluorophenyl) -1H-pyrazole-5,533 2.08 yi ________ 241 3 - (4-methylphenyl) -1H-pyrazole-5,529 2.17 yi. .. ______ 242 2- (phenylmethyl) thiazol-4-yl 546 2.26 10 243 5-methyl-1H-indazol-3-yl 503 2.04 244 (2,5,7-trimethyl-1H-indole-3) - 544 2,3 yl) methyl 245 4,5,6,7-tetrahydro-2-methyl-2H-507 1.95 indazol-3-yl 246 1H-indazol-1-ylmethyl 503 1.95 247 3- ( 2,5-dimethylphenyl) propyl 519 2.47 15 248 (IS) -1- (dimethylamino) -2-phenyl-520 2.04 ethyl 249 (2,5-dimethyl-1,3-thiazole-4,998) 87 yl) methyl 250 (4-methoxyphenyl) -5-methyl-1 H -559 2.04 pyrazol-4-yl] 251. 1- (1-cyclopentene-1-yl) butyl 495 2.47 252 cyclohex-3-en-1-yl 453 2.04 1027833 195 253 (1,3-dimethyl-1H-thieno [2,3-c] - 523 1.91 pyrazol-5-yl) 254 (2S) -1- (terfc-butoxycarbonyl) pip 556 2.3 peridin-2-yl 255 benzo [jb] thien-3-yl 505 2.21 256 4 - (5-oxazolyl) phenyl 516 1.87 5 257 3- (2-methyl-4-thiazolyl) phenyl 546 2.13 258 2-phenoxypyridin-5-yl 542 2.21 259 2-methyl-4-phenylpyrimidine- 5-yl 541 1.95 260 5-methoxy-iridol-2-yl 518 2.13 261 4-chlorobenzyl 497 2.43 10 262 1-phenylcyclopentyl 517 2.69 263 3- (4-fluorophenyl) -3-oxopropyl . 523.23.24 1,2,3,4-tetrahydronaphthalene-2-yl 503 2.23 265 cyclopentyl (phenyl) methyl 531 2.52 266 biphenyl-4-ylmethyl 539 2.37 15 267 1- (4- chlorophenoxy) -1-methyl ethyl 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 20 272 3- (4-methyl phenyl) propyl 505 2.18 273 1 H-indole-1-ylethyl 516 2.12 274 (phenylthio) methyl 495 2.08 275 1- (4 (chlorophenyl) ethyl 511 2.27 276.2,3-dihydro-1H-indene-2-ylmethyl 503 2.23

102783J

196 277 2 - [(4-chlorophenyl) thio] propyl. 558 2.47: 278 2-chloro-4-fluorobenzyl 515 2.13 279. (IR) -1-phenylpropyl 491 2.22 280 3-methoxycyclohexyl 485 1.81 5 281 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 10 286 (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 15 291 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 20 296 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 25 301 Anti-4-methyl cyclohexyl 469 2.26 1027833 197 302 3-phenyl-3- oxo-1-methyl-propyl. 519 2.09 303 2- (2-methyl phenyl) ethyl 491 2.21 304. 1-methyl-indol-3-ylmethyl 516 2.14 305 diphenylmethyl 539 2.38 5 306 1- (4-chlorophenyl) -1 -methylethyl 525 2.41 307 1 -methyl -1-phenylethyl 491 2.26 308 1-acetyloxy-1-phenylmethyl 521 2.01 309 cyclohex-1-en-1-ylmethyl 467 2.12 310 (2R) -2 -phenylpropyl 491 2.19 10 311 [(4-fluorophenyl) thio] methyl 513 2.14 312 (2R) -1- (tert-butoxycarbonyl) pip 556 2.26 peridin-2-yl 313 3- (2, 3-dihydro-1,4-benzodioxin-549 2,14 6-yl) propyl 314 6-chloro-3-oxo-2,3-dihydro-4 H-568 2,11 1,4-benzoxazin-4-yl 315 2- (4-fluorophenoxy) ethyl 511 2.16 15 316 2-hydroxychirioxalin-3-yl 517 1.57 317 5-methyl-3-phenylisoxazol-4-yl 530 2.07 318 isoquinoline-1-yl 500 1, 87 319 2-phenoxy phenyl 541 2.29 320 quinolin-2-yl 500 1.97 20 321 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 1027813, ------ 198 325 3-benzoylphenyl 553 2.21 326 1H-benzimidazol-6-yl 489 1.55 327 9-oxo-9H-fluorene -1-yl 551 2.16 328 4-methoxyquino line-2-yl 530 2.07 5 329 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 10 334 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 15 339 3-tert-butyl-1 -methyl-1H-pyra-509 2.26 zol-5-yl 340 2.1,3-benzoxazole-5-yl 491 2.26 341 5-bromo-2,3-dihydro-1-benzofu 570 2, 43 ran-7-yl 342 1- (4-chlorophenyl) cyclopropyl 523 2.27 343 5-isobutylisoxazol-3-yl 496 2.23 20 344 3- (1H-pyrazol-1-yl) phenyl 515 1.91 345 3,5-dimethylindol-2-yl 516 2.32 346 4- (tert-butoxycarbonyl) morphol 572 1.98 ne-3-ylmethyl 347 3-isobutyl-1H-pyrazol-5-yl 495 1.96; ; 10 27833 · 199 348 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-523 1.71 2-yl 5 352 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-indazole-3 493 1.81 alkyl 355-dimethyl-1 H-indol-5-yl 516 2.05 356 3.5- dimethyl-1H-pyrrol-2-yl 466 1.96 10 357 3- (3,5-dimethyl-1H-pyrazol-1 543 2-yl) phenyl 358 3 - [(3,5-dimethyl-1H-pyrazole) 1- 557 1.98 yl) methyl] phenyl 359 3'-fluorobiphenyl-4-yl 543 2.37 360 4-phenyl-1,3-thiazol-2-yl 546 2,17 361 4- (1H-pyrazole) 1-yl) phenyl 515 1.9 15 362 5,7-dimethylpyrazolo [1,5-a] 518 1,76 pyrimidin-2-yl 363 3-phenylisoxazol-5-yl 516 2,2 364 2, 3-dihydro-1-benzofuran-2-yl 491 2 365 1 H-benzimldazol-1-ylmethyl 503 1.73 366 5- (4-methoxyphenyl) -2-furyl 545 2.25 20 367 1,3-benzothiazole-2 -ylethyl 534 2.03 368 2-methyl-5-propylpyrazol-3-yl 495 1.96 1027833 200 369 1-benzyl-2-oxo-1,2-dihydropyri-556 1.85 dine-3-yl 370 1-benzyl-6-oxo-1,6-dihydropyri-556 1.75 dine-3-yl 371 2-phenyl-1,3-thiazol-4-yl 532 2.22 372 4- methyl-2-phenyl-1,3-thiazole-5,456 2.18 yi 5 373 8-methoxy-2 H-chromen-3-yl 533 2.02 374 2 H-chromen-3-yl 503 2.12 375 6 -methoxy-2H-chromen-3-yl 533 2.1 376 4- (tert-butoxycarbonyl) morphol 558 1.95 ne-3-yl 377 4-methoxy-3-thienyl 485 1.85 10 378 4- ( 1-H-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-1 H-indol-2-yl 502 2.18 15 383 1-methyl-1 H-indol-3-yl 502 2.02 384 5-fluoro -ΙΗ-indol-2-yl 506 2.13 385 6-methyl-4-oxo-4H-chromen-2-yl 531 2.02 386A 3-isopropyl-1-methylpyrazole-5- 495 1.95, yi 387 ® 5-bromo-2-methoxypyridin-3-yl 559 2.03 20 388c 5-methyl-2-phenyl-H-imidazole-4- 529 1.95 yl 1 0 2 7 8. 201 389® 3- (1-oxo-1/3-dihydro-2 H -iso-532 1.82 dool-2-yl) propyl 390 * 1-ethylpiperidin-2-yl. 484 1.91. 391r 3 - [(pyrimidin-2-ylthio) - 573 2.08 methyl] phenyl 392 ° 4 - [(pyridin-2-ylthio) methyl] phen 572 2.17nyl 5 393H 6-cyclohexyl-2-oxo 1,2,3,6-te 551 2,04 trahydropyrimidin-4-yl 394 * 5-oxo-1-propylpyrrolidin-3-yl 498 1.74 395 * 5-propylisoxazol-4-yl 482 2 A = 3 isopropyl-1-methyl-1H-pyrazole-5-carboxylic acid was used; see DE 3029281.

B = 5-bromo-2-methoxynicotic acid was used; see EP 306251, preparation I.

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

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

E = 1-ethylpiperidine-2-carboxylic acid was used; see

Journal of Inorganic and Nuclear Medicine; 1978; 40 (6); 1103-6.

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

G = 4- [(pyridin-2-ylthio) methyl] benzoic acid was used; see US 4325959, example 2.

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

I = 5-oxo-1-propylpyrrolidine-3-carboxylic acid was used; see WO 200202614.

J = 5-propylisoxazole-4-carboxylic acid was used; see J. Het. Chem. 1991; 28 (2); 453.

30 v, 202

Examples 396 - 403: 0 "Λ w /

Cl

A mixture of the correct amine from preparation 12a (1 eq.), The correct acid chloride (1.2 - 1.4 eq.) And polymer-supported N-ethyl diisopropylamine (10 eq.) In dichloromethane (16 ml / mmol) 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 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 products were purified by column chromatography on silica gel using ethyl acetate: methanol: 0.88 ammonia (90: 10: 1) as an eluent to form the title compounds.

Ex. data

Nr.

396 W = 2-CF 3; ^ -NMR (400 MHz, CDCl 3): δ 1.61 - 1.76 (m, 1H), 1.79 - 1.98 (m, 3H), 2.62 - 2.80 (m, 1H), 2.84 -2.97 (m, 2H), 3.42 (m, 1H), 4.60 (m, 1H), 5.62 (d, 2H), 6.99 (m, 2H), 7 , 20 - 7.55 (m, 6H), 7.59 (m, 1H), 7.66 (m, 1H). LCMS: m / z APCI + 516 [MH) + 1027833 203 397 W = 3-CF 3; 1 H NMR (400 MHz, CDCl 3): δ 1.80 (m, 2H), 1.98 (m, 2H), 2.70 (m, 1H), 2.88 - 3.02 (m, 2H) 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 / z APCI4 516 [MH] 4 398 W = 4-CF3; ^ -NMR (400 MHz, CD3OD): δ 1.78 - 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, 2 H). LCMS: m / z APCI4 516 [MH] 4 399a W = 2-F, 5-C1; ^ -NMR (400 MHz, CDCl 3): δ 1.78 - 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 APCI * 500 [MH] +.

400® W = 3-F; 1 H 1 NMR (400 MHz, CDCl 3): δ 1.66 - 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, 4 H), 7.15 s, 1 H), 7.37 (m, 1 H), 7.42 (d, 2 H), 7.49 (s, 2 H). LCMS: m / z APCI + 466 [MH] 4 5 401 * W = 2,3-di-F; ^ -NMR (400 MHz, CDCl 3): δ 1.74 - 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 (e, 2H), 7.01 (m, 2H), 7.07 - 7.21 (m, 3H), 7.42 ( d, 2H), 7.52 (s, 2H). LCMS: m / z APCI4 484 [MH] 4 1027833 204 402 "W = 2-F, 3-Cl; 1-NMR (400 MHz, CDCl 3): δ 1.62 - 2.00 (m, 4H), 2.70 (τη, 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 APCI + 500 [MH ] + 403® W = 4-F, 3-Cl; 1 H-NMR (400 MHz, CDCl 3): δ 1.74 - 1.85 (m, 2H), 1.98 (m, 2H), 2.70 (m, 1H), 2.82 - 2.98 (m, 2H), 3.70 - 3.88 (m, 1H), 4.40 - 4.58 (m, 1H), 5.63 (s, 2H) ), 7.02 (m, 2H), 7.17 (m, 1H), 7.23 (m, 1H), 7.42 (m, 3H), 7.49 (s, 2H). LCMS: m / z AP-CV, 500 [MH] * A = 2.5 eg triethylamine were used instead of 5 polymer-supported N-ethyldiisopropylamine.

B e 2 eg. N-methyl morpholine used instead of polymer-supported N-ethyl diisopropylamine.

Examples 404 - 405 10 "Zr ^ \

! y) \ J

15 Cl

A solution of the correct acid, ZCOaH (1.2 eq.), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (1.2 eq.), N-methylmorpholine (1 4 eq.) And the amine of preparation 12a (1 eq.) In dichloromethane (7-10 ml / mmol) was stirred at room temperature for 24 hours. The reaction mixture was partitioned between a sodium hydroxide solution and dichloromethane and the layers were then separated. The organic solution was washed with an ammonium chloride solution, dried over MgSO 4 and 1027833 205 evaporated under reduced pressure. The crude product was purified by. by column chromatography on silica gel using. an elution gradient of dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) to form the title compounds.

Ex. data

Nr.

404 Z 3-fluoro-5-chlorophenyl / 1-NMR (400 MHz, CDCl 3): δ 1.80 (m, 2H), 1.98 (m, 2H), 2.70 (m, 1H), 2, 95 (m, 2 H), 3.78 (m, 1 H), 4.48 (m, 1 H), 5.63 (s, 2 H), 6.99 (m, 3 H), 7.15 (m, 2H), 7.42 (d, 2H), 7.50 (s, 2H): LCMS: m / z APCl * 500 [M] * 10 405 Z = indazol-3-yl; ^ -NMR (400 MHz, DMSO-d 6): δ 1.63 - 1.82 (m, 4H), 2.78 - 2.90 (m, 2H), 3.18 (m, 1H)., 4 45 (m, 1H), 4.62 (m> 1H), 5.77 (s, 2H), 7.18 (m, 1H), 7.32-7.40 (m, 3H), 7, 58 (m, 3H), 7.63 (s, 2H), 7.90 (d, 1H). LCMS: m / z ES * 486 [M-H] *

All compounds shown as an example above showed a Ki value of less than 500 nM when tested in screening 1.0 (V1A filter binding assay) as described above.

Examples of specific connections are illustrated below:

Example no. Ki (nM) 20 165. 2.98 206 2.43 399 1.99 405 1.11 1027833

Claims (20)

A compound of formula (I):. V x Z y or a pharmaceutically acceptable derivative thereof, wherein: X represents - [CH 2] a-R or - [CH 2] a-0- [CH 2] b-R; a represents a number selected from 0-6; 15. represents a number selected from 0-6; R represents H, CF3 or Het; It represents a 5 or 6 membered, saturated, partially saturated or aromatic heterocyclic ring with either (a) 1 to 4 nitrogen atoms, (b) 1 acid-20. substance atom or 1 sulfur atom, either (c) 1 oxygen atom or 1. sulfur atom and 1 or 2 nitrogen atoms, optionally substituted with one or more groups independently selected from W; 25. represents one or more substituents independently selected from - [0] c- [CH 2] d-RV which may be the same or different at each occurrence; c for each occurrence independently represents a number selected from 0 or 1; d for each occurrence independently represents a number selected from 0-6; R1 stands at each occurrence independently for H, halogen, CP3, CN or Het1; Het1 represents, at each occurrence, independently a 5 or 6 membered unsaturated heterocyclic ring, which either (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 ° 27833J sulfur atom or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms; V stands for a direct bond or -0-; Ring A represents a 5 or 7 membered saturated heterocyclic ring comprising either (a) 1-4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom or (c) 1 oxygen atom or 10 1 sulfur atom and 1 or 2 nitrogen atoms ; wherein ring A is optionally substituted with one or more groups selected from C 1-4 alkyl, phenyl or hydroxy; Q represents a direct bond or -N (R2) -; A compound according to claim 1, wherein X represents - [CH 2] a-R. 3. A compound according to claim 2, wherein R represents Het. A compound according to any one of claims 1-3, wherein Y represents halogen. A compound according to any of claims 1-4, wherein V stands for a direct bond. A compound according to any one of claims 1-5, wherein Q represents a direct bond. 25 " A compound according to any one of claims 1-6, wherein ring λ represents a six-membered ring. A compound according to any one of claims 1-7, wherein Z represents phenyl. The compound of any one of claims 1 to 8, wherein Z is substituted with halogen. 35 .10. Compound according to claim 1, selected from 1027833 • 210 (3-Chlorophenyl) - {4- [4- (4-chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4 H- [1 2,4] triazol-3-yl] -piperidin-1-yl} -methanone; (4-Chlorophenyl) - {4- [4- (4-chlorophenyl) -5- [1,2,3] -5 triazol-2-ylmethyl-4H- (1,2,4] triazol-3-yl] -piperidin-1-yl} -methanone; (5-Chloro-2-fluorophenyl) - {4- [4- (4-chlorophenyl) -5- [1.2.3] triazol-2-ylmethyl-4H- [1, 2,4] triazol-3-yl] piperidin-1-yl} -methanone, * 10 {4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl thyl-4H- (1,2,4] triazol-3-yl] -piperidin-1-yl} - (3,5-difluorophenyl) -methanone; {4- [4- (4-Chlorophenyl) -5 - [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl} - (3-fluorophenyl) methanone; {4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl } - (2,3-difluorophenyl) -methanone; (3-chloro-2-fluorophenyl) - {4- [4- (4-chlorophenyl) -5-20 [1,2,3] triazole-2- ylmethyl-4H- [1,2,4] tria2001-3-yl] -piperidin-1-yl} -methanone; (3-Chloro-4-fluorophenyl) - {4- [4- (4-chlorophenyl)] -5- [1.2.3] triazol-2-ylmethyl-4H- [1,2,4-triazol-3-yl] -piperidin-1-yl} -methanone; 25 {4- [4- (4-Chlorophenyl) ) -5- (1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -p iperidin-1-yl} - (4-trifluoromethylphenyl) methanone; {4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl } -U-trifluoro-methyl-phenyl-methanone; {4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl } - (2-trifluoromethylphenyl) methanone; (3-Chloro-5-fluorophenyl) - {4- [4- (4-chlorophenyl) -5-35 [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazole-3 -yl] -piperidin-1-yl} -methanone; 1027833 {4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidine-1- yl} - (4-difluoro-methylphenyl) methanone; {4 - [4 - (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1 ^ 2,4] triazol-3-yl] -piperidine-1- yl.} - (1H-indazol-3-yl) -methanone; and pharmaceutically acceptable derivatives thereof. 11. Use of a compound according to any of claims 1 to 10 as a medicine. 12. Use of a compound according to any of claims 1-10 in the preparation of a medicament for the treatment of a disorder for which a Vla antagonist is indicated. 13. Use of a compound according to any of claims 1 to 10 in the preparation of a medicament for the treatment of anxiety, cardiovascular disease (including angina, atherosclerosis, hypertension, cardiac insufficiency, edema, hypernatremia), dysmenorrhea (primary and secondary), endometriosis, emesis (including movement disorder), intrauterine growth retardation, inflammation (including rheumatoid arthritis), "mittleschmerz", preeclampsia, premature ejaculation, premature contractions or Raynaud's disease. Use according to claim 12 or claim 13, wherein the disorder is dysmenorrhea (primary or secondary). 30 A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, together with a pharmaceutically acceptable excipient, diluent or carrier. 35 1027833 R2 represents hydrogen or C1-6 alkyl; Z represents - [O] e- [CH 3 f -R 3, a phenyl ring (optionally condensed to a benzene ring or Het 2 and wherein the group as a whole is optionally substituted with one or more groups independently selected from w) or Het 3 (optionally condensed on a benzene ring or Het 4 and wherein the group as a whole is optionally substituted with one or more groups independently selected from W); R 3 represents C 1-6 alkyl (optionally substituted with one or more groups independently selected from W), C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl (optionally substituted with one or more groups independently selected from W ), Het5 or NR4R5; * 30 e represents a number selected from 0 or 1; f represents a number selected from 0-6; Het 2 and Het 5 independently represent a 5 or 6 membered, saturated or partially saturated or aromatic heterocyclic ring, which either (a) 1-4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom or (c) 1 oxygen atom or comprises 1 sulfur atom and 1 or 2 nitrogen atoms, 1027833 optionally substituted with one or more groups selected from W; Het 3 represents a 4 to 6 membered, saturated, partially saturated or aromatic heterocyclic ring, which either (a) 1-4 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 with one or more groups selected from W; Het 4 represents a 6-membered aromatic heterocyclic ring comprising either (a) 1-4 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 with one or more groups selected from W; R 4 and R 5 independently represent hydrogen, C 1-6 alkyl, C 1-4 alkyloxy, C 3-8 cycloalkyl (optionally condensed with C 3-8 cycloalkyl) or Het 6; wherein R 4 and R 5 are optionally independently substituted with one or more groups selected from C 1-8 alkyl, C 1-6 alkyloxy, C 3-8 cycloalkyl (optionally condensed with C 3-8 cycloalkyl) or phenyl; Het 6 represents a 5- or 6-membered, saturated, partially saturated or aromatic heterocyclic ring, which either (a) 1-4 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 with one or more groups selected from W; At each occurrence, W represents independently halogen, [0] gR 6, SO 3 R 6, SR 6, SO 2 NR 6 R 7, [O] h [CH 3] 3 A 3, [O] jCHF a, phenyl (optionally substituted with halogen, C 1-6 alkyl or C 1. g-alkyloxy), CN, phenoxy (optionally substituted with halogen), OH, benzyl, NR6R7, NCRO6, benzyloxy, oxo, CONHR6, NSOaR6R1 COR6, C1-4 alkylene NCOR7, Het7; R 6 represents hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl or C 1-6 alkylene-O-C 1-6 alkyl; R 7 represents hydrogen or C 1-4 alkyl; i represents a number selected from 0-6; 1027833 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 heterocyclic ring, which comprises either (a) 1-4 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 with R * and / or R7 and / or an oxo group. 10 A combination of (A) a compound according to any of claims 1 to 10 and (B) another pharmacologically active ingredient. The combination of claim 16, wherein (B) is an oral contraceptive, a PDEV inhibitor, a COX inhibitor, an NO donor or L-arginine. The use of a combination according to claim 10 or claim 17 for the preparation of a medicament for combination therapy by simultaneous, sequential or separate administration in the treatment of dysmenorrhea. 19. Pharmaceutical product that a. Combination of (A) and (B) according to claim 16 or claim 17, as a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhea (primary or secondary). 20-0-0-1027833