EA010132B1 - Triazole derivatives as vasopressin antagonists - Google Patents

Abstract

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

Description

This invention relates to triazole derivatives and to methods for producing such derivatives, to intermediates used in the preparation of such derivatives, to compositions containing such derivatives, and to applications of such derivatives.

The triazole derivatives of the present invention are vasopressin antagonists. In particular, they are antagonists of the U1a receptor and have many therapeutic applications, in particular in the treatment of dysmenorrhea (primary and secondary).

In the area of menstrual irregularities, there is a high unmet need, and it is estimated that up to 90% of all menstruating women are affected to some extent. Up to 42% of women miss work or other activities due to menstrual pain, and as a result, an estimated 600 million work hours per year are lost in the United States {Soso, A.8. (1999). Rpshagu Pukteeioggyoea | Ρονίο \ ν | [30 gsG5 |. Atepsai RatPu Ryu51S1ai, 60, 489-96}.

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

Primary dysmenorrhea is diagnosed when a deviation from the norm that causes this condition is not detected. This affects up to 50% of the female population {Soso, A.8. (1999). RPtagu bukteioggyoea. | K.е \ '1е \ у | [30 geGD. Atepsai RatPu Ryu51S1ai, 60, 489-96; 8th Peg, W. & 8aiGShrro, 1.8. (1999). Eukhteioggyoea aib reMS rus t aPo1e5sei15. | K.su1s \ y | [78 gay]. ReP1a (s1 Syshsk city no. 111 Atensa, 46, 555-71}. In the presence of a major gynecological disorder such as endometriosis, pelvic inflammatory disease (RGO), fibroids or cancers, secondary dysmenorrhea is diagnosed. Secondary dysmenorrhea is diagnosed only in approximately 25% of women with dysmenorrhea Dysmenorrhea can occur in combination with menorrhagia, which accounts for about 12% of visits to gynecological outpatient facilities.

Currently, women suffering from primary dysmenorrhea are being treated with non-steroidal anti-inflammatory drugs (I8AGO) or oral contraceptive pills. In cases of secondary dysmenorrhea, surgery may be undertaken to correct the underlying gynecological disorder.

Women with dysmenorrhea have blood levels of vasopressin that are higher than healthy women at the same time of the menstrual cycle. Inhibition of the pharmacological effects of vasopressin on uterine vasopressin receptors can prevent dysmenorrhea.

Thus, the compounds of the present invention are potentially useful in the treatment of a wide range of disorders, in particular aggression, Alzheimer's disease, anorexia nervosa, anxiety, anxiety disorder, asthma, atherosclerosis, autism, cardiovascular disease (including angina pectoris, atherosclerosis, hypertension, heart failure , edema, hypernatremia), cataracts, diseases of the central nervous system, cerebrovascular ischemia, cirrhosis, cognitive impairment, Cushing's disease, depression, diabetes mellitus, dys menorrhea (primary and secondary), vomiting (including seasickness), endometriosis, gastrointestinal disease, glaucoma, gynecological disease, heart disease, intrauterine growth retardation, inflammation (including rheumatoid arthritis), ischemia, coronary heart disease, lung tumor, urination disorders, abdominal pain that occurs during ovulation, neoplasm, nephrotoxicity, non-insulin-dependent diabetes, obesity, obsessive-compulsive disorder, increased intraocular pressure, preeclamp this, premature ejaculation, premature birth, pulmonary disease, Raynaud's disease, kidney disease, renal failure, male or female sexual dysfunction, septic shock, sleep disturbance, spinal cord injury, thrombosis, urinary tract infections or urolithiasis.

Of particular interest are the following diseases or disorders: anxiety, cardiovascular disease (including angina pectoris, atherosclerosis, hypertension, heart failure, edema, hypernatremia), dysmenorrhea (primary and secondary), endometriosis, vomiting (including seasickness), intrauterine growth retardation, inflammation (including rheumatoid arthritis), abdominal pain that occurs during ovulation, preeclampsia, premature ejaculation, premature birth 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 U1a receptor (and therefore are likely to have reduced side effects), they can start their action faster, they can act stronger, they can act longer, they may have better bioavailability or they may have other properties more desirable than compounds of the prior art.

In accordance with the present invention, a compound of formula (I) is provided

- 1 010132

(I) or a pharmaceutically acceptable derivative thereof, wherein

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

a represents a number selected from numbers from 0 to 6;

B is a number selected from numbers from 0 to 6;

K represents H, CE ₃ or Not !;

Not! represents a 5- or 6-membered saturated, partially saturated or aromatic heterocyclic ring containing either (a) 1 to 4 nitrogen atoms, or (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 a sulfur atom and 1 or 2 nitrogen atoms, possibly substituted by one or more groups independently selected from V;

Υ represents substituents in an amount of one or more, independently selected from - [O] _with [CH ₂ ] _th —K ¹ , which in each case may be the same or different;

c in each case independently represents a number selected from 0 or 1;

d in each case independently represents a number selected from numbers from 0 to 6;

K ¹ in each case independently represents H, halogen, CE ₃ , CU or Not! ¹ ;

Not! ¹ in each case independently represents a 5- or 6-membered unsaturated heterocyclic ring containing either (a) 1 to 4 nitrogen atoms, or (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 a sulfur atom and 1 or 2 nitrogen atoms;

V is a direct bond or —O—;

ring A is a 5-7 membered saturated heterocyclic ring containing either (a) 1 to 4 nitrogen atoms, or (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, wherein ring A is optionally substituted with one or more groups selected from _C1-6 alkyl, phenyl or hydroxy;

O represents a direct bond or —Y (K ² ) -;

K ² represents a hydrogen atom or a C1 _-6 alkyl;

Ζ represents - [O] _e - [CH ₂ ] _£ -K ³ , a phenyl ring (possibly fused to a benzene ring or He! ² , and this group as a whole is possibly substituted by one or more groups independently selected from V) or Not ! ³ (possibly fused to a benzene ring or He! ⁴ , moreover, this group as a whole is possibly substituted by one or more groups independently selected from V);

K ³ represents a C1 _-6 alkyl (optionally substituted with one or more groups independently selected from V), C _3-6 cycloalkyl, C ₃ - ₆ cycloalkenyl, phenyl (optionally substituted with one or more groups independently selected from V), not ! ⁵ or YK ⁴ K ⁵ ;

e is a number selected from 0 or 1;

£ represents a number selected from numbers from 0 to 6;

Not! ² and not! ⁵ independently represent a 5- or 6-membered saturated, partially saturated or aromatic heterocyclic ring containing either (a) 1 to 4 nitrogen atoms, or (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, possibly substituted by one or more groups selected from V;

Not! ³ represents a 4-6 membered saturated, partially saturated or aromatic heterocyclic ring containing either (a) 1 to 4 nitrogen atoms, or (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 a sulfur atom and 1 or 2 nitrogen atoms, possibly substituted by one or more groups selected from V;

Not! ⁴ is a 6-membered aromatic heterocyclic ring containing either (a) 1 to 4 nitrogen atoms, or (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 atoms nitrogen optionally substituted with one or more groups selected from V;

K ⁴ and K ⁵ independently represent a hydrogen atom, C 1-6 alkyl, C 1-6 alkyloxy, C 3-8 cycloalkyl (possibly condensed with C 3-8 cycloalkyl) or Not! ^6, and K ⁴ and K ⁵ is optionally independently substituted with one of more groups selected from C £ -6alkila, C1 _-6 alkyloxy, _C3-8 cycloalkyl (optionally fused with S3-8tsikloalkilom) or phenyl;

Not! ⁶ is a 5- or 6-membered saturated, partially saturated or aromatic heterocyclic ring containing either (a) 1 to 4 nitrogen atoms, or (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, possibly substituted by one or more groups selected from V;

V independently in each case is halogen, [O] _d K ⁶ , 8O2K ⁶ , 8K ⁶ , 8O2K ⁶ K ⁷ ,

- 2 010132 [O] ₁ [CH ₂ ] ₁ CE ₃ . | About || CHE ₂ . phenyl (possibly substituted by halogen, C _1-6 alkyl or C1. balkyloxy), ΟΝ, phenoxy (possibly substituted by halogen). IT. benzyl. ΝΚ ⁶ Κ ⁷ . Ν ^ Κ ⁶ . benzyloxy. oxo. No.ΝΗΚ. ⁶ , Ν8Ο2Κ ⁶ Κ ⁷ . JUICE ⁶ . C1-6 alkylene-HIGH ⁷ . Not! ⁷ ;

K ⁶ represents hydrogen. C _1-6 alkyl, C _3-6 cycloalkyl, C ₃ - ₆ cycloalkenyl or C _{1-6 alkylene-O-C1-6} alkyl;

K ⁷ represents hydrogen or C _1-6 alkyl;

ί is a number. selected from numbers from 0 to 6;

represents a number. selected from 0 or 1;

q is a number. selected from 0 or 1;

_) is a number. selected from 0 or 1;

Not! ⁷ represents a 5- or 6-membered saturated. partially saturated or aromatic heterocyclic ring. containing either (a) from 1 to 4 nitrogen atoms. or (b) 1 oxygen atom or 1 sulfur atom. or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms. possibly substituted K ⁶ . and / or K ⁷ . and / or oxo group.

In an alternative embodiment, a compound of formula (I ′) is provided

(0 or a pharmaceutically acceptable derivative thereof. Where

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

but represents a number. selected from numbers from 0 to 6;

B is a number. selected from numbers from 0 to 6;

K represents N. CE ₃ or Not !;

Not! represents a 5- or 6-membered heterocyclic ring. containing either (a) from 1 to 4 nitrogen atoms. (b) 1 oxygen atom or 1 sulfur atom. either (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms;

Υ represents - [O] _s - [CH ₂ ] _Y -K ¹ ;

Υ 'represents - [OfDSNSC-K ¹ ';

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

ά and 6 'independently represent a number. selected from numbers from 0 to 6;

K ¹ and K ¹ independently represent N. halogen. CE ₃ or Not! ¹ ;

Not! ¹ represents a 5- or 6-membered unsaturated heterocyclic ring. containing either (a) from 1 to 4 nitrogen atoms. (b) 1 oxygen atom or 1 sulfur atom. either (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atom;

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

Ζ represents - [O] _e - [CH ₂ ] _£ -K ² . phenyl ring (possibly fused to a phenyl ring or a 5- or 6-membered saturated. partially unsaturated or aromatic heterocyclic ring and / or possibly substituted by one or more groups independently selected from XV) or a 6-membered aromatic heterocyclic ring (possibly fused to a phenyl ring or a 6-membered aromatic heterocyclic ring and / or optionally substituted with one or more groups independently selected from V);

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

e is a number. selected from 0 or 1;

£ is a number. selected from numbers from 0 to 6;

V is halogen. [O] _d K ³ . §O2K ³ . 8K ³ . 8Ο2ΝΚ ³ Κ ⁴ . [O] b [CH2] 1CE3. OCHE2. phenyl. ΟΝ. phenoxy (possibly substituted by halogen). IT. benzyl. ΝΟΟΚ ³ . benzyloxy. oxy. SOYAN ³ . Ν8Ο2Κ ³ Κ ⁴ . Juice ³ . C _1-6 alkylene-HYSOC ³ . Not! ² ;

K ³ represents hydrogen. C _1-6 alkyl. C _3-6 cycloalkyl or C _1-6 alkylene-O-C _1-6 alkyl;

K ⁴ represents hydrogen or C _1-6 alkyl;

ί is a number. selected from numbers from 0 to 6;

represents a number. selected from 0 or 1;

q is a number. selected from 0 or 1;

Not! ² represents a 5- or 6-membered saturated. a partially unsaturated or aromatic heterocyclic group. containing either (a) from 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. and this heterocyclic

The 010132 group is optionally substituted with R ³ and / or R ⁴ and / or an oxy group.

In the above definitions, halo means fluoro, chloro, bromo or iodo. The alkyl, alkylene and alkyloxy groups containing the indicated number of carbon atoms may be unbranched or branched. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Examples of alkyloxy include methoxy, ethoxy, n-propoxy, isopropoxy, nbutoxy, isobutoxy, sec-butoxy and tert-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. Not! represents a heterocyclic group, examples of which include tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathanyl, 3 4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2Nopyranyl, 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, 1oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5- diazolyl, 1 -oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 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 a compound in which X is CH ₂ OCH ₃ . More preferred is a compound in which X is - [CH ₂ ] _a Y.

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

A preferred compound is a compound in which I am H. A more preferred compound is a compound in which I am Not !. Even more preferred is a compound in which I am triazolyl.

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

A preferred compound is a compound in which Υ is halogen. A more preferred compound is one in which Υ represents chloro and / or fluoro.

A preferred compound is a compound in which V is a direct bond. A preferred compound is a compound in which it is a direct bond. A more preferred compound is a compound in which both V and V are a direct bond.

A preferred compound is a compound in which ring A contains 2 nitrogen atoms. A more preferred compound is a compound in which ring A contains 1 nitrogen atom.

A preferred compound is a compound in which ring A is a 5 membered ring. A more preferred compound is one in which ring A is a 6 membered ring. An even more preferred compound is a compound in which ring A is piperidinyl.

A preferred compound is a compound in which ring A is attached to V via a nitrogen atom. A more preferred compound is a compound in which ring A is attached to via a nitrogen atom. A preferred compound is a compound in which ring A is attached to both ^ and V through a nitrogen atom.

A preferred compound is one in which Ζ is He! ³ . Not! ³ may be an optionally substituted group selected from indazolyl, indolyl, indenyl, pyrazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, benzothienyl, benzothiazolyl, quinolinyl, benzoxazinyl, isoxazolyl, imidazolinyl, chenyl, phenyl, chromyl, furyl their derivatives. A more preferred compound is a compound in which Ζ is phenyl.

A preferred compound is a compound in which Ζ is mono- or disubstituted. A more preferred compound is one in which Ζ is monosubstituted.

A preferred compound is a compound in which Ζ is substituted with trifluoromethyl. A more preferred compound is a compound in which Ζ is substituted by halogen. A more preferred compound is one in which Ζ is substituted with chloro and / or fluoro.

Specific preferred compounds of the invention are those listed in the Examples section below and their pharmaceutically acceptable salts, in particular (3-chlorophenyl) - {4- [4- (4-chlorophenyl) -5- [1,2,3 ] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] piperidin1-yl} methanone,

- 4010132 (4-chlorophenyl) - {4- [4- (4-chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl ] piperidin1-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] triazol-3-yl] piperidin-1-yl} - (3,5difluorophenyl) 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} - (2,3difluorophenyl) methanone, (3-chloro-2-fluorophenyl) - {4- [4 - (4-chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazo -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, {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} - (3trifluoromethylphenyl) 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- [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] triazol-3-yl] piperidin-1-yl} - (4difluoromethylphenyl) methanone, {4- [4- (4-chlorophenyl) -5- [1, 2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] piperidin-1-yl} - (1indindazol-3-yl) methanone and their pharmaceutically acceptable derivatives.

Pharmaceutically acceptable derivatives of the compounds of formula (I) of the invention include salts, solvates, complexes, polymorphs, prodrugs, stereoisomers, geometric isomers, tautomeric forms and isotopic variations of the compounds of formula (I). Preferred pharmaceutically acceptable derivatives of the compounds of formula (I) include salts, solvates, esters and amides of the compounds of formula (I). More preferred pharmaceutically acceptable derivatives of the compounds of formula (I) are salts and solvates.

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

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include salts of acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, gibenzate, hydrochloride / hydrochloride, hydrochloride / chloride, / iodide, isothionate, Ό- and L-lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-napzilate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, sugar, steccate sulfate, Ό- and b-tartrate, 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 aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

For a review of suitable salts, see 81a111 apb \ Usggppi111. Nabbyok ίί Ryagtaseibs1 8a11§: Rogregbek, 8e1es1yup apb Ike, Beu-USN, Esheyt, Oegtapu (2002).

A pharmaceutically acceptable salt of a compound of formula (I) can easily be prepared by mixing together solutions of a compound of formula (I) and a desired acid or base, where appropriate. The salt may be precipitated from the solution and collected by filtration, or it may be isolated by evaporation of the solvent. The degree of ionization of the salt can vary from completely ionized to almost non-ionized.

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

The scope of the invention includes complexes, such as clathrates, host drug inclusion complexes, where, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. The scope of the invention also includes drug complexes containing two or more organic and / or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. Semi

- 010132 complexes can be ionized, partially ionized, or non-ionized. A review of such complexes can be found in 1 Ryatt 8 8ΐ, 64 (8), 1269–1288 Lü Na1eL11ap (Aidiz! 1975).

Further, all references to compounds of formula (I) and pharmaceutically acceptable derivatives include references to their salts, solvates and complexes, and to solvates and complexes of their salts.

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

As indicated, this invention encompasses all polymorphs of the compounds of formula (I) as defined above.

Also included in the scope of this invention are the so-called prodrugs of the compounds of formula (I). Thus, some derivatives of the compounds of formula (I), which themselves may have little pharmacological activity or may not have pharmacological activity, when introduced into or on the body, can be converted, for example, by hydrolytic cleavage, into compounds of formula (I) having the desired activity. Such derivatives are called prodrugs. Further information on the use of prodrugs can be found in Rtobtidz ayou1 Eekuyu Zuz1esh5. Yo1. 14, NES Zutrozsht Zepez (T. Shdisy apb. 81e11a) and in Vyuetuetz1e Sagpegs ίη Egid Eezdp, Regdatop Przez, 1987 (eb. E.V. Vosie, Ltepsap Ryattaseibsa1 Lzzoaabop).

Prodrugs in accordance with the invention can be obtained, for example, by replacing the corresponding functional group present in the compounds of formula (I) with certain moieties known to those skilled in the art as groupings, as described, for example, in Ex. Rtobtidus bh N Vipbdaagb (E1zeu1et, 1985).

Some examples of prodrugs in accordance with the invention include:

(1) if the compound of formula (I) contains a functional carboxylic acid group (—COOH), then its ester, for example, substitution of a hydrogen atom by C1 _-8 alkyl;

(2) when the compound of formula (I) contains an alcohol functionality (-OH), its ether, e.g., replacement of the hydrogen atom of a C1 _-8 alkanoyloxymethyl; and (3) if the compound of formula (I) contains a functional primary or secondary amino group (-ΝΗ ₂ or -ΝΗΒ, where R # H), its amide, for example, replacement of one or both of the hydrogen atoms of a C1 _- 1 ₀ alkanoyl.

Further examples of substituent groups according to the above examples and examples of other types of prodrugs can be found in the above references.

Finally, some compounds of formula (I) themselves can act as prodrugs of other compounds of formula (I).

Metabolites of the compounds of formula (I) are also included in the scope of the invention upon their formation.

Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. If the compound of formula (I) contains an alkenyl or alkenylene group, geometric cis / trans (or Ζ / E) isomers are possible, and if the compound contains, for example, a keto or oxime group or an aromatic group, tautomeric isomerism (tautomerism) may occur. It follows that a single compound may exhibit more than one type of isomerism.

The scope of the present invention includes 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 than one of them. Acid or base addition salts are also within the scope of the invention, wherein the counterion is optically active, for example Ό-lactate or L-lysine, or racemic, for example E-tartrate or E-arginine.

Cis / trans isomers can be separated by conventional methods well known in the art, for example, fractional crystallization and chromatography.

Conventional methods for preparing / isolating individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of a racemate (or salt or derivative racemate) 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, when the compound of formula (1) contains an acidic or basic moiety, with 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 one or both diastereomers can be converted into the corresponding (e) pure (e) enantiomer (s) by methods well known to one skilled in the art.

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

Stereoisomeric conglomerates can be separated by conventional methods known in the art.

- 6010132 to the socialists, see, for example, 81еgeosyeshytu οί Ogdashe Soshroipbz bj E. Eee1 (X-UPeu, Νονν Wagk, 1994).

The present invention also encompasses all pharmaceutically acceptable isotopic variations of a compound of formula (I), wherein one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number different from that of the atomic mass or mass number commonly found ( wow) in nature.

Examples of isotopes suitable for incorporation into the compounds of the invention include hydrogen isotopes such as ² N and ³ N, carbon such as ¹¹ C, ¹³ C and ¹⁴ C, nitrogen such as ¹³ Ν and ^{| 5} N oxygen such as ¹⁵ O, ¹⁷ O and ¹⁸ O, phosphorus such as ³² P, sulfur such as ³⁵ 8, fluorine such as ¹⁸ E, iodine such as ¹²³ 1 and ¹²⁵ 1, and chlorine such as ³⁶ C1.

Some isotope-labeled compounds of formula (I), for example those into which a radioactive isotope is introduced, are useful in studies of the tissue distribution of a drug and / or substrate. Radioactive isotopes of tritium, i.e. ³ N, and carbon-14, i.e. ¹⁴ C are especially useful for this purpose because of their ease of administration and ready-made detection tools.

Substitution with heavier isotopes such as deuterium, i.e. ² N, can give certain therapeutic advantages due to greater metabolic stability, for example, increased half-life ίη у1уо, or reduced dosage requirements and, therefore, may be preferred in some cases.

18 15 13

Substitution with positron-emitting isotopes, such as C, E, O, and может, may be useful in positron emission tomography (PET) studies to study substrate population by receptors.

Isotopically labeled compounds of formula (I) can generally be prepared by conventional methods known to those skilled in the art, or by methods similar to those described in the accompanying examples and preparatory examples using the appropriate isotopically labeled reagents instead of the unlabeled reagents used previously.

Pharmaceutically acceptable solvates in accordance with the invention include solvates, where the crystallization solvent may be isotopically substituted, for example, B ₂ O. b ₆ -acetone and b ₆ -BM8O.

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

The compounds of the invention have U1a antagonist activity. In particular, they are useful in treating a number of conditions, including aggression, Alzheimer's disease, anorexia nervosa, anxiety, anxiety disorder, asthma, atherosclerosis, autism, cardiovascular disease (including angina pectoris, atherosclerosis, hypertension, heart failure, edema, hypernatremia), cataracts, diseases of the central nervous system, cerebrovascular ischemia, cirrhosis, cognitive impairment, Cushing's disease, depression, diabetes mellitus, dysmenorrhea (primary and secondary), vomiting (including seasickness n), endometriosis, gastrointestinal disease, glaucoma, gynecological disease, heart disease, intrauterine growth retardation, inflammation (including rheumatoid arthritis), ischemia, coronary heart disease, lung tumor, urination disorders, abdominal pain that occurs during ovulation neoplasm, nephrotoxicity, insulin-independent diabetes, obesity, obsessive-compulsive disorder, increased intraocular pressure, preeclampsia, premature ejaculation, premature (premature) childbirth, pulmonary disease, Raynaud’s disease, kidney disease, renal failure, male or female sexual dysfunction, septic shock, sleep disturbance, spinal cord injury, thrombosis, urinary tract infection or urolithiasis. Of particular interest is dysmenorrhea (primary or secondary), more specifically primary dysmenorrhea.

Thus, a further aspect of this invention is a method of treating a mammal, including a human, for treating a disorder in which a U1a antagonist is indicated comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to a mammal. In particular, the compounds of formula (I) are useful in the treatment of anxiety, cardiovascular disease (including angina pectoris, atherosclerosis, hypertension, heart failure, edema, hypernatremia), dysmenorrhea (primary and secondary), endometriosis, vomiting (including seasickness), delays fetal development, inflammation (including rheumatoid arthritis), abdominal pain that occurs during ovulation, preeclampsia, premature ejaculation, premature birth or Raynaud's disease. Even more specifically, they are useful in the treatment of 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 manufacture of a medicament for the treatment of a disorder in which a U1a receptor antagonist is indicated.

All compounds of formula (I) can be obtained by the methods described in the General methods presented below, or by specific methods described in the “Examples” and in the “Preparatory Examples”, or their generally accepted modifications. The present invention also encompasses any or one or more of these processes for the preparation of compounds of formula (I), in addition to

- 7 010132 to any new intermediates used in them.

Unless otherwise indicated, in this description of the invention ^ 8SI1 means 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, ESA means Ν, Ν'-dicyclohexylcarbodiimide, BUT AT means 1-hydroxy-7-azabenzotriazole, and HOBT means 1hydroxybenzotriaz ;

RuVOR® means benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate, RuVOR® means bromo-tris-pyrrolidinophosphonium hexafluorophosphate, and NVTI means O-benzotriazol-1-ylΝ, Ν, Ν ', Ν ония tetrafluoro;

tCPBA means methachloroperbenzoic acid, AcOH means acetic acid, HCl means hydrochloric acid, TEA means trifluoroacetic acid, and p-T8A means p-toluenesulfonic acid;

Ε! ₃ Ν means triethylamine, and ΝΜΜ means Ν-methylmorpholine;

K ₂ CO ₃ means potassium carbonate, and KO-Vi means potassium tert-butoxide;

No. 1ON. KOH and OH are sodium, potassium and lithium hydroxide, respectively;

Boc means tert-butoxycarbonyl, and CB / means benzyloxycarbonyl;

PTEE means polytetrafluoroethylene, teflon;

Me1 means methyl iodide;

Metohyla! E means methyl p-toluenesulfonate;

MeOH means methanol, E! OH means ethanol, and n-ViOH means n-butyl alcohol;

E! OAc means ethyl acetate, ΜеСN means acetonitrile, TНE means tetrahydrofuran, EM8O means dimethyl sulfoxide, ESM means dichloromethane, ΌΜΕ means Ν, Ν-dimethylformamide, IIM means No. methyl-2-pyrrolidinone, and OMA means dimethylacetamide;

Me means methyl, E! is ethyl, C1 is chloro, and OH is hydroxy;

sa! means catalyst or catalytic.

In the following general methods B, K ¹ , B ² , B ³ , ring A, V, X, O, Ζ, Υ, Υ ', Not !, Not! ¹ and not! ² such as defined above for the compounds of formula (I), unless otherwise specified. If O represents ΝΒ ² or O represents a direct bond attached to the nitrogen atom in ring A, then the compounds of formula (I) can be obtained according to scheme 1.

Scheme 1

RS is a suitable protecting group for Ν, usually benzyl, BOC or CB /, and preferably BOC.

The compounds of formula (II) can be obtained as described in \ UO 9703986 A1 19970206 or by reacting the corresponding lower alkyl ester (e.g. methyl or ethyl) with hydrazine under standard conditions, as illustrated in the preparatory examples below.

Stage (a). Compounds of formula (III) can be prepared by reacting hydrazine (II) with a suitable acetal (e.g., Ν, Ν-dimethylacetamide-dimethylacetal) in a suitable solvent, such as THE or OME, at a temperature of from room temperature to about 60 ° C, for up to 18 hours. The resulting intermediate can then be treated under acid catalysis (e.g. p-T8A or TEM) in a high boiling solvent (e.g. toluene or xylene) for about 18 hours to give a compound of formula (III). Preferred Conditions: 1.5-2.0 eq. acetal (e.g., Ν, Ν-dimethylacetamide-dimethylacetal, triethyl orthopropionate) in THE or OME at room temperature to 60 ° C for about 18 hours and then p-T8A or TEM (catalyst) in toluene at reflux for 18 hours

Stage (b). The 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 TEM or p-T8A, in a suitable high boiling solvent (e.g. toluene or xylene) with

- 8 010132 high temperature. Preferred Conditions: 0.5-1.0 eq. TEL, 1.0-2.0 eq. aniline in toluene at approximately reflux for up to 18 hours

Stage (c). The removal of the protective group from compound (IV) is carried out using a standard methodology as described in Prgozysius Soyirk ίη Ogdashs Zuisheksch Lu T. ^. Ohiyee R.I. \ ¥ and 1x. When RS is BOC, preferred conditions are: 4M HC1 in dioxane in MeOH, dioxane or Όί, Μ at a temperature of from room temperature to about 50 ° C. for up to 18 hours; or 2.2 M HC1 in MeOH for up to 18 hours at room temperature; or TEM in Όί, 'Μ at room temperature for about 1 hour. Alternatively, when RS is BOC, compound (V) can be obtained directly from compound (III) by treatment with an excess of TEM, usually 1.1-1.5 equiv., and the corresponding aniline in toluene at a reflux temperature of the reaction mixture for up to 4 days.

Stage (g). Compounds of formula (I) can be prepared by reacting an amine (V) with a sub

walking acid or acid chloride ( ^{ζ τ} ·, where T represents OH or C1). The coupling reaction can be carried out using any of (1) acyl chloride ^{ζ C1} + amine (V) with an excess of acid base in a suitable solvent or (2) acid 2CO ₂ N with a conventional coupling agent + amine (V), possibly in the presence of a catalyst with excess base in a suitable solvent.

In typical cases, the conditions are as follows:

BUT.

(1) acid chloride ^{1 2 C |} · Amine (V) (possibly with an excess of triamine, such as Εΐ ₃ Ν, Hünig base or ΝΜΜ) in ΌΟΜ or THE, without heating, for a period of 1 to 24 hours; or (2) acid 2CO ₂ H, HUSSOYUSS and NOVT / NOAT, amine, excess ΝΜΜ, Εΐ ₃ Х or Hünig base, in THE, Όί''Μ. ΌΜΑ or EYAc, at room temperature for a period of 4 to 48 hours; or acid 2CO ₂ N, RUVOR® / RuVYUR® / O-benzotriazol-1-yl-C ^ No, No.-tetramethyluronium hexafluorophosphate, excess amine, excess избы, Εΐ ₃ Ν or Hunig base, in THE, Όί ^ 'Μ, ^ ΜΑ or EJAc, at room temperature for 4 to 24 hours.

Preferred conditions are eq. amine (V), 1.0-1.5 equiv. ^{2 C1} > 1.5-5 equiv. ΝΜΜ, Εΐ ₃ Ν or Hyunig bases in ΟΕ ^ Μ at room temperature for up to 18 hours;

or 1 eq. amine (V), 1.2 eq. 2CO ₂ N, 1.2-1.5 equiv. NOVT, 1.2-1.5 equiv. SSOE 2-4 equiv. Εΐ ₃ Ν, in 1) С \ 1 at room temperature for 24 hours;

or 1 eq. amine (V), 1.2-1.5 equiv. 2CO ₂ N, 1.2-2.0 equiv. NVTI, 5 eq. Εΐ ₃ Ν or ΝΜΜ in ^ ΜΑ or ΌΟΜ, at a temperature between room temperature and 60 ° C for up to 24 hours.

The compounds of formula (IV), where O represents ΝΚ ² or O represents a direct bond attached to the nitrogen atom in ring A, which in turn is attached to the triazole ring through a nitrogen atom, can alternatively be obtained as described in scheme 2 below, and they are represented as compounds of DUA).

Scheme 2 (VI)

P6

I

ABOUT.

RS

but.

Υ (ΥΝΙΑ) (> ΧΑ) ^Υ

Υ (1UA)

Stage (d). Compounds of formula (ASA) can be prepared by reacting approximately equimolar amounts of isothiocyanate (VI) and amine (VII) in a suitable solvent (for example Ε JUN or ΌΟΜ) at room temperature for 2 to 72 hours. Preferred conditions: 1-1.1 eq. (VI), 1 equiv. (VII), in ΕΕΕ or ΌΟ ^ 'Μ, at room temperature for 0.5-2 hours.

The compounds of formulas (VI) and (VII) are commercially available or can be obtained from known compounds

- 1010323 ny using standard chemical transformations.

Stage (e). Compounds of formula (ΙΧΑ) can be prepared by methylation of thiourea (USA) using a suitable methylating agent (e.g. Me1 or MeToku1a1e) in the presence of a suitable base (e.g. KO'-Vi) in a suitable solvent (e.g. THP or ether) at a temperature between 0 ° C and the reflux temperature of this reaction mixture for about 18 hours. Preferred conditions: 1 equiv. (USHA), 1-1.2 equiv. KO'-Vee. 1-1.2 equiv. Ме1 or МеТо§у1а1е, in ТНР, at a temperature between 10 ° С and room temperature for up to 18 hours.

Stage (g). Compounds of formula (1AA) can be prepared by reacting compound (ΙΧΑ) with a suitable hydrazide (CHSONHHN ₂ ), possibly under conditions of acid catalysis (e.g. TPA or p-T8A) in a suitable solvent (e.g. THP or n-ViOH), at a temperature between room temperature and reflux temperature of the reaction mixture. Preferred Conditions: 0.5 eq. TPA, excess hydrazide (HCHONNH ₂ ), in THP at reflux for up to 18 hours

Compounds of the formula (USA), where O is ΝΚ ² or O is a direct bond attached to the 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.

Scheme 3

(VI) (XI) ^Υ 0 / 1MA) ^D

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

Compounds of formula (XI) can be prepared from isothiocyanate (VI) and amine (X) by methods analogous to the methods described above for step (e).

Stage (h). Compounds of the formula (USA) can be prepared by protecting a reactive nitrogen atom using a standard methodology as described in Prgoechene Soyirk ίη Ogdashs 8u1ye815 Liu T. ^. Sgeepe apy R. When RS is BOC, preferred conditions are 1 equiv. amine (XI), 1 equiv. di-tert-butyl dicarbonate in an ESM and dioxane, at room temperature, for about 3 hours

The compounds of formula (VIII), where O represents ΝΚ ² or O represents a direct bond attached to the nitrogen atom in ring A, which in turn is attached to the triazole ring through a carbon atom, can be obtained as shown in scheme 4, where they presented as compounds (USB).

Scheme 4 about

(XIII) (ХГ7) (USHB)

Stage (s). Compounds of formula (X1U) can be prepared by combining aniline (XIII) with acid (XII) in a manner analogous to the method described above in step (d). Preferred Conditions: 1 eq. acid (XII), 1.1 eq. amine (XIII), 1.2 eq. ΧΥδΟΌΓ 3 equiv. Εΐ ₃ Ν in MeCN at room temperature for approximately 3 days.

Stage (k). A compound of formula (USB) is prepared by thionation of compound (XIU) by treatment with a suitable thionic agent, such as Lawesson's reagent, in a high boiling solvent (e.g. toluene) at a temperature between room temperature and reflux temperature of the reaction mixture. Preferred Conditions: 1 eq. (XIU), 0.5 equiv. Lawesson's reagent in toluene, at a temperature between room temperature and reflux temperature, for up to 18 hours

The compounds of formula (III), where O represents ΝΚ ² or O represents a direct bond that is attached to the nitrogen atom in ring A, can alternatively be obtained as shown in scheme 5.

- 10 010132

Stage (L). Diacylhydrazides (XV) can be prepared by combining hydrazides (II) with an acid or o

Lt with acid chloride! where T represents C1 or OH) in a manner analogous to the method described above in step (g). Preferred Conditions: 1 eq. hydrazide (II), 1.1 eq. HCO ₂ N, 1.1 eq. \ ν8ί.ΌΙ, 1.1 equiv. NOVT, 1.2 eq. Εΐ ₃ Ν, in ΌΜΕ at room temperature for 18 hours

Stage (m). Oxadiazole (III) can be prepared by cyclization of compound (XV), usually under acid catalysis (e.g. polyphosphoric acid, POC1 ₃ , trifluoromethyl sulfonic anhydride / pyridine or 1-methylimidazole), possibly in a suitable solvent (e.g. ESM). at a temperature between 0 ° C and the reflux temperature of the reaction mixture. Preferred Conditions: 1 eq. (XV), excess pyridine or 1-methylimidazole, 1.5-2 eq. trifluoromethyl sulfonic anhydride, in an ESM, at a temperature between 0 ° C and room temperature for up to 3 hours.

Compounds of formula (XV) can alternatively be prepared by combining an acid (XII) with a suitable hydrazide (XCONHNH ₂ ) in a manner analogous to the method described above in step (d). Preferred Conditions: 1 eq. acid (XII), 1 equiv. hydrazide, 1.02 eq. νδΌΟ, in Όί, 'Μ at a temperature between 0 ° C and room temperature.

The compounds of formula (III), where X is C'NA-linked-HeP can alternatively be obtained as shown in scheme 6.

Scheme 6

Stage (n). 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., Εΐ ₃ Ν or ΝΜΜ) in a suitable solvent (e.g., EuAc or Όί, 'Μ) at a temperature between 0 ° C and room temperature for about 18 hours. Preferred conditions: 1 equiv. (II), 1 equiv. acetyl chloride, 1.1 eq. ΝΜΜ, in an ESM, at a temperature of 10 ° C to room temperature, for a period of time up to 18 hours

Compounds of formula (XVII) can be prepared by cyclization of compound (XVI) in a manner analogous to the method described in step (m) above.

Stage (o). Compounds of formula (III) can be prepared by reacting compound (XVII) with a suitable He! (containing reactive atom Ν) in the presence of a suitable base (e.g. Ε! ₃ Ν or K ₂ CO ₃ ), in a suitable solvent (e.g. ΌΜΕ or ΜеСN), at a temperature between room temperature and reflux temperature of the reaction mixture, for about 18 hours Preferred Conditions: 1 eq. (Xvii), 1.4 equiv. K ₂ CO ₃ , 2 eq. Not !, in ΌΜΕ at room temperature for 18 hours.

The compounds of formula (I), where O represents ΝΚ ² , or O represents a direct bond that is attached to the nitrogen atom in ring A, can alternatively be obtained as shown in scheme 7.

- 11 010132

Scheme 7

It is C _3-4 alkyl or benzyl and is preferably Me or E !.

Stage (p). The compound of formula (XIX) can be obtained by reacting an amine (XVIII) with about

A suitable acid or acid chloride is 7 ^t · where T is OH or C1) in a manner analogous to the method described above in step (d). Preferred Conditions: 1 eq. (Xviii), 0.9 equiv. 2C0C1, 1.1 eq. Εΐ ₃ Ν, in the ESM. at a temperature between 10 ° C and room temperature for about 3 hours

Stage (p). The hydrazide of formula (XX) can be obtained by treating the ester (XIX) with an excess of hydrazine in a suitable solvent (for example, E! OH or MeOH) at a reflux temperature of the reaction mixture for up to 18 hours. Preferred conditions: 1 equiv. (XIX), 2-4 equiv. hydrazine, in Meon at a temperature of reflux, for a time between 10 and 48 hours

about

X

Compounds of formula (XXI) can be prepared by reacting hydrazide (XX) with ^{ζ t} using the methods described above in step (l).

Compounds of formula (XXII) can be prepared by cyclization of compound (XXI) using the methods described above in step (m).

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

Alternatively, compounds of formula (XXII) can be prepared directly from compound (XX) by reaction with the corresponding acetal (e.g., triethylorthopropionate, Ν, Ν-dimethylacetamide dimethylacetal) in a manner analogous to the method described above in step (a).

Compounds of formula (XXII) wherein X is CH3 ^ -linked-HeT can alternatively be prepared as shown in Scheme 8.

Scheme 8

Compounds of formula (XXIII) can be prepared by reacting hydrazide (XX) with chloroacetyl chloride in a manner analogous to the method described above in step (n).

Oxadiazole (XXIV) can be obtained by cyclization of compound (XXIII) in a manner analogous to the method described above in step (m).

Compound (XXII) can be prepared by reacting compound (XXIV) with a suitable He! (containing reactive atom Ν) as described above in step (o).

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

- 12 010132

Scheme 9 \ ² / = O> = O

(VI) (XXVI) (XX'D

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

Compounds of formula (XXVI) can be prepared by reacting compound (XXV) with the corresponding isothiocyanate (VI) in a manner analogous to the method described above in step (e).

The compound of formula (XXVII) can be obtained by alkylation of the compound (XXVI) in a manner analogous to the method described above in step (e).

A compound of formula (I) can be prepared by reacting a compound (XXVII) with a suitable hydrazide as described above in step (g).

The compounds of formula (I), where O is a direct bond that is attached to the carbon atom in ring A, which in turn is attached to the triazole ring through a nitrogen atom in ring A, and Ζ is ΝΚ ⁴ Κ ⁵ , can be obtained as shown in diagram 10.

Pattern 10

Ka is C _1-4 alkyl or benzyl and is preferably Me or ΕΙ.

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

Compounds of formula (XXIX) can be prepared by reacting compound (XXVIII) with the corresponding isothiocyanate (VI) in a manner analogous to the method described above in step (e).

The compound of formula (XXX) can be obtained by alkylation of compound (XXIX) in a manner analogous to the method described above in step (e).

A compound of formula (XXXI) can be prepared by reacting a compound (XXX) with a suitable hydrazide as described above in step (g).

Stage (s). Hydrolysis of the ester (XXXI) using a suitable acid or base catalyst, preferably an alkali metal base (e.g. ΝαΟΗ, KOH or OH) in a suitable aqueous solvent (e.g. dioxane or MeOH) at a temperature between

- 13 010132 at the natural temperature and the reflux temperature of the reaction mixture, for a period of time from 2 to 48 hours. Preferred conditions: 1 equiv. (Xxxi), 5-10 equiv. ΝαΟΗ solution in dioxane at a temperature between room temperature and reflux temperature for a period of 2 to 16 hours

Compounds of formula (I) can be prepared by reacting Ζ-H (containing reactive atom Ν) with acid (XXXII) in a manner analogous to the method described above for step (d). Preferred Conditions: 1 eq. acid (XXXII), 1.5 equiv. amine (ΖΗ), 4 equiv. Εΐ ₃ Ν, 1.5 equiv. AZSOk 1.5 equiv. ΗΟΒΤ, in an ESM at room temperature, for 24 hours

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

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

Scheme 11

(Xxxiii)

Compounds of formula (XXXIII), where O is a direct bond and ring A is attached to the triazole ring via a nitrogen atom, can be obtained from the corresponding isothiocyanate (VI)

N and nitrile containing ring A, by methods similar to the methods described in scheme 9.

The compounds of formula (I), where V represents an oxygen atom, can be obtained as shown in scheme 12.

Pattern 12

X

Stage (t). A compound of formula (XXXV) can be prepared by reacting hydrazide (XCΟNΗNΗ ₂ ) with isothiocyanate (VI) in a manner analogous to the method described above in step (e). Preferred Conditions: 1 eq. isothiocyanate, 1 equiv. hydrazide, in ΕΐΟΗ at room temperature for 72 hours

Stage (s). Compounds of formula (XXXVI) can be prepared by cyclization of compound (XXXV) under acidic or alkaline conditions, preferably under basic catalysis (e.g. alkali metal hydroxide) in an aqueous solvent (e.g. water / ΕΐΟΗ) at an elevated temperature for about 24 hours. Preferred Conditions: 1 eq. (XXXV), 10 equiv. Water ΝαΟΗ ^^) in ΕΐΟΗ at 80 ° С for 18 h.

Stage (f). Alkylation of compound (XXXVI) to give compound (XXXVII) can be achieved by treating with a suitable alkylating agent (e.g. MeI or Mc-Toxu1a1c) in a manner analogous to the method described above in step (e). Preferred Conditions: 1 eq. (XXXVI), 1 equiv. ΚΟ ^ΐ -Βυ, 1 equiv. Ms-To5u1a1s. in ΤΗΕ, at a temperature between room temperature and reflux temperature, for 3 hours

Stage (x). Compounds of formula (XXXVIII) can be prepared by oxidation of compound (XXXVII) by treatment with a suitable oxidizing agent (e.g., tCRPA or hydrogen peroxide) in a suitable solvent (e.g., ESM) at room temperature for about 18 hours. Preferred conditions: 1 equiv. (XXXVII), 4 equiv. tSRVA, in ESM, at room temperature, for 18 hours

Stage (c). Compounds of formula (I) can be prepared by reacting a sulfoxide

- 14 010132 (XXXVIII) with an excess of alcohol (XXXIX) in the presence of a suitable base (e.g. Na. Or KO! Vi). in a suitable solvent (eg. TUE or ether) at a temperature between 0 ° and room temperature for up to 18 hours. Preferred conditions: 1 eq. (XXXVIII). 2 eq. No. 1H. 2 eq. alcohol (XXXIX). in TUE for 18 hours at room temperature.

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

Some compounds of formulas (I). (III). (Iv). (V). (XXII) and (XXXI) can be subjected to mutual transformations of functional groups (e.g., alkylation or hydrolysis) to give alternative compounds of formulas (I). (III). (Iv). (V). (XXII) or (XXXI) respectively.

Compounds of the invention. intended for pharmaceutical use. can be administered as crystalline or amorphous products. They can be obtained. eg. in the form of solid masses. powders or films in such ways. like precipitation. crystallization. freeze-drying. spray drying or evaporative drying. For this purpose, you can use microwave or radio frequency drying.

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). Usually. they will be administered in the form of a composition together with one or more pharmaceutically acceptable excipients. The term excipient is used herein to describe any ingredient. other than the compound (s) of the invention. The choice of excipient to a large extent depends on such factors. as a specific route of administration. the effect of the excipient on the solubility and stability and nature of the dosage form.

Another aspect of the present invention is a pharmaceutical composition. containing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable excipient. diluent or carrier. In yet another embodiment, a pharmaceutical composition is provided for administration or for prophylaxis. or when the pain begins.

Pharmaceutical Compositions suitable for delivery of the compounds of the present invention. and methods for their preparation will be apparent to those skilled in the art. Such compositions and methods for their preparation can be found. eg. at Kestdfi'k Riattasei! 1sa1 8s1eise5. 191st Εάί! Ίοη (Musk RybShypd Sotrapu. 1995).

The compounds of the invention can be administered orally. Oral administration may include swallowing. so that the compound enters the gastrointestinal tract. or buccal or sublingual administration may be used. in which the compound enters the bloodstream directly from the oral cavity.

Preparations. suitable for oral administration. include solid preparations. such as pills. capsules. which contain particles. liquids or powders. cakes (including filled with liquid). chewing gum. multi- and nanoparticles. gels. solid solutions. liposomes. films. ovuli. sprays and liquid preparations.

Liquid preparations include suspensions. solutions. syrups and elixirs. Such preparations can be used as fillers in soft or hard capsules. and. usually. they contain a carrier. like water. ethanol. polyethylene glycol. propylene glycol. methyl cellulose or a suitable oil. and one or more emulsifying agents and / or suspending agents. Liquid preparations can also be obtained by diluting a solid. for example from sachets.

The compounds of the invention can also be used in instant ones. rapidly disintegrating dosage forms. such as described in Exreg! Ορίηίοη ίη TyegareiDs Ra! Ep! §. 11 (6). 981986. Lew Mand ηηά Syen (2001).

For tablet dosage forms, depending on the dose, the drug can comprise from 1 to 80 wt.% By weight of the dosage form. in more typical cases, from 5 to 60 wt.% by weight of the dosage form. In addition to the drug, tablets usually contain a cultivator. Examples of disintegrants include sodium starch glycolate. carboxymethyl cellulose in sodium form. carboxymethyl cellulose in calcium form. croscarmellose sodium. crospovidone. polyvinylpyrrolidone. methyl cellulose. microcrystalline cellulose. hydroxypropyl cellulose substituted by lower alkyl. starch. pregelatinized starch and sodium alginate. Typically, the baking powder is from 1 to 25 wt.%. preferably from 5 to 20 wt.% by weight of the dosage form.

Binding agents are commonly used to impart cohesive properties to a tablet preparation. Suitable binding agents include microcrystalline cellulose. gelatin. Sahara. polyethylene glycol. natural and synthetic gums. polyvinylpyrrolidone. pregelatinized starch. hydroxypropyl cellulose; and hydroxypropyl methyl cellulose. Tablets may also 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 also contain surface active agents. such as laurilsul

- 15 010132 fat sodium and polysorbate 80, and glidants, such as silicon dioxide and talc. If present, surface active agents may comprise from 0.2 to 5% by weight of the tablet, and glidants may comprise from 0.2 to 1% by weight of the tablet.

Tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants typically comprise from 0.25 to 10 wt.%, Preferably from 0.5 to 3 wt.%, Based on the weight of the tablet.

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

Typical tablets contain up to about 80% of the drug, from about 10 to about 90% by weight of a binder, from about 0 to about 85% by weight of a diluent, from about 2 to about 10% by weight of a disintegrant and from about 0.25 to about 10 wt.% a lubricant.

Tablet mixtures can be pressed directly or using a roller until the tablets are molded. Alternatively, tablet mixtures or batches of mixtures may be subjected to wet, dry or melt granulation, melt-solidification, or extrusion before tabletting. The final preparation may contain one or more layers and may be coated or may be uncoated and may even be encapsulated.

The manufacture of tablets is considered in Ryagtaseibs1 Eokad Rogtk: TaYeK ^ 1. 1, b. N. biebtai apb b. Lätai (Magse 1 Eekkeg. Youe ΥογΙζ. 1980).

Consumable oral films for use in veterinary medicine or for humans are usually water-soluble or water-swellable, thin-film dosage forms that can be instant or mucoadhesive, and typically contain a compound of formula (I), a film-forming polymer, a binder, a solvent, a humectant, a plasticizer , a stabilizer or emulsifier, a viscosity modifying agent, and a solvent. Some components of this drug may perform more than one function.

The compound of formula (I) may be soluble or insoluble in water. The water-soluble compound in typical cases is from 1 to 80 wt.%, In more typical cases, from 20 to 50 wt.% Of the solutes. Less soluble compounds can make up the majority of the composition, typically up to 88% by weight of solutes. Alternatively, the compound of formula (I) may be in the form of granules consisting of many particles.

The film-forming polymer may be selected from natural polysaccharides, proteins or synthetic hydrocolloids, and in typical cases it is present in the range from 0.01 to 99% by weight, in more typical cases in the range from 30 to 80% by weight.

Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives, salivating agents, cooling agents, cosolvents (including oils), emollients, fillers, antifoam agents, surfactants, and taste masking agents.

Films in accordance with the invention are usually obtained by evaporative drying a thin aqueous film deposited on a detachable substrate or paper. This can be done in an oven or in a tunnel kiln, usually in a combined apparatus for applying and drying the coating, or by freeze-drying, or by vacuum.

Solid preparations for oral administration with immediate and / or modified release can be prepared. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations.

Suitable modified release formulations for the purposes of this invention are disclosed in US Pat. No. 6,106,864. Details of other suitable release techniques, such as high-energy dispersions and osmotic and coated particles, are described in Ryagtasei! 25 (2), 1-14, Hu Weta e! A1 (2001). The use of chewing gum to achieve controlled release is described in \ UO 00/35298.

The compounds of the invention can also be administered directly into the bloodstream, into a muscle, or into an internal organ. Suitable parenteral routes of administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrathoracic, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needleless injectors and infusion equipment.

Parenteral preparations are usually aqueous solutions that may contain excipients, such as salts, carbohydrates and buffering agents (preferably up to pH 3 to 9), but for some applications they may be more preferably prepared as a sterile non-aqueous solution or as a dry forms for use with a suitable carrier, such as sterile pyrogen-free water.

- 16 010132

The preparation of parenteral preparations under sterile conditions, for example, by lyophilization, can easily be carried out according to standard pharmaceutical techniques well-known to those skilled in the art.

The solubility of the compounds of formula (I) used in the preparation of parenteral solutions can be increased using appropriate preparation methods, such as the administration of solubility enhancing agents.

Preparations for parenteral administration with immediate and / or modified release may be prepared. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations. Thus, the compounds of the invention can be prepared as a solid, semi-solid or thixotropic liquid for administration as an implantable depot providing a modified release of the active compound. Examples of such preparations include drug-coated stents and microspheres of a copolymer of b1-lactic acid and glycolic acid (PCBL).

The compounds of the invention can also be administered topically to the skin or mucous membrane, i.e., dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting agents, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Permeability enhancers can be introduced, see, for example, I Riagt 8c1, 88 (10), 955-958, Liu Rppt apb Mogdap (Osnob 1999).

Other topical routes of administration include electroporation delivery, iontophoresis, phonophoresis, sonophoresis, and a microneedle or needleless (eg, Po ^ hebes! ™, B1o) ec1 ™, etc.) injection.

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

The compounds of the invention can also be administered intranasally or by inhalation, usually in the form of a dry powder (either alone as a mixture, for example as a dry mixture with lactose, or as a particle of mixed components, for example mixed with phospholipids such as phosphatidylcholine) from a dry powder inhaler or in the form of an aerosol spray from a container under pressure, a pump, a spray bottle, a spray bottle (preferably a spray bottle with electrodynamic production of fine mist) or a nebulizer with or without use anija suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may contain a bioadhesive agent, for example chitosan or cyclodextrin.

The pressure container, pump, nebulizer, nebulizer or nebulizer contains a solution or suspension of the compound (s) of the invention, containing, for example, ethanol, aqueous ethanol or a suitable alternative agent for dispersing, solubilizing or prolonging the release of the active component, the propellant (s) as a solvent and optionally a surfactant such as sorbitan trioleate, oleic acid or oligolactic acid.

Before use in the preparation of a preparation in the form of a dry powder or suspension, the drug product is micronized to a size suitable for delivery by inhalation (usually less than 5 microns). This can be achieved by any suitable milling method, such as milling in a vortex mill, milling in a fluidized bed, treatment with a supercritical fluid to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropyl methylcellulose), blisters and cartridges for use in an inhaler or insufflator that contain a powder mixture of a compound of the invention, a suitable powder base such as lactose or starch, and a performance modifier such as 1-leucine, mannitol or magnesium stearate. Lactose may be anhydrous or in the form of a monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution preparation for use in a nebulizer using electrodynamics to produce fine mist may contain from 1 μg to 20 mg of the compound of the invention per actuation, and the actuation volume can vary from 1 to 100 μl. A typical preparation may contain a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable formulations, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to the preparations of the invention that are intended for inhalation / intranasal administration.

Formulations for inhalation / intranasal administration with immediate and / or modified release can be prepared using, for example, PCL. Drugs with mo

- 17 010132 differential release include drugs with a delayed, prolonged, pulsed, controlled, targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined using a valve that delivers a measured amount. The total daily dose should usually be in the range of 0.01 μg to 15 mg, which can be administered in a single dose or, as a rule, in divided doses throughout the day.

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 the traditional suppository base, but various alternatives can be used where appropriate.

Preparations for rectal / vaginal administration with immediate and / or modified release may be prepared. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations.

The compounds of the invention can also be administered directly into the eye or ear, usually in the form of droplets of a micronized suspension or solution in isotonic pH-adjusted sterile saline. Other formulations suitable for ophthalmic and ear administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, plates, lenses, and particle or bubble systems such as niosomes or liposomes. Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example hydroxypropyl methylcellulose, hydroxyethyl cellulose or methyl cellulose, or heteropolysaccharide polymers, for example gelan gum, can be incorporated together with a preservative. Such drugs can also be delivered by iontophoresis.

Formulations for ocular / ear administration with immediate and / or modified release may be prepared. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations.

The compounds of the invention can be combined with soluble macromolecular substances, such as cyclodextrin and its suitable derivatives or polyethylene glycol-containing polymers, to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for administration by any of the aforementioned methods.

For example, it has been found that drug complexes with cyclodextrin are usually useful for most dosage forms and routes of administration. Both inclusion complexes and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrin can be used as an auxiliary additive, i.e. as a carrier, diluent or solubilizer. Most often, alpha, beta and gamma cyclodextrins are used for these purposes, examples of which can be found in international applications Nos. AO 91/11172, AO 94/02518 and AO 98/55148.

Since it may be desirable to administer a combination of active compounds, for example, to treat 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 contains a compound of the invention, can be combined form of a kit suitable for co-administration of the compositions.

Thus, the kit according to the invention contains two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) in accordance with this invention, and a means for separately containing said compositions, such as a container, section bottle or section bag from foil. An example of such a kit is the well-known blister pack used for packaging tablets, capsules and the like.

The kit of the invention is particularly suitable for administering various dosage forms, for example, oral and parenteral, for administering separate compositions at different dosage intervals, or for titration of individual compositions relative to one another. To help comply with the treatment regimen, the kit usually contains instructions for administration and can be equipped with a so-called memo.

For administration to human patients, the total daily dose of the compounds of the invention is usually in the range of 0.01 to 15 mg, of course, depending on the route of administration. The total daily dose can be administered in single or divided doses, and at the discretion of the doctor, it may go beyond the typical range given here.

These dosages are for an average human subject having a weight of from about 60 to about 70 kg. The doctor can easily determine the dose for subjects whose mass is outside this range, such as infants and the elderly.

For the avoidance of doubt, here treatment includes curative, palliative and preventive treatment.

Compounds of the present invention can be tested in the screenings set forth

- 18 010132 below.

1.0. The binding analysis of _1A on the filter.

1.1. Getting membranes.

Receptor binding assays were performed on cell membranes obtained from CHO cells (Chinese hamster ovaries) stably expressing human ν _1Α receptors (CHO-11U _1A ). The cell line SNO-11U _1A was kindly provided under a license agreement by Mark Tibonye (Mags Tnopyeg), Ber !. OG Mebuche, Sase \ Ues1egp Vesegue Iyuegzyu 8syoo1 OG Mebushe, C1eue1appb, Oyo. As usual, CHO-11U _1A cells were kept at 37 ° C in a humidified atmosphere with 5% CO ₂ in the BMEM / Nutz B12 nutrient mixture supplemented with 10% fetal bovine serum, 2 mM Glutamine, 15 mM HEPE8 and 400 μg / ml 0418. For mass production of cell pellet, adherent CHO-11U _1A cells were grown to 90-100% confluency in 850 cm ² roller bottles containing a medium containing a nutrient mixture of BMEM / Nutz B12 supplemented with 10% fetal bovine serum , 2 mM L-glutamine and 15 mm HEPE8. Confluent CHO-11U _1A cells were washed with phosphate-buffered saline (PB8), collected in ice-cooled PB8 and centrifuged at 1000 rpm. The cell pellet was stored at -80 ° C until use. The cell pellet was thawed on ice and homogenized in a buffer to obtain membranes consisting of 50 mM Tris-HC1, pH 7.4, 5 mM MdC1 ₂ and enriched with a cocktail of protease inhibitors (Rosier). The cell homogenate was centrifuged at 1000 rpm, 10 min, 4 ° C, and the supernatant was removed and stored on ice. The remaining precipitate was homogenized and centrifuged as described above. Superantants were pooled and centrifuged at 25,000 x d for 30 min at 4 ° C. The pellet was resuspended in freezing buffer consisting of 50 mM Tris-HCl, pH 7.4, 5 mm MdCl ₂ and 20% glycerol, and stored in small aliquots at -80 ° C until use. Protein concentration was determined using Bradford reagent (WgabHogb) and bovine serum albumin (B8A) as a standard.

1.2. Linking U1 _A on the filter.

Protein linearity studies were performed on each new batch of membranes, followed by saturation binding. The concentration of the membranes was chosen so as to obtain specific binding on the linear part of the curve. Then saturation binding studies were performed using various concentrations of [ ³ H] -arginine-vasopressin, [ ³ H] -AUR, (0.05-100 nM) and K _b and _{C max were} determined.

Compounds were tested for their effect on the binding of [ ³ H] -AUR to CHO-11U1A membranes ( ³ H-AUR; specific activity 65.5 Ci / mmol; ΝΉΝ Г е 8s1epsez). Compounds were dissolved in dimethyl sulfoxide (BM8O) and diluted to a working concentration of 10% BM8O with assay buffer containing 50 mM Tris-HCl pH 7.4, 5 mM MdC12 and 0.05% B8A. 25 μl of the compound and 25 μl of [ ³ H] -AUR (final concentration at or below K _b determined for the batch of membranes, usually 0.5-0.6 nM) were applied to a 96-well round-bottom polypropylene plate. The binding reaction was initiated by the addition of 200 μl of membranes and the plates were gently shaken for 60 min at room temperature. The reaction was stopped by rapid filtration using a B11! Eta Ce11 Nague1g cell harvesting device (Raskagb! Pz1gitep1z) through a 96-well plate of UD1! EG OB / B, which was pre-soaked in 0.5% polyethyleneimine to prevent peptide adhesion. 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 MdCl ₂ . The plates were dried, and 50 μl of M1cgossc! -0 (Raskagb! Pz1gishep1z) was added to each well. The tablets were sealed and read on a TorSoip scintillation counter! М1сгор1а! Е 8сш! 111а! Юп Соип! Е (Raskagb ShzyiteShz). Nonspecific binding (ΝΈΕ) was determined using 1 μM unlabeled b (CH ₂ ) ₅ Tug (Me) AUR ([b-mercapto-b, b-cyclopentamethylene propionyl, 0-Me-Tug ² , Agd ⁶ ] -vazopressin) (vMSRUR) (81dta). The radioligand binding data was analyzed using a four-parameter logistic equation with a minimum of 0%. The slope was approximated freely, and for valid curves it was between -0.75 and -1.25. Specific binding was calculated by subtracting the average cf. (number of pulses per minute) N8B from the average total cf. For the tested compounds, the amount of ligand bound to the receptor was expressed as% binding = (cf. sample - average cf. L8B) / cf. specific binding x 100.% Bindings were plotted against the concentration of the test compound and a sigmoid curve was constructed. The inhibitory dissociation constant (K ₁ ) was calculated using the Cheng-Prussoff equation (SNepd-PrgizoGG): K ^ СЗУЦ + ^ / КД, where [b] means the concentration of the ligand present in the well, and К _б means the radioligand dissociation constant obtained in the result of the analysis of the Scatchard plot (8ca! syagb).

2.0. Functional analysis U _1A . Inhibition of AUR / Y _1A -B-mediated Ca ²⁺ mobilization using BFRS (B1iogessep! Bpaddsd P1a! E Weabeg, plate reader with fluorometric imaging) (Mo1eci1ag Beguise).

The release of intracellular calcium was measured in CHO-11U _1A cells using HFRS, which allows calcium to be quickly detected after receptor activation. The cell line SNOYU1 _A was kindly provided under a license agreement by Mark Tibonye (Mags Tybopsheg), Ber !. OG Mebuche, Sase \ Uez1egp Vesegue Iyuegzyu 8s1yu1 OG Mebushe, S1eue1appb, Oyo. As usual, CHO-U _A1 cells were kept at 37 ° C in a humidified atmosphere with 5% CO ₂ in the nutrient mixture BME / Natz

- 19 010132

E12 supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 15 mM HEPE8 and 400 μg / ml 0418. At noon before analysis, cells were seeded at a density of 20,000 cells per well in black sterile 96-well plates with a clear bottom, allowing you to check cells and measure fluorescence through the bottom of each well. Wash buffer containing phosphate buffered Dulbecco's physiological solution (ΌΡΒ8) and 2.5 mM probenecid and a loading dye consisting of a cell culture medium containing 4 μM E1io-3-LM (dissolved in EM8O and pluronic acid) (Mo1ci1ag Prgoec) and 2.5 mM probenecid was prepared on the day of analysis. Compounds were dissolved in EM8O and diluted in assay buffer consisting of ΌΡΒ8 containing 1% EM8O. 0.1% Β8Α and 2.5 mM probenecid. Cells were incubated with 100 μl loading dye per well for 1 h at 37 ° C in a humidified atmosphere with 5% CO ₂ . After loading with dye, the cells were washed three times in 100 μl of wash buffer using a Denly plate washer (Pei1eu). 100 μl of wash buffer was left in each well. Intracellular fluorescence was measured using EIBC. The fluorescence data was read at intervals of 2 s with 50 μl of the test compound added after 30 s. Then 155 additional measurements were made at 2-second intervals to detect any agonistic activity of the compound. Then, 50 μl of arginine-vasopressin (ΑνΡ) was added so that the final sample volume was 200 μl. Additional fluorescence readings were performed at intervals of 1 s for 120 s. Responses were measured as peak fluorescence intensity (ΕΙ). For pharmacological characterization, basal ΕΙ was subtracted from each fluorescent response. For dose-response curves, the ΑνΡ response each response was expressed as% of the response to the highest concentration of ΑνΡ in this series. To determine 1C _50, each response was expressed as% of the response to ΑνΡ. The 1C ₅₀ values were converted to modified K _b values using the Cheng-Prussoff equation, which takes into account the agonist concentration, [A], EC ₅₀ agonist and slope (curve): K _b = 1C ₅₀ / (2+ [A] / A ₅₀ ] ^p ) ^{1 / p} -1, where [A] means the concentration of ΑνΡ, A ₅₀ means EC ₅₀ ΑνΡ from the dose-response curve, and n means the slope of the dose-response curve of ΑνΡ-response.

The compounds of the invention may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or in any combination thereof). The compounds of the present invention can be administered in combination with an oral contraceptive. Thus, in yet another aspect of the invention, there is provided a pharmaceutical product comprising an ν1α 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 phosphodiesterase-5 inhibitor (ΡΌΕ5). Thus, in yet another aspect of the invention, there is provided a pharmaceutical product comprising an ν1α antagonist and an ΡΌΕν inhibitor as a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhea.

ΡΌΕν Inhibitors useful for combination with ν1α antagonists include, but are not limited to:

(1) ΡΌΕ5 inhibitors mentioned in publications of international patent applications VO 03/000691, VO 02/64590, VO 02/28865, VO 02/28859, VO 02/38563, VO 02/36593, VO 02/28858, VO 02 / 00657, VO 02/00656, VO 02/10166, VO 02/00658, VO 01/94347, VO 01/94345, VO 00/15639 and VO 00/15228;

(2) the ΡΌΕ5 inhibitors mentioned in US Pat. Nos. 6,143,746, 6,143,747 and 6,043,252;

(3) pyrazolo [4,3th] pyrimidin-7-ones disclosed in EP-A-0463756; pyrazolo [4.3th] pyrimidine-7ones disclosed in EP-A-0526004; pyrazolo [4,3th] pyrimidin-7-ones disclosed in the publication of international patent application VO 93/06104; isomeric pyrazolo [3,4th] pyrimidin-4-ones disclosed in the publication of international patent application VO 93/07149; quinazolin-4-ones disclosed in the publication of international patent application VO 93/12095; pyrido [3,2th] pyrimidin-4-ones disclosed in the publication of international patent application VO 94/05661; purin-6-ones disclosed in the publication of the international patent application VO 94/00453; pyrazolo [4,3th] pyrimidin-7-ones disclosed in the publication of international patent application VO 98/49166; pyrazolo [4,3th] pyrimidin-7-ones disclosed in the publication of international patent application VO 99/54333; pyrazolo [4.3th] pyrimidin-4-ones disclosed in EP-A0995751; pyrazolo [4,3th] pyrimidin-7-ones disclosed in the publication of international patent application VO 00/24745; pyrazolo [4.3th] pyrimidin-4-ones disclosed in EP-A-0995750; hexahydropyrazino [2 ', 1': 6,1] pyrido [3,4-b] indole-1,4-dione disclosed in published international application VO 95/19978; pyrazolo [4.3th] pyrimidin-4-ones disclosed in VO 00/27848; imidazo [5.1- £] [1,2,4] triazinones disclosed in EP-A-1092719 and in the publication of international application VO 99/24433, and bicyclic compounds disclosed in the publication of international application VO 93/07124; pyrazolo [4,3th] pyrimidine-7ones disclosed in the publication of international application VO 01/27112; pyrazolo [4,3th] pyrimidin-7-ones disclosed in the publication of international application VO 01/27113; compounds disclosed in EP-A-1092718 and compounds disclosed in EP-A-1092719; tricyclic compounds disclosed in EP-A-1241170; alkyl sulfonic compounds disclosed in the publication of international application VO 02/074774; the compounds disclosed in the publication of international application VO 02/072586; compounds disclosed to the public

- 20 010132 of the international application AO 02/079203, and the compounds disclosed in AO 02/074312;

(4) preferably 5 - [2-ethoxy-5 - (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-

1,6-dihydro-7H-pyrazolo [4,3-6] pyrimidin-7-one (sildenafil, for example, sold as U1adga®), also known as 1 - [[3- (6,7-dihydro-1- methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-6] pyrimidin-5-yl) -4ethoxyphenyl] sulfonyl] -4-methylpiperazine (see EP-A-0463756); 5- (2-ethoxy-5-morpholinoacetylphenyl) 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-6] pyrimidin-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 [4,3-6 ] pyrimidin-7-one (see AO 98/49166); 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (pyridin-2-yl) methyl-2,6-dihydro 7H-pyrazolo [4.3-6] pyrimidin-7-one (see AO 99/54333); (+) - 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (K) -methylethoxy) pyridin-3yl] -2-methyl-2,6- dihydro-7H-pyrazolo [4,3-6] pyrimidin-7-one, also known as 3-ethyl-5- {5- [4 ethylpiperazin-1-ylsulfonyl] -2 - ([(1K) -2-methoxy- 1-methylethyl] oxy) pyridin-3-yl} -2-methyl-2,6-dihydro-7H-pyrazolo [4,3-6] pyrimidin-7-one (see AO 99/54333); 5- [2-ethoxy-5- (4-ethylpiperazin-1ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7H-pyrazolo [4,3-6 ] pyrimidin-7-one, also known as 1- {6-ethoxy-5- [3-ethyl-6,7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4,36] pyrimidin-5-yl] -3-pyridylsulfonyl} -4-ethylpiperazine (see AO 01/27113, example 8); 5- [2isobutoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- (1-methylpiperidin-4-yl) -2,6-dihydro-7H-pyrazolo [4,3 -6] pyrimidin-7-one (see AO 01/27113, example 15); 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo [4,3-6] pyrimidine -7-one (see AO 01/27113, example 66); 5- (5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-6] pyrimidin-7- he (see AO 01/27112, example 124); 5- (5acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-6] pyrimidin-7- he (see AO 01/27112, example 132); (6K, 12aK) -2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4methylenedioxyphenyl) pyrazino [2 ', 1': 6,1] pyrido [3,4-b ] indole-1,4-dione (tadalafil, HS-351, Είαΐίδ®). that is, the compound of examples 78 and 95 from the publication of international application AO 95/19978, as well as the compound of examples 1, 3, 7 and 8; 2- [2-ethoxy-5- (4-ethylpiperazin-1-yl-1-sulfonyl) phenyl] -5-methyl-7-propyl3H-imidazo [5.1-E] [1,2,4] triazine -4-one (vardenafil, ^ ΕVIΤKΑ®). also known as 1 - [[3- (3,4-dihydro5-methyl-4-oxo-7-propylimidazo [5,1-E] -az-triazin-2-yl) -4-ethoxyphenyl] sulfonyl] -4 -ethylpiperazine, that is, the compound of examples 20.19, 337 and 336 from the publication of international application AO 99/24433; the compound of example 11 from the publication of the international application AO 93/07124 (EEZAC; compounds 3 and 14 from Co1e11a Ό P, 1. Me6. Siet., 2000, 43, 1257; 4- (4-chlorobenzyl) amino-6,7,8 -trimethoxyquinazoline; Ν - [[3- (4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-6] pyrimidin-5-yl) -4-propoxyphenyl] sulfonyl] -1methyl-2-pyrrolidine propanamide [ΌΑ-8159 (example 68 from AO 00/27848)] and 7,8-dihydro-8-oxo-6- [2propoxyphenyl] -1H-imidazo [4,5-d] quinazoline and 1 - [3- [1 - [(4-fluorophenyl) methyl] -7,8-dihydro-8-oxo-1 Nimidazo [4,5-d] quinazolin-6-yl] -4-propoxyphenyl] carboxamide;

(5) 4-bromo-5- (pyridylmethylamino) -6- [3 - (4-chlorophenyl) propoxy] -3 (2H) pyridazinone; 1 - [4 - [(1,3 benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinosolinyl] -4-piperidine-carboxylic acid monosodium salt; (+) - cis-5,6a, 7,9,9,9a-hexahydro-2- [4- (trifluoromethyl) phenylmethyl-5-methylcyclopent [4,5] imidazo [2,1-b] purin-4 ( 3H) he; furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydrocyclopent [4,5] imidazo [2,1-b] purin-4-one; 3-acetyl-1 - (2-chlorobenzyl) -2-propylindole-6-carboxylate; 3-acetyl-1 - (2chlorobenzyl) -2-propylindole-6-carboxylate; 4-bromo-5- (3-pyridylmethylamino) -6- (3- (4-chlorophenyl) propoxy) -3 - (2H) pyridazinone; 1-methyl-5- (5-morpholinoacetyl-2-n-propoxyphenyl) -3-n-propyl-1,6-dihydro-7H-pyrazolo (4.3-6) pyrimidin-7-one; 1- [4 - [(1,3-benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinazolinyl] 4-piperidinecarboxylic acid monosodium salt; Ryagtargo) EU15 No. 4516 (C1Aho Ae11sote); Ryagtargo) EU15 No. 5051 (Vaueg); Ryagtargo) ec15 No. 5064 (Kuo ^ a Nakko; see AO 96/26940); Ryagtargo) ec15 No. 5069 (Zyepid P1oy§b); CE-196960 (C1axo Ae11sote); E-8010 and E-4010 (E18a1); Wow-38-3045 and 38-9456 (Woweg); ЕК229934 and ЕК226807 (Еирзата) and ЗСН-51866.

The contents of the publications of patent applications and journal articles, and in particular the general formulas of therapeutically active compounds of the claims and the examples of compounds given therein, are incorporated by reference in their entirety.

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

Most preferably, the ΡΌΕ5 inhibitor is sildenafil and its pharmaceutically acceptable salts. Sildenafil citrate is a preferred salt.

The compounds of the present invention can be administered in combination with NΟ donors. Thus, in yet another aspect of the invention, there is provided a pharmaceutical product comprising a U1a antagonist and an NΟ donor 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 b-arginine or as an arginate salt. Thus, in a further aspect of the invention, there is provided a pharmaceutical product, with

- 21 010132 holding the antagonist U1a and b-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 cyclooxygenase (COX) inhibitor. Thus, in a further aspect of the invention, there is provided a pharmaceutical product comprising a Y1a antagonist and a COX inhibitor as a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhea.

COX inhibitors useful for combination with the compounds of the present invention include, but are not limited to:

(1) The ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, prapoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac , diclofenac, fenclofenac, aclofenac, ibufenac, isoxepac, furofenac, thiopinac, zidomethacin, acetylsalicylic acid, indomethacin, piroxicam, tenoxicam, nabumetone, ketorolac, azapropazone, mefenamfluzoic acid, tolfenamic acid, tolfenamic acid, tolfenamic acid, tolfenamic acid Podophyllotoxin, Acetamacin, Droxicam, Flocaphenin, Oxyphenbutazone, Phenylbutazone, Proglumetacin, Acemetacin, Fentiazas, Didanac, Oxypinac, Mefenamic Acid, Meclofenamic Acidum, Magnofenofenol Acidum, Nitrofenofenoxenolum , salicylate, benorylate, fentiazac, clopinac, feprazone, isoxicam and 2 fluoro-a-methyl [1,1'-biphenyl] -4-acetic acid 4- (nitrooxy) butyl ether (see \ Usp. s1 a1., Egor. 1. Ryattaeo 1. 453: 319-324 (2002));

(2) meloxicam (CA8 registration number 71125-38-7; described in US patent No. 4233299), or its pharmaceutically acceptable salt, or its prodrug;

(3) the substituted benzopyran derivatives disclosed in US Pat. No. 6,272,253, as well as the benzopyran derivatives described in US Pat. Nos. 6,034,256 and 6,077,850 and in international publications νθ 98/47890 and νθ 00/23433;

(4) chromen selective COX-2 inhibitors described in US patent No. 6077850 and US patent No. 6034256;

(5) the compounds described in the publications of international patent applications VO 95/30656, VO 95/30652, VO 96/38418 and VO 96/38442, and the compounds described in the publication of European patent application No. 799823, together with their pharmaceutically acceptable derivatives ;

(6) celecoxib (US patent No. 5466823), valdecoxib (US patent No. 5633272), deracoxib (US patent No. 5521207), rofecoxib (US patent No. 5474995), etoricoxib (publication of international patent application VO 98/03484), TTE-522 (Japanese Patent Application Publication No. 9052882), or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

(7) parecoxib (described in US patent No. 5932598), which is a therapeutically effective prodrug of a tricyclic selective COX-2 inhibitor valdecoxib (described in US patent No. 5633272), in particular parecoxib sodium salt;

(8) ABT-963 (described in the publication of international patent application VO 00/24719);

(9) nimesulide (described in U.S. Pat. No. 3,805,597), flosulide (reviewed in 1. Site. Exp. Orsh. Thiet. Ra1epy. 8 (1), 21-29 (1997)), N8-398 (disclosed in U.S. Pat. No. 4885367), 8Ό8381 (described in US patent No. 6034256), BM8-347070 (described in US patent No. 6180651), 8-2474 (described in European patent publication No. 595546) and MK-966 (described in US patent No. 5968974 );

(10) the compounds and pharmaceutically acceptable derivatives described in US Pat. No. 6,395,724, US Pat. No. 6,077,868, US Pat. No. 5,994,381, US Pat. No. 6,362,209, US Pat. No. 6,080,876, US Pat. No. 6,133,292, US Pat. No. 6,338,275, US Pat. No. 6,127,545 , US patent No. 6130334, US patent No. 6204387, US patent No. 6071936, US patent No. 6001843, US patent No. 6040450, publication of international patent application VO 96/03392, publication of international patent application VO 96/24585, US patent No. 6340694, patent US No. 6376519, US patent No. 6153787, US patent No. 6046217, US patent No. 6329421, US patent No. 6239137, US patent No. 6136831, US patent No. 6297282, US patent No. 6239173, US patent No. 6303628, US patent No. 6310079, US patent No. 6300363, US patent No. 6077869, US patent No. 6140515, US patent No. 5994379, US patent No. 6028202, US patent No. 6040320, US patent No. 6083969, US patent No. 6306890, US patent No. 6307047, US patent No. 6004948, US patent No. 6169188, US patent No. 6020343, US patent No. 5981576, US patent No. 6222048, US patent No. 6057319, US patent No. 6046236, US patent No. 6002014, US patent No. 5945539, US patent No. 6359182, publication of international patent application VO 97/13755, publication of international patent application VO 96 / 25928, publication of the international patent application VO 96/374679, publication of the international patent application VO 95/15316, publication of the international patent application VO 95/15315, publication of the international patent application VO 96/03385, publication of the international patent application VO 95/00501, publication of the international patent application VO 94/15932, publication of the international patent application VO 95/00501, publication of the international patent application VO 94/27980, publication of the international patent application VO 96/25405, publication of the international patent application VO

- 22 010132

96/03388, publication of international patent application \ UO 96/03387, US patent No. 5344991, publication of international patent application XVO 95/00501, publication of international patent application HUO 96/16934, publication of international patent application VO 96/03392, publication of international patent application VO 96/09304, publication of the international patent application VO 98/47890 and the publication of the international patent application VO 00/24719.

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

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

The spectra of ¹ H-nuclear magnetic resonance (NMR) in all cases correspond to the proposed structures. Characteristic chemical shifts (δ) are given in parts per million descending from tetramethylsilane using conventional abbreviations for the main peaks: for example, 8, singlet; b, doublet; !, triplet; q, quartet; t, multiplet; Bg wide. Mass spectra (t / ζ) were recorded using either electrospray ionization (ERI) or chemical ionization at atmospheric pressure (HIAD). The following abbreviations are used for well-known solvents: SIS1 ₃ , deuterated chloroform; And ₆ -IM8O, deuterodromethyl sulfoxide; SI ₃ OI, deuteriomethanol; TUE, tetrahydrofuran. Ammonia refers to a concentrated solution of ammonia in water having a specific gravity of 0.88. If thin layer chromatography (TLC) was used, this refers to TLC on silica gel using silica gel plates 60 E254, Br means the distance traveled by the compound divided by the distance traveled by the solvent front on the TLC plate. When microwave radiation is used, the two used microwave devices are Etu8 Sréa! Og and Etu8 L1 ега!! Ог og, both supplied by Reg8op1 Szet18! Power range 15-300 watts at 2.45 GHz. The effective power supply varies during the interaction to maintain a constant temperature.

Preparatory Example 1. 4- (5-Methyl- [1,3,4] oxadiazol-2-yl) piperidin-1-carboxylic acid tert-butyl ether.

To a solution of 9.0 g of 4-hydrazinocarbonylpiperidin-1-carboxylic acid tert-butyl ester (see VO 9703986 A1 19970206) (37 mmol, 1 eq.) In 40 ml of TOH 8.1 ml of dimethylformamide dimethyl acetal (55.4 mmol , 1.5 equiv.). This reaction mixture was then stirred at 50 ° C. for 4 hours under nitrogen. The solvent was removed under reduced pressure, the residue was dissolved in 40 ml of toluene, and 400 mg of paratoluenesulfonic acid was added. This mixture was then heated at 100 ° C. under nitrogen for 18 hours, volatiles were removed under reduced pressure, and the residue was partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate and filtered. Volatiles were removed under reduced pressure, and the residue was purified by silica gel column chromatography using methylene chloride / methanol as an eluent (from 98: 2 v / v to 95: 5 v / v) to obtain 8.07 g of a compound, indicated in the title as a white solid (81%).

Ή-NMR (400 MHz, SI ₃ OI): δ 1.42 (8, 9Н), 1.70 (t, 2Н), 2.05 (t, 2Н), 2.50 (8, 3Н), 3.00 (t, 2Н), 3.15 ( t, 1H); 4.05 (t, 2H); LC-MS (liquid chromatography / mass spectrometry): t / ζ CHIAD ³ , 268 [MH] ⁺ ; Found: C, 58.26%; H 7.96%; Ν 15.78%; C1 ₃ H ₂₁ No., O ₃ requires: C 58.41%, H 7.92%, Ν 15.72%.

Preparatory example 2a. 4- [4- (4-Chlorophenyl) -5-methyl-4H- [1,2,4] triazol-3-yl] piperidine.

C1

4.0 g of the compound of Preparation 1 (15 mmol, 1 equiv.) Was dissolved in 100 ml of toluene, 2.1 g of parachloraniline (16.5 mmol, 1.1 equiv.) Was added and then 2 ml of TEM. The solution was heated at 110 ° C. for 16 hours, 2 ml of TEM was added and the solution was heated at 110 ° C. for an additional 48 hours. Then the reaction mixture was cooled, 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 with

- 23 010132 obtaining 2.90 g of the title compound as a white solid. 'H-NMR (400 MHz, COC1 ₃ ): δ 1.60-2.00 (t), 2.20 (5, 3H), 2.40-2.80 (t, 5H), 3.10 (t, 2H), 7.10 (b, 2H), 7.55 (b, 2H); LC-MS: t / ζ CHIAD '. 277 [MH] ⁺ .

Preparatory example 2b. 4- [4- (4-Chlorophenyl) -5-methyl-4H-1,2,4-triazol-3-yl] piperidine hydrochloride.

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

^! H-NMR (400 MHz, ΌΜ8Ο-6 ₆ ): δ 1.86 (t, 4H), 2.25 (t, 3H), 2.80-2.97 (t, 3H), 3.22 (t, 2H), 7.64 (t, 2H) 7.77 (b, 2H).

Preparatory Example 3. 1- (3-Chlorobenzoyl) piperidine-4-carboxylic acid ethyl ester.

A solution of ethyl isonipecotate (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) ), cooled to a temperature of 10 to 15 ° C. This 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 1N. hydrochloric acid, sodium carbonate solution (x3) and brine. It was then dried over MgSO ₄ and evaporated under reduced pressure to give the title compound as a solid, 44.4 g.

^! H-NMR (400 MHz, COC1 ₃ ): δ 1.24 (ΐ, 3H), 1.62-2.10 (t, 4H), 2.58 (t, 1H), 2.98-3.16 (t, 2H), 3.70 (t, 1H) 4.15 (t 2H), 4.49 (t, 1H), 7.24 (t, 1H), 7.31-7.40 (t, 3H). MCHP (LKM8, low resolution mass spectrometry): t / ζ (CHIAD ') 296 [MH] ⁺ .

Preparatory Example 4. 1- (3-Chlorobenzoyl) piperidine-4-carboxylic acid hydrazide.

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

^! H-NMR (400 MHz, COC1 ₃ ): δ 1.62-1.98 (t, 4H), 2.36 (t, 1H), 2.78-3.09 (t, 2H), 3.64-4.00 (t, 2H), 4.65 (t, 1H), 7.04 (t, 1H), 7.26 (t, 1H), 7.36 (t, 3H). MCHP: t / ζ (CHIAD ') 282 [MH] ⁺ .

1- (3-Chlorobenzoyl) piperidine-4-carboxylic acid L '- (2-chloro) Preparation 5. Acetyl) hydrazide.

- 24 010132

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

^! H-NMR (400 MHz, SEZOE): δ 1.66-1.84 (t, 3H), 1.98 (t, 1H), 2.61 (t, 1H), 2.99 (t, 1H), 3.19 (t, 1H), 3.74 ( t, 1H), 4.14 (8, 2H), 4.60 (t, 1H), 7.35 (bb, 1H), 7.46 (t, 3H). MCHR: t / ζ (ERI ⁺ ) 358 [MH] ⁺ .

Preparatory Example 6. [4- (5-Chloromethyl- [1,3,4] oxadiazol-2-yl) piperidin-1-yl] - (3chlorophenyl) methanone.

ABOUT

Trifluoroacetic anhydride (9.45 ml, 57 mmol) was added dropwise over 30 min to a cooled solution (0-5 ° C) of compound of preparation 5 (10.2 g, 28.5 mmol) and pyridine (11.5 ml , 142.5 mmol) in dichloromethane (300 ml). Immediately after the addition was complete, the resulting pink suspension was stirred for the next 90 minutes at 10 ° C. This reaction mixture was carefully poured into saturated sodium bicarbonate solution (600 ml) and the layers were separated. The organic phase was washed with an additional saturated sodium bicarbonate solution (x2), dried over MgSO ₄ and treated with decolorizing charcoal. The mixture was then filtered and the filtrate was evaporated under reduced pressure to obtain the title compound, 13 g.

^! H-NMR (400 MHz, SE ₃ OE): δ 1.80-1.97 (t, 2H), 2.08 (t, 1H), 2.22 (t, 1H), 3.15-3.40 (t, 3H), 3.76 (t, 1H) ), 4.56 (t, 1H), 4.84 (8, 2H), 7.37 (t, 1H), 7.48 (t, 3H). MCHP: t / ζ (HILD ') 340 [MH] ⁺ .

Preparatory Example 7. 4- [L '- (2-Chloroacetyl) hydrazinocarbonyl] piperidine-1-carboxylic acid tert-butyl ether.

4-Hydrazinocarbonylpiperidin-1-carboxylic acid tert-butyl ether (see AO 2000039125, Preparation 27) (25 g, 103 mmol) was dissolved in dichloromethane (300 ml) and then 4 methylmorpholine (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. This reaction mixture was then allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was partitioned with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and the filtrate was evaporated to give the title compound as an off-white solid (29 , 6 g). MCHP t / ζ HILD '318 [M – H] ^- .

Preparatory Example 8. 4- (5-Chloromethyl- [1,3,4] oxadiazol-2-yl) piperidin-1-carboxylic acid tert-butyl ether.

The hydrazide of Preparation 7 (5.0 g, 15.6 mmol) was suspended in dichloromethane (200 ml) and then pyridine (6.4 ml, 78 mmol) was added and 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 stirred at room temperature for 3 hours. Then, 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 silica gel chromatography using methanol in dichloromethane as an eluent (2:98) to obtain the title compound as a white solid (2.95 g).

^! H-NMR (400 MHz, SE ₃ OE): δ 1.45 (8, 9H), 1.74 (t, 2H), 2.19 (t, 2H), 3.04 (t, 2H), 3.24 (t, 1H), 4.09 ( t, 2H); 4.85 (8, 2H).

Preparatory example 9a. 4- (5- [1,2,3] Triazol-2-ylmethyl- [1,3,4] oxadiazol-2-yl) piperidin-1 carboxylic acid tert-butyl ether and 4- (5- [1,2, 3] triazol-1-ylmethyl- [1,3,4] oxadiazol-2-yl) pipe-tert-butyl ester of ridin-1-carboxylic acid.

A mixture of the compound of Preparation 8 (8 g, 26.5 mmol), triazole (3.7 g, 53 mmol) and potassium carbonate (5.2 g, 38 mmol) in Ν, Ν-dimethylformamide (60 ml) was stirred at room temperature temperature for 18 hours. Then the mixture was 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 Mg _{4 4} and concentrated under reduced pressure to obtain the title compounds as a mixture of isomers.

Ή-NMR (400 MHz, SP ₃ OE): δ 1.43 (q, 9H), 1.62-1.78 (t, 2H), 2.02 (t, 2H), 3.00 (t, 2H), 3.19 (t, 1H), 4.03 (t, 2H), 5.95, 5.99 (2x8, 2H), [7.77 (k), 7.80 (b), 8.18 (k) total 2H].

Preparatory example 9b. 4- (5- [1,2,3] Triazol-2-ylmethyl- [1,3,4] oxadiazol-2-yl) piperidin-1 carboxylic acid tert-butyl ether.

Dichloromethane (500 ml) was added to a suspension of hydrazide of Preparation 170 (132.3 g, 375 mmol) in 1-methylimidazole (120 ml) and the resulting solution was cooled in an ice / acetone bath. Trifluoromethyl sulfonic anhydride (92 ml, 561 mmol) was added dropwise over 2.5 hours to maintain the temperature of this reaction mixture below 0 ° C. Upon completion of the addition, this reaction mixture was stirred for the next 20 minutes. Then it was quenched by the addition of 2M 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 evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane as an eluent to obtain the title compound as a viscous oil.

Preparatory Example 10. (3-Chlorophenyl) - [4- (5- [1,2,3] triazol-2-ylmethyl- [1,3,4] oxadiazol-2yl) piperidin-1-yl] methanone.

Ν-Ν

A mixture of the compound of Preparation 6 (2 g, 5.9 mmol), triazole (810 mg, 11.75 mmol) and potassium carbonate (1.2 g, 8.85 mmol) in acetonitrile (20 ml) was stirred at room temperature in for 30 minutes, and then another 1 hour at 50 ° C. This 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, then brine. The solution was dried over MgSO ₄ and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using dichloromethane: methanol (100: 0 to 95: 5) to obtain the title compound (202 mg).

Я-NMR (400 MHz, SE ₃ OE): δ 1.76-1.90 (t, 2H), 2.02 (t, 1H), 2.18 (t, 1H), 3.12-3.38 (t, 3H), 3.72 (t, 1H ), 4.50 (t, 1H), 5.97 (q, 2H), 7.37 (bb, 1H), 7.41-7.51 (t, 3H), 7.78 (q, 2H). MCHR: t / ζ (ERI *) 373, 375 [MH] ⁺ .

Preparatory example 11a. 4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3yl] piperidine-1-carboxylic acid tert-butyl ether.

Trifluoroacetic acid (1 ml, 13.2 mmol) was added to a solution of the compounds of Preparation 9a (8.8 g, 26.5 mmol) and 4-chloroaniline (5 g, 39.75 mmol) in toluene (200 ml) and this the reaction mixture was stirred at reflux for 5 hours. The cooled mixture was diluted with dichloromethane, then washed with 1N. sodium hydroxide solution and brine and evaporated under reduced pressure. The remaining brown oil was purified by silica gel column chromatography with gra

- 26 010132 by elution with dichloromethane: methanol: ammonia 0.88 (from 100: 0: 0 to 90: 10: 1) and then repeated column chromatography with gradient elution with ethyl acetate: methanol: ammonia 0.88 (from 100: 0: 0 up to 90: 10: 1) to obtain the title compound (2.3 g).

Ή-NMR (400 MHz, SP ₃ OE): δ 1.42 (q, 9H), 1.68-1.82 (t, 4H), 2.62-2.78 (t, 3H), 4.08 (t, 2H), 5.70 (q, 2H) ), 7.24 (s, 2H), 7.56 (s, 2H), 7.59 (q, 2H). MCHR: t / ζ (HIAD +) 444 [MH] ⁺ .

Preparatory example 11b. 4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol3-yl] piperidin-1-carboxylic acid tert-butyl ether.

Ν-Methylimidazole (4.66 g, 56.75 mmol) and dichloromethane (20 ml) were added to the bis-acyl hydrazide of Preparation 170 (5.00 g, 14.19 mmol) and the resulting solution was cooled to -20 ° C. Trifluoromethanesulfonic anhydride (6.00 g, 21.28 mmol) was added, keeping the temperature below 0 ° C. After the addition was complete, the reaction mixture was warmed to ambient temperature and stirred for 15 hours. The reaction mixture was quenched with H2O (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 off and replaced with toluene in vacuo to give a toluene solution of the intermediate oxadiazole (volume of about 20 ml). To this toluene solution was added 4-chloroaniline (1.90 g, 14.90 mmol), then trifluoroacetic acid (0.81 g, 7.09 mmol), and this reaction mixture was stirred at 85 ° C for 5.5 hours. The mixture was cooled to ambient temperature and mixed with 1.8 N. aqueous ammonia (14 ml) for 5 minutes 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, washing with tert-butyl methyl ether (2x5 ml) to obtain the title compound as a beige solid ( 2.72 g).

Ή-NMR (400 MHz, SES1 ₃ ): δ 1.43 (q, 9H), 1.72 (s, 2H), 1.85 (bm, 2H), 2.56 (t, 1H), 2.66 (b, 2H), 4.09 (b , 2H), 5.64 (q, 2H), 7.01 (s, 2H), 7.43 (s, 2H), 7.50 (q, 2H).

Preparatory example 12a. 4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3yl] piperidine.

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

Ή-NMR (400 MHz, SP ₃ OE): δ 1.79 (t, 4H), 2.48 (t, 2H), 2.65 (t, 1H), 3.02 (t, 2H), 5.70 (q, 2H), 7.22 ( th, 2H), 7.55 (s, 2H), 7.59 (q, 2H). MCHP: t / ζ (HILD ') 344 [MH] ⁺ .

Preparatory example 12b. 4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol3-yl] piperidine bis-p-toluenesulfonate salt.

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

Ή-NMR (400 MHz, EM8O minutes _6): δ 1.85 (t, 4H), 2.26 (q, 6H), 2.83 (t, 3H), 3.24 (t, 2H), 5.68 (q, 2H), 7.10 (s, 4H), 7.32 (s, 2H), 7.47 (s, 4H), 7.54 (s, 2H), 7.65 (q, 2H), 8.29 (t, 1H), 8.49 (t, 1H). MCHP: t / ζ (HILD ') 344 [MH] ⁺ .

- 27 010132

Preparatory Example 13. Methyl-T-tetrazol-1-yl acetate.

О N ^ 4 н ₃ s .. ₀ D _Dd . ^M ^ ^m

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 under reflux for 18 hours. The cooled mixture was evaporated under reduced pressure to obtain the compound indicated in the title.

Ή-NMR (400 MHz, ΌΜ8Ο-ά ₆ ): δ 3.74 (δ, 3Η), 5.58 (δ, 2Н), 9.39 (8, 1Η); LC-MS: t / ζ CHIAD + 143 [MH] ⁺ .

Preparatory Example 14. (3-Methylisoxazol-5-yl) acetyl chloride.

Oh Ο-Ν _C] JAA ^to 'SNZ

Ν, Ν-Dimethylformamide (a few drops), then oxalyl chloride (9.5 ml, 106 mmol) was added dropwise to a cooled (10 ° C) solution of (3-methylisoxazol-5-yl) acetic acid (5 g, 35.4 mmol) in dichloromethane (50 ml) and the solution was allowed to warm to room temperature. This reaction mixture was stirred for the next 3 hours, then concentrated under reduced pressure. The residue was azeotroped with toluene to give the title compound.

Ή-NMR (400 MHz, SES1 ₃ ): δ 2.30 (δ, 3Η), 4.32 (δ, 2Н), 6.18 (δ, 1Η).

Preparatory Example 15. Ethyl- (2-methyl-1H-imidazol-1-yl) acetate.

Potassium carbonate (8.42 g, 61 mmol) was added to a solution of 2-methylimidazole (5 g, 61 mmol) in tetrahydrofuran (100 ml), and this 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, washed with a mixture of dichloromethane: methanol (90:10). The filtrate was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography using dichloromethane: methanol: ammonia 0.88 (93: 7: 0.5) as an eluent to obtain the title compound as an oil, 5.28 g.

Ή-NMR (400 MHz, SES1 ₃ ): δ 1.26 (ΐ, 3Η), 2.35 (δ, 3Η), 4.22 (φ 2Η), 4.58 (δ, 2Н), 6.81 (δ, 1Н), 6.94 (δ, 1H). LC-MS: t / ζ HIAD / 169 [MH] ⁺ .

Preparatory Example 16. 2- (1H-Tetrazol-1-yl) acetohydrazide.

O Ν = Ν ^Η 2 ^ _ν Α / ^Ν '^' ν Η

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

Ή-NMR (400 MHz, ΌΜ8Ο-ά ₆ ): δ 5.18 (δ, 2Η), 9.38 (δ, 1Η). LC-MS: t / ζ CHIAD + 143 [MH] ⁺ .

Preparatory Example 17. [1,2,3] Triazol-1-yl-acetic acid ethyl ester and [1,2,3] triazol-2-yl-acetic acid ethyl ester.

1,2,3-Triazole (19.00 kg, 275 mol) was loaded for 30 min in a suspension of potassium carbonate (42.15 kg, 305 mol) in ethanol (80 L) and washed with ethanol (2 L). A solution of ethyl bromoacetate (45.8 kg, 274 mol) in ethanol (30 L) was slowly added and washed with ethanol (2 L). During this time, the reaction temperature was kept below 20 ° C. Then the reaction mixture was warmed to room temperature and stirred overnight. The suspension was filtered by washing the residue with ethanol (25 L and 17 L) and then the filtrate was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate (120 L) and this solution was washed with 1N. hydrochloric acid (1x40 l, 7x20 l, 4x15 l). The aqueous washings were combined and extracted with ethyl acetate (3x21 L). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated to dryness to give a mixture of the title compounds (25 kg). Spectroscopic ¹ H-NMR analysis showed that it was a mixture of Ν-2 / Ν-1 isomers in a ratio of 6: 5.

- 28 010132

Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.25 (t, 2H, Ν-1 isomer), 4.25 (t, 2H, Ν-2 isomer), 5.20 (s, 2H, Ν -1 isomer), 5.22 (s, 2H, Ν-2 isomer), 7.70 (s, 2H, Ν-2 isomer), 7.77 (s, 2H, Ν-1 isomer).

Preparatory Example 18. [1,2,3] Triazol-2-yl-acetic acid hydrazide.

Hydrazine hydrate (8.65 kg, 270 mol) was added to a cooled (below 10 ° C) solution of the mixture of esters of preparation 17 (19 kg) in ethanol (69 L), keeping the temperature below 20 ° C during the addition. This reaction mixture was stirred at a temperature between 14 and 19 ° C. for 3 hours, then more ethanol (25 L) was added to it and the product was collected by filtration and washed with ethanol (10 L). The crude solid was purified by recrystallization from ethanol (120 L), then three times recrystallization from methanol (105 L, 120 L and 90 L) to obtain the title compound (4.53 kg) after drying in vacuo.

Ή-NMR (400 MHz, ΌΜ8Ο-6 ₆ ): δ 4.33 (s, 2H), 5.02 (s, 2H), 7.77 (s, 2H), 9.40 (s, 1H).

Preparatory Example 19. 2- (2-Methyl-1H-imidazol-1-yl) acetohydrazide.

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

Ή-NMR (400 MHz, SOCC): δ 2.35 (s, 3H), 4.60 (s, 2H), 6.81 (s, 1H), 6.99 (s, 1H).

LC-MS: t / ζ HILD '155 [MH] ⁺ .

Preparatory Example 20. 2- (3-Methyl-1,2,4-oxadiazol-5-yl) acetohydrazide.

The title compound was prepared from 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid methyl ester (IL 7807076) and hydrazine following the procedure described in Preparation 16 except that 8 equivalents were used. . hydrazine and used isopropanol as a reaction solvent.

Ή-NMR (400 MHz, COC1 ₃ ): δ 2.42 (s, 3H), 3.86 (s, 2H), 6.89 (bs, 1H), 8.18 (bs, 1H).

Preparatory Example 21. 2- (Pyrimidin-2-yloxy) acetohydrazide.

A mixture of ethyl 2-pyrimidinyl oxyacetate (CB 2373186, stage 1, example 368) (4.4 g, 24.15 mmol) and hydrazine hydrate (5 ml, 160 mmol) in isopropanol (30 ml) was heated under reflux for 1 h This mixture was then cooled and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using dichloromethane: methanol: ammonia 0.88 (100: 0: 0 to 100: 10: 1) to obtain the title compound, 600 mg .

Ή-NMR (400 MHz, SCC1 ₃ ): δ 4.98 (s, 3H), 7.04 (t, 1H), 8.58 (b, 2H); LC-MS: t / ζ HILD '169 [MH] ⁺ . Preparatory Example 22. Tert-Butyl-2 - [(3-methylisoxazol-5-yl) acetyl] hydrazinecarboxylate.

To a cooled (10 ° C.) solution of the acid chloride of Preparation 14 (5.64 g, 35.4 mmol) in dichloromethane (200 ml), triethylamine (24 ml, 17 mmol) was slowly added and then tert-butyl carbazate (5.6 g, 42.5 mmol) and this reaction mixture was stirred at room temperature for 18 hours. 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 silica gel column chromatography, and gradient eluting with ethyl acetate: pentane (50:50 to 100: 0) gave the title compound

- 29 010132 trap.

Ή-NMR (400 MHz. SES1 ₃ ): δ 1.47 (8. 9H). 2.30 (8.3H). 3.77 (8. 2H). 6.15 (8. 1H). 6.45 (bg8. 1H). 7.59 (bg8. 1H).

Preparatory Example 23. Tert-Butyl-2- [3- (3.5-dimethylisoxazol-4-yl) propanoyl] hydrazinecarboxylate.

Oxalyl chloride (5.16 ml. 59.2 mmol) was added to a solution of b- (3.5-dimethyl-4-isoxazolyl) propionic acid (1. Ogd. C1et. 59 (10); 1994; 2882) (2.5 g. 14.8 mmol) in dichloromethane ( 50 ml) and Ν.Νdimethylformamide (1 drop) and the solution was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure and the residue was subjected to azeotropic distillation with dichloromethane (5x) to give a brown liquid. It was dissolved in dichloromethane (25 ml) and tert-butylcarbazate (2.93 g, 22.2 mmol) was added portionwise. The mixture was diluted with additional dichloromethane (23 ml) and the reaction mixture was stirred for 18 hours at room temperature. 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 silica gel column chromatography with gradient elution with dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5 to 90: 10: 1) to obtain the title compound as an oil. 3.08 g.

^! H-NMR (400 MHz. SES1 ₃ ): δ 1.45 (8. 9H). 2.21 (8. 3H). 2.36 (t. 4H). 2.45 (t. 1H). 2.60-2.73 (t, 2H). 6.48 (bt, 8.1H). 7.42 (bt, 8.1H). LC-MS: t / ζ ERI ⁴ 306 [M #] ⁺ .

Preparatory Example 24. 2- (3-Methylisoxazol-5-yl) acetohydrazide hydrochloride.

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

^! H-NMR (400 MHz. ΌΜ8Ο-ά ₆ ): δ 2.20 (8.3 H). 3.86 (8. 2H). 6.24 (8. 1H). LC-MS: t / ζ HILD '156 [MH] ⁺ .

Preparatory Example 25. 3- (3.5-Dimethylisoxazol-4-yl) propanohydrazide hydrochloride.

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

Ή-NMR (400 MHz. ΌΜ8Ο-ά ₆ ): δ 2.22 (8.3 H). 2.27 (!. 2H). 3.35 (8.3 H). 2.66 (!. 2H). 6.75 (bg8. 1H). LCMS: t / ζ HILD '184 [MH] ⁺ .

Preparatory Example 26. Tert-Butyl-2- (hydrazinocarbonyl) morpholine-4-carboxylate.

A mixture of 4- (tert-butyl) -2-methyl 2.4-morpholinocarboxylate (νΟ 03/018576. Example 1. part ί) (2.03, 8.3 mmol). hydrazine hydrate (1.2 ml. 24 mmol) and methanol (50 ml) were 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

- 30 010132 is lowered pressure to give the title compound, 1.92 g LCMS: m / ζ ESI ⁴²⁶⁸ [ΜΝα] ^+.

Preparatory Example 27. Tert-Butyl-3- (hydrazinocarbonyl) piperidine-1-carboxylate.

Hydrazine hydrate (75 ml, 1.5 mol) was added to a solution of 1-ethyl, 3-tert-butyl ether of piperidine-1-3-dicarboxylic acid (I8 200 200 99035, example 12) (72 g, 280 mmol) in ethanol (250 ml ) and this reaction mixture was refluxed for 18 hours. The cooled mixture was concentrated under reduced pressure, 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 Μd8O ₄ and evaporated under reduced pressure. The product was azeotroped with ether to give the title compound as a colorless resin, 59.8 g.

Ή-NMR (400 MHz, SES1 ₃ ): δ 1.40-1.50 (t, 11H), 1.63 (t, 1H), 1.83 (t, 2H), 2.25 (t, 1H), 2.97 (t, 1H), 3.16 (t, 1H), 3.78-3.98 (t, 3H), 7.40-7.60 (bt, 1H).

Preparatory Example 28. Ethyl 1- (4-chlorobenzoyl) piperidine-4-carboxylate.

The title compound was obtained as a yellow oil from ethyl isonipecotate and 4 chlorobenzoyl chloride, following the procedure described in Preparation 3.

Ή-NMR (400 MHz, C1) C1 _; ): δ 1.24 (ΐ, 3H), 1.62-2.06 (t, 4H), 2.59 (t, 1H), 3.03 (t, 2H), 3.72 (t, 1H), 4.17 (t, 2H), 4.54 (t , 1H), 7.36 (s, 2H), 7.39 (s, 2H). LC-Μϋ: t / ζ HIAD 296rChN] ⁺ .

Preparatory Example 29. 1- (4-Chlorobenzoyl) piperidine-4-carbohydrazide.

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. Then hydrazine hydrate (50 g, 1.0 mol) was added and this reaction mixture was stirred at 60 ° C for another 3 hours. TLC analysis showed that the starting material remained, therefore, additional hydrazine hydrate (50 ml, 1.0 mol) was added and stirred the reaction mixture for an additional 48 hours at 75 ° C. The cooled mixture was concentrated under reduced pressure, the residue was suspended in dichloromethane (1 L) and washed with water (2x). The organic solution was dried over Μd8O ₄ and evaporated under reduced pressure to give the title compound as a white solid, 119 g

Я-NMR (400 MHz, SES1 ₃ ): δ 1.65-1.94 (t, 4H), 2.35 (t, 1H), 2.80-3.06 (t, 2H), 3.79 (t, 1H), 4.65 (t, 1H) 7.10 (q, 1H); 7.38 (t, 4H). LC-MS: t / ζ CHIAD + 282 [MH] ⁺ .

Preparatory Example 30. 1- (4-Chlorobenzoyl) -I '- (trifluoroacetyl) piperidine-4-carbohydrazide.

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 Ν-methylmorpholine (1.29 ml, 11.7 mmol) in dichloromethane (50 ml) and this reaction mixture was stirred at room temperature for 18 hours. The resulting precipitate was filtered off, washed with dichloromethane and dried to obtain the title compound, 1.78 g.

Я-NMR (400 MHz, 1) \ 18О-I.): Δ 1.56 (t, 2Н), 1.64-1.84 (t, 2Н), 2.56 (t, 1Н), 2.85 (t, 1Н), 3.08 (t ,

- 31 010132

1H), 3.58 (t, 1H), 4.40 (t, 1H), 7.40 (b, 2H), 7.50 (b, 2H), 10.20 (8, 1H), 11.15 (bg8, 1H). Preparatory Example 31. 1- (4-Chlorobenzoyl) -I '- (ethoxyacetyl) piperidine-4-carbohydrazide.

Ν-Methylmorpholine (2.60 g, 26.6 mmol) and then ethoxyacetyl chloride (AO 01/46150, example 33A) (1.09 g, 8.87 mmol) were added to the solution of the compound of preparation 29 (2.5 g, 8.87 mmol) in dichloromethane (70 ml) and this reaction mixture was stirred at room temperature for 18 hours. The mixture was washed with water, then with a solution of ammonium chloride and, finally, with a solution of sodium carbonate. The mixture was dried over § eDigO ₄ and evaporated under reduced pressure to give the title compound.

Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.22 (!, 3Н), 1.72-1.99 (t, 4Н), 2.56 (t, 1Н), 2.86-3.06 (t, 2Н), 3.60 (f 2Н), 3.80 (t, 1H), 4.04 (8, 2H), 4.62 (t, 1H), 7.38 (t, 4H), 8.90 (b, 1H), 8.99 (b, 1H). LC-MS: t / ζ ERI '368, 370 [MH] ⁺ .

Preparatory Example 32. 1- (3-Chlorobenzoyl) -I '- (ethoxyacetyl) piperidine-4-carbohydrazide.

The title compound was obtained in 91% yield from the compound of Preparation 4 and ethoxyacetyl chloride (AO 01/46150, Example 33A), following the procedure described in Preparation 31.

Ή-NMR (400 MHz, SES1 ₃ ): δ 1.22 (!, 3Н), 1.72-2.00 (t, 4Н), 2.56 (t, 1Н), 2.84-3.10 (t, 2Н), 3.60 (f 2Н), 3.79 (t, 1H), 4.04 (8, 2H), 4.62 (t, 1H), 7.26 (t, 1H), 7.38 (t, 3H), 8.61 (b, 1H), 8.75 (b, 1H). LC-MS: t / ζ HILD '368, 370 [MH] ⁺ .

Preparatory Example 33. tert-Butyl-4 - {[((4-chlorophenyl) amino] carbonyl} piperidine-1 carboxylate.

1-BOC-piperidine-4-carboxylic acid (100 g, 437 mmol), 4-chloroaniline (61.2 g, 480 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (100 g, 524 mmol) and triethylamine (182.6 ml, 1.31 mol) was dissolved in cold (10 ° C) acetonitrile (1.75 L). This reaction mixture was stirred for 54 hours at room temperature 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, dissolved in dichloromethane, the solution was dried over §д§О ₄ and evaporated under reduced pressure. The residue was triturated with ether to give the title compound as a white solid.

The filtrate was separated and the organic layer was washed with 2n. hydrochloric acid (2x), dried over Μ ^^ ζΐ and evaporated under reduced pressure. The solid was triturated with ether to give an additional amount of the compound as a white solid, overall yield 99.4 g.

Ή-NMR (400 MHz, SES1 ₃ ): δ 1.46 (8, 9Н), 1.68-1.80 (t, 2Н), 1.90 (t, 2Н), 2.39 (t, 1Н), 2.79 (t, 2Н), 4.19 (t, 2H), 7.10 (8, 1H), 7.26 (b, 2H), 7.46 (b, 2H). LC-MS: t / ζ HILD '339 [MH] ⁺ .

Preparatory Example 34. tert-Butyl-4 - {[((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 L) was heated under reflux for 1 h, then was stirred at room temperature for the next 18 h. TLC analysis showed that the starting material remained, therefore, an additional amount of Lawesson's reagent (11.1 mmol) was added and this reaction mixture was heated under reflux for another hour. The cooled mixture was concentrated under reduced pressure and the residue was subjected to azeotropic distillation with ethyl acetate. The crude product was triturated with hot ethyl acetate, the resulting solid was filtered

- 32 010132 and dried to obtain the title compound as a white solid, 53 g. LCMS: t / ζ CHIAD * 353 [M-H] ^- .

Preparatory Example 35. Ethyl-1 - {[(4-chlorophenyl) amino] carbonothioyl} piperidine-4 carboxylate.

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

Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.24 (ΐ, 3Н), 1.82 (t, 2Н), 1.99 (t, 2Н), 2.60 (t, 1Н), 3.34 (t, 2Н), 4.19 (I , 2H), 4.38 (t, 2H), 7.09 (b, 2H), 7.17 (bt, 1H), 7.30 (b, 2H). LC-MS: t / ζ CHIAD * 327 [MH] ⁺ .

Preparatory Example 36. No. (4-Chlorophenyl) -3-methylpiperazine-1-carbothioamide.

A solution of 4-chlorophenylisothiocyanate (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). Upon completion of the addition, this reaction mixture was stirred at room temperature for one hour. This reaction mixture was then washed with water (3x), dried over MgSO ₄ and concentrated under reduced pressure to obtain the title compound as a white solid, 11.8 g.

Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.08 (b, 3Н), 2.70 (t, 1Н), 2.88 (t, 2Н), 3.02 (t, 2Н), 4.43 (t, 2Н), 7.10 (t , 2H); 7.29 (t, 2H). LC-MS: t / ζ ERI * 270.1 [MH] ⁺ .

Preparatory Example 37. No. (4-Chlorophenyl) -4- (2,2-dimethylpropanoyl) -3-methylpiperazine-1carbothioamide.

Di-tert-butyl dicarbonate (9.30 g, 42.6 mmol) was added to a solution of compound of Preparation 36 (11.5 g, 42.6 mmol) in dichloromethane (300 ml) and dioxane (100 ml) and this reaction mixture 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 again from methanol to give the title compound, 9.64 g.

Ή-NMR (400 MHz, OM8О-b ₆ ): δ 1.05 (b, 3H), 1.39 (q, 9H), 3.17-3.36 (t, 2H), 3.58 (t, 1H), 3.77 (t, 1H) 4.14 (t, 1H), 4.40 (t. 2H), 7.32 (t, 4H), 9.36 (q, 1H). LC-MS: t / ζ CHIAD * 370 [MH] ⁺ .

Preparatory Example 38. No. (4-Chlorophenyl) -4- (2,2-dimethylpropanoyl) -2-methylpiperazine-1carbothioamide.

A solution of 4-chlorophenylisothiocyanate (5.1 g, 30 mmol) and 4-No. BOC-2-methylpiperazine (6.0 g, 30 mmol) in dichloromethane (250 ml) was stirred at room temperature for 2 hours. This reaction mixture was evaporated under reduced pressure to obtain the title compound as a white foam. LC-MS: t / ζ CHIAD * 370 [MH] ⁺ .

Preparatory Example 39. Ethyl-1 - {[(4-chlorophenyl) amino] carbonothioyl} -4-methylpiperidin-4 carboxylate.

- 33 010132

A mixture of 4-chlorophenylisothiocyanate (2.36 g, 13.98 mmol) and ethyl 4-methylpiperidin-4-carboxylate (I8 2002/0086887, example 532C) (2.17 g, 12.71 mmol) in dichloromethane (50 ml ) was stirred at room temperature for 30 minutes. This 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 silica gel column chromatography using dichloromethane: ethyl acetate (100: 0 to 90:10) to obtain the title compound as a white solid, 3.46 g.

Ή-NMR (400 MHz, COC1 ₃ ): δ 1.22 (t, 6H), 1.58 (t, 2H), 2.18 (t, 4H), 3.30 (t, 2H), 4, 19 (q, 2H), 4.24 (t, 1H), 7.09 (b, 2H), 7.28 (b, 2H); LC-MS: t / ζ HILD '341 [MH] ⁺ .

Preparatory Example 40. I- (4-Chlorophenyl) -4-cyano-4-phenylpiperidin-1-carbothioamide.

Triethylamine (1.4 ml, 10 mmol) was added to a suspension of 4-chlorophenylisothiocyanate (1.69 g, 10 mmol) and 4-cyano-4-phenylpiperidine hydrochloride (2.22 g, 10 mmol) in dichloromethane (100 ml) and then this reaction mixture was stirred at room temperature for 20 minutes. The mixture was washed with 2n. hydrochloric acid, then brine, dried over MgSO ₄ and evaporated under reduced pressure to obtain the title compound as a white solid, 3.62 g.

Ή-NMR (400 MHz, СОС1 ₃ ): δ 2.18 (t, 4Н), 3.50 (t, 2Н), 4.78 (t, 2Н), 7.08 (b, 2Н), 7.27-7.48 (t, 7Н). Preparatory Examples 41-44.

A mixture of 4-chlorophenylisothiocyanate (1 equivalent) and the corresponding amine (1 equivalent) in ethanol (0.8-1.28 ml mmol ^-1 ) was stirred at room temperature for 30 minutes. Then this reaction mixture was evaporated under reduced pressure to obtain these compounds as a white solid.

Will prepare. example number Data 41 CH ₃ n ₃ s% - ° _х / - \ НзС Ν- О ^λ ' Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.45 (s, EN), 3.50 (t, 4H), 3.80 (t, 4H), 7.10 (b, 2H), 7.25 (b, 2H), 7.80 (s , 1H). LC-MS: t / ζ CHIAD ⁺ 356 [MH] * 42 H ₃ C / —y O ⁴ --- ⁷ Ή-NMR (400 MHz, СОС1 ₃ ): δ 2.10 (s, 3Н), 3.60 (t, 2Н), 3.78 (t, 4Н), 4 02 (t, 2Н), 7.14 (6, 2Н), 7.30 ( b, 2H). LC-MS: t / ζ CHIAD * 298 [MH] ⁺ 43 _N DX> NZS I SNZ Ή-NMR (400 MHz, С0С1з): δ 2.04-2.24 (t, 4H), 2.85 (t, 1H), 2.94 (s, 3H), 3.62 (t. 2H), 3.95 (t, 2H), 5.25 ( t, 1H), 6.60 (s, 1H), 7.30 (s, 4H). LC-MS: t / ζ HIAD ⁺ 312 {MN] * 44 о> ---- _χ НЗС —N— (Ν- * н ₃ сД— О ^Н '- ^/ Н ₃ s Я-NMR (400 MHz, COC! ₃ ): δ 1.29-1.54 (t, 11H), 2.01 (t, 2H), 3.20 (t, 2H), 3.74 (Lg s, 1H), 4.35-4.55 (t, 3H), 7.09 (ά, 2H), 7.17 (bg s, 1H), 7.32 (6, 2H).

Preparatory Example 45. tert-Butyl-4 - {[((4-chlorophenyl) amino] carbonothioyl} -1,4-diazepam-1 carboxylate.

- 34 010132

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

Я-NMR (400 MHz, SOzOO): δ 1.45 (8, 9Н), 1.98 (t, 2Н), 3.43 (t, 2Н), 3.64 (t, 2Н), 3.94-4.10 (t, 4Н), 7.28 ( 8.4H). LCMS: m / ζ APCI ⁴³⁷⁰ [MH] ^+.

Preparatory Example 46. Tert-Butyl-4 - ^) - [(4-chlorophenyl) imino (methylthio) methyl] piperidine 1-carboxylate.

Potassium tert-butoxide (20.1 g, 0.18 mol) was added portionwise to a cooled (10 ° C) solution of the compound of Preparation 34 (53 g, 0.15 mol) in tetrahydrofuran (1 L) so as to maintain a temperature of 10 ° C. Methyl iodide (11.2 ml, 0.18 mol) was added dropwise to maintain a temperature of 10 ° C, and then the reaction mixture was allowed to slowly warm to room temperature. The reaction mixture was stirred for another 90 minutes, then quenched by addition of water. This reaction mixture was diluted with ethyl acetate and washed with water. The phases were separated, the aqueous layer was extracted with additional ethyl acetate, and the combined organic solutions were dried over MgSO ₄ and evaporated under reduced pressure. The remaining oil was adsorbed onto silica gel and purified by silica gel column chromatography using pentane: ethyl acetate (75:25) as an eluent to obtain the title compound as an oil which crystallized upon standing. Я-NMR (400 MHz, СОС1 ₃ ): δ 1.43 (8, 9Н), 1.57-1.82 (t, 5Н), 2.35 (8, 3Н), 2.42-2.62 (t, 1Н), 2.78 (t, 1Н) 4.16 (t, 2H); 6.65 (b, 2H); 7.26 (b, 2H). LC-MS: t / ζ ERI ⁴ 391 [MEa] ⁴ .

Preparatory Example 47. Ethyl-1 - [(7) - [(4-chlorophenyl) imino] (methylthio) methyl] piperidine-4 carboxylate.

Potassium tert-butoxide (2.58 g, 23.1 mmol) was added portionwise to a solution of compound of Preparation 35 (6.27 g, 19.2 mmol) in tetrahydrofuran (100 ml), and this reaction mixture was stirred for 10 minutes. Methyl iodide (1.44 ml, 23.1 mmol) was added and the reaction mixture was stirred at room temperature for another 30 minutes. 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 silica gel column chromatography using dichloromethane as an eluent to obtain the title compound as an oil, 3.6 g.

Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.25 (!, 3Н), 1.78 (t, 2Н), 1.98 (t, 2Н), 2.04 (8, 3Н), 2.56 (t, 1Н), 3.01 (t , 2H), 4.12-4.23 (t, 4H), 6.80 (b, 2H), 7.20 (b, 2H); LC-MS: t / ζ ERI ⁴ 341 [MH] ⁴ .

Preparatory Example 48. Ethyl-1 - [(2) - [(4-chlorophenyl) imino] (methylthio) methyl] -4-methylpiperidin-4-carboxylate.

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

Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.25 (t, 6Н), 1.50 (t, 2Н), 2.04 (8, 3Н), 2.18 (t, 2Н), 3.19 (t, 2Н), 3.98 (t , 2H), 4.19 (f 2H), 6.80 (t, 2H), 7.20 (b, 2H); LC-MS: t / ζ ERI ⁴ 355 [MH] ⁴ .

Preparatory Examples 49-55.

- 35 010132 potassium tert-butoxide (1.1 eq.) And then methyl p-toluenesulfonate (1.1 eq.) Was added to a solution of a compound selected from compounds of preliminary examples 37, 38, 40-42 and 45, (1 equiv.) in tetrahydrofuran, and this reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water, the layers were separated, and the organic solution was washed with water (3x), dried over MgO ₄ and evaporated under reduced pressure to obtain these compounds.

Will prepare.

49 СНз Н ₃ С - ^ - О / у Н _Э С У-Ν Ν-. o y - ¹ n ₃ s ¹ H-NMR (400 MHz, SOC): 6 1.20 (s, 3H), 1.44 (s, 9H), 2.00 (s, 3H), 2.99 (hl, 1H), 3.19 (t, 2H), 3.88 (t , 1H), 4.16 (t, 1H), 4.20-4.36 (t, 2H), 6.83 (t, 2H), 7.21 (rp, 2H). LC-MS: t / ζ CHIAD * 384 [MH] * fifty CH ₃ n, с4-о, - _χ Н ₃ С Ν Ν- »о M СНз ¹ H-NMR (400 MHz, SOC < ₃ ): δ 1.21 (ά, ЗН), 1.42 (δ, 9Н), 2.00 (h, ЗН), 2.80-3.30 (t, ЗН), 3.80-4.18 (t, ZN), 4.54 (t, 1H), 6.80 (t, 2H), 7.20 (t, 2H). LC-MS: t / ζ CHIAD * 384 [MH] * 51 Xg CH ₃ ¹ H-NMR (400 MHz, СОС1 ₃ ): 5 2.06 (8, ЗН), 2.17 (t, 2Н), 3.38-3.52 (t, 4Н), 4.50 (t, 2Н), 6.83 (ά, 2Н), 7.22 (s, 2H), 7.38 (t, 1H), 7.42 (t, 2H), 7.52 (s, 2H). 52 СН ₃ НзС —— О / у Н ₃ С Ν Ν- »О ⁴ (СНз ¹ H-NMR (400 MHz, SOC! S): δ 1.46 (s, 9H), 2.02 (5, 3H), 3.48 (t, 4H), 3.58 (t, 4H), 6.80 (ό, 2H), 7.20 (th, 2H). 53 CH ₃ / - \) “Ν bH ⁰ m CH ₃ ¹ H-NMR (400 MHz, СОС1 ₃ ): 5 2.01 (5, ЗН), 2.10 (5, ЗН), 3.48-3.76 (t, 8Н), 6.80 (d, 2Н), 7.19 (d, 2Н). LC-MS: t / ζ CHIAD * 312 [MH] * 54 N ₃ S ^NEs ? G> ¹ H-NMR (400 MHz, COC): δ 1.98 (δ, 3H), 2.09 (8, 3H), 2.84 (t, 1H), 2.90 (5, 3H), 3.38 (t, 1 H>, 3.46 ( t, 1H), 3.77 (t, 2H), 5.22 (t, 1H), 6.82 (6, 2H), 7.19 (ά, 2H). LC-MS: t / ζ CHIAD * 326 [MN] * 55 ^A ΑνΟ ⁷ NZS £ 'H-NMR (400 MHz, C0 ₃ 00): 5 1.45 (2x5, 9H), 1.90 (t, 5H), 3.44 (t, 2H), 3.60 (t, 2H), 3.76 (t, 2H), 3.80 (t, 2H), 6.85 (6, 2H), 7.20 (s, 2H).

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

Preparatory Example 56. Methyl-4 - [(tert-butoxycarbonyl) amino] -Y- (4-chlorophenyl) piperidine-1-carbimidothioate.

- 36 010132

SNZ About

Potassium tert-butoxide (12.8 g, 114 mmol) was added to a suspension of 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 another 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 obtain the title compound.

Ή-NMR (400 MHz, SIS1 ₃ ): δ 1.34-1.52 (t, 11H), 2.00 (t, 2H), 2.05 (8, 3H), 3.04 (t, 2H), 3.68 (L8 8, 1H), 4.19 (t, 2H), 4.50 (bg 8, 1H), 6.80 (b, 2H), 7.20 (b, 2H). LC-MS: t / ζ ERI ³ 384 [MH] ⁺ .

Preparation 57. Tert-Butyl-4- [5- (methoxymethyl) -1,3,4-oxadiazol-2-yl] piperidine-1 carboxylate.

Potassium tert-butoxide (3.40 g, 30.3 mmol) was added to a solution of compound of Preparation 8 (7.62 g, 25.25 mmol) in methanol (120 ml), and this reaction mixture was stirred at room temperature for 18 h. TLC analysis showed that the starting material remained, therefore, additional potassium tert-butoxide (1 g, 8.9 mmol) was added and this reaction mixture was stirred at 50 ° C for 2 hours. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and a solution of ammonium chloride. The layers were separated, the organic phase was dried over MgSO ₄ and evaporated under reduced pressure to obtain the title compound as a yellow oil, 7.30 g.

Ή-NMR (400 MHz, SIS1 ₃ ): δ 1.45 (8, 9Н), 1.82 (t, 2Н), 2.08 (t, 2Н), 2.96 (t, 2Н), 3.08 (t, 1Н), 3.44 (8 , 3H), 4.10 (t, 2H), 4.61 (8, 2H). LC-MS: t / ζ HILD '298 [MH] ⁺ .

Preparatory Example 58. tert-Butyl-4- {5 - [(2,2,2-trifluoroethoxy) methyl] -1,3,4-oxadiazole-2yl} piperidine-1-carboxylate.

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 then the mixture was heated at 50 ° C for 2 hours. This reaction mixture was quenched by the addition of ammonium chloride solution, then the organic layer was decanted and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, the solution was washed with brine, dried over MgSO ₄ and then evaporated under reduced pressure to obtain the title compound as a yellow oil, 8.15 g.

Ή-NMR (400 MHz, SIS1 ₃ ): δ 1.43 (8, 9Н), 1.80 (t, 2Н), 2.06 (t, 2Н), 2.97 (t, 2Н), 3.10 (t, 1Н), 3.96 (I , 2H), 4.12 (t, 2H), 4.82 (8, 2.H).

Preparatory Example 59. tert-Butyl-4- [5- (hydroxymethyl) -1,3,4-oxadiazol-2-yl] piperidine1-carboxylate.

Potassium acetate (5.2 g, 53.0 mmol) was added to a solution of compound of preparation 8 (8 g, 26.5 mmol) in acetonitrile (150 ml) and this reaction mixture was heated at 80 ° C for 18 hours. Chilled the mixture was concentrated under reduced pressure, the residue was partitioned between water and ethyl acetate, and the layers were separated. The organic phase was washed with brine, dried over MgSO ₄ 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) were added. The mixture was stirred at room temperature for 2 hours and then evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO ₄ and evaporated under reduced pressure to obtain the title compound as an off-white solid, 7.16 g.

Ή-NMR (400 MHz, SIS1 ₃ ): δ 1.45 (8, 9Н), 1.81 (t, 2Н), 2.04 (t, 2Н), 2.17 (t. 1Н), 2.97 (t, 2Н), 3.08

- 37 010132 (t, 1H), 4.11 (t, 2H), 4.82 (8, 2H). LC-MS: t / ζ ERI ⁺ 306 [M #] ⁺ .

Preparatory Example 60. Tert-Butyl-4- [5- (morpholin-4-ylmethyl) -1,3,4-oxadiazol-2yl] piperidin-1-carboxylate.

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

^! H-NMR (400 MHz, CO ₃ OD): δ 1.45 (8, 9H), 1.65-1.78 (t, 2H), 2.04 (t, 2H), 2.58 (t, 4H), 3.00 (t, 2H), 3.10 (t, 1H), 3.68 (ΐ, 2H), 3.81 (8, 2H), 4.06 (t, 2H). LC-MS: t / ζ ERI ⁺ 353 [MH] ⁺ .

Preparatory Example 61. tert-Butyl-4 - {[2- (ethoxyacetyl) hydrazino] carbonyl} piperidine-1 carboxylate.

A mixture of 4-hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (AO 2000039125, Preparation 27) (3 g, 12.33 mmol), ethoxyacetic acid (1.28 ml, 13.56 mmol), 1- (3-dimethylaminopropyl ) -3-ethylcarbodiimide hydrochloride (2.6 g, 13.56 mmol), 1-hydroxybenzotriazole hydrate (1.83 g, 13.56 mmol) and triethylamine (2.1 ml, 14.8 mmol) in Ν, Ν -dimethylformamide (15 ml) was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and aqueous sodium carbonate. The layers were separated, the organic phase was dried over MgSO ₄ and evaporated under reduced pressure to obtain the title compound as an oil, which crystallized upon standing.

^! H-NMR (400 MHz, COC1 ₃ ): δ 1.24 (ΐ, 3H), 1.45 (8, 9H), 1.58-1.78 (t, 2H), 1.81 (t, 2H), 2.38 (t, 1H), 2.74 -2.82 (t, 2H), 3.60 (f 2H), 4.04-4.21 (t, 2H), 8.26 (bg 8, 1H), 8.82 (bg 8, 1H). LC-MS: t / ζ CHIAD ⁺ 330 [MN] ⁺ .

Preparatory Example 62. Tert-Butyl-4 - {[2- (3,3,3-trifluoropropanoyl) hydrazino] carbonyl} piperidine-1-carboxylate.

The title compound was prepared from 4-hydrazinocarbonylpiperidin-1-carboxylic acid tert-butyl ester (AO 2000039125, Preparation 27) and 3.3,3-trifluoropropionic acid, following the procedure described in Preparation 61.

^! H-NMR (400 MHz, CO ₃ OD): δ 1.44 (8, 9H), 1.60 (t, 2H), 1.80 (t, 2H), 2.43 (t, 1H), 2.81 (t, 2H), 3.22 ( I, 2H), 4.10 (t, 2H). LC-MS: t / ζ CHIAD ⁺ 352 [M-H] ^- .

Preparatory Example 63. Tert-Butyl-4- [5- (ethoxymethyl) -1,3,4-oxadiazol-2-yl] piperidine-1 carboxylate.

ABOUT

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). Then, trifluoromethanesulfonic anhydride (4.2 ml, 24.6 mmol) was added dropwise over 20 minutes, and the solution was stirred for one hour at 0 ° C. The solution was then stirred for another hour at room temperature. The mixture was basified 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 silica gel column chromatography using dichloromethane: methanol: ammonia 0.88 (97: 3: 0.3) to obtain the title compound as a yellow oil, 1.25 g.

^! H-NMR (400 MHz, COC1 ₃ ): δ 1.23 (ΐ, 3H), 1.44 (8, 9H), 1.81 (t, 2H), 2.04 (t, 2H), 2.96 (t, 2H), 3.10 (t , 1H), 3.60 (d, 2H), 4.14 (t, 2H), 4.66 (8, 2H). LC-MS: t / ζ CHIAD '312 [MH] ⁺ .

- 38 010132

Preparation 64. tert-Butyl-4- [5- (2,2,2-trifluoroethyl) -1,3,4-oxadiazol-2-yl] piperidine-1-carboxylate.

The title compound was obtained as a pale yellow solid from the compound of Preparation 62, following the procedure described in Preparation 63.

Ή-NMR (400 MHz, COC1 ₃ ): δ 1.42 (q, 9H), 1.81 (t, 2H), 2.04 (t, 2H), 2.98 (t, 2H), 3.08 (t, 1H), 3.76 (q , 2H); 4.10 (t, 2H). LC-MS: t / ζ HILD '358 | M \ a |'.

Preparation 65. 1- (4-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 29 (9.0 g, 31.94 mmol) in Ν, Ν-dimethylformamide (100 ml) and this reaction mixture was stirred for 3 hours at 50 ° C. The mixture was concentrated under reduced pressure and the residue was suspended in toluene (150 ml). P-Toluenesulfonic acid (1 g, 5.26 mmol) was added and this reaction mixture was heated at 110 ° C for 18 hours. The reaction mixture was diluted with ethyl acetate (100 ml), washed with brine, water and then again with brine. This solution was dried over MgSO ₄ and then evaporated under reduced pressure. The crude product was purified by column chromatography using a silica gel cartridge and dichloromethane: methanol (100: 0 to 90:10) as an eluent to give the title compound as a white solid, 4.25 g.

LC-MS: t / ζ, CHIAD ⁺ 292 [MH] ⁺ .

Preparatory Example 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 this reaction mixture was stirred for 18 h at 50 ° C. TLC analysis showed that the starting material remained, so additional количество, Ν-dimethylformamide-dimethyl acetal (15 mmol) was added and stirring was continued for another 2 hours. The mixture was concentrated under reduced pressure and the residue was suspended in toluene (32 ml). P-Toluenesulfonic acid (1 g, 5.26 mmol) was added and the reaction mixture was heated at 110 ° C for 18 hours.

The reaction mixture was diluted with ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution (2x) and brine, then dried over # 8O ₄ and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, gradient eluting with dichloromethane: methanol: ammonia 0.88 (100: 0: 0 to 90: 10: 1) to obtain the title compound.

Я-NMR (400 MHz, СОС1 ₃ ): δ 1.95 (t, 2Н), 2.04-2.28 (t, 2Н), 3.12-3.30 (t, 3Н), 3.80 (t, 1Н), 4.58 (t, 1Н) 7.28 (t, 2H); 7.39 (t, 2H); 8.40 (q, 1H). LC-MS: t / ζ CHIAD '292 [MH] ⁺ .

Preparatory Example 67. 1- (4-Chlorobenzoyl) -4- (5-methyl-1,3,4-oxadiazol-2-yl) piperidine.

Ν, Ν-dimethylformamide-dimethylacetal (6.38 g, 47.9 mmol) was added to a solution of the compound of Preparation 29 (9.0 g, 31.94 mmol) in Ν, Ν-dimethylformamide (20 ml) and this reaction mixture stirred at room temperature for 1 hour. Then it was stirred for another 2 hours at 40 ° C. The mixture was diluted with toluene (150 ml), heated to 110 ° C. and then ptoluenesulfonic acid (400 mg, 2.22 mmol) was added thereto. This reaction mixture was heated at 110 ° C for 18 hours, then cooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate.

- 39 010132 tate, washed with a solution of ammonium chloride and brine, then dried over MgO ₄ and evaporated under reduced pressure to obtain the title compound as an oil, 9.75 g.

Я-NMR (400 MHz, SES1 ₃ ): δ 1.81-1.97 (t, 2Н), 2.00-2.22 (t, 2Н), 2.56 (δ, 3Н), 3.18 (t, 3Н), 3.90 (t, 1Н) 4.58 (t, 1H); 7.38 (t, 4H). LC-MS: t / ζ CHIAD ⁺ 306 [MH] ⁺ .

Preparatory Example 68. 1- (4-Chlorobenzoyl) -4- (5-ethyl-1,3,4-oxadiazol-2-yl) piperidine.

ABOUT

C1 H ₃ s

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 Ν, Ν-dimethylformamide (10 ml) and stirred at 60 ° C. for 3 hours TLC analysis showed that the starting material remained, so an additional amount of triethyl orthopropionate (0.5 g, 2.83 mmol) was added and the reaction mixture was stirred at 60 ° C for another 18 hours. The mixture was concentrated under reduced pressure, the residue was suspended in toluene (15 ml) and trifluoroacetic acid (5 drops) was added. This reaction mixture was refluxed for 18 hours, then cooled and concentrated under reduced pressure. The crude product was purified by column chromatography using a silica gel cartridge and dichloromethane: methanol (100: 0 to 95: 5) as an eluent to give the title compound as an oil, 1.6 g.

Ή-NMR (400 MHz, SES1 ₃ ): δ 1.38 (ί, 3Н), 1.90 (t, 2Н), 2.00-2.21 (t, 2Н), 2.85 (f 2Н), 3.19 (t, 3Н), 3.80 ( t, 1H), 4.58 (t, 1H), 7.38 (t, 4H). LC-MS: t / ζ ERI ⁺ 320, 322 [MH] ⁺ .

Preparatory Example 69. 1- (3-Chlorobenzoyl) -4- [5- (ethoxymethyl) -1,3,4-oxadiazol-2-yl] piperidine.

Pyridine (1.8 g, 22.84 mmol) and then trifluoromethanesulfonic anhydride (3.22 g, 11.42 mmol) were added to an ice-cooled solution of compound of Preparation 32 (2.80 g, 7.61 mmol) in dichloromethane ( 50 ml). Then this reaction mixture was stirred at room temperature for 2 hours. The mixture was washed with a solution of ammonium chloride (3x), then with a saturated aqueous solution of sodium carbonate, dried over MgO ₄ and treated with activated carbon. This mixture was then filtered and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography using a silica gel cartridge and gradient elution with dichloromethane: methanol (100: 0 to 95: 5) to give the title compound as a yellow oil, 566 mg.

Ή-NMR (400 MHz, SES1 ₃ ): δ 1.23 (ί, 3Н), 1.83-2.24 (t, 3Н), 3.14-3.26 (t, 4Н), 3.62 (f 2Н), 3.80 (t, 1Н), 4.59 (t, 1H), 4.67 (δ, 2H), 7.25 (t, 1H), 7.40 (t, 3H). LC-MS: t / ζ HILD '350 [MH] ⁺ .

Preparatory Example 70. 1- (4-Chlorobenzoyl) -4- [5- (ethoxymethyl) -1,3,4-oxadiazol-2yl] piperidine.

ABOUT

The title compound was obtained as a crystalline solid from the compound of Preparation 31 following the procedure described in Preparation 69.

Ή-NMR (400 MHz, SES1 ₃ ): δ 1.23 (ί, 3Н), 1.83-1.99 (t, 2Н), 2.04-2.22 (t, 2Н), 3.14-3.26 (t, 3Н), 3.62 (I, 2H), 3.79-3.90 (t, 1H), 4.59 (t, 1H), 4.67 (δ, 2H), 7.40 (t, 4H). LC-MS: t / ζ HILD '350 [MH] ⁺ .

Preparatory Example 71. 1- (4-Chlorobenzoyl) -4- [5- (trifluoromethyl) -1,3,4-oxadiazol-2yl] piperidine.

- 40 010132

Trifluoromethanesulfonic anhydride (1.98 ml, 11.7 mmol) was added to an ice-cooled solution of the compound of Preparation 30 (1.77 g, 4.69 mmol) and pyridine (1.53 ml, 18.74 mmol) in dichloromethane (40 ml). Then this mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was diluted with dichloromethane, washed with 2N. hydrochloric acid, then saturated aqueous sodium bicarbonate, was dried over Μ§8Ο ₄ and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, gradient eluting with dichloromethane: methanol (99: 1 to 96: 4) to give the title compound as a brown oil, 620 mg.

Ή-NMR (400 MHz, SISI): δ 1.60 (t, 1Η), 1.97 (t, 3Η), 2.20 (t, 2Η), 3.20 (t, 2Η), 3.34 (t, 1Η), 7.39 (t, 4Η). LC-MS: t / ζ HILD '360 [MH] ⁺ .

Preparatory Examples 72-74

General structure compounds

were obtained from Ν, Ν-dimethylacetamide-dimethylacetal and the corresponding hydrazide, following the procedure described in preparatory example 67.

Prepare example No. / ν ^ζ (A 1 L Data 72 XX Ή-NMR (400 MHz, COS): δ 1.46 (s, 9H), 2.58 (s, 3H), 3.15 (t, 1H), 3.37 (t, 1H), 3.68 (t, 1H), 3.92 (t, 1H), 4.00 (t, 1H), 4.21 (t, 1H), 4.70 (t, 1H). LC-MS: t / ζ CHIAD * 270 [MN] * 73 BUT Я-NMR (400 MHz, OM8O-PD δ 1.38 (t, 11H), 1.73 (t, 2H), 2.06 (6.1H), 2.46 (s, 3H), 3.04 (t, 2H), 3.63 (s, 1H), 3.95 (s, 1H). 74 ⁱ Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.44 (s, 9Н), 2.19-2.38 (t, 2Н), 2.54 (s, ЗН), 3.44 (t, 1Н), 3.60 (HZ, ЗН), 3.80 (t, 1H).

A = used 3-hydrazinocarbonylpyrrolidine-1-carboxylic acid tert-butyl ester (obtained from CB K &apos;

Preparatory Example 75. 1- (3-Chlorobenzoyl) -4- [5- (1H-pyrazol-1-ylmethyl) -1,3,4-oxadiazol-2yl] piperidine.

ABOUT

A mixture 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 Ν, Ν-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. Then it was dried over Μ§8Ο ₄ . The crude product was purified by silica gel column chromatography using dichloromethane: methanol: ammonia 0.88 (from 100: 0: 0 to 95: 5: 0.5) to obtain the title compound

- 41 010132 catching the connection. 550 mg

Ή-NMR (400 MHz. SOzOO): δ 1.76-1.92 (t, 3H). 1.99-2.22 (t. 3H). 3.18 (t, 1H). 3.70 (t. 1H). 4.50 (t, 1H). 5.63 (8. 2H). 6.35 (ά. 1H). 6.38 (ά. 1H). 7.37 (ά. 1H). 7.44 (t, 2H). 7.52 (8. 1H). 7.80 (8. 1H); LC-MS: t / ζ ERI ⁴ 372 [MH] ⁴ .

Preparatory Example 76. Tert-Butyl-4- [4- (4-chlorophenyl) -5- (2-morpholin-4-yl-ethyl) -4H-1.2.4triazol-3-yl] piperidine-1-carboxylate.

Trifluoroacetic acid (0.35 ml. 4.3 mmol) was added to the hydrazide of 4-morpholinepropanoic acid (Comp. E8 KeLi8 άe8 8eaise8e П ^ Fapie άe8 8c е η се 8 8. (1.5 g. 8.7 mmol) and the compound of Preparation 46 (2.7 g. 7.25 mmol) in tetrahydrofuran (18 ml) and this reaction mixture was heated under reflux for 8 hours. The cooled mixture was diluted with dichloromethane. washed with 1n. sodium hydroxide solution and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, gradient eluting with dichloromethane: methanol: ammonia 0.88 (100: 0: 0 to 10: 10: 1) to obtain the title compound. 2.2 g

Ή-NMR (400 MHz. COC1 ₃ ): δ 1.45 (8. 9H). 1.59-1.95 (t. 4H). 2.40 (t. 4H). 2.58 (t, 1H). 2.61-2.80 (t. 6H). 3.64 (t, 4H). 4.10 (t, 2H). 7.19 (ά. 2H). 7.57 (ά. 2H); LC-MS: t / ζ Hyad ⁴ 476. 478 [MH] ⁴ .

Preparatory Examples 77-87.

were obtained from the compound of Preparation 46 and the corresponding hydrazide. following the procedure. described in Preparatory Example 76.

Prepare example No. Data 77 X = 2-oxo-1-pyrrolidinylmethyl Ή-NMR (400 MHz, СОС1 _Э ): δ 1.42 (δ, 9Н), 1.71 (t, 2Н), 1.77-2.00 (t, 4Н), 2.20 (ί, 2Н) , 2.56-2.74 (t, 3Н), 3.45 (ί, 2Н), 4.06 (t, 2Н), 4.42 (5, 2Н), 7.19 (ά, 2Н), 7.54 (ά, 2Н). LC-MS: t / ζ CHIAD * 460 [MH] ⁺ beats * X = imidazol-1-ylmethyl Ή-NMR (400 MHz, COS): δ 1.41 (v, 9H), 1.70 (t, 2H), 1.83 (t, 2H) 2.55 (t, 1H), 2.65 (t, 2H), 4.10 (t, 2H), 5.17 (s, 2H), 6.78 (s, 1H),

- 42 010132

6.90 (b, 2H); 7.01 (5, 1H). 7.19 (s, 1H); 7.52 (ά, 2H). LC-MS: t / g HIAD * 443 [MN] * 79 ^b X = 2-methyl-'H-imidazol-1-ylmethyl Ή-NMR (400 MHz, СОС1з): δ 1.43 (s, 9H), 1.70 (t, 2H), 1.84 (t, 2H), 2.01 (s, 3H), 2.52 (t, 1H), 2.66 (t. 2H), 4.10 (t, 2H), 5.02 (s, 2H). 6.55 (s, 1H), 6.85 (t, 3H), 7.53 (ΰ, 2H). LC-MS: t / ζ HIAD * 457 [MN] * 80 X = 1,2,4-triazol-1-ylmethyl Ή-NMR (400 MHz, COC! ₃ ): δ 1.42 (s, 9H), 1.76 (t, 2H), 1.86 (t, 2H), 2.55-2.75 (t, 3H), 4.12 (t, 2H), 5.39 (s, 2H), 7.12 (b, 2Η), 7.57 (b, 2H), 7.82 (s, 1H) .8.05 (3.1H). LC-MS: t / ζ CHIAD * 444 [MH] * 81 X = tetrazol-1-methylmethyl Ή-NMR (400 MHz, COS): δ 1.43 (s, 9H), 1.63-1.95 (t, 4H), 2.582.75 (t, 3H), 4.11 (t, 2H), 5.60 (3, 2H), 7.15 (b, 2H), 7.59 (b, 2H), 8.81 (s, 1H). LC-MS: t / ζ ERI * 445 [MH] * 82 " X = 3-methylisoxazol-5-ylmethyl Ή-NMR (400 MHz, СОС): δ 1.37 (З. 9Н), 1.60-1.82 (t, 4Н), 2.14 (e, ЗН), 2.45-2.65 (t, ЗН), 3.96-4.05 (t, 4Н), 5.82 (5, 1Н), 7 06 (b, 2Н), 7.44 (ά, 2Н). LC-MS: t / ζ CHIAD * 458 [MH] * 83 X i 3-methyl-1,2,4-oxadiazol-5-ylmethyl ’H-NMR (400 MHz, COC): δ 1.44 (s, 9H), 1.62-1.95 (t, 4H), 2.32 (s, ZN), 2.70 (t, ZN), 4.10 (t, 2H), 4.24 (s, 2H), 7.18 (b, 2H), 7.54 (b, 2H). LC-MS: t / ζ CHIAD * 459 [MH] * 84 X = lyrimidin-2-yloxymethyl ¹ H-NMR (400 MHz, СОС1 ₃ ): δ 1.41 (8, 9Н), 1.59-76 (t, 2Н), 1.86 (t, 2Н), 2.58-2.76 (t, ЗН ), 4.10 (t, 2H), 5.39 (8, 2H), 6.95 (t, 1H), 7.26 (b, 2H), 7.43 (b, 2H), 8.42 (8, 2H). LC-MS: t / ζ CHIAD * 471.473 [MN] * 85 X = 2-piperidin-1-yl-ethyl

- 43 010132 ¹ H-NMR (400 MHz, СОС): δ 1.39-1.78 (t, 19Н), 1.78-1.86 (t, 2Н), 2.28-3.04 (t, ЗН), 2.56-2.82 (t, 6H), 4.08 (t, 2H), 7.19 (Y. 2H), 7.58 (y. 2H).

LC-MS: t / ζ HIAD * 474 [MN] *

86 ⁱⁿ X = 2-pyridin-2-yl-ethyl Ή-NMR (400 MHz, С0С1з): δ 1.42 (5, 9Н), 1.66 (t, 2Н), 1.78-1.90 (t, 2Н), 2.56 (t, 1Н), 2.60-2.74 (t, 2Н), 2.98 (1, 2H), 3.26 (1, 2H), 4.06 (t, 2H), 7.03 (s, 2H), 7.12 (t, 1H), 7.18 (s, 1H), 7.50 (s, 2H), 7.58 (t, 1H), 8.42 (s, 1H). LC-MS: t / ζ CHIAD * 468 [MH] * 87 X = 2- (3,5-dimethylisoxazol-4-yl) ethyl ¹ H-NMR (400 MHz, С0С1з): δ 1.42 (8, 9Н), 1.70 (t, 2Н), 1.79-1.93 (t, 5Н) , 2.04 (8, 3H), 2.54 (t, 1H), 2.60-2.80 (t, 4H), 4.10 (t, 2H), 5.32 (s, 2H), 6.90 (s, 2H), 7.56 (s, 2H) ) LC-MS: t / ζ CHIAD * 486 [MH] *

A = used 1-imidazol-1-yl-acetic acid hydrazide obtained as described in Bo11. Sat. Eagt. 114 (2); 70-72; 1975.

B = the reaction mixture was stirred for 18 hours under reflux.

B = used 1 equiv. hydrazide.

Preparatory Example 88. Tert-Butyl- {1- [4- (4-chlorophenyl) -5-methyl-4H-1,2,4-triazol-3yl] piperidin-4-yl} carbamate.

Acetic hydrazide (16.9 g, 228 mmol) and then trifluoroacetic acid (4.4 ml, 57.1 mmol) were added to a solution of compound of Preparation 58 (43.6 g, 114 mmol) in tetrahydrofuran (250 ml) and this the mixture was refluxed for 7 hours. The cooled mixture was then washed with a diluted ammonia solution, the layers were separated, and the aqueous phase was then extracted with ethyl acetate. The combined organic solutions were dried over §д§О ₄ and evaporated under reduced pressure. The residue was triturated with ether (100 ml) and the resulting crystals were filtered and dried in vacuo to give the title compound, 32.4 g.

Я-NMR (400 MHz, COC1 ₃ ): δ 1.32 (t, 2H), 1.40 (q, 9H), 1.85 (t, 2H), 2.22 (q, 3H), 2.84 (t, 2H), 3.24 (t , 2H), 3.52 (t, 1H), 4.44 (t, 1H), 7.24 (s, 2H), 7.51 (s, 2H); LC-MS: t / ζ CHIAD ⁴ 392 [MH] ⁺ .

Preparatory Example 89. Tert-Butyl-4- {4- (4-chlorophenyl) -5-methyl-4H-1,2,4-triazol-3-yl] -1,4-diazepan-1-carboxylate.

The title compound was obtained in 75% yield from the compound of Preparation 55 and acetic hydrazide, following the procedure described in Preparation 88, except that 2 equiv. acetic hydrazide.

Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.41 (q, 9H), 1.58 (t, 1H), 1.72 (t, 1H), 3.02 (t, 1H), 3.20 (t, 1H), 3.243.44 (t, 5H), 3.52 (t, 2H), 4.24 (q, 2H), 7.38 (t, 2H), 7.50 (s, 2H); LC-MS: t / ζ CHIAD ⁴ 422 [MH] ⁺ .

Preparatory Example 90. Ethyl 1- [4- (4-chlorophenyl) -5-methyl-4H-1,2,4-triazol-3-yl] piperidine 4-carboxylate.

- 44 010132

Trifluoroacetic acid (0.84 ml, 10.85 mmol) and then acetic hydrazide (2.41 g, 32.6 mmol) were added to a solution of compound of Preparation 47 (7.38 g, 21.7 mmol) in tetrahydrofuran (100 ml) and this reaction mixture was refluxed 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 give the title compound as a white solid, 5.04 g.

Я-NMR (400 MHz, СОС1 ₃ ): δ 1.22 (!, 3Н), 1.60 (t, 2Н), 1.83 (t, 2Н), 2.22 (8, 3Н), 2.38 (t, 1Н), 2.82 (t , 2H), 3.28 (t, 2H), 4.14 (f 2H), 7.25 (s, 2H), 7.55 (s, 2H); LC-MS: t / ζ CHIAD ⁺ 349 [MH] ⁺ .

Preparatory Example 91. Ethyl-1- [4- (4-chlorophenyl) -5- (2H-1,2,3-triazol-2-ylmethyl) -4H-1,2,4triazol-3-yl] piperidin-4 carboxylate.

C1

Trifluoroacetic acid (0.41 ml, 5.3 mmol) was added to the hydrazide solution 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 this reaction mixture was refluxed 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 MgSO ₄ and evaporated under reduced pressure to give the title compound as a gum.

Я-NMR (400 MHz, СОС1 ₃ ): δ 1.21 (!, 3Н), 1.58 (t, 2Н), 1.82 (t, 2Н), 2.38 (t, 1Н), 2.86 (t, 2Н), 3.38 (t , 2H), 4.12 (f 2H), 5.59 (8, 2H), 7.15 (s, 2H), 7.40 (s, 2H), 7.50 (8, 2H).

Preparatory Example 92. Ethyl 1- [4- (4-chlorophenyl) -5-methyl-4H-1,2,4-triazol-3-yl] -4-methylpiperidin-4-carboxylate.

The title compound was obtained as a clear oil in 86% yield from the compound of Preparation 48 and acetic hydrazide, following the procedure described in Preparation 91.

Ή-NMR (400 MHz, SES1 ₃ ): δ 1.18 (8, 3H), 1.23 (!, 3H), 1.40 (t, 2H), 2.00 (t, 2H), 2, 23 (8, 3H), 2.90 (t, 2H), 3.18 (t, 2H), 4.14 (φ 2H), 7.26 (s, 2H), 7.57 (s, 2H) ; LC-MS: t / ζ CHIAD ⁺ 363 [MH] ⁺ .

Preparatory Example 93. Tert-Butyl-4- [4- (4-chlorophenyl) -5- (methoxymethyl) -4H-1,2,4-triazole-3yl] -2-methylpiperazine-1-carboxylate.

Methoxyacetic acid hydrazide (1.95 g, 18.75 mmol) was added to a solution of compound of Preparation 48 (4.80 g, 12.50 mmol) in tetrahydrofuran (200 ml) and the solution was stirred for 10 minutes. Trifluoroacetic acid (710 mg, 6.25 mmol) was added and this reaction was stirred.

45 010132 mixture at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the crude product was purified by column chromatography using a silica gel cartridge and dichloromethane: methanol (100: 0 to 90:10) as an eluent and repeated using ethyl acetate as eluent to afford the title compound as a foam, 1.84 g.

Ή-NMR (400 MHz, SIS1 ₃ ): δ 0.98 (b, 3H), 1.42 (q, 9H), 2.82-3.05 (t, 4H), 3.24 (t, 1H), 3.34 (q, 3H), 3.80 (t, 1H), 4.18 (t, 1H), 4.34 (q, 2H), 7.40 (b, 2H), 7.64 (b, 2H); LC-MS: t / ζ CHIAD * 363 [MH] *.

Preparatory Example 94. Tert-Butyl-4- [4- (4-chlorophenyl) -5- (methoxymethyl) -4H-1,2,4-triazol-3yl] -3-methylpiperazine-1-carboxylate.

The title compound was obtained in 67% yield from the compound of Preparation 50 following the procedure described in Preparation 93, except that the reaction mixture was refluxed. LC-MS: t / ζ CHIAD * 363 [MH] *.

Preparatory Example 95. Tert-Butyl-4- [4- (4-chlorophenyl) -5-methyl-4H-1,2,4-triazole-3yl] piperazine-1-carboxylate.

Acetic acid hydrazide (6.51 g, 88 mmol) was added to a solution of compound of Preparation 52 (32.46 g, 88 mmol) in n-butanol (250 ml), and this reaction mixture was heated under reflux for 18 hours. Reaction the mixture was heated for another 5 days under reflux with periodic addition of additional acetic hydrazide (36.5 g in total). The cooled mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5) to obtain the title compound as a white foam.

Ή-NMR (400 MHz, SIS1 ₃ ): δ 1.42 (q, 9H), 2.24 (q, 3H), 3.01 (t, 4H), 3.38 (t, 4H), 7.25 (b, 2H), 7.54 (b) , 2H). LC-MS: t / ζ CHIAD * 378 [MH] *.

Preparatory Example 96. 1- [4- (4-Chlorophenyl) -5-methyl-4H-1,2,4-triazol-3-yl] -4 phenylpiperidin-4-carbonitrile.

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

Ή-NMR (400 MHz, SIS1 ₃ ): δ 1.97-2.16 (t, 4H), 2.24 (q, 3H), 3.35 (t, 2H), 3.42 (t, 2H), 7.22-7.45 (t, 7H) 7.56 (b, 2H); LC-MS: t / ζ ERI * 400 [M№] *.

Preparatory Example 97. Tert-Butyl-4- [4- (4-chlorophenyl) -5- (methoxymethyl) -4H-1,2,4-triazole-3yl] piperidine-1-carboxylate.

- 46 010132

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 this reaction mixture was heated under reflux for 18 h. The cooled solution was concentrated under reduced pressure, and the residue was purified by column chromatography using a silica gel cartridge and gradient elution with dichloromethane: methanol (from 100: 0 to 90:10) to obtain the indicated in the title compound as an oil, 4.25 g.

^! H-NMR (400 MHz, SbZOB): δ 1.45 (s, 9H), 1.67-1.83 (t, 4H), 2.68-2.83 (t, 3H), 3.32 (s, 3H), 4.08 (t, 2H), 4.39 (s, 2H), 7.46 (b, 2H), 7.63 (b, 2H); LC-MS: t / ζ CHIAD + 407 [MH] ⁺ .

Preparatory Example 98. Tert-Butyl-4- [4- (4-chlorophenyl) -5- (hydroxymethyl) -4H-1,2,4-triazol3-yl] piperidine-1-carboxylate.

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 mmol) in toluene (40 ml) was stirred at 100 ° C for 18 hours. 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 silica gel column chromatography using ethyl acetate: methanol: ammonia 0.88 (95: 5: 0.5 to 90: 10: 1) to obtain the title compound as an off-white solid, 7.1 g.

Ή-NMR (400 MHz, SBS1 ₃ ): δ 1.42 (s, 9H), 1.75 (t, 2H), 1.82 (t, 2H), 2.59-2.76 (t, 3H), 3.00 (Lh, 1H), 4.10 (t, 2H), 4.58 (s, 2H), 7.30 (b, 2H), 7.58 (b, 2H); LC-MS: t / ζ CHIAD 393 [MH] ⁺ .

Preparatory examples 99-101.

Compounds of General Formula

were obtained from the corresponding compound selected from the compounds of Preparations 60, 63 and 64 and 4-chloroaniline, following the procedure described in Preparation 98.

- 47 010132

Will prepare. example number Data 99 * X = ethoxymethyl ¹ H-NMR <400 MHz, С0С1з): δ 1.09 (1, ЗН), 1.43 (8, 9Н), 1.68 (t, 2Н), 2.59-2.78 (t, ЗН), 3.42 (η, 2Н ), 4.14 (t, 2H), 4.42 (e, 2H), 7.24 (b, 2H), 7.57 (b, 2H). LC-MS: t / ζ CHIAD * 421 [MH] * Ϊ00 * X = 2,2,2-trifluoroethyl Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.42 (s, 9H), 1.72 (t, 2H), 1.87 (t, 2H), 2.58 (t, 1H), 2.66 (t, 2H), 3.45 (t, 2H), 4.10 (t, 2H), 7.19 (ά, 2H), 7.60 (ά, 2H). LC-MS: t / ζ HIAD * 445 [MH] * 101 ^b X = morpholin-4-ylmethyl 'H-NMR (400 MHz, COC1 ₃ ): δ 1.41 (v, 9H), 1.65-1.96 (t. 4H), 2.38 (t, 4H), 2.58-2.77 (t, 3H) ), 3.57 (hl, 4H), 4.08 (t, 2H), 7.23 (6, 2H), 7.56 (ά, 2H). LC-MS: t / ζ CHIAD * 462 [MH] *

A = 0.8 equiv. trifluoroacetic acid.

B = used 1 equiv. trifluoroacetic acid.

Preparatory Example 102. Tert-Butyl 2- [4- (4-chlorophenyl) -5-methyl-4H-1,2,4-triazole-3yl] morpholine-4-carboxylate.

The title compound was obtained as an oil in 75% yield from the compound of Preparation 72 and 4-chloraniline, following the procedure described in Preparation 98, except that 1 equiv. trifluoroacetic acid and 2 eq. 4-chloraniline. LCMS: t / ζ CHIAD ⁴ 393 [MH] ⁴ .

Preparatory Example 103. Tert-Butyl-3- [4- (4-chloro-2-methylphenyl) -5-methyl-4H-1,2,4-triazol3-yl] piperidine-1-carboxylate.

4-Chloro-2-methylaniline (3.78 g, 26.3 mmol) and p-toluenesulfonic acid (50 mg) were added to a solution of oxadiazole in Preparation 73 (2.33 g, 8.9 mmol) in xylene (10 ml ) and this reaction mixture was refluxed for 24 hours. The cooled reaction mixture was purified directly by silica gel column chromatography using ethyl acetate: methanol: dichloromethane (from 100: 0: 0 to 0: 5: 95). The product was subjected to azeotropic distillation with dichloromethane to give the title compound as a purple crystalline solid.

Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.39 (t, 10Н), 1.69 (t, 1Н), 1.80-1.97 (t, 2Н), 1.98, 2.01 (8, 2x8, 3Н), 2.17 (8, 3H), 2.32 (t, 1H), 2.59-3.17 (t, 2H), 4.10 (t, 2H), 7.05, 7.12 (t, 1H), 7.38 (!, 1H), 7.44 (b, 1H); LCMS: t / ζ HIAD ⁴ 391 [MN] ⁴

Preparatory Example 104. Tert-Butyl-3- [4- (4-chloro-2-methylphenyl) -5-methyl-4H-1,2,4-triazol3-yl] pyrrolidine-1-carboxylate.

- 48 010132

A mixture of the compound of Preparation 74 (1.50 g, 5.92 mmol), trifluoroacetic acid (528 μl, 7.1 mmol) and 4-chloroaniline (1.68 g, 11.8 mmol) in toluene (20 ml) was heated at 110 ° C for 18 hours. The cooled mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with dichloromethane: methanol: triethylamine (from 98: 1.5: 0.5 to 90: 10: 1 to 80: 20: 1) to give the title compound, 810 mg.

Ή-NMR (400 MHz, SIS1 ₃ ): δ 1.44 (8, 9Н), 2.01 (8, 3Н), 2.22 (t, 5Н), 2.94-3.70 (t, 5Н), 7.08 (t, 1Н), 7.37 -7.46 (t, 2H); LC-MS: t / ζ HILD '377 [MH] ⁺ .

Preparatory Example 105. Tert-Butyl-4- [4- (4-chloro-2-methoxyphenyl) -5-methyl-4H-1,2,4triazole-3-yl] piperidine-1-carboxylate.

A mixture of the compound of Preparative Example 1 (2 g, 7.5 mmol), 4-chloro-2-methoxyaniline (Vyuoguds apb Meb1sta Sjet18! Gu bе !! eg8, 1999; 9 (19); 2805-2810) (1.77 g , 11.2 mmol) and trifluoroacetic acid (0.29 ml, 3.7 mmol) in toluene (20 ml) were stirred at 85 ° C for 5 hours. The cooled mixture was diluted with ethyl acetate and washed with 2M sodium hydroxide solution. The aqueous solution was extracted with dichloromethane (2x) and the combined organic solutions were dried over No. ₂ 8O ₄ and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using a mixture of dichloromethane: methanol: ammonia 0.88 (from 100: 0: 0 to 90: 10: 1) to obtain the title compound 2 g.

Я-NMR (400 MHz, SISOI): δ 1.46 (8, 9Н), 1.63-1.84 (t, 4Н), 2.18 (8, 3Н), 2.59-2.81 (t, 3Н), 3.86 (8, 3Н), 4.05 (t, 2H), 7.20 (bb, 1H), 7.39 (t, 2H); LC-MS: t / ζ CHIAD ³ 407 [MH] ⁺ .

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

The title compound was prepared from oxadiazole in Preparation Example 1 and 2,4-dichloroaniline following the procedure described in Preparation 105, except that 2 equiv. aniline.

Я-NMR (400 MHz, SIS1 ₃ ): δ 1.42 (8, 9Н), 1.65-1.94 (t, 4Н), 2.20 (8, 3Н), 2.42 (t, 1Н), 2.61-2.78 (t, 2Н) 4.10 (t, 2H), 7.22 (b, 1H), 7.46 (b, 1H), 7.66 (8, 1H).

Preparatory Examples 107-116

The corresponding aniline ^ T-PYAN ^ (1-1.1 equiv.) And then trifluoroacetic acid (0.5 equiv.) To

- 49 010132 was added to a solution of the compound of Preparation 9 (1 equiv.) In toluene (1.6 ml mmol ^-1 ) and the reaction mixture was heated under reflux. The reaction was monitored by TLC and at the end of the reaction (from 45 minutes to 9 hours) the mixture was allowed to cool. This reaction mixture was washed with dilute ammonia and brine, then dried over MgSO ₄ and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using dichloromethane: methanol (95: 5) as an eluent to obtain the indicated compounds.

Prepare example No. Data 107 Υ = Η; Υ '= H; Ή-NMR (400 MHz, СОС1з): 5 1.42 (s, 9H), 1.74 (t, 2H), 1.87 (t, 2H), 2.51-2.73 (t, 3H), 4.08, (t, 2H), 5.63 (h, 2H), 7.05 (Y, 2H), 7.40-7.55 (5H, t). LC-MS: t / ζ ERI * 432 [MEa] * 108 Υ = 4-OCH; Υ '= H; ¹ H-NMR (400 MHz, COC1 ₃ ): δ 1.42 (s, 9H), 1.74 (t, 2H), 1.86 (t, 2H), 2.53-2.71 (t, 3H), 3.84 (s, 3H), 4.08 (t, 2H), 5.61 (s, 2H), 6.91 (s, 2H), 6.96 (s, 2H), 7.50 (s, 2H). LC-MS: t / ζ ERI * 462 [M№] * 109 γ * 4-E; γ · = H; Ή-NMR (400 MHz, COC): 3 1.42 (s, 9H), 1.72 (t, 2H), 1.89 (t, 2H). 2.56 (t, 1H), 2.65 (t, 2H), 4.09 (h, 2H), 5.62 (s, 2H), 7.06 (Y, 1H), 7.13 (t, 2H), 7.48 (s, 2H). LC-MS: t / ζ ERI * 428 [M№] * But* Υ = 4-Vg; Υ '= H; Ή-NMR (400 MHz, СОС1з): 3 1.46 (s, 9H), 1.74 (t, 2H), 1.92 (t, 2H), 2.59 (t, 1H), 2.68 (t, 2H), 4.12 (t, 2H), 5.66 (s, 2H), 6.98 (s, 2H), 7.52 (s, 2H), 7.61 (s, 2H). LC-MS: t / ζ ERI * 510 [M№] ’ 111 Υ = 4-CPz; γ is H; Ή-NMR (400 MHz, SES1 ₃ ): δ 1.42 (s, 9H), 1.74 (t, 2H), 1.90 (t, 2H). 2.54 (t, 1H), 2.65 (t, 2H), 4.10 (t, 2H), 5.67 (s, 2H), 7.21 (s, 2H),

- 50 010132

7.47 (δ, 2H); 7.73 (ά, 2H). LC-MS: t / g ERI * 500 [ΜΝβ] ⁺ 112 Υ = 4-CH3; Υ '= H; ¹ H-NMR (400 MHz, COC1 ₃ ): δ 1.42 (s, 9H), 1.74 (t, 2H), 1.87 (t, 2H). 2.41 (s, 3H), 2.54-2.73 (t, 3H), 4.07 (t. 2H), 6.94 (ά, 2H), 7.26 (6, 2H), 7.52 (δ, 2H). LC-MS: t / g ERI * 446 [M№] * 113 Υ = 4-ΟΝ; Υ '= H; ¹ H-NMR (400 MHz, COC1 ₃ ): δ 1.42 (δ, 9H), 1.72 (t, 2H), 1.92 (t, 2H), 2.55 (t, 1H), 2.66 (t, 2H), 4.09 ( t, 2H), 5.68 (s, 2H), 7.28 (ά, 2H), 7.52 (δ, 2H), 7.79 (ά, 2H). LC-MS: t / ζ ERI * 435 [MH] * ΪΪ4 * Υ = 4-C1; Υ ¹ = 2-CH ₃ ; ¹ H-NMR (400 MHz, SEC): δ 1.45 (β, 9H), 1.62-1.78 (t, 3H), 1.86 (s, 3H), 2.00 (t, 1H), 2.41 (t, 1H), 2.67 (t, 2H), 4.01-4.18 (t, 2H), 5.52 (6, 1H), 5.67 (6, 1H), 6.87 (6, 1H), 7.25 (6, 1H), 7.34 (δ, 1H), 7.48 (s, 2H). LC-MS: t / g ERI * 458 [MH] * 115 Υ = 4-C1; Υ * = 3-P; ¹ H-NMR (400 MHz, SES1 ₃ ): δ 1.44 (s, 9H), 1.73 (t, 2H), 1.89 (t, 2H), 2.57 (t, 1H), 2.68 (t. 2H), 4.11 ( hp, 2H), 5.67 (s, 2H), 6.84-6.92 (pl. 2H), 7.46-7.54 (t, 3H). LC-MS: t / g ERI * 462 [MH] * 116 Υ = 4-C1; Υ '= 3-C1; ¹ H-NMR (400 MHz, SES1 ₃ ): δ 1.42 (δ, 9H), 1.73 (t, 2H), 1.88 (t, 2H), 2.55 (t, 1H), 2.70 (t, 2H), 4.08 ( t, 2H), 5.67 (s, 2H), 6.97 (6, 1H), 7.07 (6, 1H), 7.52 (s, 2H), 7.55 (ά, 1H). LC-MS: t / g ERI * 478 [MN] * ·

A = 1.5 equiv. aniline.

Preparatory Example 117. Tert-Butyl-4- [4- (4-chlorophenyl) -5 - ({[((methylthio) carbonothioyl] oxy} methyl) -4H-1,2,4-triazol-3-yl] piperidin- 1-carboxylate.

Sodium hydride (60% dispersion in mineral oil, 112 mg, 2.8 mmol) was added to an ice-cooled solution of compound of preparation Example 98 (1 g, 2.55 mmol) in tetrahydrofuran (20 ml) and the solution was stirred for one hour at room temperature temperature. Carbon disulfide (230 μl, 3.83 mmol) and then methyl iodide (238 μl, 3.83 mmol) were added and this reaction mixture was stirred at room temperature for another 2 hours. Water (1 ml) was added, the mixture was concentrated under reduced pressure. and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phase was dried over MgSO ₄ and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, gradient eluting with dichloromethane: methanol: ammonia 0.88 (97: 3: 0.3 to 95: 5: 0.5) to give the title compound as a pale yellow solid, 460 mg

Я-NMR (400 MHz, SIS): δ 1.42 (8, 9Н), 1.77 (t, 2Н), 1.90 (t, 2Н), 2.54 ( ₈ , 3Н), 2.58-2.77 (t, 3Н), 4.13 ( t, 2H), 5.56 (8, 2H), 7.20 (6, 2H), 7.57 (6, 2H); LC-MS: t / ζ CHIAD 483 [MH] ⁺ .

Preparatory Examples 118-137.

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4M hydrochloric acid in dioxane (from 8 to 30 equiv.) Was added to a solution of the corresponding protected piperidine selected from compounds of Preparatory Examples 76, 77, 80-85 and 105-116 (1 equiv.), In methanol (from 9 to 22, 5 ml-mmol ^-1 ), and this 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 1M sodium hydroxide solution and the layers were separated. The organic solution was dried over MdZO ₄ and evaporated under reduced pressure to obtain these compounds.

Will prepare.

Data

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ZN), 3.16 (6, 2H), 5.62 (s, 2H), 7.02 (ό, 2H), 7.12 (ί, 2H), 7.49 (s. 2H). LC-MS: t / ζ ERI ⁺ 328 [MH] ⁺ 124 Υ = 4-Vg; Υ '= Η; X = 1,2,3-triazol-2-ylmethyl 'H-NMR (400 MHz, СОС1з): δ 1.79 (t, 2Н), 1.87 (t, 2Н), 2.54-2.65 (t, ЗН), 5.64 ( c, 2H), 6.93 (b, 2H), 7.52 (c, 2H), 7.59 (ά, 2H). LC-MS: t / ζ ERI ⁺ 388 [MH] ⁺ 125 Υ = 4-C1; Υ '= 3-P; X = 1,2,3-triazol-2-ylmethyl ¹ H-NMR (400 MHz, СОС1з): δ 1.80 (t, 2Н), 1.93 (t, 2Н), 2.54-2.66 (t, ЗН), 3.22 ( b, 2H), 5.66 (s, 2H), 6.80-6.88 (t, 2H), 7.47-7.53 (t, ZN). LC-MS: t / ζ ERI ⁺ 362 [MH] ⁺ 126 Υ = 4-C1; Υ '= 3-C1; X = 1,2,3-triazol-2-ylmethyl ¹ H-NMR (400 MHz, СОС1з): δ 1.80 (t, 2Н), 1.91 (t, 2Н), 2.52-2.66 (t, ЗН), 3.20 ( b, 2H), 5.66 (s, 2H), 6.94 (b, 1H), 7.07 (b, 1H), 7.52 (s, 2H), 7.54 (6, 1H). LC-MS: t / ζ ERI ⁺ 378 [MH] ⁺ 127 Υ = Υ '= y · x = ΐ, 2,3-triazol-2-ylmethyl' H-NMR (400 MHz, СОС1з): δ 1.76 (t, 2Н), 1.87 (t, 2Н), 2.56 (t, ZN), 3.14 (6, 2H), 5.66 (s, 2H), 7.20 (b, 2H), 7.46 (3, 2H), 7.64 (b, 2H). LC-MS: t / ζ ERI ⁺ 378 [MH] ⁺ 128 Υ = 4-C1; Υ '= 2-CH ₃ ; X = 1,2,3-triazol-2-ylmethyl ¹ H-NMR (400 MHz, COC): δ 1.68-1.87 (t, 5H), 1.91-2.15 (t, 2H), 2.45 (t, 1H), 1.55-1.72 (t, 2H), 3.17 (ά, 1H), 3.28 (6, 1H), 5.47 (6, 1H), 5.64 (6, 1H), 6.84 (6, 1H), 7.20 (b, 1H) 7.31 (6. 1H); 7.46 (s, 2H). . LC-MS: t / ζ ERI ⁺ 358 (MH] ⁺ 129 Υ = 4-CH ₃ ; Υ '= Η; X = 1,2,3-triazol-2-ylmethyl 'H-NMR (400 MHz, СОС1з): δ 1.74-1.98 (t, 4Н), 2.43 (s, ЗН), 2.552.68 (t, ЗН), 3.20 (6, 2H), 5.60 (s, 2H), 6.92 (6, 2H), 7.24 (ά, 2H), 7.51 (s, 2H). LC-MS: t / ζ ERI ⁺ 324 [MH] ' 130 Υ = 4-OCH ₃ ; Υ '= Η; X = 1,2,3-triazol-2-ylmethyl 'H-NMR (400 MHz, С0 ₃ СУ): δ 1.72-1.79 (t, 4H), 2.45 (t, 2H), 2.65

- 53 010132

(t, 1H), 3.00 (b, 2H), 3.82 (8, 3H), 5.62 (s, 2H>, 7.00 (ά, 2H), 7.11 (b, 2H), 7.57 (δ, 2H). LC-MS: t / ζ ERI * 340 [MH] * 131 Υ = 4-SY; Υ '= Η; X = 1,2,3-triazol-2-ylmethyl Ή-NMR (400 MHz, suck: δ 1.61-1.95 (t, 4H), 2.44-2.60 (t, 3H), 3.16 (t, 2H), 5.66 ( 8, 2H), 7.21 (b, 2H), 7.48 (8, 2H), 7.76 (ά, 2H). LC-MS: t / ζ ERI ⁺ 335 [MN] * 132 ^A Υ = 4-C1; Υ '= Η; X = tetrazol-1-methylmethyl ¹ H-NMR (400 MHz, 0Μ5Μ-ά ₆ ): δ 1.80-1.98 (hl, 4H), 2.80 (t, 3H), 3.20 (t, 2H), 3.56 (s, 4H ), 5.77 (δ, 2H), 7.43 (b, 2H), 7.60 (b, 2H), 8.75 (bg 8, 1H), 8.94 (bg 8. 1H), 9.18 (b, 1H). LC-MS: t / ζ ERI * 345, 347 [MH] * ~ 133 ^A Υ = 4-C1; Υ '= Η; X = 3-methylisoxazol-5-ylmethyl Я-NMR (400 MHz, CO.sub.N.): δ 2.05 (t, 2H), 2.20 (t, 2H), 3.00 (t, 2H), 3.18 (t, 1H), 3.38 (t, 2H), 3.54 (s, 3H), 4.25 (8, 2H), 7.48 (t, 2H), 7.58 (b, 2H). LC-MS: t / ζ CHIAD * 358 [MH] * 134 ^a Υ = 4-C1; Υ '= Η; X = 3-methyl-1,2,4-oxadiazol-5-ylmethyl Ή-NMR (400 MHz, SOzOO): δ 2.12 (t, 4H), 2.34 (8, 3H), 3.02 (t, 2H), 3.15 (t, 1H), 3.43 (t, 2H), 3.64 (s, 2H), 7.57 (t, 2H), 7.68 (b, 2H). LC-MS: t / ζ CHIAD * 359 [MH] * 135 Υ = 4-C1; Υ '= Η; X = pyrimidin-2-yloxymethyl Ή-NMR (400 MHz, СОС1 ₃ ): δ 2.05 (t, 4Н), 2.80-2.95 (t, ЗН), 3.46 (t, 2Н), 5.40 (t, 2Н), 6.98 (t, 1H), 7.20-7.34 (t, 1H), 7.41-7.58 (t, 3H), 8.44 (t, 2H). LC-MS: t / ζ CHIAD * 371 [MH] * 136 Υ = 4-C1; Υ '= Η; X = 2-piperidin-1-yl-ethyl Я-NMR (400 MHz, SOS: δ 1.41 (t, 2H), 1.56 (t, 4H), 1.78-1.97 (t, 4H), 2.20-2.40 (t, 6H), 2.60-2.78 (t, 5H) 3.22 (t, 2H); 7.18 (b, 2H); 7.57 (b, 2H). LC-MS: t / ζ CHIAD * 374 [MH] * 137 Υ = 4-C1; Υ '= Η; X = 2-morpholin-4-yl-ethyl Ή-NMR (400 MHz, СОС1з): δ 1.70-1.90 (t, 4Н), 2.38 (t, 4Н), 2.58 (t, ЗН), 2.70 (з, 4Н), 3.14 (t, 2Н), 3.61 ( t, 4H), 7.18 (b, 2H), 7.57 (b, 2H). LC-MS: t / g HIAD * 376 [MN] *

A = The reaction mixture was evaporated under reduced pressure, after which it was processed to isolate the hydrochloride salt of the indicated compound.

A solution of the corresponding protected piperidine selected from the compounds of Preparative Examples 78-79 and 86-87 (1 equiv.) In 2.2 M methanol hydrochloric acid (13 ml mmol ^-1 ) was stirred at room temperature for 18 hours This mixture was concentrated under reduced pressure and the residue was subjected to azeotropic distillation with toluene. The crude product was partitioned between dichloromethane and 1M sodium hydroxide solution and the layers were separated. The organic solution was dried over MgSO ₄ and evaporated under reduced pressure to obtain the indicated compounds.

Prepare an example No. X Data 138 ID \ = Ν ¹ H-NMR (400 MHz, COC): δ 1.78 (t, 2H), 1.80-1.88 (t, 2H), 2.56 (h, 3H), 3.16 (t, 2H), 5.12 (s, 2H), 6.75 (h, 1H), 6.84 (ά, 2H), 7.00 (ά, 2H), 7.50 (b, 2H). LC-MS: t / ζ CHIAD * 343 [MH] * 139 ) = Ν Н ₃ С ¹ H-NMR (400 MHz, COC1 ₃ ): δ 1.74-1.97 (t, 4H), 2.04 (t, 3H), 2.48-2.64 (t, 3H), 3.19 (gl. 2H), 5.00 (3, 2H) ), 6.46 (s, 1H), 6.82 (8, 2H), 6.85 (b 2H), 7.48 (b, 2H). LC-MS: t / ζ HIAD ⁺ 357 [Mnr Ϊ40 * PE ¹ H-NMR (400 MHz, COC1 ₃ ): δ 2.06-2.19 (t, 4H), 3.03 (t, 2H), 3.18-3.22 (t, 1H), 3.30 (t, 2H), 3.44 (t, 2H) ), 3.60 (t, 2H), 7.77 (s, 4H), 7.98 (t, 1H), 8.05 (6, 1H), 8.58 (t, 1H), 8.78 (6, 1H). LC-MS: t / ζ CHIAD ⁺ 368 [MH] * 14Ϊ * CH ₃ yes. Snlo ¹ H-NMR (400 MHz, CO.sub.SU): δ 1.99 (s, 3H), 2.12 (t, 7H), 2.78 (1, 2H), 2.97 (1, 2H), 3.00-3.18 (t, 3H), 3.43 (t, 2H), 7.54 (6, 2H), 7.78 (6, 2H). LC-MS: t / ζ CHIAD * 386 [MH] ⁺

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

Preparatory Example 142. 4- [4- (4-Chlorophenyl) -5- (methoxymethyl) -4H-1,2,4-triazol-3yl] piperidine.

4M hydrochloric acid in dioxane (60 ml) was added to a solution of compound of preparation 97 (3.75 g, 9.22 mmol) in dioxane (50 ml) and this reaction mixture was stirred at room temperature for 3 hours. The mixture was evaporated under reduced pressure and the residue was dissolved in dichloromethane and washed with aqueous ammonia, 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 and dichloromethane: methanol: ammonia 0.88 (90: 10: 1) as an eluent to obtain the title compound 1.99 g.

^! H-NMR (400 MHz, SBS1 ₃ ): δ 1.80-1.98 (t, 4H), 2.57-2.70 (t, 3H), 3.20 (t, 2H), 3.25 (s, 3H), 4.38 (s, 2H) 7.22 (b, 2H); 7.57 (b, 2H). LC-MS: t / ζ CHIAD ⁺ 307 [MH] ⁺ .

Preparatory Example 143. 4- [4- (4-Chlorophenyl) -5- (ethoxymethyl) -4H-1,2,4-triazol-3yl] piperidine hydrochloride.

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

Ή-NMR (400 MHz, СО ₃ OD): δ 1.02 (!, 3Н), 1.80 (t, 4Н), 2.55 (t, 2Н), 2.76 (t, 1Н), 3.05 (t, 2Н), 3.38 ( C, 2H), 4.42 (s, 2H), 7.45 (b, 2H), 7.63 (b, 2H); LC-MS: t / ζ HILD '321 [MH] ⁺ .

Preparatory Example 144. 1- [4- (4-Chlorophenyl) -5-methyl-4H-1,2,4-triazol-3-yl] piperazine dihydrochloride.

4M hydrochloric acid in dioxane (13.75 ml) was added to a solution of compound of Preparation 95 (4.12 g, 110 mmol) in dichloromethane (50 ml), and this 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, СОС1 ₃ ): δ 2.23 (s, 3H), 2.80 (t, 4H), 3.05 (t, 4H), 7.25 (b, 2H), 7.50 (b, 2H).

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

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

Ή-NMR (400 MHz, CO ₃ OD): δ 1.65 (t, 2H), 1.96 (t, 2H), 2.36 (s, 3H), 3.07 (t, 2H), 3.36 (t, 1H), 3.47 ( t, 2H), 7.66 (b, 2H), 7.75 (b, 2H). LC-MS: t / ζ HILD '292 [MH] ⁺ .

Preparatory Example 146. 3- [4- (4-Chloro-2-methylphenyl) -5-methyl-4H-1,2,4-triazol-3yl] piperidine.

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

Ή-NMR (400 MHz, COC1 ₃ ): δ 1.49 (t, 1H), 1.68-1.93 (t, 3H), 1.97 (s, 3H), 2.16 (s, 3H), 2.59 (t, 1H),

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2.80 (t, 1H), 3.03 (t, 1H), 3.16 (t, 1H), 7.06 (2x6, 1H), 7.35 (2ht, 1H), 7.42 (2x6, 1H); LC-MS: t / ζ CHIAD * 291 [MH] *.

Preparatory Example 147. 4- (4-Chloro-2-methylphenyl) -3-methyl-5-pyrrolidin-3-yl-4H-1,2,4triazole.

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

Я-NMR (400 MHz, СОС1 ₃ ): δ 2.00 (t, 5Н), 2.20 (t, 5Н), 2.80-3.02 (t, 2Н), 3.10-3.27 (t, 1Н), 7.05 (b, 1Н) 7.38 (b, 1H); 7.41 (q, 1H); LC-MS: t / ζ CHIAD * 277 [MH] *.

Preparatory Example 148. 1- [4- (4-Chlorophenyl) -5- (methoxymethyl) -4H-1,2,4-triazol-3-yl] -1,4-diazepane.

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

Ή-NMR (400 MHz, CO ₃ OD): δ 1.78 (t, 2H), 2.84 (t, 4H), 3.21 (q, 3H), 3.30 (t, 4H), 4.24 (q, 2H), 7.50 ( b, 2H); 7.60 (b, 2H); LC-MS: t / ζ CHIAD * 322 [MH] *.

Preparatory Example 149. 1- [4- (4-Chlorophenyl) -5- (methoxymethyl) -4H-1,2,4-triazol-3-yl] -2methylpiperazine.

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

Ή-NMR (400 MHz, COC1 ₃ ): δ 1.14 (b, 3H), 2.10 (bg, 1H), 2.60 (t, 1H), 2.82 (t, 2H), 2.97 (t, 1H), 3.07 ( t, 2H), 3.35 (q, 3H), 4.28 (b, 1H), 4.40 (b, 1H), 7.38 (b, 2H), 7.50 (b, 2H); LC-MS: t / ζ CHIAD * 322 [MH] ^* .

Preparatory Example 150. 1- [4- (4-Chlorophenyl) -5- (methoxymethyl) -4H-1,2,4-triazol-3-yl] -3methylpiperazine.

Trifluoroacetic acid (25 ml) was added to an ice-cooled solution of the compound of Preparation Example 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 dissolved in ethyl acetate, then washed with 1N. sodium hydroxide solution. 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 and gradient elution with dichloromethane: methanol: ammonia 0.88 (100: 0: 0 to 90: 10: 1) to give the title compound as an oil, 780 mg.

Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.19 (s, 3Н), 2.98 (t, 2Н), 3.02-3.23 (t, 5Н), 3.36 (8, 3Н), 4.34 (8, 2Н), 7.40 (st, 2H); 7.52 (s, 2H); LC-MS: t / ζ CHIAD ⁺ 322 [MH] ⁺ .

Preparatory Example 151. 4- [4- (4-Chloro-2-methylphenyl) -5-methyl-4H-1,2,4-triazol-3-yl] piperidine.

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) was stirred at room temperature to 110 ° C for 18 hours. The cooled mixture was concentrated under reduced pressure, a 2M sodium hydroxide solution (10 ml) was added, and the mixture was subjected to azeotropic distillation with toluene. The crude product was purified by silica gel column chromatography using dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5 to 80: 20: 3) to obtain the title compound as an off-white foam, 1.45 g .

Я-NMR (400 MHz, СО ₃ OD): δ 1.81 (t, 2Н), 1.92 (t, 2Н), 2.00 (8, 3Н), 2.19 (8. 3Н), 2.60-2.78 (t, 3Н), 3.20 (t, 2H), 7.38 (s, 1H), 7.46 (s, 1H), 7.59 (8, 1H); LC-MS: t / ζ CHIAD + 291 [MH] ⁺ .

Preparatory Example 152. 4- [4- (4-Chloro-2-fluorophenyl) -5-methyl-4H-1,2,4-triazol-3-yl] piperidine ditrifluoroacetate.

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 μl, 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 subjected to azeotropic distillation with toluene and the crude product was purified by silica gel column chromatography with gradient elution with dichloromethane: methanol: ammonia 0.88 (90: 10: 1 to 80: 20: 3) to obtain the title compound as an off-white foam 985 mg.

Ή-NMR (400 MHz, СОС1 ₃ ): δ 2.02-2.30 (t, 7Н), 2.80 (t, 1Н), 3.10 (t, 2Н), 3.59 (t, 2Н), 3.86 (t, 1Н), 7.26 (t, 1H), 7.40 (t, 2H), 9.34 (L8, 1H), 10.10 (L8, 1H); LC-MS: t / ζ CHIAD + 295 [MH] ⁺ .

Preparatory Example 153. 4- {4- (4-Chlorophenyl) -5 - [(2,2,2-trifluoroethoxy) methyl] -4H-1,2,4triazol-3-yl} piperidine.

Trifluoroacetic acid (2.49 g, 21.8 mmol) was added to a solution of 4-chloroaniline (3.63 g, 28.4 mmol) and the compound of Preparation 58 (8.0 g, 21.9 mmol) in toluene (50 ml), and this reaction mixture was heated under reflux for 48 hours. TLC analysis showed that the starting material remained, therefore, additional trifluoroacetic acid (8 ml) was added and this reaction mixture was heated for another 4 hours under reflux. Chilled mixture

- 58 010132 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 evaporated under reduced pressure. The crude product was purified by column chromatography using a silica gel cartridge and gradient elution with dichloromethane: methanol: ammonia 0.88 (100: 0: 0 to 85: 15: 1.5) to give the title compound. 4.34 g

Ή-NMR (400 MHz. COC1 ₃ ): δ 1.86-2.04 (t, 4H). 2.78 (t. 3H). 3.37 (t, 2H). 3.82 (f 2H). 4.22-4.41 (Lt 8. 1H). 4.58 (8. 2H). 7.22 (ά. 2H). 7.58 (ά. 2H); LC-MS: t / ζ ERI ⁴ 375.1 [MH] ⁴ .

Preparatory Example 154. 4- {4- (4-Chlorophenyl) -5 - [(trifluoromethoxy) methyl] -4H-1.2.4-triazol3-yl} piperidine.

Pyridine hydrofluoride (0.35 ml. 13.2 mmol) and then 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 (283 mg. 1.0 mmol) in dichloromethane (5 ml ) at -78 ° C. This reaction mixture was allowed to warm to room temperature over 30 minutes. then it was stirred for an additional hour. The mixture was washed with 1N. sodium hydroxide solution. dried over MgSO ₄ and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using dichloromethane: methanol: ammonia 0.88 (90: 10: 1) as an eluent to obtain the title compound as a yellow oil. 45 mg LC-MS: t / ζ CHIAD ⁴ 361 [MH] ⁴ .

Preparatory Example 155. 4- [4- (4-Chlorophenyl) -5-methyl-4H-1.2.4-triazol-3-yl] benzonitrile.

Trifluoroacetic acid (600 μl. 8.1 mmol) was added to a suspension of 4-chloroaniline (2.1 g. 16.2 mmol) and 4- (5-methyl-1.3.4-oxadiazol-2-yl) benzonitrile (1Oi1 &gt; RgacFsNe Sket1e 1994; 336 (8); 67885) (3.0 g. 16.2 mmol) in tetrahydrofuran (50 ml) and this reaction mixture was heated under reflux for 22 hours. The cooled mixture was partitioned between ethyl acetate (300 ml) and 20% aqueous ammonia 0.88 (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 minimum volume of ethyl acetate to give the title compound as a white crystalline solid. 2.82 g.

Ή-NMR (400 MHz. COC1 ₃ ): δ 2.38 (8.3H). 7.19 (ά. 2H). 7.55 (t, 4H). 7.60 (ά. 2H); LCMS: m / ζ ESI ⁴²⁹⁵ [M-H] ^4.

Preparatory Example 156. 4- [4- (4-Chlorophenyl) -5-methyl-4H-1.2.4-triazol-3-yl] benzoic acid.

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

Ή-NMR (400 MHz. CO ₃ OD): δ 2.38 (8.3 H). 7.19 (t. 4H). 7.58 (ά. 2H). 7.90 (ά. 2H); LC-MS: t / ζ ERI ^-

- 59 010132

312 [MH] ^- .

Preparatory Example 157. 4- [4- (4-Chlorophenyl) -5-methyl-4H-1,2,4-triazol-3-yl] benzoyl chloride.

Oxalyl chloride (3 ml, 32 mmol) and then Ν, Ν-dimethylformamide (5 drops) were added to the acid solution of Preparation 156 (2 g, 6.4 mmol) in dichloromethane (200 ml) and the mixture was stirred at room temperature for 2 h. The mixture was filtered, the filtrate was evaporated under reduced pressure, and the residue was subjected to azeotropic distillation with dichloromethane (3x200 ml) to obtain the title compound as an orange oil, 2.01 g.

Ή-NMR (400 MHz, SIS1 ₃ ): δ 2.78 (8, 3Н), 7.58 (b, 2Н), 7.63 (b, 2Н), 7.74 (t, 2Н), 8.06 (b, 2Н).

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

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

Ή-NMR (400 MHz, SI ₃ OD): δ 1.52-1.61 (t, 2Н), 1.81 (t, 2Н), 2.21 (8, 3Н), 2.40 (t, 1Н), 2.81 (t, 2Н), 3.21-3.36 (t, 2H), 7.47 (b, 2H), 7.62 (b, 2H).

Preparatory Example 159. 1- [4- (4-Chlorophenyl) -5- (2H-1,2,3-triazol-2-ylmethyl) -4H-1,2,4triazol-3-yl] piperidine-4-carboxylic acid.

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

Я-NMR (400 MHz, SI ₃ OD): δ 1.48-1.60 (t, 2H), 1.81 (t, 2H), 2.40 (t, 1H), 2.82 (t, 2H), 3.32 (t, 2H), 5.64 (8, 2H), 7.30 (b, 2H), 7.50 (b, 2H), 7.58 (8, 2H); LC-MS: t / ζ HILD '388 [MH] ⁺ .

Preparatory Example 160. 1- [4- (4-Chlorophenyl) -5-methyl-4H-1,2,4-triazol-3-yl] -4 methylpiperidin-4-carboxylic acid.

A mixture of the ether of Preparation 92 (1.45 g, 4.0 mmol) and 4N. a solution of sodium hydroxide (5 ml, 20 mmol) in dioxane (50 ml) was stirred under reflux for 16 hours. TLC analysis showed that the starting material remained, therefore, additional sodium hydroxide (4N, 5 ml, 20 mmol) was added. ) and heated this reaction mixture under reflux for

- 60 010132 for another 18 hours. The cooled mixture was partitioned between ethyl acetate and water and the layers were separated. The aqueous phase was acidified to pH 3.5 2N. hydrochloric acid and was extracted with ethyl acetate (2x). The combined organic extracts were dried over MgSO ₄ and evaporated under reduced pressure. The product was triturated with ethyl acetate. The resulting solid was filtered and dried to give the title compound as a white solid, 800 mg.

Ή-NMR (400 MHz, CO ₃ OD): δ 1.18 (s, 3H), 1.38 (t, 2H), 1.99 (t, 2H), 2.21 (s, 3H), 2.92 (t, 2H), 3.16 ( t, 2H), 7.49 (b, 2H), 7.63 (b, 2H). LC-MS: t / ζ CHIAD '335 [MH] ⁺ .

Preparatory Example 161. I- (4-Chlorophenyl) -2- (2H-1,2,3-triazol-2-ylacetyl) hydrazinecarbothioamide.

4-Chlorophenylisothiocyanate (8.58 g, 50.6 mmol) was added portionwise to a suspension of hydrazide of 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.

Ή-NMR (400 MHz, CO ₃ OD): δ 5.30 (s, 2H), 7.36 (b. 2H), 7.44 (b, 2H), 7.78 (s, 2H).

Preparatory Example 162. 4- (4-Chlorophenyl) -5- (2H-1,2,3-triazol-2-ylmethyl) -2,4-dihydro-3H1,2,4-triazol-3-thion.

A solution of the compound of Preparation 161 (14.5 g, 465 mmol) and a 2M solution of sodium hydroxide (232 ml, 465 mmol) in ethanol (36 ml) were stirred at 80 ° C for 18 hours. This cooled mixture was acidified to pH 9 s using concentrated hydrochloric acid, then was extracted with dichloromethane (6x250 ml). The combined organic solutions were evaporated under reduced pressure to obtain the title compound as a white solid, 7.5 g.

Ή-NMR (400 MHz, СОС1 ₃ ): δ 5.54 (s, 2H), 7.05 (b, 2H), 7.42 (b, 2H), 7.58 (s, 2H).

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

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

Ή-NMR (400 MHz, СОС1 ₃ ): δ 2.70 (s, 3H), 5.64 (s, 2H), 7.02 (b, 2H), 7.41 (b, 2H), 7.54 (s, 2H). LC-MS: t / ζ ERI ⁴ 329 [Mia] ⁺ .

Preparatory Example 164. 2 - {[4- (4-Chlorophenyl) -5- (methylsulfonyl) -4H-1,2,4-triazol-3yl] methyl} -2H-1,2,3-triazole.

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Metachloroperbenzoic acid (3.4 g, 19.56 mmol) was added to a solution of compound of Preparation 163 (1.5 g, 4.90 mmol) in dichloromethane (60 ml) and this reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane, then washed with saturated sodium bicarbonate solution (300 ml) and brine (200 ml). The organic solution was dried over Να ₂ 8Ο. ₄ and concentrated under reduced pressure. The remaining solid was washed with ethanol, then dried in vacuo to give the title compound as a white solid, 1.40 g.

Ή-NMR (400 MHz, C1) C1 _; ): δ 3.46 (δ, 3Η), 5.69 (δ, 2H), 7.18 (b, 2Η), 7.41 (b, 2H), 7.57 (δ, 2Η); LC-MS: t / ζ ERI * 361 | M # 1 | '.

Preparatory Example 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 the addition was complete, this reaction mixture was stirred in for one hour. The mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and this solution was washed with water (x2), then brine. The solution was dried over Μд8Ο. · Ι and evaporated under reduced pressure to obtain the title compound as a solid, 3.45 g.

Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.49 (ΐ, 3Η), 4.19 (φ 2Η), 7.00 (b, 1Η), 7.05 (δ, 1Н), 7.81 (b, 1Η). Preparatory Example 166. 4-Chloro-2-ethoxyaniline.

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 mg, 7.4 mmol) in water (5 ml) and ethanol (30 ml) was heated under reflux for 3.5 hours. The cooled mixture was filtered through Ce1Pe® 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. This solution was dried over Μд8Ο ₄ and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography with gradient elution with pentane: ethyl acetate (100: 0 to 0: 100) to give the title compound as an oil, 2.4 g.

Ή-NMR (400 MHz, SIS): δ 1.42 (ΐ, 3Η), 402 (φ 2Η), 6.61 (b, 1Η), 6.76 (t, 2H).

Preparatory Example 167. 1- (5-Chloro-2-nitrobenzyl) pyrrolidine.

Pyrrolidine (4 ml, 48.5 mmol) was added to a solution of 5-chloro-2-nitrobenzaldehyde (6 g, 32.2 mmol) in dichloromethane (150 ml) and the solution was stirred at room temperature for 30 minutes. This solution was then cooled with ice and sodium triacetoxyborohydride (10.3 g, 48.5 mmol) was added portionwise. Upon completion of the addition, this reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with sodium carbonate solution, dried over Μd8Μ ₄ and evaporated under reduced pressure. The remaining oil was purified by silica gel column chromatography using ethyl acetate: pentane (86:14) to obtain the title compound as a pale yellow solid, 6.3 g.

- 62 010132

Ή-NMR (400 MHz, COC1 ₃ ): δ 1.82 (t, 4H), 2.58 (t, 2H), 3.98 (q, 2H), 7.37 (b, 1H), 7.80 (q, 1H), 7.87 (b) , 1H). LC-MS: t / ζ CHIAD * 241 [MH] *.

Preparatory Example 168. 4-Chloro-2- (pyrrolidin-1-ylmethyl) aniline.

A mixture of the compound of Preparation 167 (6.2 g, 25.8 mmol) and Kapeu® nickel (400 mg) in ethanol (200 ml) was hydrogenated at a pressure of 40 psi. inch (276 kPa) and at room temperature for 2 hours. The mixture was filtered through Arbose1® and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography with gradient elution with dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5 to 90: 10: 1) to obtain the title compound as a solid, 3.95 g.

Ή-NMR (400 MHz, COC1 ₃ ): δ 1.78 (t, 4H), 2.48 (t, 2H), 3.59 (q, 2H), 4.65-4.90 (bg, 2H), 6.56 (b, 1H), 6.98 (q, 1H), 7.00 (b, 1H). LC-MS: t / ζ CHIAD * 211 [MH] *.

Preparatory Example 169. 4 - {[4- (4-Chlorophenyl) -5-piperidin-4-yl-4H-1,2,4-triazol-3yl] methyl} morpholine.

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

LC-MS: t / ζ CHIAD * 362 [MH] *.

Preparatory Example 170. Tert-Butyl-4 - {[2- (2H-1,2,3-triazol-2-yl-acetyl) hydrazino] carbonyl} piperidine-1-carboxylate.

A suspension of Вос-Boc-isonipecotic acid (30.0 g, 130.8 mmol) and hydrazide of Preparation 18 (18.5 g, 130.8 mmol) in dichloromethane (150 ml) were cooled in an Ν ₂ ice bath. 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (25.6 g, 133.5 mmol) was added through a funnel and the funnel was washed with additional dichloromethane (10 ml). The resulting solution was heated to ambient temperature. After the reaction was completed, isopropanol (150 ml) was added and the homogeneous solution was concentrated in vacuo to approximately 165 ml, heated to approximately 70 ° C and allowed to cool to ambient temperature with stirring. The resulting thick white suspension was filtered in vacuo, washed with isopropanol (15 ml and 30 ml) and dried in vacuo at 50 ° C to give the title compound as a white solid, 25.3 g (55%). The filtrates from the filtration were concentrated under reduced pressure to a small volume, the resulting syrup was treated with water (50 ml) and stirred vigorously to obtain a thick suspension within 2 minutes. After granulating overnight, this suspension was filtered (quick filtration), the residue was washed with water (2x10 ml) and dried in vacuo at 50 ° C to give an additional amount of product, 8.5 g (18%).

Ή-NMR (SPS1 ₃ ) δ: 1.42 (q, 9H), 1.50-1.85 (t, 4H), 2.41 (t, 1H), 2.73 (ΐ, 2H), 4.12 (b, 2H), 5.21 (q, 2H), 7.70 (q, 2H), 9.15 (b, 1H), 9.75 (b, 1H).

Examples 1-162.

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The compounds of examples 1-162, illustrated below, were synthesized as a library. The following solutions were used:

carboxylic acid, 2CO ₂ N, was dissolved in dimethylacetamide (^ ΜΑ) (anhydrous) plus 3.75% triethylamine in a 0.2 M concentration;

the amine of Preparation 2 was dissolved in ^ ΜΑ (anhydrous) plus 3.75% triethylamine in a 0.2 M concentration;

NVTI was dissolved in ^ ΜΑ (anhydrous) in 0.2 M concentration.

(Ν.Ε. If necessary, to dissolve the monomers, soft sonication was used in a warm water bath (temperature below 40 ° C).

The experimental technique.

The reaction scale was from 20 to 30 μmol per well (the details of the experiments are shown for a 20 μmol reaction; the scale can be set accordingly within this range). Reactions were carried out in a polypropylene 96-well plate.

a) Amine solutions (0.1 ml, 20 μmol, 1 equiv.) were added to the wells.

b) Carboxylic acid solutions (0.15 ml, 30 μmol, 1.5 equiv.) were added to the wells.

c) An NVTI solution (0.15 ml, 30 μmol, 1.5 equiv.) was added to each well.

d) A 96-well polypropylene plate was sealed with a PTT (polytetrafluoroethylene, teflon) gasket and rubber and clamped between a pair of metal plates.

d) The tablet was heated in a thermostat for 6 hours at 60 ° C and then left to cool in a thermostat overnight.

f) The cooled plate was disconnected from the plate and placed in Sieuuas to remove the solvent.

g) Samples were dissolved in ^ Μ§O / water (9: 1) (500 μl), and all solid particles were removed by filtration.

h) Purification was carried out by reverse phase HPLC.

HPLC purification conditions.

Column: Ryeyoteeeh Liia C18, 10 microns, 150x 10 mm east (inner diameter).

Temperature: ambient temperature.

Eluent A: 0.05% diethylamine in water.

Eluent B: acetonitrile.

Samples were dissolved in 90% dimethyl sulfoxide in water.

Samples were added using a Sykoi automatic pipette in an injection volume of 550 μl.

Initial conditions for the Sykoi LC pump:

Solvents

A% 80.0

B% 20.0

Flow (ml / min) 8,000

Gradient timeline graph for Sykoi LC pump

Time BUT% B% Flow (ml / min) 0.00 80.0 20,0 8,000 0.20 80.0 20,0 8,000 7.00 5,0 95.0 8,000 9.00 5,0 95.0 8,000 9.10 80.0 20,0 8,000 10.50 80.0 20,0 8,000

Monitoring by the Sykoi 119 UV detector at 254 nm: The collector is set to 225 nm.

Double sensitivity 200.

Peak Sensitivity 80.

Peak Width 0.3 min.

HPLC conditions and mass spectrometer details:

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Column: Rielot-uleh Beela C18.5 microns. 30x4.6 mm east

Eluent A: 0.05% diethylamine in water.

Eluent B: Acetonitrile.

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

Sample injection using 6ί18οη Οιιηά Ζ with an injection volume of 5 μl. Initial conditions for a binary LC pump \ ν; · ιΕΓ8 1525:

Solvents:

A% 95.0

B% 5.0

Flow (ml / min)

Temperature (° C)

2.5 (per channel) ambient temperature

LC gradient timeline graph

Time

0.00

3.00

3,50

BUT%

B%

95.0

5,0

95.0

Flow (ml / min)

2,500

2,500

2,500

Total lead time: 4.50 min

Detection:

Two-wave detector \ ν; · ιΕΓ8 2488.

UV1 (nm) 225.

UV2 (nm) 225. and

HER (euarot! 1ue 11db! -8sa! 1gtd Be! Es! ^ Οη. Detection of light scattering upon evaporation): Ролутета8; temperature: 75 ° C; gas flow: 1.2 bar (120 kPa)

Mass spectrometer:

Va! E ^ 8 ΖΟ 2000 4 \ tau ΜυX.

ERI ⁴ Voltage on the cone: 26 V. Capillary: 3.85 kV.

ERI ^- Voltage on the cone: 30 V. Capillary: -3.00 kV.

Desolvation gas: 800 l / min.

Source temperature: 300 ° C.

Scan Range: 160-1000 Yes.

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Example No. Ζ Product ion mass detected HPLC retention time (minutes) one 2-methoxy-pyridin-3-yl 412.15 1.55 2 3-trifluoromethylphenyl 449.13 2 3 2-methoxy-phenyl 411.15 1.35 4 2-methanesulfonyl-phenyl 459.12 1,6 5 3-methanesulfonyl-phenyl 459.12 1.55 6 phenyl 381.14 1.72 7 3-methoxy-phenyl 411.15 1,67 8 4-fluoro-phenyl 399.13 1.74 nine 2-chloro-phenyl 415.1 1.8 10 4-chloro-phenyl 415.1 1.92 eleven 4-methanesulfonyl-phenyl 459.12 1.49 12 2,4-dichloro-phenyl 449.06 1.99 thirteen 3,4-dichloro-phenyl 449.06 2.04 14 2,5-dichloro-phenyl 449.06 1.99 fifteen 4-ethoxy-phenyl silt 425.17 1.77 sixteen 4-methylsulfanyl-phenyl 427.13 1.85 17 4-chloro-2-methoxy-phenyl 445.11 1.89 eighteen 2 is xi-hair silt 425.17 1.84 nineteen isoquinolin-1-yl 432.15 1,6 twenty 2,6-dimethyl-phenyl 409.17 1.82 21 quinolin-2-yl 432.15 1.74 22 QUINOLIN-4-IL 432.15 1,6 23 QUINOLIN-Z-IL 432.15 1,57 24 2-chloro-6-fluoro-phenyl silt 433.09 1,54 25 2,3-dichloro-phenyl 449.06 . 1.95 26 2,5-difluoro-phenyl 417.12 1.82 27 2,5-di methoxyphenyl 441.16 1.55 28 2,3-difluoro-phenyl 417.12 1.8 29th 2,4-difluoro-phenyl 417.12 1.8 thirty 3,4-difluoro-phenyl 417.12 1.85 31 4-isopropyl-phenyl 423.19 2 32 6-methyl-pyridin-3-yl 396.15 1.45

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33 4-fluoro-naphthalene-1 -yl 449.15 2 34 3,5-difluoro-phenyl 417.12 1.87 35 3-aminosulfonyl-4-chloro-phenyl 494.07 1.5 36 1 H-benzimidazol-5-yl 421.15 1.37 37 2-chloro-4-fluoro-phenyl 433.09 1.85 36 4-trifluoromethoxy-phenyl 465.12 2.07 39 1 I-benzotriazol-5-yl 422.14 1.34 40 4-methoxy-quinolin-2-yl 462.16 1.82 41 2-fluoro-4-trifluoromethyl-phenyl 467.12 2.04 42 2,3,6-trifluoro-phenyl 435.11 1.87 43 2-methyl-pyridin-3-yl 396.15 1.32 44 2,4,5-trifluoro-phenyl 435.11 1.85 45 4-propyl-phenyl 423.19 2.15 46 2-fluoro-3-trifluoromethyl-phenyl 467.12 1.92 47 3-fluoro-2-methyl-phenyl 413.15 1.82 48 2,4-dichloro-5-fluoro-phenyl 467.05 2.05 49 3-fluoro-4-methoxy-phenyl 429.14 1.8 fifty 4-isopropoxy-phenyl 439.18 1.89 51 4-propoxy-phenyl 439.18 2.02 52 3-chloro-4-fluoro-phenyl 433.09 1.95 53 2,6-dimethoxy-pyridin-3-yl 442.16 1.7 54 2-fluoro-5-methyl-phenyl 413.15 1.85 55 Z-fluoro-5-three fluoromethyl-fe n and l 467.12 2.09 56 4-difluoromethoxy-phenyl 447.13 1.79 57 biphenyl-2-yl 457.17 2.02 58 4-aminosulfonyl-phenyl 460.11 1.45 59 3-chloro-phenyl 415.1 1.9 60 4-cyano-phenyl 406.14 1,6 61 2,3-di methoxy-phenyl 441.16 1.68 62 2,6-dimethoxy-phenyl 441.16 1.68 63 3,5-dimethoxy-phenyl 441.16 1.82 64 3-fluoro-4-methyl-phenyl 413.15 1.8

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65 3-fluoro-phenyl 399.13 1.75 66 3-methoxy-4-methyl-phenyl 425.17 1.9 67 Naphthalene-1-yl 431.16 1.95 68 pyridin-3-yl 382.14 1.3 69 pyridin-2-yl 382.14 1.42 70 6-methyl-pyridin-2-yl 396.15 1,52 71 M’TOLIL 395.16 1.85 72 / 7-yl silt 395.16 1.74 73 4-fluoro-3-methoxy-phenyl 429.14 1.79 74 3-chloro-4-methyl-phenyl 429.12 2 75 5-chloro-2-methyl-phenyl 429.12 1.97 76 3-chloro-2,6-dimethoxy-phenyl 475.12 1.82 77 3-chloro-2-fluoro-phenyl 433.09 1.89 78 2-phenoxy-pyridin-3-yl 474.16 1.82 79 2-trifluoromethoxy-phenyl 465.12 1.99 80 3-ethoxy-phenyl 425.17 1.79 81 3-chloro-4-methoxy-phenyl 445.11 1.85 82 3,5-dimethoxy-4-methyl-phenyl 455.18 1.99 83 4-chloro-3-methyl-phenyl 429.12 2.05 84 2-chloro-3,4-dimethoxy-phenyl 475.12 1.72 85 3-cyclopentyloxy-4-methoxy-phenyl 495.21 2 86 4-methoxy-3-propoxy-phenyl 469.19 1.89 87 3-isopropoxy-4-methoxy-phenyl 469.19 1.85 88 3-butoxy-4-methoxy-phenyl 483.21 1.95 89 4-trifluoromethyl-pyridin-3-yl 450.12 . 1.65 90 6- (2,2,2-trifluoroethoxy) -pyridin-3-yl 480.13 1.95 91 2- (4-fluoro-phenoxy) -pyridin-3-yl 492.15 1.9 92 2-chloro-3-trifluoromethyl-phenyl 483.09 1.97 93 2-difluoromethoxy-phenyl 447.13 1.82 94 3-difluoromethoxy-phenyl 447.13 1.89 95 6-trifluoromethyl-pyridin-3-yl 450.12 1.84 96 2-methyl- [1,8] naphthyridin-3-yl 447.16 1.32

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97 2-methyl- [1,6] naphthyridin-3-yl 447.16 1.42 98 2,3-dihydro-benzofuran-7-ip 423.15 1,57 99 2-chloro-3-methyl-phenyl 429.12 1.92 one hundred 4-methoxy-3-methyl-phenyl 425.17 1.92 101 2-ethoxy-pyridin-3-yl 426.16 1,6 102 2-ethoxy-naphthalen-1-yl 475.18 2.02 103 3- (dimethylamino) sulfonyl-phenyl 488.14 1.72 104 2-propoxy-pyridin-3-yl 440.18 1.84 105 2- (4-chlorophenoxy) pyridin-3-yl 508.12 1.93 106 2-methyl-1 H-benzimidazol-5-yl 435.16 1.4 107 6-hydroxy-pyridin-2-yl 398.13 1.32 108 2- (5-methyl- [1,2,4] oxadiazol-3-yl) - pyridin-4-yl 464.15 1.45 109 4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl 463.16 1,67 110 4- (5-ethyl- [1,2,4) oxadiazol-3-yl) - Articulated 477.17 1.92 111 3- (5-methyl- [1,2,4] oxadiazol-3-yl) - phenyl 463.16 1.68 112 3- (5-ethyl- [1,2,4] oxadiazol-3-yl) phenyl 477.17 1.9 113 2-hydroxy-liridin-4-yl 398.13 1.25 114 2-benzyl phenyl 471.19 2.17 115 3,5-dichloro-feni l 449.06 2 116 3-chloro-2-methyl-phenyl 429.12 1.93 117 2,3-dihydro-benzofuran-5-yl 423.15 1.74 118 2- (3-methyl- [1,2,4] oxadiazol-5-yl) - pyridin-4-yl 464.15 1.49 119 3-hydroxy-2-methyl-phenyl 411.15 1,54 120 2-fluoro-5-trifluoromethyl-phenyl 467.12 2.02 121 4-methoxy-2-methyl-phenyl 425.17 1.82 122 3-methoxy-2-methyl-phenyl 425.17 1.82 123 2-hydroxy-5-methyl-phenyl 411.15 1.68

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124 3,5-dichloro-4-hydroxy-phenyl 465.06 1.57 125 2-hydroxy-3-isopropyl-phenyl 439.18 2.93 126 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 1.77 131 3,4-dimethoxy-2-methyl-phenyl 455.18 1.79 132 6- (acetylamino) -pyridin-3-yl 439.16 1.35 133 2,6-dimethoxy-4-methyl-phenyl 455.18 1.8 134 2-benzyloxy-phenyl 487.18 2.07 135 6-methoxy-quinolin-2-yl 462.16 1.82 136 quinoxaline-6-yl 433.15 1.42 137 1,2-dimethyl-1H-benzimidazol-5-yl 449.18 1.49 138 1 H-indol-5-yl 420.15 1.7 139 2- (3,5-dimethyl-1H-pyrazol-4-yl) -5- methoxy phenyl 505.2 1,6 140 8-methyl-2-oxo-1,2-dihydroquinolin-6- silt 462.16 1.45 141 3-aminosulfonyl-phenyl 460.11 1,5 142 4- (3-methyl-6-oxo-3-liperidinyl) phenyl 492.21 1,54 143 2- (2-methoxy-ethoxy) phenyl 455.18 1,62 144 2-hydroxy-4-methyl-phenyl 411.15 1.68 145 3-chloro-4-hydroxy-phenyl 431.1 1,64 146 3-hydroxy-4-methyl-phenyl 411.15 1.75 147 3-methoxy-5- (methylsulfonyl) aminophenyl 504.14 1,57 148 2 - {[(2,2- dimethylpropyl) amino] carbonyl} phenyl 494.22 1.85 149 5-acetyl-2-ethoxypyridin-3-yl 468.17 1.7 150 2- (2-methoxy-ethoxy) -pyridin-3-yl 456.17 1,62 151 Isoquinolin-4-yl 432.15 1,52 152 2-ethoxy-3-methoxy-phenyl 455.18 1.8 153 4 - [(1 I) -1 - (acetylamino) ethyl] phenyl 466.19 1.47 154 4-pyrimidin-4-yl-phenyl 459.16 1,6 155 3-methyl-2-propoxy-phenyl 453.2 2 156 4-ethoxy-pyridin-3-yl 426.16 1,5 157 2-chloro-4-methylsulfonyl aminophenyl 508.09 1,64 158 2-ethoxy-5-methanesulfonyl-phenyl 503.14 1.68 159 4-hydroxy-2- (2,2,2-trifluoro-ethoxy) phenyl 495.13 1.65 160 4-hydroxy-2-methoxy-phenyl 427.15 1,52 161 4-cyano-pyridin-2-yl 407.13 1.55 162 2-pyridin-4-yl-ZN-benzimidazol-5-yl 498.17 1,5

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Example 163. (3-Chlorophenyl) - {4- [4- (4-chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3yl] piperidine -1-yl} methanone.

A mixture of the compound of Preparation 10 (202 mg, 0.54 mmol), 4-chloroaniline (140 mg, 1.1 mmol) and trifluoroacetic acid (42 μl, 0.54 mmol) in toluene (2 ml) was heated at 170 ° C. for 20 minutes under the influence of microwave radiation. The cooled mixture was diluted with ethyl acetate, washed with 1N. a solution of sodium hydroxide and brine, then dried over No. ₂ 8O ₄ and concentrated under reduced pressure. The product was purified by silica gel column chromatography using dichloromethane: methanol: ammonia 0.88 (100: 0: 0 to 90: 10: 1) to obtain the title compound (234 mg).

Я-NMR (400 MHz, SOzOO): δ 1.80-1.97 (t. 4H), 2.86 (t, 2H), 3.08 (t, 1H), 3.70 (t, 1H), 4.58 (t, 1H), 5.72 ( 8, 2H), 7.26 (t, 2H), 7.32 (t, 1H), 7.41-7.54 (t, 5H), 7.59 (8, 2H).

MCHR: t / ζ (HIAD ⁴ ) 482 [MH] ⁺ .

Example 164. (4-Chlorophenyl) - {4- [4- (4-chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3yl] piperidine -1-yl} methanone.

4-Chlorobenzoyl chloride (49 μl, 0.38 mmol) was added to a mixture of compound of Preparation 12a (120 mg, 0.35 mmol) and Ν-methylmorpholine (77 μl, 0.70 mmol) in dichloromethane (2 ml), then this the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane, washed with 1N. with sodium hydroxide solution and the aqueous wash liquid was back-extracted with dichloromethane. The combined organic solutions were evaporated under reduced pressure to give an oil. It was purified by silica gel column chromatography using dichloromethane: methanol: ammonia 0.88 (90: 10: 1) to give the title compound as a white solid (160 mg).

Ή-NMR (400 MHz, 1) \ 18О-с1 ₆ ): δ 1.60-1.82 (t, 4H), 2.70-3.04 (t, 3H), 3.54 (t, 1H), 4.33 (t, 1H), 5.66 (8, 2H), 7.34 (b, 2H), 7.39 (b, 2H), 7.48 (b, 2H), 7.57 (b, 2H), 7.64 (8, 2H).

MCHR: t / ζ (HIAD ⁴ ) 482 [MH] ⁴ .

Example 165a. {4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] piperidin-1-

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

Ή-NMR (400 MHz, CO ₃ OD): δ 1.80-1.98 (t, 4H), 2.84 (t, 2H), 3.09 (t, 1H), 3.65 (t, 1H), 4.58 (t, 1H), 5.72 (8, 2H), 7.05 (t, 3H), 7.24 (t, 2H), 7.57 (b, 2H), 7, 59 (8, 2H).

MCHR: t / ζ (HIAD ⁴ ) 484 [MH] ⁴ .

Example 165b. {4- [4- (4-Chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] piperidin-1yl} - (3, 5-difluorophenyl) methanone.

Triethylamine (3.2 ml, 23.0 mmol) was added to a suspension of the bis salt of Preparation 12b (4.89 g, 7.12 mmol) in dichloromethane (25 ml) to give a pale yellow solution. This solution was cooled in an ice bath and then 3,5-difluorobenzoyl chloride (0.95 ml, 8.09 mmol) was added. This reaction mixture was stirred for 30 minutes and then water (20 ml) was added. After stirring still in

- 71 010132, the phases were separated for 20 min and the organic phase was washed successively with aqueous citric acid, water, aqueous sodium bicarbonate and semi-saturated brine. The clear dichloromethane solution was then dried over magnesium sulfate and concentrated to give a white foam. Recrystallization from ethyl acetate gave the title compound as a white solid (2.69 g), identical to the material obtained as described in Example 165a.

Examples 166-167.

The corresponding acid chloride (1.2 equiv.) Was added to a solution of the amine of Preparation 2 (1 equiv.) And и-methylmorpholine (1.5 equiv.) In dichloromethane (5.5 ml-mmol ^-1 ) and this 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 solution of ammonium chloride was added, then the mixture was stirred for 20 minutes and the layers were separated using a hydrophobic membrane. The organic phase was washed with saturated sodium bicarbonate solution, the layers were separated, and the organic solution was evaporated under reduced pressure to obtain the indicated compounds.

Example No. Ζ Exit (%) Data 166 Neopentyl 39 Ή-NMR (400 MHz, CuCl3): δ 1.00 (5, 9H), 1.71 (t, 2H), 1.82 (t, 1H), 1.98 (t, 1H). 2.20 (5, 2H), 2.24 (5, 3H), 2.57 (t, 1H), 2.65 (t, 1H), 3.00 (t, 1H), 3.98 (t, 1H), 4.57 (t, 1H), 7.20 (th, 2H), 7.57 (th, 2H). LC-MS: t / ζ CHIAD + 375 [MH] +. 167 Cyclopropyl 39 Ή-NMR (400 MHz, СОС1 ₃ ): б 0.73 (t, 2Н), 0.94 (t, 2Н), 1.70 (t, ЗН), 1.88 (t, 1Н), 2.02 (t, 1Н), 2.22 ($ , ZN), 2.58-2.75 (t, 2H), 3.08 (t, 1H), 4.23 (t, 1H), 4.44 (t, 1H), 7.20 (6, 2H), 7.58 (d, 2H). LC-MS: t / ζ CHIAD * 347 [MH] *

Examples 168-173.

A mixture of the corresponding amine or amine salt selected from the compounds of Preparations 12a, 100, 118, 119, 143 and 152 (1 eq.), The corresponding acid chloride (^ -PyCOС1) (1.2 to 1.4 eq. ) and Ν-ethyldiisopropylamine (4 equiv.) in dichloromethane (16 ml-mmol ^-1 ) was stirred at room temperature for 2 hours. Tris- (2-aminoethyl) amine polystyrene was then added and the mixture was stirred for one more hour. Then the mixture was washed with 1N. sodium hydroxide solution, the aqueous solution was extracted with dichloromethane (2x) and the combined organic solutions were concentrated under reduced pressure. The crude products were purified by silica gel column chromatography using ethyl acetate: methanol: ammonia 0.88 (90: 10: 1) as an eluent to obtain the indicated compounds.

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Example No. Data 168 νν = 3-E, 4-CH3; Υ = 4-C1; Υ '= 2-C1; X = CH, Ή-NMR (400 MHz, SES1 ₃ ): δ 1.77-1.99 (t, 4H), 2.19 (e, 3H), 2.26 (s, 3H), 2.59 (t, 1H), 2.84-3.02 ( t, 2H), 3.83 (t, 1H), 4.55 (t, 1H), 7.02 (t, 2H), 7.18-7.28 (t, 2H), 7.48 (t, 1H), 7.66 (s, 1H). LC-MS: t / ζ CHIAD * 447 [M№] * 169 * νν = 3-P, 4-CH ₃ ; Υ = 4-C1; Υ * = 2-E; X = CH ₃ Ή-NMR (400 MHz, С0С1з): δ 1.75-2.00 (t, 4H), 2.24 (t, 6H), 2.63 (t, 1H), 2.92 (t, 2H), 3.81 (t, 1H ), 4.56 (t, 1H), 7.02 (t, 2H), 7.19 (t, 1H), 7.40 (t, 3H). LC-MS: t / ζ CHIAD * 431 [MH] * 170 νν = 3,5-di-C1; Υ = 4-C1; Υ '= 2-OCH ₃ ; X = CH ₃ Ή-NMR (400 MHz, СО ₃ СУ): δ 1.70-2.00 (t, 4Н), 2.17 (s, ЗН), 2.72-2.92 (t, 2Н), 3.1 (t. 1Н), 3.62 (t, 1H); 3.84 (t, 3H). 4.56 (t, 1H), 7.20 (t, | 1H), 7.39 (t, 4H), 7.58 (e, 1H). LC-MS: t / ζ HIAD * 480 [MN] * 171 ^A νν = 2-E, 3-C1; Υ = 4-C1; Υ '= Η; X = CH ₂ OCH ₂ CH ₃ Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.08 (ί, ЗН), 1.64-1.81 (t, 2Н), 1.84-2.01 (t, 2Н), 2.79 (t, 1Н ), 2.85-3.17 (t, 2H), 3.41 (ς, 2H), 3.62 (t, 1H), 4.41 (3, 2H), 4.62 (t. 1H), 7.17 (t, 1H), 7.23 (t. ZN), 7.43 (t, 1H), 7.58 (ά, 2H). LC-MS: t / ζ HIAD * 477 [M] * 17? νν = 4-C |; Υ = 4-C1; Υ '= Η; X = CH _g CE ₃ Ή-NMR (400 MHz, C0Cl1): δ 1.81 (t, 2H), 1.98 (t, 2H). 2.70 (t, 1H). 2.80-3.02 (t, 2H), 3.44 (η, 2H), 3.81 (t, 1H), 4.59 (t, 1H), 7.19 (ά, 2H), 7.38 (t, 4H), 7.60 (b, 2H) . LC-MS: t / ζ CHIAD * 483 [M] * 173 ^e νν = 2-OCE ₃ ; Υ = 4-C1; Υ '= Η; X = [1,2,3] -triazol-2-ylmethyl Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.76 (t, 1Н), 1.79-2.02 (t, ЗН), 2.68 (t, 1Н), 2.82-3.02 (t, 2H), 3.58 (t, 1H), 4.59 (t, 1H), 5.62 (s, 2H), 6.99 (t, 2H), 7.22-7.42 (t, 6H), 7.50 (s, 2H). LC-MS: t / ζ CHIAD * 532 [MH] *

A = used 4 equiv. triethylamine and the crude product were not treated with an amine supported on the polymer.

B = instead of Ν-ethyldiisopropylamine, 10 equiv. Ν-ethyldiisopropylamine deposited on the polymer.

Examples 174-187.

The corresponding acid chloride (\ U-P11COС1) (1.0-1.5 equiv.) Was added to a solution of the corresponding amine or amine hydrochloride selected from the compounds of Preparations 120-121, 132, 134-135, 137, 139-142, 151 , 153-154 and 169 (1 equiv.) And triethylamine (1.2 to 5 equiv.) In dichloromethane (from 10 to 25 ml-mmol ^-1 ). This reaction mixture was stirred at room temperature for 18 hours. Then

- 73 010132 the mixture was diluted with dichloromethane. washed with saturated sodium carbonate solution and then with ammonium chloride solution and then concentrated under reduced pressure. The crude products were purified by silica gel column chromatography using dichloromethane: methanol (100: 0 to 90:10) as an eluent to obtain the indicated compounds.

Example No. Data 174 ^A And / = 3-C1; Υ = 4-C1; V = 2-CH ₃ ; X = CH ₃ Ή-NMR (400 MHz, COS): δ 1.65-2.02 (t, 7H), 2.18 (5, 3H), 2.55 (t, 1H), 2.78-3.01 (t, 2H), 3.79 (t . 1H), 4.58 (t, 1H), 7.03 (t, 1H), 7.207.39 (t, 5H), 7.41 (s, 1H). LC-MS: t / ζ HIAD * 451 [Mia] * 175 ^e νν = 3,5-di-C1; Υ = 4-C1; Υ '= Η; X = CH ₂ OCH ₃ Ή-NMR (400 MHz, СО ₃ ОО): δ 1.81-1.98 (t, 4H), 2.86 (t, 2H), 3.12 (t, 1H), 3.20 (s, 3H), 3.64 (t, 1H), 4.38 (s, 2H), 4.58 (t, 1H), 7.40 (s, 2H), 7.46 (8, 2H), 7.58 (s, 1H), 7.62 (ά, 2H). LC-MS: t / ζ CHIAD * 479.481 [MH] * 176 ³ νν = 4-C1; Υ = 4-C1; Υ '= Η; X = CH ₂ OCP ₃ Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.81 (t, 2Н), 1.98 (t, 2Н), 2.78 (t, 1Н), 2.96 (t, 2Н), 3.75-3.90 ( t, 1H), 4.40-4.60 (t, 1H), 4.97 (s, 2H), 7.21 (t, 2H), 7.37 (t, 4H), 7.59 (8, 2H). LC-MS: t / ζ CHIAD * 499 [M] * _177b ........ νν = 3,5-di-P; Υ = 4-C1; Υ '= Η; X = CH ₂ OCH ₂ СР ₃ Я-NMR (400 MHz, СОС1з): δ 1.80-2.02 (t, 4Н), 2.79 (t, 1Н), 2.83-3.05 (t, 2Н), 3.80 (t, ЗН) 4.58 (t, 3H), 6.85 (t, 3H), 7.22 (8, 2H), 7.57 (8, 2H). LC-MS: t / ζ HIAD * 515 [MN] * 178 νν = 3-C1; Υ = 4-C1; Υ ’= Η; X = (2-oxopyrrolidin-1-yl) methyl Ή-NMR (400 MHz, СОС! З): δ 1.78-2.00 (t, 6Н), 2.22 (ί, 2Н), 2.75 (t, 1H), 2.97 (t, 2H), 3.48 (ί, 2H), 3.80 (t, 1H), 4.42 ($, 2H), 4.58 (t. 1H),

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7.00 (ά, 2H), 7.23 (ά, 1H), 7.38 (t, 3H), 7.58 (ά, 2H). LC-MS: t / ζ CHIAD * 499, 501 [MH] * 179 ^th YU = 3,5-di-C1; Υ = 4-C1; Υ '= Η; X = morpholin-4-ylmethyl ¹ H-NMR (400 MHz, СОС1з): δ 1.78-2.02 (t, 4H), 2.40 (t, 4H), 2.78 (gp, 1H), 2.78-3.04 (t, 2H) 3.41 (s, 2H), 3.58 (t, 4H), 3.78 (t, 1H), 4.58 (t, 1H), 7.23 (t, 5H), 7.56 (ά, 2H). LC-MS: t / ζ CHIAD * 534 [M] * 180 YU = 3-E; Υ = 4-C1; Υ ’= Η; X = ’H-tetrazol-D-ylmethyl 'H-NMR (400 MHz, SOC! S): δ 1.60-1.83 (t, 4H), 2.60-2.78 (t, 2H), 3.00 (t, 1H), 3.90 (t, 1H), 4.50 (t, 1H), 5.58 (s, 2H), 6.98 (t, 2H), 7.50 (t, 2H), 7.29 (t, 1H), 7.60 (ά, 2H), 8.79 (s, 1H). LC-MS: t / ζ ERI * 481.483 [MH] * 181 YU = 3-C1; Υ = 4-C1; Υ '= Η; X = 2-methylimidazo-3-ylmethyl ¹ H-NMR (400 MHz, COC1z). δ 1.77-1.83 (t, 2H), 1.89-2.00 (t, 2H), 2.14 (s, 3H), 2.64 (t, 2H), 2.94 (t, 1H), 3.82 (t, 1H), 4.58 (t , 1H), 5.08 (s, 2H), 6.60 (s, 1H), 6.96 (t, 3H), 7.24 (t, 1H), 7.32-7.40 (t, 3H), 7.58 (6, from b.4 1 LC-MS: t / ζ Chiad ⁺ 495, 497 [MH] * 182 YU = 3-C1; Υ = 4-C1; Υ '= Η; X = 3-methyl- [1,2,4] oxadiazol-5-ylmethyl 'H-NMR (400 MHz, COC! S): δ 1.80 (t, 2H), 1.98 (t, 2H), 2.30 (s, ZN) 2.76 (t, 1H), 2.95 (t, 2H), 3.80 (t, 1H), 4.22 (s, 2H), 4.58 (t, 1H), 7.19 (ά, 2H), 7.24 (b, 1H), 7.37 (t, 3H), 7.52 (ά, 2H). LC-MS: t / ζ HIAD * 497, 499 [MN] * 183 YU = 3,5-di-E; Υ = 4-C1; Υ '= Η; X = [1,2,4] -triazol-1-ylmethyl ¹ H-NMR (400 MHz, С0С1з): δ 1.82 (t, 2H), 2.00 (t, 2H), 2.75 (t, 1H), 2.80- 3.08 (t, 2H), 3.80 (t, 1H), 4.58 (t, 1H), 5.40 (s, 2H), 6.89 (t, 3H), 7.15 (t, 2H), 7.58 (b, 2H), 7.82 (s, 1H), 8.04 (s, 1H). LC-MS: t / ζ HIAD * 484, 486 [MH] * 184 ^e YU = 2-E, 3-C1; Υ = 4-C1; Υ '= Η; X = pyrimidin-2-yloxymethyl ¹ H-NMR (400 MHz, С0С1з): δ 1.75 (t, 2Н), 1.97 (t, 2Н), 2.81 (t, 1Н), 2.88-3.15 (t, 2Н), 3.62 (t, 1H); 4.62 (t, 1H). 5.43 (s, 2H), 6.98 (t, 1H), 7.16 (t, 1H), 7.25 (pp, 1H), 7.36 (b, 2H), 7.44 (t, 3H), 8.44 (ά, 2H). LC-MS: t / ζ CHIAD * 527 [M] *

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185 "= 2-E, 3-C1; Υ = 4-C1; Υ '= Η; X = 2-pyridin-2-yl-ethyl 'H-NMR (400 MHz, СОС1з): δ 1.58-1.98 (t, 4Η), 2.75 (t, 1H), 2.90-3.00 (t, 2H), 3.04-3.18 ( t, 2H), 3.42 (h, 2H), 3.61 (t, 1H), 4.60 (t, 1 K), 7.10-7.27 (t, 6H), 7.42 (t, 1H), 7.56 (6, 2H), 7.82 (t, 1H); 8.48 (s, 1H).

LC-MS: t / ζ CHIAD * 524 [MH] *

Ϊ86 V / = 3-С1Л = ”4-С1; Υ '= Η; X = 2-morpholin-4-yl-ethyl ¹ H-NMR (400 MHz, COC! ₃ ): 3 1.80 (t, 2H), 1.97 (t, 2H), 2 40 (t, 4H),

187

2.64-3.02 (t, 7H), 3.59-3.90 (t, 5H), 4.58 (t, 1H), 7.19 (ά, 2H), 7.24 (t. 2H), 7.36 (t, 2H), 7.58 (6, 2H).

LC-MS: t / ζ CHIAD * 514 [M] *

VI = 5-C1, 2-E; Υ = 4-C1; Υ '= Η; X = 2- (3,5-dimethyl-isoxazol-4-yl) ethyl ¹ H-NMR (400 MHz, СОС1з): δ 1.75-1.98 (pl, 7H), 2.04 (s, 3H), 2.63-2.80 ( t, 5H), 2.86-3.08 (t, 2H), 3.62 (h, 1H), 4.59 (t, 1H), 6.75 (t, 2H), 7.01 (t, 1H), 7.37 (t, 2H), 7.57 (ΰ, 2H).

LC-MS: t / ζ CI AD ’542, 544 [MN] *

A = ethyl acetate: methanol: ammonia 0.88 was used as the column eluent.

B = instead of triethylamine, 2 equiv. Ν-methylmorpholine.

In = instead of triethylamine used 3 equiv. Ν-methylmorpholine.

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

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

¹ H-NMR (400 MHz, SBS1 ₃ ): δ 1.01 (s, 9H), 1.70-1.85 (t, 2H), 1.98 (t, 3H), 2.22 (t, 2H), 2.55-2.66 (t, 2H) ), 3.00 (t, 1H), 4.00 (t, 1H), 4.59 (t, 1H), 5.18 (s, 2H), 6.60 (s, 1H), 6.90 (t, 2H), 7.00 (s, 1H), 7.20 (s, 1H), 7.52 (t, 2H); LC-MS: t / ζ CHIAD + 441 [MH] ⁺ .

Examples 189-198.

Υ

The corresponding acid chloride, 2COC1, (1.0 eq.) Was added to a solution of the corresponding amine selected from amines of Preparations 122-131 (1 eq.) And triethylamine (1.1 eq.) In dichloromethane (4 ml mmol ^-1 ) . This reaction mixture was stirred at room temperature for 1 hour. Then it was 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 silica gel column chromatography using ethyl acetate: dichloromethane: methanol (from 100: 0: 0 to 0: 95: 5) as an eluent. The products were subjected to azeotropic distillation with ether to obtain these compounds as a white foam.

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Example No. Data 189 Ζ = 3-Chloro-2-fluorophenyl; Υ = Η; Υ * = H; 'H-NMR (400 MHz, COC1 ₃ ): δ 1.68-2.07 (t, 4H), 2.75 (t, 1H), 2.92 (t, 1H), 3.01 (t, 1H), 3.61 (t, 1H), 4.60 (t, 1H). 5.64 (8, 2H), 7.06 (6, 2H), 7.13 (1, 1H), 7.38-7.57 (t, 7H). LC-MS: t / ζ ERI * 488 [Mia] * 190 Ζ = 3-Chlorphenip; Υ = 4-OCH ₃ ; Υ '= H; 'H-NMR (400 MHz, SES1 ₃ ): δ 1.75-2.20 (t, 4H), 2.79 (t, 1H}, 2.93 (t, 2H), 3.80 (t, 1H), 3.84 (s, 3H), 4.56 (t, 1H), 5.66 (s, 2H), 6.94 (t, 2H), 7.01 (t, 2H), 7.26 (t, 1H), 7.28-7.40 (t, 3H), 7.51 (s, 2H) LC-MS: t / ζ ERI * 500 [M№] * 191 Ζ = 3-Chloro-2-fluorophenyl; Υ = 4-P; Υ- H; ¹ H-NMR (400 MHz, ses): δ 1.72-2.07 (t, 4H), 2.77 (t, 1H), 2.90 (t, 1H), 3.02 (t, 1H), 3.62 (t, 1H). 4.61 (t, 1H), 5.64 (β, 2H), 7.05-7.19 (t, 6H), 7.41 (1, 1H), 7.49 (3, 2H). LC-MS: t / ζ ERI * 503 [MEa] * 192 Ζ = 3-Chloro-2-fluorophenyl; Υ = 4-Vg; Υ '= H; 'H-NMR (400 MHz, COC1CH): δ 1.71-2.06 (t, 4H), 2.72 (t, 1H), 2.94 (t, 1H), 3.05 (t, 1H), 3.63 (t, 1H), 4.62 (t. 1H), 5.65 (s, 2H), 6.95 (6, 2H), 7.14 (1, 1 H>, 7.27 (t, 1H), 7.43 (1, 1H), 7.49 (s, 2H), 7.60 (6, 2H). LC-MS: t / ζ ERI * 546 [MH] * 193 Ζ = 3-Chloro-2-fluoro-phenyl; Υ = 4-CP ₃ ; Υ '= H; 'H-NMR (400 MHz, SES1 ₃ ): 6 1.75-2.15 (t, 4H), 2.76-2.94 (t, 2H), 3.05 (t, 1H), 3.62 (t, 1H), 4.67 (t, 1H) ), 5.76 (s, 2H), 7.14 (66, 1H), 7.20-7.30 (t, 2H), 7.36-7.50 (t, 4H), 7.75 (6, 2H). LC-MS: t / ζ ERI * 556 [M№] * 194 7 -.. Л л п Ь и ин ин-- V = V '= H "- - ar · * * a - -" ^_ ms a ^ | a - a, 'H-NMR (400 MHz, SES1 ₃ ): δ 1.88 (t, 2H), 2.06 (t, 2H), 2.42 (s, 3H), 2.79-3.00 (t, 3H), 3.80 (t , 1H), 4.59 (t, 1H), 5.70 (s, 2H), 7.07 (6, 2H), 7.23-7.40 (t, 6H), 7.53 (s, 2H). LC-MS: t / ζ ERI * 484] M№) * 195 Ζ = 3-Chloro-2-fluoro-phenyl; Υ = 4-CP1; Υ * = H; 'H-NMR (400 MHz, SES1 ₃ ): δ 1.67-2.00 (t, 4H), 2.67 (t, 1H), 2.80-3.08 (t, 2H), 3.60 (t, 1 H>, 4.58 (t, 1H), 5.64 (s, 2H), 7.11 (ί, 1H), 7.16-7.25 (t, 3H), 7.41 (ί, 1H), 7.46 (s, 2H), 7.75 (6, 2H). LC-MS : t / ζ ERI * 513 [Mia] * 196 Ζ = 3-Chloro-2-fluorophenyl; Υ = 4-C1; Υ '= 2-CH ₃ ; 'H-NMR (400 MHz, COC1 ₃ ): 6 1.68-1.98 (t, 6H), 2.07 (t, 1H), 2.60 (t, 1H), 1.80-3, 13 (t, 2H), 3.60 (6, 1H), 4.60 (6, 1H), 5.55 (6, 1H), 5.67 (6, 1H), 6.86-7.50 (t, 8H). LC-MS: t / ζ ERI * 536 [MYa] * 197 Ζ = 3-chlorophenyl; Υ = 4-C1; Υ '= 3-P; ’H-NMR (400 MHz, SOCC): δ 1.84 (t, 2H), 2.00 (t, 2H), 2 72 (t, 1H), 2.94 (t, 2H), 3.83 (t, 1H), 4.55 (t, 1H). 5.67 (s, 2H), 6.90 (6, 2H), 7.26- 7.41 (t, 4H); 7.50-7.56 (t, ZN). LC-MS: t / ζ ERI * 500 [MH] * 198 Ζ = 3-Chloro-2-fluoro-phenyl; Υ = 4-C1; Υ '= 3-C1; 'H-NMR (400 MHz, COC1 ₃ ): δ 1.80 (t, 1H), 1.86-2.05 (t, 3H), 2.74 (t, 1H), 2.92 (t, 1H), 3.04 (t, 1H), 3.61 (t, 1H), 4.61 (t, 1H), 5.70 (s, 2H), 7.05-7.16 (t, 3H), 7.27 (bg s, 1H), 7.40 (1, 1H), 7.50 (s, 2H) ), 7.55 (6.1H). LC-MS: t / ζ ERI * 534 [M№] *

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Examples 199-201.

A mixture of the corresponding acid, 2CO ₂ N, (1.2 eq.), 1-hydroxybenzotriazole hydrate (1.2 eq.), Triethylamine (2 to 4 eq.), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.2 equiv.) And the corresponding amine or amine hydrochloride selected from the compounds of Preparations 2 and 143 (1 equiv.) In dichloromethane (26 ml-mmol ^-1 ) was stirred at room temperature for 24 hours. Then this reaction the mixture was washed with 2n. sodium hydroxide solution and the organic solution was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography with gradient elution with ethyl acetate: methanol: ammonia 0.88 (from 100: 0: 0 to 95: 5: 0.5) to obtain the indicated compounds.

Example No. Data 199 Ζ = cyclopropylmethyl; X = CH ₂ OCH _g CH ₃ 'H-NMR (400 MHz, COC! ₃ ): δ 0.18 (t, 2H), 0.58 (t, 2H), 1.06 (1, ZN), 1.70-1.90 (t, ZN ), 2.00 (t, 2H), 2.22 (t, 2H), 2.59-2.77 (t, 2H), 3.02 (t, 1H), 3.40 (H, 2H), 3.92 (t, 1H), 4.40 ( a, 2H), 4.55 (t, 1H), 7.22 (s, 2H), 7.54 (s, 2H). LC-MS: t / ζ CHIAD * 403 [MH] * 200 * Ζ = 5-trifluoromethylpyridin-2-yl; X = CH ₂ OCH ₂ CH ₃ 'H-NMR (400 MHz, С0С1з): δ 1.08 (ί, ЗН), 1.79-2.04 (t, 4Н), 2.60 (t, 1Н), 2.95-3.17 (t, 2Н) ), 3.20 (s, 2H), 3.78 (t, 1H), 4.41 (s, 2H), 4.59 (t, 1H), 7.22 (s, 2H), 7.57 (s. 2H), 7.77 (s, 1H) 7.95 (s, 1H); 8.55 (s, 1H). LC-MS: t / ζ CHIAD * 494 [MH] * 201 ^b Ζ = Ή-Indazol-Z-yl; Υ = 4-C1; Υ '= Η; X = CH 'H-NMR (400 MHz, С0С1з): δ 1.65-1.88 (t, 4Н), 2.15 (δ, ЗН), 2.80-2.97 (t, 2Н), 3.08 (t, 1Н), 4.42-4.62 (t, 2H), 7.20 (st, 1H), 7.40 (st, 1H), 7.57 (t, 3H), 7.65 (st, 2H), 7.90 (st. 1H), 13.42 (s, 1H). LC-MS: t / ζ CHIAD * 421 [MH] *

A = 5- (trifluoromethyl) -2-pyridinecarboxylic acid was used and can be obtained as described in 1. Ogd. Siet. ^ Spree) 2003; (8); 1559-1568.

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

Examples 202-204.

A solution of the corresponding acid, 2CO ₂ H, (1.5 equiv.), O-benzotriazol-1-yl-S, ^ No., No. tetramethyluronium hexafluorophosphate (2 equiv.), Ν-methylmorpholine (5 equiv.) And the corresponding amine hydrochloride selected from the compounds of preliminary examples 2 and 133 (1 equiv.), in dichloromethane (8 ml-mmol ^-1 ) was stirred at room temperature for 24 hours. Then this reaction mixture was washed with sodium hydroxide solution and the organic solution was evaporated under reduced pressure. . The crude product was purified by silica gel column chromatography with gradient elution with dichloromethane: methanol: ammonia 0.88 (from 100: 0: 0 to 90: 10: 1) to obtain the indicated compounds.

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Example No. Data 202 Ζ = 4-Chlor-3-fluorophenyl; X = CH3; 'H-NMR (400 MHz, 0ϋ 00 _3): δ 1.79-1.99 (hl, 4H), 2.23 (s, SH), 2.85 (t, 2H), 3.11 (br, 1H), 3.70 (t, 1H) 4.58 (t, 1H), 7.22 (8, 1H), 7.37 (ά, 1H), 7.45 (ά, 2H), 7.58 (t, 1H), 7.64 (8, 2H). LC-MS: t / ζ CHIAD * 433 [M] ⁺ 203 Ζ = 2,3,4-trifluorophenyl; X is CH ₃ ; ¹ H-NMR (400 MHz, 0ϋ _3, 00): δ 1.82 (m, SH), 1.98 (t, 1H), 2.22 (s, SH), 2.89 (t, 2H), 3.15 (t, 1H), 3.60 (t, 1H), 4.60 (t, 1H), 7.12 (t, 2H), 7.44 (t, 2H), 7.66 (t, 2H). LC-MS: t / ζ CHIAD * 435 [M] * 204 Ζ = 1H-Indazol-3-yl; X = 3-methyl-isoxazol-5-ylmethyl; ¹ H-NMR (400 MHz, SS) CI3): δ 1.80-2.15 (t, 5H), 2.18 (s, 3H), 2.75 (t, 1H), 2.80-2.92 (t, 2H), 3.17 (t, 1H), 4.04 (a, 2H), 4.62-4.81 (t, 2H), 4.86 (s, 1H), 7.15 (t, ZN), 7.30 (88, 1H), 7.50 (t, ZN), 8.00 (8 , 1H), 11.90 (L3, 1H). LC-MS: t / ζ ERI * 500, 502 [Mr

Examples 205-207.

A solution of the corresponding acid, Ζ No. ₂ Π (1.2 equiv.), O-benzotriazol-1-yl-HSGSGS, HStetramethyluronium hexafluorophosphate (1.2 equiv.), Ν-methylmorpholine (1.4 equiv.) And the corresponding amine, selected from the compounds of preliminary examples 12 and 136 (1 equiv.), in dichloromethane (7-10 ml-mmol ^-1 ) was stirred at room temperature for 24 hours. Then this reaction mixture was partitioned between sodium hydroxide solution and dichloromethane and the layers were separated. The organic solution was washed with a solution of ammonium chloride, dried over MgSO ₄ and then evaporated under reduced pressure. The crude product was purified by silica gel column chromatography with gradient elution with dichloromethane: methanol: ammonia 0.88 (from 100: 0: 0 to 90: 10: 1) to obtain the indicated compounds.

Example No. Data 205 * Ζ = 3-difluoromethylphenyl; X = [1,2,3] -triazol-2-ylmethyl ¹ H-NMR (400 MHz, С0С1з): δ 1.78-2.02 (hl, 4H), 2.70 (t, 1H), 2.95 (t, 2H), 3.80 (t, 1H), 4.58 (t, 1H), 5.63 (s, 2H), 6.50-6.80 (1, 1H), 7.01 (8, 2H), 7.42-7.58 (t, 3H). LC-MS: t / ζ HIAD * 498, 500 [MN] * 206 ^b '“ Ζ = 4-difluoromethyl-phenyl; X = [1,2,3] -triazol-2-ylmethyl 'H-NMR (400 MHz, С0С1з): δ 1.78 (t, 2H), 1.97 (gp, 2H), 2.66 (t, 1H), 2.90 ( t, 2H), 3.78 (t, 1H), 4.58 (t, 1H), 5.61 (s, 2H), 6.46-6.78 (1, 1H), 6.98 (8, 2H), 7.22 (a, 2H), 7.39 -7.57 (t, 8H). LC-MS: t / ζ HIAD * 498, 500 [MN] * 207 Ζ = Ή-Indazol-Z-yl; X = 2-piperidin-1-yl-ethyl; 'H-NMR (400 MHz, С0С1з): δ 1.38 (t, 2H), 1.50 (t. 4H), 1.74-2.18 (t, 4H), 2.30 (t, 4H), 2.72 (t, 6H), 2.88 (t, 1H), 3.19 (t, 1H), 4.61-4.88 (t, 2H), 7.18 (t, 3H), 7.30 (t, 1H), 7.54 (t, 3H), 8.02 (8, 1H). LC-MS: t / ζ CHIAD * 518 [M] *

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A = 3-difluoromethylbenzoic acid was used, which can be obtained in accordance with Tehayebbop 31; 1977; 391-401.

B = used 4-difluoromethylbenzoic acid, which can be obtained in accordance with TeDayebgoi 31; 1977; 391-401.

B = the product was further recrystallized from isopropyl alcohol and 2.8 equiv. Ν-methylmorpholine.

Examples 208-210.

A mixture of the corresponding oxadiazole selected from the compounds of preliminary examples 66 and 67 (1 equiv.), The corresponding aniline from preliminary examples 166 and 168 or the commercially available 4-chloro-2- (trifluoromethoxy) phenylamine (1.5-2.0 equiv.) and trifluoroacetic acid (0.5-1.0 equiv.) in toluene (2.5 to 9.5 ml mmol ^-1 ) was heated at 110 ° C for 18 hours. The cooled mixture was distributed between dichloromethane and sodium carbonate solution and the layers were then separated. The organic phase was dried over § § § ₄ and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using dichloromethane: methanol: ammonia 0.88 (from 100: 0: 0 to 90: 10: 1) as an eluent to obtain the indicated compounds.

Example No. Data 208 Ζ = 3-chlorophenyl; Υ = 4-C1; Υ '= 2-OCH _g CH ₃ ; X = H ¹ H-NMR (400 MHz, CO.sub.CNS): δ 1.23 (ί, 3H), 1.78-1.98 (ηη, 4H), 2.92 (t 2H), 3.16 (t, 1H), 3.70 (t, 1H) 4.14 (η, 2H), 4.58 (t, 1H), 7.18 (b, 1H) 7.34 (t, 2H), 7.42 (t, 3H), 8.43 (®, 1H). LC-MS: t / ζ CHIAD * 445 [M] * 209 Ζ = 3-chlorophenyl; Υ = 4-C !; Υ '= 2-OCP ₃ ; X = H. ¹ H-NMR (400 MHz, CO ₃ SD): δ 1.80-1.98 (t, 4H), 2.84-2.99 (t, 2H), 3.103.20 (t, 1H), 3.72 (t, 1H), 4.60 ( t, 1H), 7.37 (b, 1H), 7.44 (t, 3H), 7.70 (t, 2H), 7.78 (5, 1H), 8.62 (5, 1H). LC-MS: t / ζ CHIAD * 485 [M] * 210 Ζ = 4-chlorophenyl; Υ = 4-C1; Υ '= 2-pyrrolidin-1-ylmethyl; X = CH ₃ 'H-NMR (400 MHz, COC | ₃ ): δ 1.64-1.84 (t, 7H), 2.18 (s, 3H), 2.37 (t, 4H), 2.58 (t, 1H), 2.78- 2.99 (t, 2H), 3.16-3.20 (t, 2H), 3.64-3.95 (t, 1H), 4.45-4.70 (t, 1H), 7.09 (t, 1H), 7.30-7.44 (t, 5H), 7.62 (s, 1H). LC-MS: t / ζ CHIAD * 498 [M] *

Examples 211-216.

A mixture of the corresponding oxadiazole selected from the compounds of preliminary examples 6669, 71 and 75 (1 equivalent), aniline (1.5-2.0 equivalent) and trifluoroacetic acid (0.5 to 1.0 equivalent) in toluene ( 1,0-

2.5 ml-mmol ^-1 ) was heated at a temperature of from 170 to 185 ° C for 20 min under the influence of microwave radiation. The crude solution was purified by silica gel column chromatography using dichloromethane: methanol: ammonia 0.88 (from 100: 0: 0 to 90: 10: 1) as an eluent to obtain the indicated compounds.

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Example No. Data 211 Ζ = 3-chlorophenyl; Υ = 4-C1; Υ '= 2-OCH ₂ CP ₃ ; X = H ¹ H-NMR (400 MHz, COC1CH): δ 1.78-2.02 (t, 4H), 2.80 (t, 1H), 2.95-3.06 (t, 2H), 3.81 (t, 1H), 4.40 (ς , 2H), 4.58 (t, 1H), 7.17 (s, 1H), 7.25 (t, H), 7.38 (h, H), 8.18 (h, 1H). LC-MS: t / ζ CHIAD * 499 [M] ⁺ 212 * Ζ = 4-chlorophenyl; Υ = 4-C1; Υ '= Η; X = CP ₃ ; ¹ H-NMR (400 MHz, COC1 ₃ ): δ 1.82 (t, 2H), 2.00 (t, 2H), 2.76 (t, 1H), 2.83-3.02 (t, 2H), 3.83 (t, 1H), 4.60 (t, 1H), 7.22 (ά, 2H) 7.37 (6, 2H), 7.40 (ά, 2H), 7.60 (ά, 2H). LC-MS: t / ζ CHIAD ⁺ 469 [M] * 213 Ζ = 3-chlorophenyl; Υ = 4-C1; Υ '= Η; X = CH ₂ OCH ₂ CH ₃ ¹ H-NMR (400 MHz, СОС1 ₃ ): δ 1.08 (1, ЗН), 1.78-1.90 (t, 2Н), 1.92-2.02 (t, 2Н), 2.78 (t, 1H), 2.80-3.02 (t, 2H), 3.41 (η, 2H), 3.80 (t, 1H), 4.41 (s, 2H), 4.60 (t, 1H), 7.24 (t, 3H), 7.36 (t , 2H); 7.57 (ά, 2H). LC-MS: t / ζ CHIAD * 459 [M] * 214 Ζ = 4-chlorophenyl; Υ = 4-CH ₃ ; Υ '= 2-CH ₃ ; X = CH ₃ ¹ H-NMR (400 MHz, COC! S): δ 1.68-2.00 (t, 7H), 2.14 (δ, H), 2.40 (s, H), 2.58 (t, 1H), 2.78- 2.98 (t, 2H), 3.78 (t, 1H), 4.54 (t, 1H), 6.97 (t, 1H), 7.15 (t, 1H), 7.20 (s. 1H), 7.30 (ά, 2H), 7.36 (ά, 2H). LC-MS: t / ζ CHIAD * 409 [MH] * 215 Ζ = 4-chlorophenyl; Υ = 4-C1; Υ '= 2-CH ₃ ; X = CH ₂ CH ₃ ¹ H-NMR (400 MHz, COC1 ₃ ): δ 1.20 (ΐ, H), 1.68-2.02 (t, 6H), 2.14 (t, 1H), 2.38-2.58 (t, H) 2.79-2.98 (t, 2H), 3.80 (t, 1H), 4.58 (t, 1H), 7.04 (t, 1H), 7.26-7.39 (t, 5H), 7.41 (s, 1H). LC-MS: t / ζ ERI * 443.446 [MH] * 216 Ζ = 3-chlorophenyl; Υ = 4-C1; Υ '= Η; X = pyrazol-1-ylmethyl ¹ H-NMR (400 MHz, CO.sub.2SO): δ 1.80-1.97 (t, 4H), 2.82 (t, 2H), 3.06 (t, 1H), 3.69 (t, 1H), 4.58 (t, 1H), 5.41 (s, 2H), 6.18 (s, 1H), 7.20 (t, 2H), 7.30 (t. 2H). 7.38-7.57 (t, 5H). LC-MS: t / ζ CHIAD * 481 [M] *

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

Examples 217-222.

A solution of the corresponding acid selected from Preliminary Examples 158 and 159 (1 equiv.), 1hydroxybenzotriazole hydrate (1.5 equiv.), Triethylamine (4 equiv.) And 1- (3-dimethylaminopropyl) -3 ethylcarbodiimide hydrochloride (1.5 equiv. ) in dichloromethane (3.5 ml-mmol ^-1 ) was added to a solution of the corresponding amine (4ΝΚ ⁴ Κ ⁵ ) (1.5 equiv.) in dichloromethane (2.5 ml-mmol ^-1 ), and this reaction mixture was stirred at room temperature for 24 hours. Then the reaction mixture was washed with a solution of ammonium chloride, and the organic solution was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography with gradient elution with dichloromethane: methanol: ammonia 0.88 (from 100: 0: 0 to 95: 5: 0.5) to obtain these compounds.

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Example No. Data 217 ^a K ⁴ = H; I * = bicyclo [1.1.1] pent-1-yl; X = CH3 ¹ H-NMR (400 MHz, SOS: δ 1.58-1.78 (t, 4H), 1.86 (t, 3H), 2.02 (t, 5H), 2.22 (5, 3H), 2.79 (t, 2H) 3.32 (t, 2H), 5.90 (s, 1H), 7 24 (ά, 2H), 7.54 (b, 2H). LC-MS: t / ζ CHIAD * 386 [MH] * 218 And * = H; K ^b = tert-butyl; X = [1,2,3] -triazol-2-ylmethyl 'H-NMR (400 MHz, suck: δ 1.29 (s, 9H), 1.55-1.74 (t, 4H), 1.99-2.09 (t, 1H) 2.80 (t, 2H), 3.38 (t, 2H>, 5.23 (t, 1H), 5.59 (s, 2H), 7.10 (ά, 2H), 7.40 (8, 2H), 7.52 (s, 2H). LC-MS: t / ζ CHIAD * 443 [MH] * 219 ΝΡΉ ”= azetidin-1-yl; X = [1,2,3] -triazol-2-ylmethyl ¹ H-NMR (400 MHz, suck: 6 1.56-1.68 (hl, 4H), 2.18-2.30 (t, 3H), 2.80 (t. 2H) 3.37 (t, 2H), 3.98 (ί, 2H), 4.16 ((, 2H), 5.59 (s, 2H), 7.10 (ά, 2H), 7.40 (ά, 2H), 7.55 (s, 2H). LC-MS: t / ζ ERI * 427 [MH] * 220 ΝΚ ⁴ Ρ ⁵ = pyrrolidin-1-yl; X = [1,2,3] -triazol-2-ylmethyl ¹ H-NMR (400 MHz, SOS: δ 1.59-1.76 (t, 4H), 1.82 (t, 2H), 1.95 (t, 2H), 2.41 (t, 1H), 2.82 (t, 2H), 3.36-3.46 (t, 6H), 5.59 (s, 2H), 7.15 (6, 2H), 7.40 (ά, 2H), 7.55 (s, 2H). LC-MS: t / ζ ERI * 441 [MH] ⁺ 221 = morpholin-4-yl; X = [1,2,3] -triazol-2-ylmethyl 'H-NMR (400 MHz, suck: δ 1.58-1.78 (gp, 4H), 2.56 (t, 1H), 2.82 (t, 2H), 3.38 (t, 2H), 3.44 (t, 2H), 3.60 ( t, 2H), 3.62 (t, 4H), 5.60 (s, 2H), 7.12 (6, 2H), 7.40 (6, 2H), 7.52 (s, 2H). LC-MS: t / ζ ERI * 457 [MH] * 222 P ⁴ = Η; E ⁵ = 2-phenylethyl; X = [1,2,3] -triazol-2-ylmethyl 'H-NMR (400 MHz, SOS: 3 1.52-1.68 (t, 4H), 2.04 (t, 1H), 2.79 (t, 4H), 3.36 (t, 2H), 3.47 (t, 2H), 5.40 (pl, 1H), 5.59 (s, 2H), 7.10 (ό, 2H) .7.17 (ό, 2H), 7.20-7.36 (t, ZN ), 7.40 (0, 2H), 7.54 (s, 2H). LC-MS: t / ζ ERI * 491 [MN] *

A = 1-bicyclo [1,1,1] pentylamine hydrochloride (see 1.O.S. 2001; 66 (19); 6282-6285).

Example 223. 1 - [4- (4-Chlorophenyl) -5-methyl-4H-1,2,4-triazole-3-yl] -No isopropyl-4-methylpiperidine 4-carboxamide.

Oxalyl chloride (0.04 ml, 0.55 mmol) was added to the acid solution of Preparation 160 (50 mg, 0.15 mmol) in dichloromethane (50 ml) and the solution was stirred at room temperature for 20 minutes. Additional oxalyl chloride (0.02 ml, 0.27 mmol) was added and the solution was stirred for another 10 minutes. Then the solution was evaporated under reduced pressure and the residue was subjected to azeotropic distillation with dichloromethane (3x). The oily residue was dissolved in dichloromethane (10 ml). Isopropylamine (0.19 ml, 2.25 mmol) was added to the solution, and then the mixture was stirred at room temperature for 18 hours. Then this reaction mixture was washed with a solution of ammonium chloride, dried over MgO ₄ and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane: methanol: ammonia 0.88 (95: 5: 1) as an eluent. The product was triturated with ether to give the title compound as a solid, 30 mg.

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Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.15 (t, 9Н), 1.42 (t, 2Н), 1.95 (t. 2Н), 2.22 (8, 3Н), 3.02 (t, 2Н), 3.18 (t , 2H), 4.03 (t, 1H), 5.38 (t, 1H), 7.26 (b, 2H), 7.57 (b, 2H); LCMS: m / ζ APCI ⁴³⁷⁶ [MH] ^4.

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

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

Я-NMR (400 MHz, CO ₃ OD): δ 1.55 (t, 2H), 1.86 (t, 2H), 2.22 (8. 3H), 2.93 (t, 2H), 3.52 (t, 2H), 3.97 ( t, 1H), 7.42 (!, 2H), 7.45-7.53 (t, 3H), 7.63 (b, 2H), 7.75 (b, 2H); LC-MS: t / ζ CHIAD ⁴ 418 [МЫа] ⁴ .

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

1-Hydroxybenzotriazole hydrate (150 mg, 1.1 mmol), 1- (3-dimethylaminopropyl) -3 ethylcarbodiimide hydrochloride (225 mg, 1.17 mmol), triethylamine (0.4 ml, 2.7 mmol) and amine of preparation 144 (250 mg, 0.9 mmol) were successively added to a solution of benzoic acid (110 mg, 0.9 mmol) in dichloromethane (10 ml). This reaction mixture was then stirred at room temperature for 18 hours. The mixture was partitioned between a 2M sodium hydroxide solution and dichloromethane, 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 silica gel column chromatography, gradient eluting with dichloromethane: methanol: ammonia 0.88 (100: 0: 0 to 95: 5: 0.5) to give the title compound as a white foam, 182 mg.

Ή-NMR (400 MHz, СОС1 ₃ ): δ 2.22 (8, 3Н), 3.08 (t, 4Н), 3.38-3.78 (t, 4Н), 7.25 (b, 2Н), 7.39 (t, 4Н), 7.54 (b, 3H). LC-MS: t / ζ CHIAD ⁴ 382 [MH] ⁴ ; Microanalysis found: C 61.66; H 5.32; N, 17.22; With ₂₀ N ₂₀ C1M ₅ O-0.14 CH ₂ Cl ₂ requires: C 61.43; H 5.19; Ν, 17.79%.

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

Triethylamine (100 μl, 0.71 mmol) and then benzoyl chloride (82 μl, 0.71 mmol) were added to a solution of compound of Preparation 149 (150 mg, 0.47 mmol) in dichloromethane (10 ml), and then this reaction mixture was 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 silica gel column chromatography using ethyl acetate: methanol: ammonia 0.88 (95: 5: 0.5) as an eluent to obtain the title compound as a white solid, 120 mg.

Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.01-1.16 (t, 3Н), 3.18-3.23 (t, 3Н), 3.30 (8, 3Н), 3.39- 3.48 (t. 3Н), 3.83 (t, 1H), 4.04 (t, 1H), 4.28 (b, 1H), 4.38 (b, 1H), 7.39 (t, 7H), 7.52 (b, 2H); LC-MS: t / ζ Hyad ⁴ 426 [MH] ⁴ .

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

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

Ή-NMR (400 MHz, COC1 ₃ ): δ 1.08 (s, 3H), 2.94-3.39 (t, 8H), 4.34 (q, 2H), 7.25 (s, 2H), 7.39 (t, 4H), 7.54 (th, 2H); LC-MS: t / ζ CHIAD * 460 [M] ⁺ .

Example 228. 1 - [4- (4-Chlorophenyl) -5- (methoxymethyl) -4H-1,2,4-triazol-3-yl] -4- (3-fluorobenzoyl) -1,4-diazepane.

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

Ή-NMR (400 MHz, COC1 ₃ ): δ 1.68-1.80 (t, 2H) 3.17 (t, 1H), 3.25 (q, 3H), 3.39 (t, 4H), 3.58 (t, 1H), 3.65 ( t, 1H), 3.78 (t, 1H), 4.22 (s, 2H), 7.02 (s, 1H), 7.10 (t, 2H), 7.22-7.42 (t, 3H), 7.49 (t, 2H); LC-MS: t / ζ CHIAD + 444 [M] ⁺ .

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

Trifluoroacetic acid (5 ml) was added to a cooled (5 ° C) solution of the compound of Preparation 102 (1.3 g, 3.43 mmol) in dichloromethane (5 ml) and the solution was then stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure 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) aminopolystyrene (500 mg) was added and the mixture was stirred for another 24 hours. Then the mixture was diluted with an aqueous solution of ammonium chloride, the layers were separated using a hydrophobic membrane and the organic solution was purified directly using a silica gel cartridge and dichloromethane: methanol ( from 100: 0 to 95: 5) as an eluent to give the title compound.

Ή-NMR (400 MHz, СОС1 ₃ ) (rotamers): δ 2.23.2.34 (2x8, 3Н), 3.00-3.62 (t, 3Н), 3.64-4.00 (t, 2Н), 4.11-4.40 (t, 1Н) 4.58, 4.90 (2ht, 1H), 7.17-7.40 (t, 6H), 7.56 (t, 2H); LC-MS: t / ζ ERI * 439 [M #] ⁺ .

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

Triethylamine (79 μl, 0.57 mmol) and then 2-benzoyl chloride (66 μl, 0.52 mmol) were added to a solution of compound of Preparation 146 (150 mg, 0.52 mmol) in dichloromethane (5 ml). This mixture was then stirred at room temperature for 18 hours. After this time, this reaction

- 84 010132 the mixture was diluted with water (5 ml) and the mixture was rapidly stirred for 30 minutes. The layers were then separated, the organic solution was evaporated under reduced pressure, and the product was azeotroped with ether to give the title compound as a white foam, 193 mg.

Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.38-1.82 (t, 3Н), 1.82-2.22 (t, 8Н), 2.54-2.87 (t, 1Н), 3.03-3.50 (t, 2Н), 4.80 ( t, 1H); 6.94-7.50 (t, 7H); LC-MS: t / ζ ERI ⁺ 451 [MEa] ⁺ .

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

A mixture of the compound of Preparation 147 (97 mg, 0.35 mmol), 2-chlorobenzoyl chloride (40.4 μl, 0.32 mmol) and Ν-methylmorpholine (58 μl, 0.53 mmol) in dichloromethane (5 ml) was stirred at room temperature for 18 hours. Then this reaction mixture was diluted with dichloromethane (20 ml), washed with 2N. hydrochloric acid (20 ml) and saturated sodium bicarbonate solution (20 ml). The organic solution was then dried over MgSO ₄ and concentrated under reduced pressure. The remaining oil was triturated with ether, the resulting solid was filtered and then dried to give the title compound 55 mg.

Ή-NMR (400 MHz, (rotamers): δ 1.84-2.62 (t, 8H), 3.00-3.20 (t, 1H), 3.22-3.42 (t, 1H), 3.443.79 (t, 2H), 3.81- 3.98 (t, 1H), 7.20-7.50 (t, 7H); LC-MS: t / ζ CHIAD + 415 [MH] ⁺ .

Example 232. Ν- {1- [4- (4-Chlorophenyl) -5- (2H-1,2,3-triazol-2-ylmethyl) -4H-1,2,4-triazol-3-yl] pyrrolidine -3-yl} -Y-methylacetamide.

The title compound was obtained as a solid in 50% yield from the compounds of Preparations 54 and 18, following the procedure described in Preparation 93.

Ή-NMR (400 MHz, (rotamers): δ 1.78-1.90 (t, 2H), 2.04 (8, 3H), 2.74 (8, 1H), 2.80 (8, 3H), 2.98 (t, 1H), 3.04 -3.18 (t, 2H), 3.22-3.38 (t, 2H), 4.40, 5.21 (2ht, 1H), 5.55 (t, 2H), 7.03 (s, 2H), 7.38 (s, 2H), 7.52 (8 , 2H); LC-MS: t / ζ ERI ⁺ 423 [MHA] ⁺ .

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

Sulfuric acid (930 mg, 95%, 9.5 mmol) was added to a solution of compound of Preparation 96 (700 mg, 1.9 mmol) in acetic acid (1.5 ml), and then this reaction mixture was heated at 100 ° C. within 3 days. The cooled mixture was carefully quenched by adding 0.88 ammonia and then extracted with dichloromethane (4x). 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 give the title compound, 282 mg.

Ή-NMR (400 MHz, СОС1 ₃ ): δ 2.06 (t, 2Н), 2.20 (8, 3Н), 2.32 (t, 2Н), 3.05-3.20 (t, 4Н), 5.20 (t, 2Н), 7.24 (t, 3H), 7.38 (t, 4H), 7.52 (s, 2H); LC-MS: t / ζ ERI ⁺ 396 [MH] ⁺ .

Example 234. tert-Butyl-4 - {[4- (4-chlorophenyl) -5- (2H-1,2,3-triazol-2-ylmethyl) -4H-1,2,4-triazol-3yl] oxy } piperidine-1-carboxylate.

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Tetrahydrofuran (2 ml) was added to sodium hydride (24 mg, 60% in mineral oil), which was previously washed with pentane (2 ml) and this suspension was stirred at room temperature. Then, tert-butyl-4-hydroxy-1-piperidinecarboxylate (119 mg, 0.6 mmol) was added and the mixture was stirred at room temperature for another 30 minutes. The compound of Preparation 164 (100 mg, 0.3 mmol) was added and this reaction mixture was stirred at room temperature for the next 18 hours. Then this reaction mixture was partitioned between dichloromethane (20 ml) and brine (20 ml), the layers were separated and the organic the phase was evaporated under reduced pressure. The residue was dissolved in dichloromethane (6 ml), Ρ8-ΌΙΕΑ (polystyrene-linked diisopropylethylamine) (Agdopai! Tse11po1od1cz) (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 solution of potassium carbonate and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using dichloromethane: methanol (99: 1) as an eluent. The product was further purified by HPLC using a Riepotepech Lip C18 column and 0.1% aqueous formic acid: acetonitrile / 0.1% formic acid (80:20 to 5:95) to give the title compound, 34 mg.

Я-NMR (400 MHz, СО ₃ OD): δ 1.40 (t, 9Н), 1.62 (t, 2Н), 1.98 (t, 2Н), 3.30-3.59 (t, 4Н), 4.90-5.02 (t, 1Н) ), 5.61 (s, 2H), 7.18 (b, 2H), 7.40 (b, 2H), 7.50 (t, 2H).

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

Tert-butylamine hydrochloride (223 mg, 2.0 mmol) and then a solution of the acid chloride of Preparation 157 (150 mg, 0.4 mmol) in dichloromethane (3 ml) were added to a solution of triethylamine (300 μl, 2.0 mmol) in dichloromethane (2 ml) and this reaction mixture was stirred at room temperature for one hour. The mixture was then partitioned between dichloromethane and an aqueous solution of citric acid and the phases were separated. The aqueous layer was further extracted with dichloromethane (2x25 ml) and the combined organic solutions were dried over MgSO ₄ and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using dichloromethane: methanol: ammonia 0.88 (93: 7: 1) as an eluent to obtain the title compound 122 mg.

Ή-NMR (400 MHz, COC1 ₃ ): δ 1.42 (s, 9H), 2.40 (s, 3H), 5.98 (bg s, 1H), 7.19 (b, 2H), 7.41 (b, 2H), 7.50 ( b, 2H); 7.61 (b, 2H); LC-MS: t / ζ ERI ⁴ 391 [Mia] ⁴ .

Examples 236-395.

The corresponding acid, 2CO ₂ N, (0.25 ml, 0.2 M solution in Ν, д-dimethylformamide, 50 μmol) was neutralized, if necessary, with triethylamine (7 μl, 50 μmol per salt equivalent) and then treated with O- solution (7- azabenzotriazolyl) -I, I, I ', I'-tetramethyluronium hexafluorophosphate (0.1 ml, 0.525 M, 52.5 μmol). The solution was then treated with triethylamine (28 μl, 0.20 mmol) and amine of Preparation 12 (0.25 ml, 0.2 M solution in Ν, Ν-dimethylformamide, 50 μmol) in a 96-well polypropylene microtiter plate. The tablet was sealed and shaken for 16 hours at 40 ° C. Then the reaction mixtures were evaporated under reduced pressure, and the residues were purified by HPLC using a Va! E ^ 8 X! E ^^ a Mg C18 column and acetonitrile: 10 mM ammonium bicarbonate (adjusted to pH 10 with ammonium hydroxide) (from 5 : 95 to 98: 2) to obtain the target compounds.

Time% A% B% D

0 min 94 5 one 3.5 min 4,5 95 0.5 4.0 min 4,5 95 0.4

Example No. Ζ MS (MPR Retention Time (min) 236 5-methyl l-phenyl il-1 N-pi razol-4-l 529 2.26 237 5-methyl-1H-indol-2-yl 502 2,56 238 3- (1 H-Indo l-3-l) propyl 530 2.17 239 1-benzyl-1 H-pyrazol-4-yl 529 2 240 3- (2-fluorophenyl) -1H-pyrazol-5-yl 533 2.08 241 3- (4-methylphenyl) -1H-pyrazol-5-yl 529 2.17 242 2- (phenylmethyl) thiazol-4-yl 546 2.26 243 5-methyl-1 / - / - indazol-3-yl 503 2.04 244 (2,5,7-tr and methyl-1 / - / - and ndol-3-yl) methyl 544 2,3 245 4,5,6,7-tetrahydro-2-methyl-2H-and ndazol-3-l 507 1.95 246 1 H-indazole-1-methylmethyl 503 1.95 247 3- (2,5-dimethylphenyl) propyl 519 2.47 248 (13) -1 - (dimethylamino) -2-phenylethyl 520 2.04 249 (2,5-dimethip-1,3-thiazol-4-yl) methyl 498 1.87 250 (4-methoxyphenyl) -5-methyl-III-pyrazol-4-yl] 559 2.04 251 1 - (1-cyclopenten-1-yl) butyl 495 2.47 252 qi cloghex-3-n-1-yl 453 2.04 253 (1,3-dimethyl-1H-thieno [2,3-c] pyrazol-5-yl) 523 1.91 254 (23) -1- (tert-butoxycarbonyl) piperidin-2-yl 556 2,3 255 benz [b] thien-3-yl 505 2.21 256 4- (5-oxazolyl) phenyl 516 1.87 257 3- (2-methyl-4-azole l) phenol 546 2.13 258 2-phenoxypyridin-5-yl 542 2.21 259 2-methyl-4-phenylpyrimidin-5-yl 541 1.95 260 5-methoxy-indol-2-yl 518 2.13 261 4-chorbenzyl 497 2.43 262 1-phenylcyclopentyl 517 2.69 263 3- (4-fluorophenyl) -3-oxopropyl 523 2.03 264 1,2,3,4-tetrahydronaphthalen-2-yl 503 2.23 265 cyclopentyl (phenyl) methyl 531 2,52 266 biphenyl-4-ylmethyl 539 2,37 267 1 - (4-chlorophenoxy) -1-methylethyl 541 2,5 268 1 - (3-chlorophenoxy) ethyl 527 2.23 269 2-methyl-1-phenylbutyl 519 2.49 270 (1-naphthyloxy) methyl 529 2.13 271 (2,3-dimethylphenoxy) methyl 507 2.2 272 3- (4-methylphenyl) propyl 505 2.18

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273 1 H-indole-1-ethyl 516 2.12 274 (phenylthio) methyl 495 2.08 275 1 - (4-chlorophenyl) ethyl 511 2.27 276 2,3-dihydro-1 / - / - inden-2-ylmethyl 503 2.23 277 2 - [(4-chlorophenyl) thio] propyl 558 2.47 278 2-chloro-4-fluorobenzyl 515 2.13 279 (1 I) -1-phenylpropyl 491 2.22 280 3-methoxycyclohexyl 485 1.81 281 1-benzip-2,2-dimethylpropyl 533 2,52 282 1-methyl-2-phenylethyl 491 2.15 283 (benzyloxy) methyl 493 1.96 284 3- (4-chlorophenyl) -3-oxopropyl 539 2.17 285 [(4-chlorophenyl) thio] methyl 529 2.27 286 (benzylthio) methyl 509 2.12 287 3-chlorobenzyl 497 2.1 288 1,1-diphenyl ethyl 553 2,5 289 2,2-diphenylethyl 553 2,39 290 (2,3-dichlorophenoxy) methyl 291 4-fluorobenzyl 548 2.29 292 2-methoxybenzyl 481 1.98 293 2- (2-methoxyphenyl) ethyl 493 1.91 294 2,8-dimethylquinolin-4-yl 507 2.16 295 (2-naphthyloxy) methyl 528 2.21 296 2-naphthylmethyl 529 2.29 297 2-phenoxyethyl 513 2.26 298 1 - (2-fluorophenyl) cyclopentyl 493 2.11 299 5-methoxy-1-oxoindan-2-ylmethyl 535 2,36 300 (3-methylbenzoyl) aminomethyl 520 1.89 301 anti-4-methyl cyclohexyl 469 2.26 302 3-phenyl-3-oxo-1-methylpropyl 519 2.09 303 2- (2-methylphenyl) ethyl l 491 2.21 304 1-methyl-indol-3-ylmethyl 516 2.14

- 88 010132

305 diphenylmethyl 539 2,38 306 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-methyl 467 2.12 310 (2 /?) - 2-phenylpropyl 491 2.19 311 [(4-fluorophenyl) thio] methyl 513 2.14 312 (2P) -1- (tert-butoxycarbonyl) liperidin-2-yl 556 2.26 313 3- (2,3-di hydro-1,4-benzodioxin-6-yl) propyl 549 2.14 314 6-chloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazine- 4-yl 568 2.11 315 2- (4-fluorophenoxy) ethyl 511 2.16 316 2-hydroxyquinoxalin-3-yl 517 1,57 317 5-methyl-3-phenylisoxazol-4-yl 530 2.07 318 isoquinolin-1-yl 500 1.87 319 2-phenoxyphenyl 541 2.29 320 quinolin-2-yl 500 1.97 321 QUINOLIN-4-IL 500 1.8 322 quinolin-Z-yl 500 1.87 323 2-naphthyl 499 2.21 324 5-butylpyridin-2-yl 506 2.22 325 3-benzoylphenyl 553 2.21 326 1 H-benzimidazol-6-yl 489 1.55 327 9-oxo-9H-fluoren-1-yl 551 2.16 328 4-methoxyquinolin-2-yl 530 2.07 329 1-benzofuran-2-yl 489 2.16 330 2- (4-methylbenzoic l) pheni l 567 2.31, 331 7-methoxy-1-benzofuran-2-yl 519 2.17 332 2,6-dimethoxypyridin-3-yl 510 2,3 333 2,5-dimethyl-3-furyl 467 2.26 334 biphenyl-2-yl 525 2,52 335 5-methyl-2-thienyl 469 2,3 336 2-phenoxypyridin-3-yl 542 2.17

- 89 010132

337 1,3-benzothiazol-6-yl 506 2.08 338 3-phenylcinolin-4-yl 577 1.76 339 3-tert-butyl-1-methyl-1H-pyrazol-5-yl 509 2.26 340 2,1,3-benzoxadiazol-5-yl 491 2.26 341 5-bromo-2,3-dihydro-1-benzofuran-7-yl 570 2.43 342 1- (4-chlorophenyl) cyclopropyl 523 2.27 343 5-isobutylisoxazol-3-yl 496 2.23 344 3- (1 H-pyrazol-1-yl) phenyl 515 1.91 345 3,5-dimethylindol-2-yl 516 2,32 346 4- (tert-butoxycarbsnyl) morpholin-3-ylmethyl 572 1.98 347 3-isobutyl-1H-pyrazol-5-yl 495 1.96 348 5-propylisoxazol-3-yl 482 2.1 349 2,4-dimethyl-1,3-thiazol-5-yl 498 1,61 350 2-methylquinolin-4-yl 514 1.81 351 6-chloro-imidazo [1,2-a] pyridin-2-yl 523 1.71 352 3-phenyl-1H-pyrazol-5-yl 515 1.96 353 3-isopropyl-1 H-pyrazol-5-yl 481 1.66 354 4,5,6,7-tetrahydro-2-indazol-3-yl 493 1.81 355 2,3-dimethyl-1 H-indol-5-yl 516 2.05 356 3,5-dimethyl-1 H-pyrrol-2-yl 466 1.96 357 3- (3,5-dimethyl-1 H-pyrazol-1-yl) phenyl 543 2 358 3 - [(3,5-dimethyl-1H-pyrazol-1-yl) methyl] phenyl 557 1.98 359 3'-fluorobiphenyl-4-yl 543 2,37 360 4-phenyl-1,3-thiazol-2-ip 546 2.17 361 4- (1 H-pyrazol-1-yl) phenyl 515 1.9 362 5,7-dimethyl-pyrazolo [1,5-a] pyrimidin-2-yl 518 1.76 363 3-phenylisoxazol-5-yl 516 2.2 364 2,3-dihydro-1-benzofuran-2-yl 491 2 365 1H-benzimidazol-1-ylmethyl 503 1.73 366 5- (4-methoxyphenyl) -2-furyl 545 2.25 367 1,3-benzothiazol-2-yl-ethyl 534 2.03 368 2-methyl-5-propylpyrazol-3-yl 495 1.96

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369 1-benzyl-2-oxo-1,2-dihydropyridin-3-yl 556 1.85 370 1-benzyl-6-oxo-1,6-dihydropyridin-3-yl 556 1.75 371 2-phenyl-1,3-thiazol-4-yl 532 2.22 372 4-methyl-2-phenyl-1,3-thiazol-5-yl 546 2.18 373 8-methoxy-2H-chromen-3-yl 533 2.02 374 2/7-chromen-3-yl 503 2.12 375 6-methoxy-2H-chromen-3-yl 533 2.1 376 4- (tert-butoxycarbonyl) morpholin-3-yl 558 1.95 377 4-methoxy-3-thienyl 485 1.85 378 4- (1 H-imidazol-1-yl) phenyl 515 1.68 379 2-methyl-1 H-benzimidazol-5-yl 503 1.51 380 2,3-dihydro H-inden-2-yl 489 2.15 381 trans-2-phenylcyclopropane-yl 489 2.15 382 1-methyl-1 H-indol-2-yl 502 2.18 383 1-methyl-1 H-indol-3-yl 502 2.02 384 5-fluorine / 7-INDOL-2-IL 506 2.13 385 6-methyl-4-oxo-4H-chromen-2-yl 531 2.02 386 ^A 3-isopropyl-1-methylpyrazol-5-yl 495 1.95 387 ^b 5-bromo-2-methoxypyridin-3-yl 559 2.03 388 " 5-methyl-2-phenyl-1/7-imidazol-4-yl 529 1.95 389 ' 3- (1-oxo, 3-dihydro-2H-isoindol-2-yl [propyl 532 1.82 390 " 1-ethylpiperidin-2-yl 484 1.91 391 ^e 3 - [(pyrimidine ~ 2-ylthio) methyl] phenyl 573 2.08 392 ^w 4 - [(pyridin-2-ylthio) methyl] phenyl 572 2.17 393 ³ 6-cyclohexyl-2-oxo-1,2,3,6- tetrahydropyrimidin-4-yl 551 2.04 394 ^th 5-oxo-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 No. 3029281.

B = 5-bromo-2-methoxynicotinic acid was used, see EP 306251, Preparation I.

B = used 5-methyl-2-phenyl-1H-imidazole-4-carboxylic acid, see 1. Set 8os. 1948; 1969.

G = used 3- (1-oxo-1,3-dihydro-2H-isoindol-2-yl) propanoic acid, see 1. It. Siet. 83; 26 (2); 243.

D = 1-ethylpiperidin-2-carboxylic acid was used, see 1Ogia1 o £ Sogdachsii No. 1c1eag UeShste; 1978; 40 (6); 110 _3-6 .

Ε = 3 - [(pyrimidin-2-ylthio) methyl] benzoic acid was used, see 1. SHI Shay. 8os. (97); 74 (7); 575.

W = used 4 - [(pyridin-2-ylthio) methyl] benzoic acid, see I8 4325959, example 2.

3 = used 6-cyclohexyl-2-oxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid, see EO.C. 2000; 65 (20); 6777.

And = 5-oxo-1-propylpyrrolidine-3-carboxylic acid was used, see \ UO 200202614.

K = used 5-propylisoxazole-4-carboxylic acid, see 1. Not! Siet. 1991; 28 (2) 453.

Examples 396-403.

A mixture of the corresponding amine of Preparation 12a (1 equiv.), The corresponding acid chloride (1.2 to 1.4 equiv.) And Ν-ethyldiisopropylamine on a polymer substrate (10 equiv.) In dichloromethane (16 ml mmol ^-1 ) was stirred at room temperature for 2 hours. Tris- (2 aminoethyl) amine polystyrene was added and the mixture was stirred for one hour. Then washed it with 1N. solution

- 91 010132 sodium hydroxide. The aqueous solution was extracted with dichloromethane (2x) and the combined organic solutions were concentrated under reduced pressure. The crude products were purified by silica gel column chromatography using ethyl acetate: methanol: ammonia 0.88 (90: 10: 1) as an eluent to obtain the indicated compounds.

Example No. Data 396 νν = 2-Wed ₃ ; Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.61-1.76 (t, 1Н), 1.79-1.98 (t, ЗН), 2.622.80 (t, 1Н). 2.84-2.97 (t, 2H), 3.42 (t, 1H), 4.60 (t. 1H), 5.62 (b, 2H), 6.99 (t, 2H), 7.20-7.55 (t, 6H), 7.59 (t, 1H), 7.66 (t, 1H). LC-MS: t / ζ CHIAD * 516 [MH] * 397 νν = 3-CE ₃ ; ¹ H-NMR (400 MHz, COC1 ₃ ): δ 1.80 (t, 2H), 1.98 (t, 2H), 2.70 (t, 1H), 2.88-3.02 (t, 2H), 3.72 (t, 1H), 4.57 (t, 1H), 5.62 (3, 2H), 7.00 (t, 2H), 7.22 (b, 2H), 7.25-7.59 (t, 4H), 7.65 (t, 2H). LC-MS: t / ζ CHIAD * 516 [MH] * 398 νν = 4-CE ₃ ; Я-NMR (400 MHz, NWCO): δ 1.78-1.96 (t, 4H), 2.82 (t, 2H), 3.00-3.14 (t, 1H), 3.62 (t, 1H), 4.58 (t, 1H), 5.67 (s, 2H), 7.22 (t, 2H), 7.50 (b, oi \ 7 with? 77 / a oi \ ι /, .νν \ | 11, ΤΙ 1), 1, 1 G (M, U. LC-MS: t / ζ HIAD * 516 [MH] * 399 * νν = 2-E, 5-C1; Ή NMR (400 MHz, СОС1з): δ 1.78-2.00 (t, 4Н), 2.70 (t, 1Н), 2.91 (t, 1Н>, 3.01 (t, 1Н), 3.62 (t, 1Н), 4.58 (t , 1H), 5.63 (s, 2H), 7.01 (t, 3H), 7.30 (t, 2H), 7.42 (b, 2H), 7.50 (s, 2H). LC-MS: t / ζ CHIAD * 500 [MN] * [ 400 ⁵ νν = 3-E. Я-NMR (400 MHz, СОС! З): δ 1.66-1.81 (t, 2Н), 1.98 (t, 2Н), 2.66 (t, 1Н), 2.80-2.96 (t, 2Н), 3.74-3.82 (t , 1H), 4.45-4.60 (t, 1H), 5.62 (s, 2H), 6.99-7.12 (t, 4H), 7.15 (s, 1H), 7.37 (t, 1H), 7.42 (b, 2H), 7.49 (s, 2H). LC-MS: t / ζ CHIAD * 466 [MH] * νν = 2,3-di-E Ή-NMR (400 MHz, СОС1 ₃ ): δ 1.74-2.00 (t, 4Н). 2.72 (t, 1H), 2.79 (t, 1H), 3.01 (t, 1H), 3.62 (t, 1H), 4.60 (t, 1H), 5.62 (s, 2H), 7.01 (t, 2H>, 7.07 -7.21 (t, 3H), 7.42 (b, 2H), 7.52 (s, 2H). LC-MS: t / ζ CHIAD * 484 [MH] * 402 ⁵ νν = 2-E, 3-C1 Я-NMR (400 MHz, С0С1з): δ 1.62-2.00 (t, 4Н), 2.70 (t, 1Н), 2.82-3.06 (t, 2Н), 3.60 (t, 1Н), 4.60 (t, 1Н), 5.62 (s, 2H), 7.00 (t, 2H), 7.15 (t, 1H), 7.24 (t. 1H), 7.41 (t, 3H), 7.45 (s, 2H). LC-MS: t / ζ CHIAD * 500 [MN] * 403 ^e νν = 4-Ε, 3-C1; ¹ H-NMR (400 MHz, СОС1з): b 1.74-1.85 (t, 2H), 1.98 (t, 2H), 2.70 (t, 1H), 2.82-2.98 (t, 2H), 3.70-3.88 (t, 1H), 4.40-4.58 (t, 1H), 5.63 (s, 2H), 7.02 (t, 2H), 7.17 (t, 1H), 7.23 (t, 1H), 7.42 (t, 3H), 7.49 (s , 2H). LC-MS: t / ζ CHIAD * 500 [MN] *

A = used 2.0 equiv. triethylamine instead of Ν-ethyldiisopropylamine deposited on the polymer.

- 92 010132

B = used 2 equiv. Ν-methylmorpholine instead of Ν-ethyldiisopropylamine deposited on the polymer.

Examples 404-405.

A solution of the corresponding acid, 2CO ₂ H (1.2 equiv.), O-benzotriazol-yl-1Ν hexafluorophosphate, Ν, Ν ', Ν'-tetramethyluronium (1.2 equiv.), Ν-methylmorpholine (1.4 equiv. ) and the amine of Preparation 12a (1 equiv.) in dichloromethane (7-10 ml mmol ^-1 ) were stirred at room temperature for 24 hours. The reaction mixture was partitioned between sodium hydroxide solution and dichloromethane and the layers were then separated. The organic solution was washed with a solution of ammonium chloride, dried over MgSO ₄ and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography with gradient elution with dichloromethane: methanol: ammonia 0.88 (from 100: 0: 0 to 90: 10: 1) to obtain the indicated compounds.

Example No. Data 404 Ζ = 3-fluoro-5-chlorophenyl ¹ H-NMR (400 MHz, СОС1 ₃ ): δ 1.80 (t, 2H), 1.98 (t, 2H), 2.70 (t, 1H), 2.95 (t, 2H), 3.78 (t, 1H), 4.48 (t, 1H), 5.63 (5, 2H), 6 99 (t, 3H), 7.15 (t, 2H), 7.42 (6, 2H), 7.50 (δ, 2H). LC-MS: t / ζ CHIAD ⁺ 500 [M] ⁺ 405 Ζ = indazol-3-yl Я-NMR (400 MHz, ϋΜ30-άβ): δ 1.63-1.82 (t, 4H), 2.78-2.90 (t, 2H), 3.18 (t, 1H), 4.45 (t, 1H), 4.62 (t, 1H) ), 5.77 (s, 2H), 7 18 (t, 1H), 7.32-7.40 (t, H), 7.58 (t, H), 7.63 (h, 2H), 7.90 (6, 1H). LC-MS: t / ζ ERI ’486 [MH]’

All compounds, examples of which are given above, showed a K ₁ value _of less than 500 nM when tested in a screening of 1.0 (ν _1Α binding _assay on a filter) as described above.

Claims (23)

1. The compound of formula (I) or a pharmaceutically acceptable derivative thereof, wherein X is - [CH ₂ ] _a —K or - [CH ₂ ] _a —O— [CH ₂ ] _b —K; a represents a number selected from numbers from 0 to 6; B is a number selected from numbers from 0 to 6; - 93 010132 K represents H, CE ₃ or Not !; Not! represents a 5- or 6-membered saturated, partially saturated or aromatic heterocyclic ring containing either (a) 1 to 4 nitrogen atoms, or (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 a sulfur atom and 1 or 2 nitrogen atoms, possibly substituted by one or more groups independently selected from V; Υ represents substituents in an amount of one or more, independently selected from - [O] _with [CH ₂ ] _b -K ¹ , which in each case may be the same or different; c, in each case independently, is a number selected from 0 or 1; b, in each case independently, represents a number selected from numbers from 0 to 6; K ¹ , in each case, independently, represents H, halogen, CE ₃ , CN or Not! ¹ ; Not! ¹ , in each case, independently, is a 5- or 6-membered unsaturated heterocyclic ring containing either (a) 1 to 4 nitrogen atoms, or (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms; V is a direct bond or —O—; ring A is a 5-7 membered saturated heterocyclic ring containing either (a) 1 to 4 nitrogen atoms, or (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, wherein ring A is optionally substituted with one or more groups selected from C 1-6 alkyl, phenyl or hydroxy; 0 represents a direct bond or -Ν (Κ ² ) -; K ² represents a hydrogen atom or a C1 _-6 alkyl; Ζ represents - [O] _e - [CH ₂ ] £ -K ³ , a phenyl ring (possibly fused to a benzene ring or He! ² , and this group as a whole is possibly substituted by one or more groups independently selected from V) or Not ! ³ (possibly fused to a benzene ring or He! ⁴ , moreover, this group as a whole is possibly substituted by one or more groups independently selected from V); K ³ represents a C1 _-6 alkyl (optionally substituted with one or more groups independently selected from V), C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl (optionally substituted with one or more groups independently selected from V), not ! ⁵ or ΝΚ ⁴ Κ ⁵ ; e is a number selected from 0 or 1; ί represents a number selected from numbers from 0 to 6; Not! ² and not! ⁵ independently represent a 5- or 6-membered saturated, partially saturated or aromatic heterocyclic ring containing either (a) 1 to 4 nitrogen atoms, or (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, possibly substituted by one or more groups selected from V; Not! ³ represents a 4-6 membered saturated, partially saturated or aromatic heterocyclic ring containing either (a) 1 to 4 nitrogen atoms, or (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 a sulfur atom and 1 or 2 nitrogen atoms, possibly substituted by one or more groups selected from V; Not! ⁴ is a 6-membered aromatic heterocyclic ring containing either (a) 1 to 4 nitrogen atoms, or (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 atoms nitrogen optionally substituted with one or more groups selected from V; K ⁴ and K ⁵ independently represent a hydrogen atom, C 1-6 alkyl, C 1-6 alkyloxy, C 3-8 cycloalkyl (possibly condensed with C 3-8 cycloalkyl) or Not! ^6, and K ⁴ and K ⁵ is optionally independently substituted with one or more groups selected from C1-6 alkyl, C1 _-6 alkyloxy, _C3-8 cycloalkyl (optionally fused with S3-8tsikloalkilom) or phenyl; Not! ⁶ is a 5- or 6-membered saturated, partially saturated or aromatic heterocyclic ring containing either (a) 1 to 4 nitrogen atoms, or (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, possibly substituted by one or more groups selected from V; V, independently in each case, is halogen, [O] _d K ⁶ , 8O2K ⁶ , 8K ⁶ , 8O2XK. ⁶ TO ⁷ [O] b [CH 2] 1SR3, | O || CHE \ phenyl (optionally substituted by halo, C1-6alkyl or C1-6alkyloxy), ΟΝ, phenoxy (optionally substituted by halo), OH, benzyl, HC ⁶ K ⁷ , NSOK ⁶ , benzyloxy, oxo, SOHNA ⁶ , 8O; KK, SOK ⁶ , C1-6 alkylene-YSOK ⁷ , Not! ⁷ ; TO⁶ represents hydrogen, C1_-6alkyl, C_3-6cycloalkyl, C₃-₆cycloalkenyl or C |_-6alkylene-O-C | 6alkyl; K ⁷ is hydrogen or C1 _-6 alkyl; ί represents a number selected from numbers from 0 to 6; 11 is a number selected from 0 or 1; d is a number selected from 0 or 1; _) is a number selected from 0 or 1; Not! ⁷ represents a 5- or 6-membered saturated, partially saturated or aromatic heterocyclic ring containing either (a) 1 to 4 nitrogen atoms, or (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, possibly substituted by K ⁶ , - 94 010132 and / or K ⁷ , and / or oxo group. 2. The compound according to claim 1, where X represents - [CH ₂ ] _a -K. 3. The compound according to claim 2, where K represents He1. 4. The compound according to any one of claims 1 to 3, where Υ represents halogen. 5. The compound according to any one of claims 1 to 4, where V is a direct bond. 6. The compound according to any one of claims 1 to 5, where O represents a direct bond. 7. The compound according to any one of claims 1 to 6, where ring A is a six-membered ring. 8. The compound according to any one of claims 1 to 7, where Ζ represents phenyl. 9. The compound according to any one of claims 1 to 8, where Ζ is substituted by halogen. 10. The compound according to claim 1, selected from (3-chlorophenyl) - {4- [4- (4-chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2, 4] triazol-3-yl] piperidin- 1-yl} methanone, (4-chlorophenyl) - {4- [4- (4-chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol- 3-yl] piperidin1-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] triazol-3-yl] piperidin-1-yl} - (3,5difluorophenyl) 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} - (2,3difluorophenyl) methanone, (3-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, (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, {4- [4- (4-chlorophenyl) -5- [1, 2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] piperidin-1-yl} - (4trifluoromethylphenyl) methanone, {4- [4- (4-chlorophenyl) - 5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] piperidin-1-yl} - (3trifluoromethylphenyl) methanone, {4- [4- (4 -chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] piperidin-1-yl} - (2trifluoromethylphenyl) methanone, (3-chloro -5-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] triazol-3-yl] piperidin-1-yl} - (4difluoromethylphenyl) methanone, {4- [4- (4-chlorophenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] piperidin-1-yl} - ( 1 Nindazol-3-yl) methanone and their pharmaceutically acceptable derivatives. 11. The use of compounds according to any one of claims 1 to 10 as a medicine. 12. A method of treating a mammal, including humans, for treating a disorder in which a V1a antagonist is indicated, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 10. 13. A method for treating a mammal, including humans, for treating anxiety, cardiovascular disease (including angina pectoris, atherosclerosis, hypertension, heart failure, edema, hypernatremia), dysmenorrhea (primary and secondary), endometriosis, vomiting (including seasickness), intrauterine growth retardation fetus, inflammation (including rheumatoid arthritis), abdominal pain that occurs during ovulation, preeclampsia, premature ejaculation, premature birth or Raynaud's disease, including the introduction of therapeutic ki an effective amount of a compound according to any one of claims 1 to 10 to a patient suffering from such a disorder. 14. The treatment method according to item 12 or 13, where the disorder is dysmenorrhea (primary or secondary). 15. The use of a compound according to any one of claims 1 to 10 in the manufacture of a medicament for the treatment of a disorder in which a V1a receptor antagonist is indicated. 16. The use of a compound according to any one of claims 1 to 10 in the manufacture of a medicament for the treatment of anxiety, cardiovascular disease (including angina pectoris, atherosclerosis, hypertension, heart failure, edema, hypernatremia), dysmenorrhea (primary and secondary), endometriosis, vomiting ( including motion sickness), intrauterine growth retardation, inflammation (including rheumatoid arthritis), abdominal pain that occurs during ovulation, preeclampsia, premature ejaculation, premature birth or Raynaud's disease. 17. The use of claim 15 or 16, wherein the disorder is dysmenorrhea (primary or secondary). - 95 010132 18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, together with a pharmaceutically acceptable excipient, diluent or carrier. 19. The combination (A) of a compound according to any one of claims 1 to 10 and (B) of another pharmacologically active ingredient. 20. The combination according to claim 19, where (B) is an oral contraceptive, an inhibitor of ΡΌΕν (phosphodiesterase ν), an inhibitor of COX (cyclooxygenase), an NO donor or L-arginine. 21. The use of the combination according to claim 19 or 20 for the manufacture of a medicament for combination therapy by simultaneous, sequential or separate administration for the treatment of dysmenorrhea. 22. A method of treating dysmenorrhea, comprising administering to a subject in need of such treatment a combination of the amounts of (A) and (B) according to claim 19 or 20, which together are effective. 23. A pharmaceutical product containing a combination of (A) and (B) according to claim 19 or 20, as a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhea (primary or secondary).