JP4698604B2 - Triazole derivatives as vasopressin antagonists - Google Patents

Description

  The present invention relates to triazole derivatives, processes for the preparation of such derivatives, intermediates used in the manufacture of such derivatives, compositions containing such derivatives, and the use of such derivatives.

  The triazole derivatives of the present invention are vasopressin antagonists. In particular, the derivatives are antagonists of the V1a receptor and have many therapeutic uses, particularly in the treatment of dysmenorrhea (primary and secondary).

  There is a high degree of need that has not yet been addressed in the area of menstrual disorders, and it is estimated that up to 90% of all menstrual women are affected to some extent. It is estimated that up to 42% of women have failed work or other activities due to menstrual pain, resulting in approximately 600 million working hours lost per year in the United States {Coco, AS ( 1999). Primary dysmenorrhoea. [Review] [30 refs]. American Family Physician, 60, 489-96}.

  Menstrual pain in the lower abdomen is caused by increased myometrial activity and decreased uterine blood flow. These pathophysiological changes result in abdominal pain that spreads radially toward the back and legs. This can make women feel nauseous, have headaches, and suffer from insomnia. This condition is called dysmenorrhea and can be classified as either primary or secondary dysmenorrhea.

  Primary dysmenorrhea is diagnosed when the abnormalities that cause this condition are not identified. This affects up to 50% of the female population {Coco, AS (1999). Primary dysmenorrhoea. [Review] [30 refs]. American Family Physician, 60, 489-96; Schroeder, B. & Sanfilippo, JS ( 1999). Dysmenorrhoea and pelvic pain in adolescents. [Review] [78 refs]. Pediatric Clinics of North America, 46,555-71}. For example, secondary dysmenorrhea will be diagnosed if there is a potential gynecological disorder such as endometriosis, pelvic inflammatory disease (PID), uterine fibroids or cancer. Secondary dysmenorrhea is diagnosed in only about 25% of women suffering from dysmenorrhea. Dysmenorrhea can be associated with menorrhagia that accounts for approximately 12% of referrals to gynecological outpatient departments.

  Currently, women with primary dysmenorrhea are treated with nonsteroidal anti-inflammatory drugs (NSAID's) or oral contraceptives. In the case of secondary dysmenorrhea, surgery can be performed to treat occult gynecological disorders.

  Women with dysmenorrhea have circulating vasopressin levels that are greater than those found in healthy women at the same time of the menstrual cycle. Inhibition of the pharmacological action of vasopressin at the uterine vasopressin receptor can prevent dysmenorrhea.

  Therefore, the compounds of the present invention have a very wide range of disorders, in particular aggression, Alzheimer's disease, anorexia, anxiety, anxiety disorders, asthma, atherosclerosis, autism, cardiovascular diseases (anginal disorders, atheromas Sclerosis, hypertension, heart failure, edema, hypernatremia), cataract, central nervous system disease, cerebrovascular ischemia, cirrhosis, dementia, Cushing disease, depression, diabetes, dysmenorrhea (primary and Secondary), vomiting (including motion sickness), endometriosis, gastrointestinal disease, glaucoma, gynecological disease, heart disease, intrauterine growth retardation, inflammation (including rheumatoid arthritis), ischemia, ischemic Heart disease, lung tumor, dysuria, mittlesmerchz, neoplasm, nephrotoxicity, non-insulin dependent diabetes, obesity, obsessive / compulsive disorder, ocular hypertension, preeclampsia (preclampsia) , Premature ejaculation, premature birth (early Treatment), respiratory disease, Raynaud's disease, kidney disease, renal failure, male or female sexual dysfunction, septic shock, sleep disorder, spinal cord injury, thrombosis, urinary tract infection or urolithiasis May be useful.

  The following diseases or disorders are particularly important: anxiety, cardiovascular diseases (including angina, atherosclerosis, hypertension, heart failure, edema, hypernatremia), dysmenorrhea (primary and secondary) Endometriosis, vomiting (including motion sickness), intrauterine growth retardation, inflammation (including rheumatoid arthritis), intermediate pain, preeclampsia, premature ejaculation, premature birth (premature labor) or Raynaud's disease.

  The compounds of the invention and their pharmaceutically acceptable salts and derivatives have the advantage that they are selective inhibitors of the V1a receptor (thus appearing to have mild side effects) Compared to prior art compounds, may have a faster onset of action, may be more effective, may work longer, and may have greater bioavailability There may be other properties that are desirable or more desirable.

  According to the invention, the formula I:

Or a pharmaceutically acceptable derivative thereof: wherein:
X is, - _{[CH 2]} a -R or _{- [CH 2] a -O- [} CH 2] represent the b -R; a represents a number selected from 0 to 6; b is 0 to 6 R represents H, CF ₃ or Het; Het is (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 5- or 6-membered saturation containing one or two oxygen atoms and one or two nitrogen atoms, optionally substituted with one or more groups independently selected from W, Represents a partially saturated or aromatic heterocycle;
Y represents one or more substituents independently selected from — [O] _c — [CH ₂ ] _d —R ¹ , and can be the same or different at each occurrence, c being an occurrence Each independently represents a number selected from 0 or 1; d represents a number independently selected from 0 to 6 for each occurrence; R ¹ independently represents H, halo, CF ₃ , CN or Het ¹ ; Het ¹ is independently for each occurrence (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) oxygen atom Represents a 5- or 6-membered unsaturated heterocycle containing one or one sulfur atom and one or two nitrogen atoms;
V represents a direct bond or —O—;
Ring A contains (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms. Represents a 5- to 7-membered saturated heterocyclic ring; or ring A represents a phenylene group; ring A is optionally one or more groups selected from C ₁ -C ₆ alkyl, phenyl or hydroxy Is replaced by;
Q represents a direct bond or —N (R ² ) —; R ² represents hydrogen or C ₁ -C ₆ alkyl;
Z is — [O] _e — [CH ₂ ] _f —R ³ , a phenyl ring (optionally fused to a benzene ring or Het ^2, and the group as a whole is optionally independently selected from W Or a Het ³ (optionally fused to a benzene ring or Het ⁴ and the group as a whole is optionally one independently selected from W R ³ is C ₁ -C ₆ alkyl (optionally substituted by one or more groups independently selected from W), C ₃ -C _{6 cycloalkyl,} C 3 -C ₆ cycloalkenyl, phenyl (optionally substituted with one or more groups independently selected from W), representing the Het ⁵ or ^NR 4 ^{R 5;} e is 0 Or 1 Represents the number selected; f represents a number selected from Less than six; Het ² and Het ⁵ are independently, 1-4 (a) nitrogen atom, (b) 1 oxygen atoms or Represents a sulfur atom, or (c) a 5- or 6-membered saturated, partially saturated or aromatic heterocycle containing 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, , Optionally substituted with one or more groups independently selected from W; Het ³ is (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, Or (c) represents a 4- to 6-membered saturated, partially saturated or aromatic heterocycle containing 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, which may optionally Substituted by one or more groups independently selected from W; ⁴ includes (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms, Represents a 6-membered aromatic heterocycle, which is optionally substituted by one or more groups independently selected from W; R ⁴ and R ⁵ are independently hydrogen, C _1- C ₆ alkyl, C ₁ -C ₆ alkyloxy, C ₃ -C ₈ cycloalkyl (optionally fused to C ₃ -C ₈ cycloalkyl), or Het ⁶ ; R ⁴ and R ⁵ are optionally In some cases, one selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, C ₃ -C ₈ cycloalkyl (optionally fused to C ₃ -C ₈ cycloalkyl), or phenyl. Independently substituted by the above groups Het ⁶ includes (a) 1 to 4 nitrogen atoms, (b) one oxygen atom or one sulfur atom, or one or two (c) one oxygen atom or one sulfur atom and a nitrogen atom Represents a 5- or 6-membered saturated, partially saturated or aromatic heterocycle, which is optionally substituted by one or more groups independently selected from W;
W is independently halo, [O] _g R ⁶ , SO ₂ R ⁶ , SR ⁶ , SO ₂ NR ⁶ R ⁷ , [O] _h [CH ₂ ] _i CF ₃ , [O] _j independently for each occurrence. CHF _2, (in some cases, _halo, substituted by C 1 -C ₆ alkyl or _C 1 -C ₆ alkyl) phenyl, CN, phenoxy (optionally is substituted by halo), OH, benzyl, NR ⁶ R ^7, NCOR ^6, represents benzyloxy, ^oxo, a ^{_{CONHR 6, NSO 2 R 6 R}} 7, COR 6, C 1 -C 6 alkylene -NCOR ^7, Het ^{7; R 6} is hydrogen, _{C 1} - C _{6 alkyl,} C 3 -C _{6 cycloalkyl,} C 3 -C ₆ represents a cycloalkenyl or _C 1 -C ₆ alkylene _-O-C 1 -C ₆ alkyl; ^{R 7} is hydrogen or C -C represents a ₆ alkyl; i represents a number selected from 0 to 6; is h represents a number selected from 0 or 1; g is a number selected from 0 or 1; j Represents a number selected from 0 or 1; Het ⁷ is (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or sulfur. Represents a 5- or 6-membered saturated, partially saturated or aromatic heterocycle containing 1 atom and 1 or 2 nitrogen atoms, which in some cases is R ⁶ and / or R ⁷ and / or Substituted by an oxo group.

  In an alternative embodiment, formula (I '):

Or a pharmaceutically acceptable derivative thereof, wherein:
X is, - _{[CH 2]} a -R or _{- [CH 2] a -O- [} CH 2] represent the b -R; a represents a number selected from 0 to 6; b is 0 to 6 R represents H, CF ₃ or Het; Het is (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) Represents a 5- or 6-membered heterocycle containing one oxygen or one sulfur atom and one or two nitrogen atoms;
Y represents — [O] _c — [CH ₂ ] _d —R ¹ ;
Y ′ represents — [O] _{c ′} — [CH ₂ ] _{d ′} —R ^{1 ′} ; c and c ′ independently represent a number selected from 0 or 1; d and d ′ are And independently represents a number selected from 0 to 6; R ¹ and R ^{1 ′} independently represent H, halo, CF ₃ or Het ¹ ; Het ¹ is (a) a nitrogen atom 1 5 or 6-membered unsaturated heterocycle containing -4, (b) 1 oxygen or 1 sulfur atom, or (c) 1 or 2 oxygen atoms and 1 or 2 nitrogen atoms Represents;
Ring A represents a 5-membered or 6-membered saturated heterocyclic ring containing at least one nitrogen atom;
Z is — [O] _e — [CH ₂ ] _f —R ² , a phenyl ring (optionally fused to a phenyl ring or a 5- or 6-membered saturated, partially unsaturated or aromatic heterocycle; and / Or optionally substituted by one or more groups independently selected from W), or a 6-membered aromatic heterocycle (optionally fused to a phenyl ring or a 6-membered aromatic heterocycle, And / or optionally is substituted by one or more groups independently selected from W); R ² represents C ₁ -C ₆ alkyl, or C ₃ -C ₆ cycloalkyl; e represents a number selected from 0 or 1; f represents a number selected from 0 to 6;
W represents halo, [O] _g R ³ , SO ₂ R ³ , SR ³ , SO ₂ NR ³ R ⁴ , [O] _h [CH ₂ ] _i CF ₃ , OCHF ₂ , phenyl, CN, phenoxy (optionally Is substituted by halo), OH, benzyl, NCOR ³ , benzyloxy, oxy, CONHR ³ , NSO ₂ R ³ R ⁴ , COR ³ , C ₁ -C ₆ alkylene-NCOR ³ , Het ² ; ³ represents hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, or C ₁ -C ₆ alkylene-O—C ₁ -C ₆ alkyl; R ⁴ is hydrogen or C ₁ -C ₆ alkyl; i represents a number selected from 0 to 6; is h represents a number selected from 0 or 1; g represents a number selected from 0 or 1; Het ² is (A) Nitro 5- or 6-membered saturation containing 1 to 4 atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms Represents a partially unsaturated or aromatic heterocycle, which is optionally substituted by R ³ and / or R ⁴ and / or an oxy group.

  In the above definition, halo means fluoro, chloro, bromo and iodo. Alkyl, alkylene and alkyloxy groups containing the requisite number of carbon atoms can be unbranched or branched. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkyloxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. Examples of alkylene include methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene and 2,2-propylene. Het represents a heterocyclic group, examples of which are tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4 -Dithianyl, piperazinyl, 1,4-azathianyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2,3,4-tetrahydropyridinyl, 1,2 , 5,6-tetrahydropyridinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1-oxa-2, 3-diazolyl, 1-oxa-2,4-di Zolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5- Includes diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl.

Preferred compounds are those in which X represents CH ₂ OCH ₃ . A compound in which X is — [CH ₂ ] _a R is more preferable.
A preferred compound is a compound in which a represents a number selected from 0 to 5. A more preferable compound is a compound in which a is a number selected from 0 to 4. Still more preferred compounds are those in which a is a number selected from 0 to 3. Still more preferred compounds are those in which a is a number selected from 0-2. Most preferred is a compound in which a represents Formula 1.

Preferred compounds are those in which R represents H. More preferred compounds are those in which R represents Het. Even more preferred are compounds in which R represents triazolyl.
Preferred compounds are those in which Y represents 1 or 2 substituents. More preferred compounds are those in which Y represents a single substituent.

Preferred compounds are those in which Y represents halo. More preferred compounds are those in which Y represents chloro and / or fluoro.
Preferred compounds are those in which V represents a direct bond. Preferred compounds are those in which Q represents a direct bond. More preferred compounds are those in which both V and Q represent a direct bond.

Preferred compounds are those in which ring A contains two nitrogen atoms. More preferred compounds are those in which Ring A contains one nitrogen atom.
A preferred compound is a compound in which ring A represents a 5-membered ring. More preferred compounds are those in which ring A represents a 6-membered ring. Even more preferred compounds are those in which ring A represents piperidinylene.

  A preferred compound is a compound in which ring A is bonded to V through a nitrogen atom. A more preferable compound is a compound in which ring A is bonded to Q via a nitrogen atom. Preferred compounds are those in which ring A is bonded to both Q and V via a nitrogen atom.

Preferred compounds are those in which Z represents Het ³ . Het ³ is selected from indazolyl, indolyl, indenyl, pyrazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, benzothienyl, benzothiazolyl, quinolinyl, benzoxazinyl, isoxazolyl, imidazolyl, furyl, benzofuryl, cinnolinyl, morpholinyl, chrominyl, derivatives thereof And optionally represents a substituted group. More preferred compounds are those in which Z represents phenyl.

Preferred compounds are those in which Z is mono- or disubstituted. More preferred compounds are those in which Z is monosubstituted.
Preferred compounds are those in which Z is substituted by trifluoromethyl. More preferred compounds are those in which Z is substituted by halo. More preferred compounds are those in which Z is substituted by chloro and / or fluoro.

Certain preferred compounds according to the invention are the compounds listed in the Examples section below and their pharmaceutically acceptable salts. Particularly preferred compounds are listed below:
(3-Chloro-phenyl)-{4- [4- (4-chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3- Yl] -piperidin-1-yl} -methanone;
(4-Chloro-phenyl)-{4- [4- (4-chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3- Yl] -piperidin-1-yl} -methanone;
(5-Chloro-2-fluoro-phenyl)-{4- [4- (4-chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] Triazol-3-yl] -piperidin-1-yl} -methanone;
{4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl }-(3,5-difluoro-phenyl) -methanone;
{4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl }-(3-Fluoro-phenyl) -methanone;
{4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl }-(2,3-difluoro-phenyl) -methanone;
(3-Chloro-2-fluoro-phenyl)-{4- [4- (4-chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] Triazol-3-yl] -piperidin-1-yl} -methanone;
(3-Chloro-4-fluoro-phenyl)-{4- [4- (4-chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] Triazol-3-yl] -piperidin-1-yl} -methanone;
{4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl }-(4-trifluoromethyl-phenyl) -methanone;
{4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl }-(3-trifluoromethyl-phenyl) -methanone;
{4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl }-(2-trifluoromethyl-phenyl) -methanone;
(3-Chloro-5-fluoro-phenyl)-{4- [4- (4-chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] Triazol-3-yl] -piperidin-1-yl} -methanone;
{4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl }-(4-Difluoromethyl-phenyl) -methanone;
{4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl }-(1H-indazol-3-yl) -methanone;
And pharmaceutically acceptable derivatives thereof.

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

Pharmaceutically acceptable salts of the compound of formula (I) include the acid addition and base salts thereof.
Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, aspartate, benzoate, besylate, besylate, bicarbonate / carbonate, bisulphate, borate, camsylate, citrate, Edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride , Hydrobromide / bromide, hydroiodide / iodide, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methyl Sulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, palmoate, phosphate, hydrogen phosphate, phosphate Dihydrogen salt, saccharinate, stearate, It encompasses Haq, sulfate, D- and L- tartrate, tosylate (tosylate) and trifluoroacetic acid salt. Particularly suitable salts are the besylate derivatives of the compounds according to the invention.

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

  For a review on suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Wiley-VCH, Weinheim, Germany (2002). Pharmaceutically acceptable salts of the compound of formula (I) can be readily prepared by mixing together a solution of the compound of formula (I) and, optionally, the desired acid or base solution. The salt can be precipitated from solution and recovered by filtration, or the solvent can be evaporated to recover the salt. The degree of ionization in the salt can vary from complete ionization to almost non-ionization.

  The compounds of the invention can exist in both unsolvated and solvated forms. The term “solvate” is used herein to denote a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term “hydrate” is used when the solvent is water.

  In contrast to the solvates, complexes such as clathrates, drug-host inclusion compounds, where the drug and host are present in both stoichiometric and non-stoichiometric amounts are also present in the present invention. Included within range. Also included are drug complexes containing two or more organic and / or inorganic components, whether stoichiometric or non-stoichiometric. The resulting complex can be ionized, partially ionized, or non-ionized. For a review of such complexes, see J. Pharm. Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

  Hereinafter, all references to a compound of formula (I) and pharmaceutically acceptable derivatives thereof are to references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof. References are also included.

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

As mentioned above, the present invention encompasses all polymorphs of the compound of formula (I) as defined above.
So-called “prodrugs” of the compounds of formula (I) are also within the scope of the invention. Thus, certain derivatives of a compound of formula (I), which by themselves have little or no pharmacological activity, also have formulas that have the desired activity when administered in or on the body. (I) Can be converted to a compound (eg, hydrolysis). Such derivatives are called “prodrugs”. More information on prodrug applications can be found in “Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and“ Bioreversible Carriers in Drug Design ”, Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association).

  “Prodrugs” according to the invention are, for example, suitable functional groups present in compounds of formula (I), for example as described in “Design of Prodrugs” (Elsevier, 1985) by H. Bundgaard. It can be prepared by substituting certain moieties known to those skilled in the art as “pro-moieties”.

Some examples of prodrugs according to the invention are listed below:
(I) if the compound of formula (I) contains a carboxylic acid functional group (—COOH), substitution of H by its ester, for example C ₁ -C ₆ alkyl;
(Ii) if the compound of formula (I) contains an alcohol function (—OH), substitution of H with its ether, for example C ₁ -C ₆ alkanoyloxymethyl; and (iii) the compound of formula (I) Substitution of one or both H by its amide, eg C ₁ -C ₁₀ alkanoyl, if it contains a primary or secondary amino function (—NH ₂ or —NHR, where R is not H) .

Other examples of substituents according to the above examples and examples of other prodrug types can be found in the above references.
Finally, certain compounds of formula (I) can themselves act as prodrugs of other compounds of formula (I).

Metabolites of the compound of formula (I) are also within the scope of the invention when formed in vivo.
Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (I) contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible and the compound contains, for example, a keto or oxime group or an aromatic moiety. Tautomerism (“tautomerism”) can occur. As a result, a single compound can exhibit more than one type of isomerism.

  All stereoisomers, geometric isomers and tautomers of the compounds of formula (I) are included within the scope of the present invention, including compounds exhibiting two or more isomerisms and mixtures of one or more thereof. Is done. Also included are acid addition or base salts wherein the counterion is optically active, such as D-lactate or L-lysine, or racemates such as DL-tartrate or DL-arginine.

Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, fractional crystallization and chromatography.
Conventional techniques for preparing / isolating individual enantiomers are chiral synthesis from appropriate optically pure precursors or of racemates (or salts or derivatives of racemates) using, for example, chiral HPLC. Includes splits.

  Alternatively, the racemate (or racemic precursor) can be combined with a suitable optically active compound, such as an alcohol, or when the compound of formula (I) contains an acidic or basic moiety, such as tartaric acid or 1-phenylethylamine. Can be reacted with acids or bases. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers can be separated by the means well known to those skilled in the art by the corresponding pure enantiomer (s). ).

  The chiral compounds of the invention (and their chiral precursors) contain 0-50% isopropanol (typically 2-20%), 0-5% alkylamines, typically 0.1% It can be obtained in enantiomeric enriched form using chromatography on asymmetric resins, typically HPLC, with a mobile phase consisting of a hydrocarbon containing diethylamine, typically heptane or hexane. Concentrate the eluate to obtain an enriched mixture.

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

  The present invention also includes compounds of formula (I) wherein one or more atoms have been replaced by an atom having the same atomic number but having an atomic mass or mass number different from the atomic mass or mass number normally found in the natural state. ) Includes all pharmaceutically acceptable isotopic variations of the compound.

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

Certain isotopically-labelled Formula (I) compounds, such as those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, ie ³ H, and carbon-14, ie ¹⁴ C, are particularly useful in view of their ease of incorporation and ready means of detection.

For example deuterium, i.e., such as ^{2 H,} substitution with heavier isotopes, greater metabolic stability, attributable for example in vivo half-life or reduced dosage requirements, it is possible to provide a constant therapeutic benefit in, Therefore, it may be preferable under certain circumstances.

For example, substitution with positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N can be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy.

  Isotopically labeled compounds of formula (I) can be synthesized by using conventional techniques known to those skilled in the art or by processes similar to those described in the examples and preparations of the present specification. Alternatively, it can be produced using a suitable isotope labeling reagent.

Solvate pharmaceutically acceptable according to the invention include those wherein the solvent of crystallization may be isotopically substituted _(e.g., D 2 _O, d 6 _- acetone and d _6-DMSO) encompasses solvates.
The compounds of the present invention are useful for therapy. A further aspect of the present invention is therefore the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as a medicament.

  The compounds of the present invention exhibit activity as V1a antagonists. In particular, the compounds of the present invention may be used for the purposes of aggression, Alzheimer's disease, anorexia, anxiety, anxiety disorder, asthma, atherosclerosis, autism, cardiovascular disease (angina, atherosclerosis, hypertension, heart failure, edema, Hypernatremia), cataract, central nervous system disease, cerebrovascular ischemia, cirrhosis, dementia, Cushing disease, depression, diabetes, dysmenorrhea (primary and secondary), vomiting (motion sickness) Endometriosis, gastrointestinal disease, glaucoma, gynecological disease, heart disease, intrauterine growth retardation, inflammation (including rheumatoid arthritis), ischemia, ischemic heart disease, lung tumor, dysuria, Intermediate pain, neoplasm, nephrotoxicity, non-insulin dependent diabetes mellitus, obesity, obsessive compulsive disorder, ocular hypertension, preeclampsia, premature ejaculation, premature birth (premature labor), respiratory system disease, Raynaud's disease, renal disease, kidney Failure, male or female Many, including functional dysfunction, septic shock, sleep disorder, spinal cord injury, thrombosis, urinary tract infection or urolithiasis, sleep disorder, spinal cord injury, thrombosis, urinary tract infection, urolithiasis Useful for the treatment of conditions. In particular, dysmenorrhea (primary and secondary) is important. More specifically, primary dysmenorrhea is important.

  Therefore, a further aspect of the present invention is a method of treating mammals, including humans, for treating disorders to which a V1a antagonist is indicated, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. Alternatively, a method comprising administering to the mammal a therapeutically effective amount of a solvate. In particular, the compound of formula (I) is used for anxiety, cardiovascular diseases (including angina pectoris, atherosclerosis, hypertension, heart failure, edema, hypernatremia), dysmenorrhea (primary and secondary), For the treatment of endometriosis, vomiting (including motion sickness), intrauterine growth retardation, inflammation (including rheumatoid arthritis), intermediate pain, preeclampsia, premature ejaculation, premature birth (early delivery), or Raynaud's disease Useful. Even more specifically, the compounds of the present invention are useful in the treatment of dysmenorrhea (primary and secondary).

  A further aspect of the invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for treating a disorder to which a V1a antagonist is indicated.

  All of the compounds of formula (I) may be prepared by the methods described in the general methods presented below, by the specific methods described in the Examples and Preparations sections, or by routine modifications thereof. it can. The present invention further encompasses any or one or more of these methods for making the compound of formula (I), in addition to any novel intermediates used in these methods.

Unless otherwise specified in this specification:
WSCDI means 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, DCC means N, N′-dicyclohexylcarbodiimide, HOAT means 1-hydroxy-7-azabenzotriazole And HOBT means 1-hydroxybenzotriazole hydrate.

PyBOP® means benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate, PyBrOP® means bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, and HBTU Means O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium hexafluorophosphate;
mCPBA means meta-chloroperbenzoic acid, AcOH means acetic acid, HCl means hydrochloric acid, TFA means trifluoroacetic acid, and p-TSA means p-toluenesulfonic acid Means;
Et ₃ N means triethylamine, NMM refers to N- methylmorpholine;
K ₂ CO ₃ means potassium carbonate and KO- ^t Bu means potassium tert-butoxide;
NaOH, KOH and LiOH mean sodium hydroxide, potassium hydroxide and lithium hydroxide respectively;
BOC means tert-butoxycarbonyl and CBz means benzyloxycarbonyl;
PTFE means polytetrafluoroethane;
MeI means methyl iodide;
MeTosylate means methyl p-toluenesulfonate;
MeOH means methanol, EtOH means ethanol and n-BuOH means n-butyl alcohol;
EtOAc means ethyl acetate, MeCN means acetonitrile, THF means tetrahydrofuran, DMSO means dimethyl sulfoxide, DCM means dichloromethane, DMF means N, N-dimethyl. Means formamide, NMP means N-methyl-2-pyrrolidinone, and DMA means dimethylacetamide;
Me means methyl, Et means ethyl, Cl means chloro and OH means hydroxy;
“cat” means “catalyst” or “catalytic”.

In the following general methods, R, R ¹ , R ² , R ³ , Ring A, V, X, Q, Z, Y, Y ′, Het, Het ¹ and Het ² are the formulas (unless otherwise specified) I) As defined above for compounds. When Q represents NR ² or Q represents a direct bond attached to the nitrogen atom in ring A, the compound of formula (I) can be prepared according to Scheme 1.

PG represents a suitable N protecting group, typically a benzyl, BOC or CBz group, preferably BOC.
Scheme 1
The compound of formula (II) is a compound of the corresponding lower alkyl ester (eg methyl or ethyl) and hydrazine as described in WO 9703986 A1 19970206 or under standard conditions, as exemplified in the preparation examples below. It can obtain by reaction of.

  Step (a): The compound of formula (III) is prepared from hydrazine (II) and a suitable acetal (eg N, N-dimethylacetamide) in a suitable solvent such as THF or DMF at a temperature between room temperature and about 60 ° C. Can be prepared by reaction with dimethylacetal) for up to 18 hours. The resulting intermediate is then treated for about 18 hours under acid catalysis (eg, p-TSA or TFA) in a high boiling point solvent (eg, toluene or xylene) to give the compound of formula (III). be able to. Preferred conditions: 1.5 to 2.0 equivalents of acetal (eg, N, N-dimethylacetamide dimethyl acetal, triethylorthopropionate), THF or DMF at room temperature to 60 ° C. for about 18 hours, followed by p -TSA or TFA (cat) in toluene at reflux temperature for 18 hours.

  Step (b): The formation of triazole (IV) is carried out in a suitable high-boiling solvent (eg toluene or xylene) in the presence of a suitable acid catalyst, such as TFA or p-TSA, at elevated temperatures (III ) And a suitable aniline. Preferred conditions: 0.5-1.0 equivalents of TFA, 1.0-2.0 equivalents of aniline in toluene at about reflux temperature for up to 18 hours.

  Step (c): Deprotection of compound (IV) is performed using standard methodologies as described in “Protecting Groups in Organic Synthesis” by T.W. Greene and P. Wutz. When PG represents BOC, preferred conditions are as follows: 4M HCl in dioxane in MeOH, dioxane or DCM, room temperature to about 50 ° C., up to 18 hours; or 2.2M HCl in MeOH, room temperature Up to 18 hours; or TFA in DCM, about 1 hour at room temperature. Alternatively, when PG represents BOC, compound (V) is obtained from compound (III) with excess TFA (typically 1.1 to 1.5 equivalents) in toluene and a suitable aniline, It can be prepared directly by treatment for up to 4 days at the reflux temperature of the reaction.

  Step (d): The compound of formula (I) is prepared from an amine (V) and a suitable acid or acid chloride (

In this case, T represents OH or Cl). The coupling can be performed by using any of the following:
(I) an acyl chloride together with an excess of acid-base in a suitable solvent;

+ Amine (V); or (ii) a conventional coupling agent in an appropriate solvent with an excess of base, optionally in the presence of a catalyst + amine (V) and the acid ZCO ₂ H.

Typically, the conditions are as follows:
(I) acid chloride in DCM or THF,

Amine (V) (optionally, for example, _Et 3 N, such as Hünig's's base or NMM, with an excess of a tertiary amine), without heating for 1 to 24 hours; or (ii) THF, DCM, Acid ZCO ₂ H, WSCDI / DCC and HOBT / HOAT, amine, excess NMM, Et ₃ N or Huenig's base in DMA or EtOAc, 4-48 hours at room temperature; or acid in THF, DCM, DMA or EtOAc ZCO ₂ H, PyBOP® / PyBrOP® / O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium hexafluorophosphate, excess amine, excess NMM, Et ₃ N or Hünig's's base, at room temperature, 4 to 24 hours.

Preferred conditions are as follows:
1 equivalent of amine (V), 1.0-1.5 equivalents in DCM

, 1.5 to 5 equivalents of NMM, Et ₃ N or Hünig's's base, at room temperature, up to 18 hours; or in DCM, 1 equivalent of the amine (V), 1.2 equivalent of _ZCO 2 H, 1.2 to 1 .5 eq of HOBT, 1.2 to 1.5 equivalents of WSCDI, in 2-4 eq of _Et 3 N, room temperature, 24 hours; or in DMA or DCM, 1 equivalent of the amine (V), 1 .2 to 1.5 equivalents of ZCO ₂ H, 1.2-2.0 equivalents of HBTU, 5 equivalents of Et ₃ N or NMM, at room temperature to 60 ° C. for up to 24 hours.

A compound of formula (IV) in which Q represents NR ² or Q represents a direct bond to the nitrogen atom in ring A which itself binds to the triazole ring via the nitrogen atom It can be prepared as shown in Scheme 2 and the compound is represented as Formula (IVA).

  Step (e): The compound of formula (VIIIA) is prepared by reacting approximately equimolar amounts of isothiocyanate (VI) and amine (VII) in a suitable solvent (eg EtOH or DCM) at room temperature for 2-72 hours. It can be produced by reaction. Preferred conditions: 1 to 1.1 equivalents (VI), 1 equivalent (VII) in EtOH or DCM, 0.5 to 2 hours at room temperature.

Compounds of formula (VI) and (VII) are commercially available or can be prepared from known compounds using standard chemical transformations.
Step (f): The compound of formula (IXA) is suitable for use at 0 ° C. to the reflux temperature of the reaction in the presence of a suitable base (eg KO ^t -Bu) in a suitable solvent (eg THF or ether). It can be prepared by methylating thiourea (VIIIA) using a suitable methylating agent (eg MeI or MeTosylate). Preferred conditions: 1 equivalent of (VIIIA), 1 to 1.2 equivalents of KO ^t -Bu, 1 to 1.2 equivalents of MeI or MeTosylate in THF at 10 ° C. to room temperature for up to 18 hours.

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

A compound of formula (VIIIA) wherein Q represents NR ² or Q represents a direct bond attached to the nitrogen atom in ring A itself attached to the triazole ring via the nitrogen atom may alternatively be represented by It can be produced as shown in Scheme 3.

Compounds of formula (X) are commercially available or can be prepared from known compounds using standard chemical transformations.
The compound of formula (XI) can be produced from isothiocyanate (VI) and amine (X) by analogy with the method described above with respect to step (e).

  Step (h): The compound of formula (VIIIA) is prepared by protecting reactive nitrogen atoms using standard methodologies as described in “Protecting Groups in Organic Synthesis” by TW Greene and P. Wutz. Obtainable. When PG is BOC, the preferred conditions are as follows: 1 equivalent of amine (XI), 1 equivalent of di-tert-butyl dicarbonate in DCM and dioxane, at room temperature for about 3 hours.

A compound of formula (VIII) in which Q represents NR ² or Q represents a direct bond to the nitrogen atom in ring A which itself binds to the triazole ring via a carbon atom is shown in Scheme 4 below. And the compound is represented as (VIIIB).

Step (i): The compound of formula (XIV) can be produced by analogy with the method already described in step (d) by coupling of aniline (XIII) and acid (XII). Preferred conditions: 1 equivalent of acid (XII), 1 equivalent of amine (XIII), 1.2 equivalents of WSCDI, 3 equivalents of Et ₃ N in MeCN at room temperature for about 3 days.

  Step (j): The compound of formula (VIIIB) is treated at room temperature to the reflux temperature of the reaction with a suitable thionating agent, such as Lawesson's reagent, in a high boiling point solvent (eg, toluene). And can be produced by sulfuration of compound (XIV). Preferred conditions: 1 equivalent (XIV) in toluene, 0.5 equivalent Lawesson's reagent, at room temperature to reflux temperature for up to 18 hours.

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

In this case, T represents Cl or OH). Preferred conditions: 1 equivalent of hydrazide (II), 1.1 equivalents of XCO ₂ H, 1.1 equivalents of WSCDI, 1.1 equivalents of HOBT, 1.2 equivalents of Et ₃ N in DMF at room temperature, 18 time.

Step (l): Oxadiazole (III) is optionally reacted in an appropriate solvent (eg DCM), typically under acid catalysis (eg polyphosphoric acid, POCl ₃ , triflic anhydride / pyridine or 1 -Methylimidazole), which can be prepared by cyclization of compound (XV) from 0 ° C. to the reflux temperature of the reaction. Preferred conditions: 1 equivalent of (XV) in DCM, excess pyridine or 1-methylimidazole, 1.5-2 equivalents of triflic anhydride, 0 ° C. to room temperature for up to 3 hours.

The compound of formula (XV) can alternatively be prepared by coupling the acid (XII) with the appropriate hydrazide (XCONHNH ₂ ) by analogy with the method already described in step (d). Preferred conditions: 1 equivalent of acid (XII), 1 equivalent of hydrazide, 1.02 equivalent of WSDCI in DCM at 0 ° C. to room temperature.

Compounds of formula (III) where X represents CH ₂ N-linked Het can alternatively be prepared as shown in Scheme 6.

Step (m): The compound of formula (XVI) is prepared at 0 ° C. to room temperature in the presence of a suitable tertiary amine (eg Et ₃ N or NMM) in a suitable solvent (eg EtOAc or DCM). It can be prepared by reacting hydrazide (II) with chloroacetyl chloride for about 18 hours. Preferred conditions: 1 equivalent of (II), 1 equivalent of acetyl chloride, 1.1 equivalents of NMM in DCM at 10 ° C. to room temperature for up to 18 hours.

The compound of the formula (XVII) can be produced by cyclizing the compound (XVI) by analogy with the method described above in the step (l).
Step (n): The compound of formula (III) is combined with compound (XVII) in the presence of a suitable base (eg Et ₃ N or K ₂ CO ₃ ) in a suitable solvent (eg DMF or MeCN). Of Het (containing reactive N atoms) can be prepared by reacting at room temperature to the reflux temperature of the reaction for about 18 hours. Preferred conditions: 1 equivalent (XVII) in DMF, 1.4 equivalents K ₂ CO ₃ , 2 equivalents Het at room temperature for 18 hours.

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

Ra represents C ₁ -C ₄ alkyl or benzyl, and preferably Me or Et.
Scheme 7
Step (o): The compound of formula (XIX) is obtained by analogizing the method described in Step (d) with amine (XVIII) as an appropriate acid or acid chloride (

In this case, T represents OH or Cl). Preferred conditions: 1 equivalent of (XVIII), 0.9 equivalent of ZCOCl, 1.1 equivalent of Et ₃ N in DCM at 10 ° C. to room temperature for about 3 hours.

  Step (p): The hydrazide of formula (XX) can be reacted by reacting ester (XIX) with excess hydrazine at the reflux temperature of the reaction for up to 18 hours in a suitable solvent (eg EtOH or MeOH). Can be manufactured. Preferred conditions: 1 equivalent of (XIX), 2-4 equivalents of hydrazine in MeOH, 10 to 48 hours at reflux temperature.

  The compound of formula (XXI) can be prepared from hydrazide (XX) using the method already described in step (k).

It can manufacture by making it react.
The compound of formula (XXII) can be produced by cyclizing compound (XXI) using the method described in the step (l).

The compound of formula (I) can be prepared from oxadiazole (XXII) and a suitable aniline as already described in step (b).
Alternatively, the compound of formula (XXII) can be obtained by analogy with the method already described in step (a), by directly preparing a suitable acetal (for example, triethylorthopropionate, N, N-dimethylacetamide dimethylacetal from compound (XX)). ).

Compounds of the formula (XXII) in which X represents CH ₂ —N—linked —Het can alternatively be prepared as shown in Scheme 8.

The compound of formula (XXIII) can be produced by reacting hydrazide (XX) with chloroacetyl chloride by analogy with the method described in the step (m).
Oxadiazole (XXIV) can be produced by cyclization of compound (XXIII) by analogy with the method already described in step (l).

Compound (XXII) can be produced by reacting compound (XXIV) with appropriate Het (containing a reactive N atom) as described in step (n).
Compounds of formula (I) in which ring A is attached to the triazole ring via a nitrogen atom can alternatively be prepared as shown in Scheme 9.

Compounds of formula (XXV) are commercially available or can be prepared from commercially available compounds using standard chemical transformations.
The compound of formula (XXVI) can be prepared from the reaction of compound (XXV) with a suitable isothiocyanate (VI) by analogy with the method already described in step (e).

Compound of formula (XXVII) can be prepared by alkylation of compound (XXVI) by analogy with the method described previously in step (f).
The compound of formula (I) can be produced by reacting compound (XXVII) with a suitable hydrazide as already described in step (g).

A compound of formula (I) in which Q represents a direct bond bonded to a carbon atom in ring A which itself binds to a triazole ring via a nitrogen atom in ring A, and Z represents NR ⁴ R ⁵ , It can be produced as shown in Scheme 10.

Ra _is, C 1 -C ₄ alkyl or benzyl, preferably Me or Et.
Scheme 10
The compound of formula (XXVIII) is commercially available or can be prepared from commercially available compounds using standard chemical transformations.

The compound of formula (XXIX) can be prepared by reacting compound (XXVIII) with a suitable isothiocyanate (VI) by analogy with the method already described in step (e).
The compound of formula (XXX) can be produced by alkylation of compound (XXIX) by analogy with the method already described in step (f).

The compound of formula (XXXI) can be produced by reacting compound (XXX) with an appropriate hydrazide, as already described in step (g).
Step (q): Using a suitable acid or base catalyst, preferably an alkali metal base (eg, NaOH, KOH or LiOH) in a suitable aqueous solvent (eg, dioxane or MeOH) at room temperature to the reflux temperature of the reaction. Hydrolysis of ester (XXXI) for 2 to 48 hours. Preferred conditions: 1 equivalent of (XXXI), 5-10 equivalents of NaOH solution in dioxane, 2-16 hours at room temperature to reflux temperature.

The compound of formula (I) can be prepared by reacting ZH (containing a reactive N atom) and an acid (XXXII) by analogy with the method already described in step (d). Preferred conditions: 1 equivalent of acid (XXXII), 1.5 equivalents of amine (ZH), 4 equivalents of Et ₃ N, 1.5 equivalents of WSCDI, 1.5 equivalents of HOBT in DCM, 24 hours at room temperature .

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

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

  A compound of formula (XXXIII) in which Q is a direct bond and ring A is bonded to the triazole ring via a nitrogen atom contains an appropriate isothiocyanate (VI) and a nitrile by analogy with the method described in Scheme 9. Ring A,

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

Step (r): The compound of formula (XXXV) can be produced by the reaction of hydrazide (XCONHNH ₂ ) and isothiocyanate (VI) by analogy with the method already described in step (e). Preferred conditions: 1 equivalent of isothiocyanate, 1 equivalent of hydrazide in EtOH, 72 hours at room temperature.

Step (s): Compound (XXXVI) The compound is prepared in an aqueous solvent (eg water / EtOH) under acid or base conditions, preferably under basic catalysis (eg alkali metal hydroxide) for about 24 hours. Embedded image (XXXV). Preferred conditions: 1 eq. (XXXV), 10 eq. NaOH _(aq) in EtOH at 80 ° C. for 18 hours.

  Step (t): Alkylation of compound (XXXVI) to give compound (XXXVII) can be accomplished by analogy with the method described previously in step (f), using an appropriate alkylating agent (eg, MeI or Me-Tosylate). Can be achieved by processing. Preferred conditions: 1 equivalent (XXXVI), 1 equivalent KOt-Bu, 1 equivalent Me-Tosylate in THF, room temperature to reflux temperature, 3 hours.

  Step (u): Compound of formula (XXXVIII) is treated with compound (XXXVII) for about 18 hours at room temperature with a suitable oxidant (eg mCPBA or hydrogen peroxide) in a suitable solvent (eg DCM). Can be obtained by oxidation. Preferred conditions: 1 equivalent (XXXVII), 4 equivalents mCPBA in DCM, 18 hours at room temperature.

  Step (v): The compound of formula (I) is prepared in a suitable solvent (eg THF or ether) in the presence of a suitable base (eg NaH or KOt-Bu) for up to 18 hours at room temperature. , Sulfoxide (XXXVIII) and excess alcohol (XXXIX). Preferred conditions: 1 equivalent of (XXXVIII), 2 equivalents of NaH, 2 equivalents of alcohol (XXXIX) in THF at room temperature for 18 hours.

The compound of formula (XXXIX) is commercially available or can be prepared from commercially available compounds using standard chemical transformations.
Certain compounds of formula (I), (III), (IV), (V), (XXII) or (XXXI) undergo functional group exchange (eg, alkylation or hydrolysis). Alternative compounds of formula (I), (III), (IV), (V), (XXII) or (XXXI) can be produced, respectively.

  Intended for pharmaceutical use, the compounds of the present invention can be administered as crystalline or amorphous products. The compounds can be obtained, for example, as solid plugs, powders or films by methods such as precipitation, crystallization, freeze drying, spray drying or evaporation drying. For this purpose, microwave or radio frequency drying can also be used.

  The compounds can be administered alone, or in combination with one or more other compounds of the present invention, or in combination with one or more other drugs (or any combination thereof). Generally, the compound is administered as a formulation with one or more pharmaceutically acceptable excipients. In this specification, the term “excipient” is used to denote any ingredient other than the compound (s) of the invention. The choice of excipient will depend to a large extent on factors such as, for example, the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

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

Pharmaceutical compositions suitable for delivery of the compounds of the present invention and methods for their production will be readily appreciated by those skilled in the art. Such compositions and manufacturing methods, for example, can be found in ^{Remington's Pharmaceutical Sciences, 19 th Edition} (Mack Publishing Company, 1995).

  The compounds of the present invention can be administered orally. Oral administration can include swallowing such that the compound enters the gastrointestinal tract, or buccal or sublingual administration such that the compound enters the bloodstream directly from the oral cavity.

  Formulations suitable for oral administration include, for example, tablets, particles, capsules containing liquids or powders, rhomboids (including liquid-filled forms), chew, multiparticulates and nanoparticles, gels, solid solutions, liposomes, Includes solid formulations such as films, ovules, sprays and liquid formulations.

  Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules, typically a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifiers. And / or contain a suspending agent. Liquid formulations can also be produced, for example, by reconstitution of a solid from a sachet.

The compounds of the present invention may also be used in rapidly dissolving, rapidly disintegrating dosage forms as described, for example, in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 (2001) by Liang and Chen. it can.

  For tablet dosage forms, depending on the dosage, the drug may make up 1-80% by weight of the dosage form, more typically 5-60% by weight of the dosage form. Tablets generally contain a disintegrant in addition to the drug. Examples of disintegrants are sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinyl pyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropyl cellulose, Includes starch, pregelatinized starch and sodium alginate. In general, disintegrants comprise 1 to 25% by weight of the dosage form, preferably 5 to 20%.

  Binders are commonly used to impart cohesiveness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Tablets are diluted such as lactose (monohydrate, spray dried monohydrate, anhydride, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate Agents can also be included.

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

  Tablets generally also contain a lubricant such as, for example, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. Lubricants generally comprise 0.25-10% by weight of the tablet, preferably 0.5-3%.

Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives and taste-masking agents.
A typical tablet has up to about 80% drug, about 10 to about 90% by weight binder, about 0 to about 85% by weight diluent, about 2 to about 10% by weight disintegrant, and about 0.1%. Contains 25 to about 10 weight percent lubricant.

  Tablet blends can be compressed directly or by roller to form tablets. Alternatively, the tablet blend or portion of the blend can be wet, dry or melt granulated, melt coagulated, or extruded prior to tableting. The final formulation can include one or more layers, which can be coated or not; it can be encapsulated.

Tablet formulation is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1 (Marcel Dekker, New York, 1980) by H. Lieberman and L. Lachman.
Human or veterinary consumable oral films are typically flexible, water-soluble or water-swellable thin film dosage forms that can be rapidly soluble or mucoadhesive. And typically comprises a compound of formula (I), a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity modifier and a solvent. Some components of the formulation can perform more than one function.

  The compound of formula (I) can be water-soluble or water-insoluble. Water soluble compounds typically comprise 1-80% by weight of the solute, more typically 20-50% by weight. Weakly soluble compounds can comprise a greater proportion of the composition and can typically account for up to 88% by weight of the solute. Alternatively, the compound of formula (I) can be in the form of multiparticulate beads.

  The film-forming polymer can be selected from natural polysaccharides, proteins, or synthetic hydrocolloids, typically in the range of 0.01-99% by weight, more typically 30-80% by weight. Present within range.

  Other possible ingredients include antioxidants, colorants, flavors and flavor enhancers, preservatives, salivary stimulants, cooling agents, cosolvents (including oils), emollients, bulking agents , Antifoaming agents, surfactants and taste masking agents.

  Films according to the present invention are typically produced by evaporating and drying a thin aqueous film coated on a peelable backing sheet or paper. This can be done in a drying chamber or tunnel dryer, typically in a combined coater dryer, or by freeze drying or vacuuming.

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

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

  The compounds of the invention can also be administered directly into the bloodstream, into muscles or into internal organs. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, subarachnoid, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous means. Suitable devices for parenteral administration include needle (including microneedle) syringes, needleless syringes and infusion techniques.

  Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of 3-9), although for some applications, parenteral formulations are Can be formulated more appropriately as a sterile non-aqueous solution or as a dry form to be used with a suitable vehicle, such as sterile, pyrogen-free water.

The manufacture of parenteral formulations under sterile conditions, such as by lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.
The solubility of compounds of formula (I) used in the preparation of parenteral solutions can be increased by using appropriate formulation techniques such as, for example, incorporation of solubility-enhancing agents.

  Formulations for parenteral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release. Thus, the compounds of the present invention can be formulated as solids, semisolids or thixotropic liquids for administration as implantation depots that produce a controlled release of the active compound. Examples of such formulations include drug-coated stents and poly (dl-lactic-co-glycolic acid) (PGLA) microspheres.

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

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

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

  The compounds of the invention are typically mixed ingredients, eg, intranasally or by inhalation, as a dry powder (alone, eg, as a mixture in a dry blend with lactose or mixed with a phospholipid such as phosphatidylcholine). From a dry powder inhaler, in the form of particles), or from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce fine mist) or a nebulizer, for example 1,1,1 , 2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane can be administered with or without a suitable propellant. For intranasal use, the powder may contain a bioadhesive agent such as chitosan or cyclodextrin.

  Pressurized containers, pumps, sprays, atomizers or nebulizers are solvents, such as ethanol, aqueous ethanol, or other alternatives for dispersing, solubilizing or extending active ingredients, propellant (s) And a solution or suspension of the compound (s) of the present invention, including any surfactant, such as sorbitan trioleate, oleic acid or oligolactic acid.

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

  Capsules (eg manufactured from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in inhalers or insufflators are suitable powder bases such as powder mixes of compounds of the invention, eg lactose or starch, And can be made to contain a function modifier such as l-leucine, mannitol or magnesium stearate. Lactose can be anhydrous or in the form of a monohydrate, but the latter is preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

  A suitable solution formulation for use in an atomizer that utilizes electrohydrodynamics to produce a fine mist can contain from 1 μg to 20 mg of the compound of the invention per actuation, the working amount being from 1 μl to 100 μl. The range can be taken. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

  Appropriate flavors such as menthol and levomenthol, or sweeteners such as saccharin or sodium saccharin can be added to the formulations of the invention as intended for inhalation / intranasal administration.

  Formulations for inhalation / intranasal administration can be formulated to be immediate release / controlled release using eg PGLA. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release.

  In the case of dry powder inhalers and aerosols, the dosage unit can be determined using a valve that delivers the metering. The total daily dose is typically in the range of 0.01 μg to 15 mg, which can be administered in a single dose or, more usually, as 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 enemas. Cocoa butter is a traditional suppository base, but various alternatives can be used where appropriate.

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

  The compounds of the invention may also be administered directly to the eye or ear, typically in the form of a few drops of a finely divided suspension or solution in isotonic, pH adjusted, sterile saline. Other formulations suitable for administration to the eye or ear are ointments, biodegradable (eg absorbable gel sponges, collagen) and non-biodegradable (eg silicone) implants, wafers, lenses and granules. Or vesicular systems (eg, niosomes or liposomes). For example, cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose, or heteropolysaccharide polymers such as gellan gum such as benzoalkonium chloride. Can be incorporated with preservatives such as Such formulations can also be delivered by iontophoresis.

  Formulations for ophthalmic / ear administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release.

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

  For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrin can be used as an auxiliary additive, ie as a carrier, diluent or solubilizer. For these purposes, the most commonly used are α-, β- and γ-cyclodextrins, examples of which are described in international patent application no. It can be found in WO 91/11172, WO 94/02518 and WO 98/55148.

  For example, as long as it is desirable to administer a combination of active compounds to treat a particular disease or condition, two or more pharmaceutical compositions (of which at least one contains a compound according to the invention) It is within the scope of the present invention that they can be conveniently combined in the form of a kit suitable for co-administration of the composition.

  Thus, the kit of the present invention comprises two or more separate pharmaceutical compositions (at least one of which contains a compound of formula I according to the present invention) and, for example, a container, a divided bottle, or a divided Means for holding the composition separately, such as a divided foil packet. An example of such a kit is the well-known blister pack used for the packaging of tablets, capsules and the like.

  The kit of the invention is for administering different dosage forms, eg oral and parenteral, for administering different compositions at different dosing intervals, or for titrating separate compositions against each other. Especially suitable for. To assist compliance, the kit typically includes instructions for administration and can be provided with a so-called memory aid.

  For administration to human patients, the total daily dose of the compounds of the invention is typically in the range of 0.01 to 15 mg, which of course depends on the mode of administration. The total daily dose can be administered in a single dose or in divided doses, and can be outside the typical ranges described herein at the physician's discretion.

  These dosages are based on an average human subject having a weight of about 60-70 kg. The physician will readily determine dosages for subjects with weights outside this range, such as infants and the elderly.

For the avoidance of doubt, references herein to “treatment” are intended to include references to curative, palliative and prophylactic treatment.
The compounds of the present invention can be tested in the screening tests described below.

1.0 V _1A filter binding assay
1.1 Membrane production Receptor binding assays were performed on cell membranes prepared from CHO cells stably expressing the human V _1A receptor (CHO-hV _1A ). The CHO-hV _1A cell line was kindly provided by Marc Thibonnier, Dept. of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio. CHO-hV _1A cells were cultured in a DMEM / Hams F12 nutritional mix supplemented with 10% fetal calf serum, 2 mM L-glutamine, 15 mM HEPES and 400 μg / ml G418 in a humidified atmosphere containing 5% CO _2. Maintained routinely at ° C. For mass production of cell pellets, 90 adherent CHO-hV _1A cells were cultured in 850 cm ² roller bottles containing DMEM / Hams F12 nutrient mix medium supplemented with 10% fetal calf serum, 2 mM L-glutamine and 15 mM HEPES. Grow to ~ 100% confluency. Confluent CHO-hV _1A cells were washed with phosphate buffered saline (PBS), collected in ice-cold PBS, and centrifuged at 1,000 rpm. Cell pellets were stored at −80 ° C. until use. Cell pellets were thawed on ice and homogenized in membrane manufacturing buffer consisting of 50 mM Tris-HCl, pH 7.4, 5 mM MgCl ₂ and supplemented with protease inhibitor cocktail (Roche). The cell homogenate was removed and stored on ice. The remaining pellet was homogenized as before and centrifuged. The supernatants were pooled and centrifuged at 25,000 xg for 30 minutes at 4 ° C. Resuspended in freezing buffer consisting of 50 mM Tris-HCl, pH 7.4, 5 mM MgCl ₂ and 20% glycerol, divided into small aliquots and stored at −80 ° C. until use. . Protein concentration was measured using Bradford reagent and BSA as a reference.

For each new batch of 1.2 V _1A filter binding membrane, protein linear binding followed by saturation binding studies were performed. The membrane concentration that produced specific binding in the linear part of the curve was selected. Then, various concentrations of ^[3 H] - arginine ^vasopressin, using [3 H] -AVP (0.05~100nM) , performs saturation binding studies were measured _{K d} and _{B max.}

The compounds were tested for their effect on [ ³ H] -AVP binding to CHO-hV _1A membrane ( ³ H-AVP; specific activity 65.5 Ci / mmol; NEN Life Sciences). Compounds are solubilized in dimethyl sulfoxide (DMSO) and assay buffer containing 50 mM Tris-HCl, pH 7.4, 5 mM MgCl ₂ and 0.05% BSA to a working concentration of 10% DMSO. Diluted. 25 μl of compound and 25 μl of [ ³ H] -AVP (final concentration below K _d measured for membrane batch, typically 0.5-0.6 nM) were added to a 90-well round bottom polypropylene plate. 200 μl of membrane was added to initiate the binding reaction and the plate was gently shaken for 60 minutes at room temperature. The reaction was stopped by rapid filtration using a Filtermate Cell Harvester (Packard Instruments) through a 96-well GF / B UniFilter Plate presoaked in 0.5% polyethyleneimine to prevent peptide sticking. 50 mM Tris-HCl, with ice-cold wash buffer 1ml containing pH7.4 and 5 mM MgCl _2, was washed three times with the filter. The plate was dried and 50 μl of Microscint-0 (Packard Instruments) was added to each well. The plates were sealed and counted with a TopCount Microplate Scintillation Counter (Packard Instruments). Non-specific binding (NSB) is 1 μM unlabeled d (CH ₂ ) 5 Tyr (Me) AVP ([β-mercapto-β, β-cyclopentamethylenepropionyl, O-Me-Tyr ² , Arg ⁶ ] -vasopressin) Measurements were made using (βMCPVP) (Sigma). Radioligand binding data was analyzed using a four parameter logarithm, with time (min) forced to 0%. The slope was free fitted and the slope for the effective curve was -0.75 to -1.25. Specific binding was calculated by subtracting the average NSBcpm from the average total cpm. For the test compounds, the amount of ligand bound to the receptor was expressed as% binding = (sample cpm−average NSBcpm) / specific binding cpm × 100. The% binding was plotted against the concentration of test compound to fit a sigmoidal curve. Inhibitory dissociation constant (K _i ) is expressed by the Cheng-Prusoff equation: K _i = IC ₅₀ / (1+ [L] / K _d ), where [L] is the concentration of the ligand present in the hole. And K _d is the dissociation constant of the radioligand obtained from Scatchard plot analysis).

2.0 V _1A Functional Assay: Inhibition of AVP / using FLIPR to allow rapid detection of calcium after V _1A -R mediated Ca ²⁺ migration receptor activation by Fluorescent Imaging Plate Reader (FLIPR) (Molecular Devices) Intracellular calcium release was measured in CHO-hV _1A cells. The CHO-hV _1A cell line was kindly provided by Marc Thibonnier, Dept. of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio. CHO-hV _1A cells were cultured in a DMEM / Hams F12 nutritional mix supplemented with 10% fetal calf serum, 2 mM L-glutamine, 15 mM HEPES and 400 μg / ml G418 in a humidified atmosphere containing 5% CO _2. Maintained routinely at ° C. In the afternoon prior to the assay, cells were seeded from the bottom of each well at a density of 20,000 cells / well into a black sterile 96-well plate with a clear bottom to allow cytological examination and fluorescence measurements. . 1. Dulbecco's phosphate buffered saline (DPBS) and wash buffer containing 2.5 mM probenecid, 4 μM Fluo-3-AM (dissolved in DMSO and pullulonic acid) (Molecular Probes); A loading dye consisting of cell culture medium containing 5 mM probenecid was prepared on the day of the assay. Compounds were solubilized in DMSO and diluted in assay buffer consisting of DPBS containing 1% DMSO, 0.1% BSA and 2.5 mM probenecid. Cells were incubated for 1 hour at 37 ° C. in a humidified atmosphere containing 5% CO ₂ with 100 μl / well of loading dye. After loading the die, the cells were washed 3 times in 100 μl of wash buffer using a Denley plate washer. In each well, 100 μl of wash buffer was left. Intracellular fluorescence was measured using FLIPR. After 30 seconds, 50 μl of test compound was added and fluorescence readings were taken at 2 second intervals. Next, in order to detect the agonist activity of any compound, 155 measurements were performed at 2 second intervals. Next, 50 μl of arginine vasopressin (AVP) was added so that the final assay volume was 200 μl. Additional fluorescence readings were collected for 120 seconds at 1 second intervals. The reaction was measured as peak fluorescence intensity (FI). Basal FI was subtracted from each fluorescence reaction for pharmacological characterization. For the AVP dose response curve, each response was expressed as a% of response to the highest concentration of AVP in the column. For IC ₅₀ measurements, each response was expressed as a percentage of the response to AVP. IC ₅₀ value is Cheng-Prusoff equation considering agonist concentration [A], agonist EC ₅₀ and slope: K _b = IC ₅₀ / (2 + [[A] / A ₅₀ ] ⁿ ) ^{1 / n} −1 , [a] is a concentration of _{AVP, a 50} is a _{EC 50} for AVP from the dose response curve, using n = is the slope of the AVP dose response curve), was converted to modified _{K b} value.

The compounds of the present invention can be administered alone or in combination with one or more other compounds of the present invention or in combination with one or more other drugs (or as any combination thereof). . The compounds of the present invention can be administered in combination with oral contraceptives. Accordingly, another aspect of the present invention provides a drug product containing a V _1A antagonist and an oral contraceptive as a combined formulation for simultaneous, separate or sequential use in the treatment of dysmenorrhea. The compounds of the present invention can be administered in combination with a PDE5 inhibitor. Accordingly, in another aspect of the present invention, there is provided a drug product containing a V _1A antagonist and a PDE5 inhibitor as a combination formulation for simultaneous, separate or sequential use in the treatment of dysmenorrhea.

PDEV inhibitors useful for combination with V _1A antagonists include, but are not limited to:
(I) International Patent Application Publication No. WO 03/000691; WO 02/64590; WO 02/28865; WO 02/28859; WO 02/38563; WO 02/36593; WO02 / 28858; WO 02/00657; WO 02/00656; WO 02/10166; WO WO 01/94347; WO 01/94345; WO 00/15639; and PDE5 inhibitors described in WO 00/15228;
(Ii) PDE5 inhibitors described in US Pat. Nos. 6,143,746; 6,143,747 and 6,043,252;
(Iii) pyrazolo [4,3-d] pyrimidin-7-one (disclosed in EP-A-0463756); pyrazolo [4,3-d] pyrimidin-7-one (disclosed in EP-A-0526004); pyrazolo [4,3-d] pyrimidin-7-one (disclosed in published international patent application WO 93/06104); isomeric pyrazolo [3,4-d] pyrimidin-4-one (published in published international patent application WO 93/07149) Quinazolin-4-one (disclosed in published international patent application WO 93/12095); pyrido [3,2-d] pyrimidin-4-one (disclosed in published international patent application WO 94/05661); purine-6 -One (disclosed in published international patent application WO 94/00453); pyrazolo [4,3-d] pyrimidin-7-one (disclosed in published international patent application WO 98/49166); pyrazolo [4,3-d] pyrimidine -7-one (disclosed in published international patent application WO 99/54333); pyrazolo [4,3-d] pyrimidin-4-o (Disclosed in EP-A-00995751); pyrazolo [4,3-d] pyrimidin-7-one (disclosed in published international patent application WO 00/24745); pyrazolo [4,3-d] pyrimidin-4-one ( Disclosed in EP-A-00995750); hexahydropyrazino [2 ′, 1 ′: 6,1] pyrido [3,4-b] indole-1,4-dione (disclosed in published international patent application WO 95/19978) ); Pyrazolo [4,3-d] pyrimidin-4-one (disclosed in WO 00/27848); imidazo [5,1-f] [1,2,4] triazin-one (EP-A-1092719 and published) International application WO 99/24433) and bicyclic compounds (published in published international application WO 93/07124); pyrazolo [4,3-d] pyrimidin-7-one (disclosed in published international application WO 01/27112) A pyrazolo [4,3-d] pyrimidin-7-one (disclosed in published international application WO 01/27113); a compound disclosed in EP-A-1092718 and EP-A-109; Compound disclosed in 2719; Tricyclic compound disclosed in EP-A-1241170; Alkylsulfone compound (disclosed in published international application WO 02/074774); Compound disclosed in published international application WO 02/072586; Published Compounds disclosed in international application WO 02/079203; as well as compounds disclosed in WO 02/074312.
(Iv) Preferably, 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one (sold as sildenafil, eg Viagra®), 1-[[3- (6,7-dihydro-1-methyl-7-oxo-3-propyl- 1H-pyrazolo [4,3-d] pyrimidin-5-yl) -4-ethoxyphenyl] sulfonyl] -4-methylpiperazine (see EP-A-0463756); 5- (2-ethoxy-5 -Morpholinoacetylphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see EP-A-0526004); 3-ethyl- 5- [5- (4-Ethylpi Razin-1-ylsulfonyl) -2-n-propoxyphenyl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (WO98 / 49166); 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (pyridin-2-yl) Methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO99 / 54333); (+)-3-ethyl-5- [5- (4-ethylpiperazine-1) -Ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl] -2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7 -One, which is 3-ethyl-5- {5- [4-Ethylpiperazin-1-ylsulfonyl] -2-([(1R) -2-methoxy-1-methylethyl] oxy) pyridin-3-yl} -2-methyl-2,6-dihydro-7H- Also known as pyrazolo [4,3-d] pyrimidin-7-one (see WO99 / 54333); 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, which is 1- {6-ethoxy-5- [3 As ethyl-6,7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4,3-d] pyrimidin-5-yl] -3-pyridylsulfonyl} -4-ethylpiperazine Also known (WO 01/27113, implementation See Example 8); 5- [2-iso-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- (1-methylpiperidin-4-yl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO 01/27113, Example 15); 5- [2-ethoxy-5- (4-ethylpiperazine-1) -Ylsulfonyl) pyridin-3-yl] -3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO 01/27113, Example 66) ); 5- (5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] Pyrimidin-7-one (see WO 01/27112, Example 124); -(5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7 -One (see WO 01/27112, Example 132); (6R, 12aR) -2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) Pyrazino [2 ′, 1 ′: 6,1] pyrido [3,4-b] indole-1,4-dione (tadalafil, IC-351, Cialis®), ie published international application WO 95/19978 Of Examples 78 and 95 and Examples 1, 3, 7 and 8; 2- [2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulfonyl) -phenyl]- 5-Methyl-7-propyl-3H-imidazo [5,1- f] [1,2,4] triazin-4-one (Vardenafil, LEVITRA®), which is 1-[[3- (3,4-dihydro-5-methyl-4-oxo-7- Propylimidazo [5,1-f] -as-triazin-2-yl) -4-ethoxyphenyl] sulfonyl] -4-ethylpiperazine (ie Examples 20, 19, 337 of published international application WO 99/24433 and Compound of Example 11 of published international application WO 93/07124 (EISAI); compounds 3 and 14 from Rotella DP, J. Med. Chem., 2000, 43, 1257; (4-Chlorobenzyl) amino-6,7,8-trimethoxyquinazoline; N-[[3- (4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3 -D] -pyrimidin-5-yl) -4-propoxyphenyl Sulfonyl] -1-methyl 2-pyrrolidinepropanamide ["DA-8159" (Example 68 of WO 00/27848)]; and 7,8-dihydro-8-oxo-6- [2-propoxyphenyl] -1H -Imidazo [4,5-g] quinazoline and 1- [3- [1-[(4-fluorophenyl) methyl] -7,8-dihydro-8-oxo-1H-imidazo [4,5-g] quinazoline -6-yl] -4-propoxyphenyl] carboxamide.
(V) 4-bromo-5- (pyridylmethylamino) -6- [3- (4-chlorophenyl) -propoxy] -3 (2H) pyridazinone; 1- [4-[(1,3-benzodioxol-5- (Ilmethyl) amino] -6-chloro-2-quinazolinyl] -4-piperidine-carboxylic acid, monosodium salt; (+)-cis-5,6a, 7,9,9,9a-hexahydro-2- [4- (Trifluoromethyl) -phenylmethyl-5-methyl-cyclopenta-4,5-imidazo [2,1-b] purine-4 (3H) one; fradiocillin; cis-2-hexyl-5-methyl-3, 4,5,6a, 7,8,9,9a-octahydrocyclopenta [4,5] -imidazo [2,1-b] purin-4-one; 3-acetyl-1- (2-chlorobenzyl) 2-propylin 6-carboxylate; 3-acetyl-1- (2-chlorobenzyl) -2-propylindole-6-carboxylate; 4-bromo-5- (3-pyridylmethylamino) -6- (3- (4-Chlorophenyl) propoxy) -3- (2H) pyridazinone; 1-methyl-5- (5-morpholinoacetyl-2-n-propoxyphenyl) -3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-one; 1- [4-[(1,3-benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinazolinyl] -4-piperidinecarboxylic acid, monosodium Salt; Pharmapropjects No. 4516 (Glaxo Wellcome); Pharmapropjects No. 5051 (Bayer); Pharmapropjects No. 5064 (see Kyowa Hakko; WO 96/26940); Pharmapropjects No. 5069 (Schering Plough); GF-196960 (Glaxo Wellcom) e); E-8010 and E-4010 (Eisai); Bay-38-3045 & 38-9456 (Bayer); FR229934 and FR226807 (Fujisawa); and Sch-51866.
The contents of published patent applications and published articles, and in particular, the general formulas of the therapeutically effective compounds of the claims and the compounds exemplified in them are hereby incorporated by reference in their entirety. Incorporated.

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

Most preferably, the PDE5 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 a NO donor. Accordingly, in another aspect of the invention, a drug product containing a V _1A antagonist and a NO donor is provided as a combination formulation for simultaneous, separate or sequential use in the treatment of dysmenorrhea.

The compounds of the present invention can be administered in combination with L-arginine or as an alginate. Accordingly, another aspect of the present invention provides a drug product containing a V _1A antagonist and L-arginine as a combined formulation for simultaneous, separate or sequential use in the treatment of dysmenorrhea.

The compounds of the present invention can be administered in combination with a COX inhibitor. Accordingly, another aspect of the present invention provides a drug product comprising a V _1A antagonist and a COX inhibitor as a combined formulation for simultaneous, separate or sequential use in the treatment of dysmenorrhea.

COX inhibitors useful for combining with the compounds of the present invention include, but are not limited to:
(I) ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pyrprofen, carprofen, oxaprozin, plapoprofen, miloprofen, thixaprofen, suprofen, aluminoprofen, Tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetine, zomepirac, diclofenac, fenclofenac, alclofenac, ibufenac, isoxepac, flofenac, thiopinac, didometacin, methasampicin , Tenoxicam, nabumetone, ketorolac, azapropazone, mefenamic acid, tolfenamic acid, diflu Monkey, podophyllotoxin derivative, acemetacin, droxicam, fructaphenine, oxyphenbutazone, phenylbutazone, progouritacin, acemetacin, fentiazak, cridanac, oxypinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flufenisal, sudoxicam , Etodolac, piperfen, salicylic acid, choline magnesium trisalicylate, salicylate, benolylate, fenthiazac, clopinac, feprazone, isoxicam and 2-fluoro-a-methyl [1,1'-biphenyl] -4-acetic acid, 4 -(Nitrooxy) butyl ester (see Wenk et al., Europ. J. Pharmacol. 453: 319-324 (2002)).
(Ii) meloxicam (CAS Registry Number 71125-38-7; described in US Pat. No. 4,233,299) or a pharmaceutically acceptable salt or prodrug thereof;
(Iii) Substituted benzopyran derivatives described in US Pat. No. 6,271,253. Also the benzopyran derivatives described in US Patent Nos. 6,034,256 and 6,077,850 together with International Publication Nos. WO 98/47890 and WO 00/23433.
(Iv) a chromene COX2 selective inhibitor as described in US Pat. No. 6,077,850 and US Pat. No. 6,034,256;
(V) Compounds described in International Patent Application Publication Nos. WO 95/30656, WO 95/30652, WO 96/38418 and WO 96/38442, compounds described in European Patent Application Publication No. 799823, and pharmaceuticals thereof Acceptable Derivatives (vi) Celecoxib (US Patent No. 5,466,823), Valdecoxib (US Patent No. 5,633,272), Delacoxib (US Patent No. 5,521,207), Rofecoxib (US Patent No. 5,474,995), Etlicoxib (International Patent Application) Publication No. 98/03484), JTE-522 (Japanese Patent Application Publication No. 9052882) or a pharmaceutically acceptable salt or prodrug thereof;
(Vii) parecoxib (described in US Pat. No. 5,932,598), which is a therapeutically effective prodrug of the tricyclic Cox-2 selective inhibitor valdecoxib (described in US Pat. No. 5,633,272), particularly sodium parecoxib Is
(Viii) ABT-963 (described in International Patent Application Publication No. WO 00/24719);
(Ix) Nimesulide (described in US Pat. No. 3,840,597), Flosslid (discussed in J. Carter, Exp. Opin. Ther. Patents , 8 (1), 21-29 (1997)), NS-398 (US patent) No. 4,885,367), SD8381 (described in US Patent No. 6,034,256), BMS-347070 (described in US Patent No. 6,180,651), S-2474 (described in European Patent Application No. 595546) and MK-966 (US) Patent No. 5,968,974).
(X) Compounds described in the following patents and patent applications and their pharmaceutically acceptable derivatives: US Patent No. 6,395,724, US Patent No. 6,077,868, US Patent No. 5,994,381, US Patent No. 6,362,209, US Patent No. 6,080,876, US Patent No. 6,133,292, US Patent No. 6,369,275, US Patent No. 6,127,545, US Patent No. 6,130,334, US Patent No. 6,204,387, US Patent No. 6,071,936, US Patent No. 6,001,843, US Patent No. .6,040,450, International Patent Application Publication No.WO 96/03392, International Patent Application Publication No.WO 96/24585, US Patent No. 6,340,694, US Patent No. 6,376,519, US Patent No. 6,153,787, US Patent No. 6,046,217, US Patent No. 6,329,421, US Patent No. 6,239,137, US Patent No. 6,136,831, US Patent No. 6,297,282, US Patent No. 6,239,173, US Patent No. 6,303,628, US Patent No. 6,310,079, US Patent No. 6,310,079, US Patent No. 6,300,363, US Patent No. .6,077,869, US Patent No. 6,140,515, US Patent No. 5,994,379, US Patent No. 6,028,202, US Patent No. 6,040,320, U.S. Patent No. 6,083,969, U.S. Patent No. 6,306,890, U.S. Patent No. 6,307,047, U.S. Patent No. 6,004,948, U.S. Patent No. 6,169,188, U.S. Patent No. 6,020,343, U.S. Patent No. 5,981,576, U.S. Pat. 6,222,048, U.S. Patent No. 6,057,319, U.S. Patent No. 6,046,236, U.S. Patent No. 6,002,014, U.S. Patent No. 5,945,539, U.S. Patent No. 6,359,182, International Patent Application Publication No.WO 97/13755, International Patent Application Publication No.WO 96/25928, International Patent Application Publication No.WO 96/374679, International Patent Application Publication No.WO 95/15316, International Patent Application Publication No.WO 95/15315, International Patent Application Publication No.WO 96/03385, International Patent Application Publication No. WO 95/00501, International Patent Application Publication No. WO 94/15932, International Patent Application Publication No. WO 95/00501, International Patent Application Publication No. WO 94/27980, International Patent Application Publication No. WO 96 / 25405, International Patent Application Publication No.WO 96/03388, International Patent Application Publication No.WO 96/03387, US Patent No. 5,344,991, International Patent Application Publication No.WO 95/00501, International Patent Application Publication No.WO 96 / 16934, International Patent Application Publication No. WO 96/03392, International Patent Application Publication No. WO 96/09304, International Patent Application Publication No. WO 98/47890, and International Patent Application Publication No. WO 00/24719.

  The contents of any patent application, in particular, the general formulas of the therapeutically effective compounds of the claims and the compounds exemplified in these are incorporated herein by reference in their entirety. The

The following preparation examples and examples illustrate the preparation of compounds of formula (I).
¹ H nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structure. Characteristic chemical shifts (δ) are described in ppm downfield from tetramethylsilane, using conventional abbreviations for main peak symbols: eg, s, singlet; d, doublet; t, Triple line; q, quadruple line; m, multiple line; br, wide. Mass spectra (m / z) were recorded using either electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). For common solvents, the following abbreviations are used: CDCl _{3, deuterochloroform;} D 6-DMSO, Deuteroxyl dimethyl sulfoxide; _CD 3 OD, Deuteroxyl methanol; THF, tetrahydrofuran. “Ammonia” means a concentrated solution of ammonia in water having a specific gravity of 0.88. When thin layer chromatography (TLC) is used, it means silica gel TLC using silica gel 60 F254 plates, where R _f is the distance traveled by the compound divided by the distance traveled by the solvent front on the TLC plate. It is. When using microwave radiation, the two microwaves are Emrys Creator and Emrys Liberator, both provided by Personal Chemistry Ltd. The power range is 15-300 W at 2.45 GHz. The actual power supply varies during the course of the reaction in order to maintain a constant temperature.

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

  To a solution of 9.0 g (37 mmol, 1 equivalent) of 4-hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (see WO 9703986 A1 19970206) in 40 ml of THF, 8.1 ml of dimethylformamide dimethyl acetal (55 .4 mmol, 1.5 eq) was added. The 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. The mixture was then heated at 100 ° C. under nitrogen for 18 hours, the volatiles were removed under reduced pressure, and the residue was partitioned between 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 column chromatography on silica gel using methylene chloride / methanol (98: 2 v / v to 95: 5 v / v) as eluent. Was obtained as a white solid (81%).

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

  4.0 g (15 mmol, 1 equivalent) of the compound of Production Example 1 was dissolved in 100 ml of toluene. 2.1 g (16.5 mmol, 1.1 eq) of parachloroaniline was added followed by 2 ml of TFA. The solution was heated at 110 ° C. for 16 hours, 2 ml of TFA was added and the solution was heated at 110 ° C. for a further 48 hours. The reaction mixture was then cooled, aqueous sodium bicarbonate was added and the organic phase was decanted. The aqueous phase was basified with sodium carbonate and extracted four times with methylene chloride (50 ml). The methylene chloride solution was dried over magnesium sulfate and the solvent removed in vacuo to give 2.90 g of the title compound as a white solid.

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

  To a cooled solution (5 ° C.) of the compound of Preparation 1 (1.32 g, 4.76 mmol) in methanol (30 ml) was added hydrochloric acid in dioxane (4M, 10 ml) and the solution was stirred for another 90 minutes. The temperature was raised to room temperature. Tlc analysis indicated that starting material remained, so additional hydrochloric acid in dioxane (4M, 10 ml) was added and the reaction was stirred for an additional 4 hours. The mixture was concentrated under reduced pressure and the residue was azeotroped with toluene (3 ×) to give the title compound (1.4 g).

  Production Example 3: 1- (3-Chloro-benzoyl) -piperidine-4-carboxylic acid ethyl ester

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

  Production Example 4: 1- (3-Chloro-benzoyl) -piperidine-4-carboxylic acid hydrazide

  A mixture of the ester of Preparation 3 (44.4 g, 0.15 mol) and hydrazine hydrate (30 ml, 0.58 mol) in methanol (120 ml) was heated at reflux for 10 hours and then allowed to cool to room temperature. It was. 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).

  Production Example 5: 1- (3-Chloro-benzoyl) -piperidine-4-carboxylic acid N ′-(2-chloro-acetyl) -hydrazide

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

  Production Example 6: [4- (5-Chloromethyl- [1,3,4] oxadiazol-2-yl) -piperidin-1-yl]-(3-chloro-phenyl) -methanone

To a cooled solution (0-5 ° C.) of the compound of Preparation 5 (10.2 g, 28.5 mmol) and pyridine (11.5 ml, 142.5 mmol) in dichloromethane (300 ml) was added trifluoroacetic anhydride (9. 45 ml, 57 mmol) was added dropwise over 30 minutes. When the addition was complete, the resulting pink suspension was stirred at 10 ° C. for an additional 90 minutes. The reaction mixture was carefully poured into saturated sodium bicarbonate solution (600 ml) and the layers were separated. The organic phase was further washed with saturated sodium bicarbonate solution (x2), dried over MgSO ₄ and treated with decolorized activated carbon. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the title compound (13 g).

  Production Example 7: 4- [N ′-(2-Chloro-acetyl) -hydrazinocarbonyl] -piperidine-1-carboxylic acid tert-butyl ester

4-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (see reference WO 2000039125, prep27) (25 g, 103 mmol) is 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. The reaction was then warmed to room temperature and stirred for 4 hours. The reaction mixture was partitioned with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and the filtrate evaporated to give the title compound as a milky white solid (29.6 g).
LRMS m / z APCI ^- 318 [MH] ^-
Production Example 8: 4- (5-Chloromethyl- [1,3,4] oxadiazol-2-yl) -piperidine-1-carboxylic acid tert-butyl ester

  The hydrazide of Preparation Example 7 (5.0 g, 15.6 mmol) was suspended in dichloromethane (200 ml), 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. The reaction was then partitioned with water (50 ml), the organic layer was dried over magnesium sulfate, filtered and the filtrate was evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane (2:98) as eluent to give the title compound as a white solid (2.95 g).

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

A mixture of the compound of Preparation Example 8 (8 g, 26.5 mmol), triazole (3.7 g, 53 mmol) and potassium carbonate (5.2 g, 38 mmol) in N, N-dimethylformamide (60 ml) at room temperature. Stir for 18 hours. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and brine, the layers were separated, the organic solution was dried over MgSO ₄ and concentrated under reduced pressure to give the title compound as an isomeric mixture.

Production Example 9b: 4- (5- [1,2,3] triazol-2-ylmethyl- [1,3,4] oxadiazol-2-yl) -piperidine-1-carboxylic acid tert-butyl ester 1-methylimidazole To a suspension of Preparation 170 hydrazide (132.3 g, 375 mmol) in (120 ml) was added dichloromethane (500 ml) and the resulting solution was cooled in an ice / acetone bath. To maintain the reaction temperature below 0 ° C., triflic anhydride (92 ml, 561 mmol) was added dropwise over 2.5 hours. When the addition was complete, the reaction was stirred for an additional 20 minutes. It was then quenched by the addition of 2M hydrochloric acid (350ml). The phases were separated and the aqueous layer was extracted with dichloromethane (200 ml). The combined organic solution was washed with brine, dried over MgSO ₄ and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane as eluent to give the title compound as a viscous oil.

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

A mixture of the compound of Preparation 6 (2 g, 5.9 mmol), triazole (810 mg, 11.75 mmol) and potassium carbonate (1.2 g, 8.85 mmol) in acetonitrile (20 ml) was stirred at room temperature for 30 minutes. Subsequently, the mixture was further stirred at 50 ° C. for 1 hour. The mixture was filtered, washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The residual brown oil was partitioned between ethyl acetate and water, the layers were separated and the organic solution was washed with more water then brine. The solution was dried over MgSO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol (100: 0 to 95: 5) as eluent to give the title compound (202 mg).

  Production Example 11a: 4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidine- 1-carboxylic acid tert-butyl ester

  To a solution of the compound of Preparation 9a (8.8 g, 26.5 mmol) and 4-chloroaniline (5 g, 39.75 mmol) in toluene (200 ml) was added trifluoroacetic acid (1 ml, 13.2 mmol). The reaction mixture was stirred at reflux temperature for 5 hours. The cooled mixture was diluted with dichloromethane, then washed with 1N sodium hydroxide solution and brine and evaporated under reduced pressure. The remaining brown oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1), Next, column chromatography was performed again using ethyl acetate: methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) to obtain the title compound (2.3 g).

Production Example 11b: 4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidine- 1-carboxylic acid tert-butyl ester N-methylimidazole (4.66 g, 56.75 mmol) and dichloromethane (20 ml) were added to the bisacyl hydrazide (5.00 g, 14.19 mmol) from Preparation 170 to obtain The solution was cooled to -20 ° C. Trifluoromethanesulfonic anhydride (6.00 g, 21.28 mmol) was added while maintaining the temperature below 0 ° C. At the end of the addition, the reaction was allowed to warm to ambient temperature and stirred for 15 hours. The reaction was quenched with H ₂ O (10 ml), the phases were separated and the aqueous layer was extracted with dichloromethane (10 ml). The combined organic phases were dried over magnesium sulfate, filtered, dichloromethane was evaporated and replaced with toluene under vacuum to give a solution of intermediate oxadiazole in toluene (˜20 ml volume). To the toluene solution was added 4-chloroaniline (1.90 g, 14.90 mmol) followed by trifluoroacetic acid (0.81 g, 7.09 mmol) and the reaction was stirred at 85 ° C. for 5.5 hours. did. The mixture was cooled to ambient temperature and stirred with 1.8N aqueous ammonia (14 ml) for 5 minutes. The phases were separated and the organic phase was diluted with tert-butyl methyl ester (20 ml) and then stirred for 15 hours. The resulting solid precipitate was collected by filtration and washed with tert-butyl methyl ether (2 × 5 ml) to give the title compound as a beige solid (2.72 g).

  Production Example 12a: 4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidine

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

  Production Example 12b: 4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidine Bis-p-toluenesulfonate

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

  Production Example 13: Methyl 1H-tetrazol-1-yl acetate

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

  Production Example 14: (3-Methyl-isoxazol-5-yl) -acetoyl chloride

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

  Production Example 15: Ethyl (2-methyl-1H-imidazol-1-yl) acetate

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

  Production Example 16: 2- (1H-tetrazol-1-yl) acetohydrazide

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

  Production Example 17: [1,2,3] triazol-1-yl-acetic acid ethyl ester and [1,2,3] triazol-2-yl-acetic acid ethyl ester

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

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

  To a cooled (<10 ° C.) solution of the ester mixture of Preparation 17 (19 kg) in ethanol (69 L) was added hydrazine hydrate (8.65 kg, 270 mol) and the temperature was maintained below 20 ° C. throughout this addition. . The reaction mixture was stirred at 14-19 ° C. for 3 hours, then more ethanol (25 L) was added and the product was collected by filtration and washed with ethanol (10 L). The crude solid was purified by recrystallization from ethanol (120 L) followed by three recrystallizations from methanol (105 L, 120 L and 90 L), and after drying under vacuum, the title compound (4.53 kg) was obtained. Obtained.

  Production Example 19: 2- (2-Methyl-1H-imidazol-1-yl) acetohydrazide

  The title compound is obtained as a white solid from the compound of Preparation Example 15 and hydrazine according to the same method as described in Preparation Example 16 except that 5 equivalents of hydrazine is used and isopropanol is used as the reaction solvent. It was.

  Production Example 20: 2- (3-Methyl-1,2,4-oxadiazol-5-yl) acetohydrazide

  3-methyl-1,2,4-oxadiazol-5-yl- according to the same method as described in Production Example 16 except that 8 equivalents of hydrazine was used and isopropanol was used as a reaction solvent. The title compound was obtained from acetic acid methyl ester (NL7807076) and hydrazine.

  Production Example 21: 2- (pyrimidin-2-yloxy) acetohydrazide

  A mixture of ethyl 2-pyrimidinyloxyacetate (GB2373186, step I ex368) (4.4 g, 24.15 mmol) and hydrazine hydrate (5 ml, 160 mmol) in isopropanol (30 ml) was heated under reflux for 1 hour. The mixture is then cooled and concentrated under reduced pressure and the residue is columned on silica gel with dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 100: 10: 1). Purification by chromatography gave the title compound (600 mg).

  Production Example 22: tert-Butyl 2-[(3-methylisoxazol-5-yl) acetyl] hydrazine carboxylate

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

  Production Example 23: tert-butyl 2- [3- (3,5-dimethylisoxazol-4-yl) propanoyl] hydrazinecarboxylate

  Β- (3,5-dimethyl-4-isoxazolyl) propionic acid (J. Org. Chem. 59 (10) 1994; 2882) in dichloromethane (50 ml) and N, N-dimethylformamide (1 drop) (2. To a solution of 5 g, 14.8 mmol) was added oxalyl chloride (5.16 ml, 59.2 mmol) and the solution was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure and the residue was azeotroped with dichloromethane (5x) to give a brown liquid. This was dissolved in dichloromethane (25 ml) and tert-butyl carbazate (2.93 g, 22.2 mmol) was added in small portions. The mixture was diluted with additional dichloromethane (23 ml) and the reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure, the residue was suspended in dichloromethane, the resulting precipitate was filtered off and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5 to 90: 10: 1) to give the title compound as an oil (3.08 g).

  Production 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 to low volume under reduced pressure and the resulting precipitate was filtered off, washed with dichloromethane and dried to give the title compound (810 mg).

  Production 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 methanolic hydrochloric acid (50 ml) was stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure and the residue was azeotroped with toluene. The crude product was triturated with pentane / ether and then triturated with ether and the resulting solid was filtered off to give the title compound as a milky white solid (1.39 g).

  Production Example 26: tert-butyl 2- (hydrazinocarbonyl) morpholine-4-carboxylate

4- (tert-butyl) 2-methyl 2,4-morpholinecarboxylate (WO 03/018576, ex1 part1) (2.03 g, 8.3 mmol), hydrazine hydrate (1.2 ml, 24 mmol), and methanol (50 ml) was heated under reflux for 4 days. The cooled mixture was evaporated under reduced pressure, the residue was partitioned between water and ethyl acetate, and the layers were separated. The organic phase was dried over MgSO ₄ and evaporated under reduced pressure to give the title compound (1.92 g).
LCMS: m / z ES ⁺ 268 [MNa] ⁺
Production Example 27: tert-butyl 3- (hydrazinocarbonyl) piperidine-1-carboxylate

To a solution of piperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl ester (US 2002 0099035, ex12) (72 g, 280 mmol) in ethanol (250 ml) was added hydrazine hydrate (75 ml, 1.5 mol). In addition, the solution was heated at reflux 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 solution was dried over MgSO ₄ and evaporated under reduced pressure. The product was azeotropically distilled with ether to give the title compound as a colorless gum (59.8 g).

  Production 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 according to a method similar to the method described in Preparation Example 3.

  Production Example 29: 1- (4-Chlorobenzoyl) piperidine-4-carbohydrazide

A solution of the compound of Preparation 28 (148 g, 0.5 mmol) in methanol (400 ml) was heated at 70 ° C. for 30 minutes. Next, hydrazine hydrate (50 g, 1.0 mmol) was added and the reaction was stirred at 60 ° C. for an additional 3 hours. Tlc analysis indicated that starting material remained, so additional hydrazine hydrate (50 g, 1.0 mmol) was added and the reaction was stirred at 75 ° C. for an additional 48 hours. The cooled mixture was concentrated under reduced pressure and the residue was suspended in dichloromethane (1 L) and washed with water (2 ×). The organic solution was dried over MgSO ₄ and evaporated under reduced pressure to give the title compound as a white solid (119 g).

  Production Example 30: 1- (4-Chlorobenzoyl) -N ′-(trifluoroacetyl) piperidine-4-carbohydrazide

  To a solution of the compound of Preparation 29 (3.0 g, 10.65 mmol) and N-methylmorpholine (1.29 ml, 11.7 mmol) in dichloromethane (50 ml) was added trifluoroacetic anhydride (1.56 ml, 11. 18 mmol) was added dropwise and the reaction was stirred at room temperature for 18 hours. The resulting precipitate was filtered off, washed with dichloromethane and dried to give the title compound (1.78 g).

  Production Example 31: 1- (4-Chlorobenzoyl) -N ′-(ethoxyacetyl) piperidine-4-carbohydrazide

To a solution of the compound of Preparation 29 (2.5 g, 8.87 mmol) in dichloromethane (70 ml) is added N-methylmorpholine (2.60 g, 26.6 mmol) and then ethoxyacetyl chloride (WO 01/46150). , ex33A) (1.09 g, 8.87 mmol) was added and the reaction was stirred at room temperature for 18 hours. This mixture was washed with water, then with ammonium chloride solution and finally with sodium carbonate solution. This was dried over MgSO ₄ and evaporated under reduced pressure to give the title compound.

  Production Example 32: 1- (3-Chlorobenzoyl) -N ′-(ethoxyacetyl) piperidine-4-carbohydrazide

  The title compound was obtained in 91% yield from the compound of Production Example 4 and ethoxyacetyl chloride (WO 01/46150 ex33A) according to the method described in Production Example 31.

  Production 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). The reaction mixture was stirred at room temperature for 54 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and then partitioned with 2N hydrochloric acid. The resulting precipitate was filtered off, redissolved in dichloromethane, the solution was dried over MgSO ₄ and evaporated under reduced pressure. The residue was triturated with ether to give the target compound as a white solid. The filtrate was separated and the organic layer was washed with 2N hydrochloric acid (2 ×), dried over MgSO ₄ and evaporated under reduced pressure. The solid was triturated with ether to give additional compound as a white solid, combined yield 99.4g.

  Production Example 34: tert-butyl 4-{[(4-chlorophenyl) amino] carbonothioyl} piperidine-1-carboxylate

A solution of the compound of Preparation 33 (99.4 g, 294 mmol) and Lawesson reagent (30 g, 74.3 mmol) in toluene (1 L) was heated at reflux for 1 hour and then stirred at room temperature for an additional 18 hours. . Since tlc analysis showed that starting material remained, additional Lawesson reagent (11.1 mmol) was added and the reaction was heated at reflux for an additional hour. The cooled mixture was concentrated under reduced pressure and the residue was azeotropically distilled with ethyl acetate. The crude product was triturated with hot ethyl acetate and the resulting solid was filtered off and dried to give the title compound as a white solid (53 g).
LCMS: m / z APCI ^- 353 [MH] ^-
Production 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 isonipecotate (3.19 ml, 20.7 mmol) in dichloromethane (30 ml) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, the residue was triturated with ether and the resulting solid was filtered off and envisioned to give the title compound as a white solid (6.27 g).

  Production Example 36: N- (4-chlorophenyl) -3-methylpiperazine-1-carbothioamide

To an ice-cold solution of 2-methylpiperazine (9.45 g, 94.33 mmol) in dichloromethane (250 ml) was added a solution of 4-chlorophenyl isothiocyanate (8.0 g, 47.17 mmol) in dichloromethane (250 ml) for 30 minutes. Added dropwise. Once the addition was complete, the reaction was stirred at room temperature for 1 hour. The reaction was then washed with water (3 ×), dried over MgSO ₄ and concentrated under reduced pressure to give the title compound as a white solid (11.8 g).

  Production Example 37: N- (4-chlorophenyl) -4- (2,2-dimethylpropanoyl) -3-methylpiperazine-1-carbothioamide

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

  Production Example 38: N- (4-chlorophenyl) -4- (2,2-dimethylpropanoyl) -2-methylpiperazine-1-carbothioamide

A solution of 4-chlorophenyl isothiocyanate (5.1 g, 30 mmol) and 4-N-BOC-2-methylpiperazine (6.0 g, 30 mmol) in dichloromethane (250 ml) was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure to give the title compound as a white foam.
LCMS: m / z APCI ⁺ 370 [MH] ⁺
Production Example 39: Ethyl 1-{[(4-chlorophenyl) amino] carbonothioyl} -4-methylpiperidine-4-carboxylate

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

  Production Example 40: N- (4-Chlorophenyl) -4-cyano-4-phenylpiperazine-1-carbothioamide

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

  Production Examples 41 to 44:

  A mixture of 4-chlorophenyl isothiocyanate (1 equivalent) and the appropriate amine (1 equivalent) in ethanol (0.8-1.28 ml / mmol) was stirred at room temperature for 30 minutes. The reaction mixture was then evaporated under reduced pressure to give the title compound as a white solid.

  Production Example 45: tert-butyl 4-{[(4-chlorophenyl) amino] carbonothioyl} -1,4-diazepan-1-carboxylate

A mixture of 4-chlorophenyl isothiocyanate (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 give the title compound as a white foam.

  Production Example 46: tert-butyl 4-[(Z)-[(4-chlorophenyl) imino] (methylthio) methyl] piperidine-1-carboxylate

To maintain a temperature of 10 ° C. in a cooled (10 ° C.) solution of the compound of Preparation 34 (53 g, 0.15 mol) in tetrahydrofuran (1 L), potassium tert-butoxide (20.1 g, 0.18 mol) Was added in small portions. To maintain the temperature at 10 ° C., methyl iodide (11.2 ml, 0.18 mol) was added dropwise and then the reaction was allowed to warm gradually to room temperature. The reaction was stirred for another 90 minutes and then water was added to quench it. The reaction was diluted with ethyl acetate and washed with water. The phases were separated, the aqueous layer was further extracted with ethyl acetate, and the combined organic solutions were dried over MgSO ₄ and evaporated under reduced pressure. The residual oil was adsorbed onto silica gel and purified by column chromatography on silica gel using pentane: ethyl acetate (75:25) as eluent to give the title compound as an oil, which was Crystallized during standing.

  Production Example 47: Ethyl 1-[(Z)-[(4-chlorophenyl) imino] (methylthio) methyl] piperidine-4-carboxylate

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

  Production Example 48: Ethyl 1-[(Z)-[(4-chlorophenyl) imino] (methylthio) methyl] -4-methylpiperidine-4-carboxylate

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

  Production Examples 49 to 55:

To a solution of a compound selected from Preparation 37, 38, 40-42 and 45 (1 eq) in tetrahydrofuran is added potassium tert-butoxide (1.1 eq) followed by methyl p-toluenesulfonate (1 .1 equivalent) was added and the reaction was stirred at room temperature for 2 hours. The mixture is concentrated under reduced pressure, the residue is partitioned between ethyl acetate and water, the layers are separated,
The organic solution was washed with water (3x), dried over MgSO ₄ and evaporated under reduced pressure to give the title compound.

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

  Production Example 56: Methyl 4-[(tert-butoxycarbonyl) amino] -N- (4-chlorophenyl) piperidine-1-carbimidothioate

To a suspension of the compound of Preparation 44 (42.3 g, 114 mmol) in tetrahydrofuran (400 ml) was added potassium tert-butoxide (12.8 g, 114 mmol) and the suspension was stirred at room temperature for 10 minutes. Methyl p-toluenesulfonate (21.29 g, 114 mmol) was added and the reaction was stirred for 10 minutes. Additional potassium tert-butoxide (641 mg, 5.7 mmol) and methyl p-toluenesulfonate (1.08 g, 5.7 mmol) were added and the reaction was stirred for an additional 10 minutes. The mixture was diluted with ether and washed with water (200 ml) and brine, then dried over MgSO ₄ and evaporated under reduced pressure to give the title compound.

  Production Example 57: tert-butyl 4- [5- (methoxymethyl) -1,3,4-oxadiazol-2-yl] piperidine-1-carboxylate

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

  Production Example 58: tert-butyl 4- {5-[(2,2,2-trifluoroethoxy) methyl] -1,3,4-oxadiazol-2-yl} piperidine-1-carboxylate

To a solution of 2,2,2-trifluoroethanol (4.64 g, 46.4 mmol) in tetrahydrofuran (100 ml) was added potassium tert-butoxide (1.8 g, 41.8 mmol) and the solution was stirred at room temperature for 10 minutes. Stir for minutes. The compound of Preparation 8 (7.0 g, 23.2 mmol) was added and the mixture was then heated at 50 ° C. for 2 hours. Ammonium chloride solution was added to quench the reaction and the organic layer was decanted and evaporated under reduced pressure. The residue was redissolved in ethyl acetate and the solution was washed with brine, dried over MgSO ₄ and then evaporated under reduced pressure to give the title compound as a yellow oil (8.15 g). .

  Production Example 59: tert-butyl 4- [5- (hydroxymethyl) -1,3,4-oxadiazol-2-yl] piperidine-1-carboxylate

To a solution of the compound of Preparation 8 (8 g, 26.5 mmol) in acetonitrile (150 ml) was added potassium acetate (5.2 g, 53.0 mmol) and the reaction was heated at 80 ° C. for 18 hours. The cooled 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 it was 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 give the title compound as a milky white solid (7.16 g).

  Production Example 60: tert-butyl 4- [5- (morpholin-4-ylmethyl) -1,3,4-oxadiazol-2-yl] piperidine-1-carboxylate

A mixture of the compound of Preparation Example 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) at 80 ° C. Stir 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 give the title compound as an orange oil (12.06 g).

  Production Example 61: tert-butyl 4-{[2- (ethoxyacetyl) hydrazino] carbonyl} piperidine-1-carboxylate

4-hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (WO 2000039125, prep 27) (3 g, 12.33 mmol) in N, N-dimethylformamide (15 ml) and ethoxyacetic acid (1.28 ml, 13.56 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.6 g, 13.56 mmol) and 1-hydroxybenzotriazole hydrate (1.83 g, 13.56 mmol) And triethylamine (2.1 ml, 14.8 mmol) 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 and the organic phase was dried over MgSO ₄ and evaporated under reduced pressure to give the title compound as an oil that crystallized on standing.

  Production Example 62: tert-butyl 4-{[2- (3,3,3-trifluoropropanoyl) hydrazino] carbonyl} piperidine-1-carboxylate

  According to a method similar to the method described in Production Example 61, 4-hydrazinocarbonyl-carboxylic acid tert-butyl ester (WO 2000039125, prep.27) and 3,3,3-trifluoropropionic acid were used to give the title compound. Got.

  Production Example 63: tert-butyl 4- [5- (ethoxymethyl) -1,3,4-oxadiazol-2-yl] piperidine-1-carboxylate

To an ice-cold solution of the compound of Preparation 61 (4.06 g, 12.33 mmol) in dichloromethane (60 ml), pyridine (4 ml, 49.3 mmol) was added dropwise. Then triflic anhydride (4.2 ml, 24.6 mmol) was added dropwise over 20 minutes and the solution was stirred at 0 ° C. for 1 hour. This was then stirred for an additional hour at room temperature. The mixture was basified to pH 4 using aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (97: 3: 0.3) to give the title compound as a yellow oil (1.25 g). Obtained.

  Production Example 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 Example 62 according to a method similar to the method described in Preparation Example 63.

  Production Example 65: 1- (4-chlorobenzoyl) -4- (1,3,4-oxadiazol-2-yl) piperidine

To a solution of the compound of Preparation 29 (9.0 g, 31.94 mmol) in N, N-dimethylformamide (100 ml) was added N, N-dimethylformamide dimethylacetal (5.71 g, 47.9 mmol). The reaction was stirred at 50 ° C. for 3 hours. The mixture was concentrated under reduced pressure and the residue was suspended in toluene (150 ml). p-Toluenesulfonic acid (1 g, 5.26 mmol) was added and the reaction was heated at 110 ° C. for 18 hours. The reaction was diluted with ethyl acetate (100 ml) and washed with brine, water and then again with brine. The solution was dried over MgSO ₄ and then evaporated under reduced pressure. The crude product is purified by column chromatography using a silica gel cartridge and dichloromethane: methanol (100: 0 to 90:10) as eluent to give the title compound as a white solid (4.25 g). It was.
LCMS: m / z APCI ⁺ 292 [MH] ⁺
Production Example 66: 1- (3-Chlorobenzoyl) -4- (1,3,4-oxadiazol-2-yl) piperidine

To a solution of the compound of Preparation 4 (9.0 g, 31.94 mmol) in tetrahydrofuran (6 ml) was added N, N-dimethylformamide dimethyl acetal (5.71 g, 47.9 mmol), and the reaction was carried out at 50 ° C. For 18 hours. Since tlc analysis showed that starting material remained, additional N, N-dimethylformamide dimethylacetal (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 was heated at 110 ° C. for 18 hours. The reaction was diluted with ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution (2 ×) and brine, then dried over Na ₂ SO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) to give the title compound. .

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

To a solution of the compound of Preparation 29 (9.0 g, 31.94 mmol) in N, N-dimethylformamide (20 ml) was added N, N-dimethylacetamide dimethylacetal (6.38 g, 47.9 mmol). The reaction was stirred at room temperature for 1 hour. This was then stirred at 40 ° C. for a further 2 hours. The mixture was diluted with toluene (150 ml) and heated to 110 ° C. before p-toluenesulfonic acid (400 mg, 2.22 mmol) was added. The reaction was heated at 110 ° C. for 18 hours, then cooled and concentrated under reduced pressure. The residue is dissolved in ethyl acetate and washed with ammonium chloride solution and brine, then it is dried over MgSO ₄ and evaporated under reduced pressure to afford the title compound as an oil (9.75 g). Obtained.

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

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

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

To an ice-cold solution of the compound of Preparation 32 (2.80 g, 7.61 mmol) in dichloromethane (50 ml) is added pyridine (1.8 g, 22.84 mmol), then triflic anhydride (3.22 g, 11 .42 mmol) was added. The reaction was then stirred at room temperature for 2 hours. The mixture with ammonium chloride solution (3x), then with saturated aqueous sodium carbonate solution, dried over MgSO _4, treated with activated carbon. The mixture was then filtered and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography using a silica gel cartridge and an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to give the title compound as a yellow oil (566 mg).

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

  The title compound was obtained as a crystalline solid from the compound of Preparation Example 31 according to a method similar to the method described in Preparation Example 69.

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

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) was added triflic anhydride (1.98 ml, 11.7 mmol). Was added. The mixture was then warmed to room temperature and stirred for 18 hours. The reaction was diluted with dichloromethane and washed with 2N hydrochloric acid and then with saturated aqueous sodium bicarbonate. This was dried over MgSO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (99: 1 to 96: 4) to give the title compound as a brown oil (620 mg).

Production Examples 72 to 74:
The following general structural formula shown below:

Were prepared from N, N-dimethylacetamide dimethylacetal and a suitable hydrazide according to the same method as described in Preparation Example 67.

A = 3-hydrazinocarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ester was used (obtained from CB Research and Development Inc.).
Production Example 75: 1- (3-Chlorobenzoyl) -4- [5- (1H-pyrazol-1-ylmethyl) -1,3,4-oxadiazol-2-yl] piperidine

Compound of Preparation Example 6 (1 g, 2.94 mmol), pyrazole (400 mg, 5.9 mmol), potassium carbonate (610 mg, 4.4 mmol) in acetonitrile (10 ml) and N, N-dimethylformamide (10 ml) Was stirred at 100 ° C. for 18 hours. The cooled mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water (2x) and brine. This was then dried over MgSO ₄ . The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 95: 5: 0.5) to give the title compound (550 mg). Obtained.

  Production Example 76: tert-butyl 4- [4- (4-chlorophenyl) -5- (2-morpholin-4-ylethyl) -4H-1,2,4-triazol-3-yl] piperidine-1-carboxy rate

  Preparation with 4-morpholinepropanoic acid hydrazide (Comptes Rendus des Seances de I'acadamie des Sciences, Serie C; Sciences Chimiques 1976: 282 (17) 857-60) (1.5 g, 8.7 mmol) in tetrahydrofuran (18 ml) Example 46 To the compound (2.7 g, 7.25 mmol) was added trifluoroacetic acid (0.35 ml, 4.3 mmol) and the reaction was heated at reflux for 8 hours. The cooled mixture was diluted with dichloromethane, washed with 1N sodium hydroxide solution and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 10: 10: 1) to give the title compound (2.2 g). Obtained.

Production Examples 77 to 87:
The following general formula:

Was prepared from the compound of Preparation Example 46 and a suitable hydrazide according to the same method as described in Preparation Example 76.

A = 1-Imidazol-1-yl acetic acid hydrazide was used; prepared as described in Boll. Chim. Farm. 114 (2): 70-72, 1975.
B = The reaction was stirred at reflux for 18 hours.
C = 1 equivalent of hydrazide was used.

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

To a solution of the compound of Preparation 56 (43.6 g, 114 mmol) in tetrahydrofuran (250 ml) is added acetic hydrazide (16.9 g, 228 mmol) followed by trifluoroacetic acid (4.4 ml, 57.57). 1 mmol) was added and the mixture was heated under reflux for 7 hours. The cooled mixture was then washed with dilute ammonia solution, the layers were separated, and the aqueous phase was further extracted with ethyl acetate. The combined organic solution was dried over MgSO ₄ and evaporated under reduced pressure. The residue was triturated with ether (100 ml) and the resulting crystals were filtered off and dried in vacuo to give the title compound (32.4 g).

  Production 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 according to a method similar to that described in Preparation 88 except that 2 equivalents of acetic hydrazide was used.

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

To a solution of the compound of Preparation 47 (7.38 g, 21.7 mmol) in tetrahydrofuran (100 ml) is added trifluoroacetic acid (0.84 ml, 10.85 mmol), followed by acetic hydrazide (2.41 g, 32. 6 mmol) was added and the reaction was heated at reflux for 3 hours. The cooled mixture was partitioned between ethyl acetate and aqueous ammonia and the layers were separated. The organic phase was washed with brine, dried over MgSO ₄ and evaporated under reduced pressure. The crude product was triturated with ether to give the title compound as a white solid (5.04 g).

  Production Example 91: Ethyl 1- [4- (4-chlorophenyl) -5- (2H-1,2,3-triazol-2-ylmethyl) -4H-1,2,4-triazol-3-yl] piperidine -4-carboxylate

To a solution of the hydrazide of Preparation 18 (3.6 g, 10.6 mmol) and the compound of Preparation 47 (2.24 g, 15.9 mmol) in tetrahydrofuran (50 ml) was added trifluoroacetic acid (0.41 ml, 5. 3 mmol) was added and the reaction was heated at reflux for 15 hours. The cooled mixture was partitioned between ethyl acetate and brine and the layers were separated. The organic phase was filtered, dried over MgSO ₄ and evaporated under reduced pressure to give the title compound as a gum.

  Production Example 92: Ethyl 1- [4- (4-chlorophenyl) -5-methyl-4H-1,2,4-triazol-3-yl] -4-methylpiperidine-4-carboxylate

  The title compound was obtained as a clear oil in 86% yield from the compound of Preparation Example 48 and acetic hydrazide according to the method described in Preparation Example 91.

  Production Example 93: tert-butyl 4- [4- (4-chlorophenyl) -5- (methoxymethyl) -4H-1,2,4-triazol-3-yl] -2-methylpiperazine-1-carboxylate

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

  Production Example 94: tert-butyl 4- [4- (4-chlorophenyl) -5- (methoxymethyl) -4H-1,2,4-triazol-3-yl] -3-methylpiperazine-1-carboxylate

The title compound was obtained in 67% yield from the compound of Preparation 50 according to a method similar to that described in Preparation 93 except that the reaction was heated under reflux.
LCMS: m / z APCI ⁺ 363 [MH] ⁺
Production Example 95: tert-butyl 4- [4- (4-chlorophenyl) -5-methyl-4H-1,2,4-triazol-3-yl] piperazine-1-carboxylate

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

  Production Example 96: 1- [4- (4-chlorophenyl) -5-methyl-4H-1,2,4-triazol-3-yl] -4-phenylpiperidine-4-carbonitrile

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

  Production Example 97: tert-butyl 4- [4- (4-chlorophenyl) -5- (methoxymethyl) -4H-1,2,4-triazol-3-yl] piperazine-1-carboxylate

  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) was added trifluoroacetic acid (2.14 g, 18.83 mmol). ) Was added and the reaction mixture was heated at reflux for 18 hours. The cooled mixture is concentrated under reduced pressure and the residue is purified by column chromatography using a silica gel cartridge and an elution gradient of dichloromethane: methanol (100: 0 to 90:10) to give the title compound as an oil Obtained as a thing.

  Production example 98: tert-butyl 4- [4- (4-chlorophenyl) -5- (hydroxymethyl) -4H-1,2,4-triazol-3-yl] piperazine-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) Stir at 100 ° C. for 18 hours. The cooled mixture was evaporated under reduced pressure and the residue was dissolved in dichloromethane and washed with 2M sodium hydroxide solution. The organic solution was dried over MgSO ₄ and concentrated under reduced pressure. The crude product is purified by column chromatography on silica gel using ethyl acetate: methanol: 0.88 ammonia (95: 5: 0.5 to 90: 10: 1) to give the title compound as a milky white solid. (7.1 g).

Production Examples 99 to 101:
The following general formula:

Were prepared from an appropriate compound selected from Preparation Examples 60, 63 and 64 and 4-chloroaniline according to a method similar to that described in Preparation Example 98.

A = 0.8 equivalent of trifluoroacetic acid was used.
B = 1 equivalent of trifluoroacetic acid was used.
Production Example 102: tert-butyl 2- [4- (4-chlorophenyl) -5-methyl-4H-1,2,4-triazol-3-yl] morpholine-4-carboxylate

The title compound was prepared from the compound of Preparation 72 and 4-chloroaniline according to the same method as described in Preparation 98 except that 1 equivalent of trifluoroacetic acid and 2 equivalent of 4-chloroaniline were used. Obtained as an oil in 75% yield.
LCMS: m / z APCI ⁺ 393 [MH] ⁺
Production Example 103: tert-butyl 3- [4- (4-chloro-2-methylphenyl) -5-methyl-4H-1,2,4-triazol-3-yl] piperidine-1-carboxylate

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

  Production Example 104: tert-butyl 3- [4- (4-chloro-2-methylphenyl) -5-methyl-4H-1,2,4-triazol-3-yl] pyrrolidine-1-carboxylate

  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 is concentrated under reduced pressure and the residue is purified on silica gel using an elution gradient of dichloromethane: methanol: triethylamine (98: 1.5: 0.5 to 90: 10: 1 to 80: 20: 1). Purification by column chromatography above gave the title compound (810 mg).

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

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

  Production Example 106: tert-butyl 4- [4- (2,4-dichlorophenyl) -5-methyl-4H-1,2,4-triazol-3-yl] piperidine-1-carboxylate

  The title compound was prepared from the oxadiazole of Preparation Example 1 and 2,4-dichloroaniline in the same manner as described in Preparation Example 105 except that 2 equivalents of aniline were used.

  Production Examples 107 to 116:

To a solution of the compound of Preparation 9 (1 eq) in toluene (1.6 ml / mmol) is added the appropriate aniline (Y′Y-PhNH ₂ ) (1 to 1.1 eq) followed by trifluoroacetic acid. (0.5 eq) was added and the reaction mixture was heated under reflux. The reaction was monitored by tlc and the mixture was allowed to cool at the end of the reaction (45 minutes to 9 hours). The reaction was washed with dilute ammonia solution and brine, then dried over MgSO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol (95: 5) as eluent to give the title compound.

A = 1.5 equivalents of aniline were used in the reaction.
Production Example 117: tert-butyl 4- [4- (4-chlorophenyl) -5-({[(methylthio) carbonothioyl] oxy} methyl) -4H-1,2,4-triazol-3-yl] Piperidine-1-carboxylate

To an ice-cold solution of the compound of Preparation 98 (1 g, 2.55 mmol) in tetrahydrofuran (20 ml) was added sodium hydride (60% dispersion in mineral oil, 112 mg, 2.8 mmol) and the solution was allowed to cool at room temperature. Stir for 1 hour. Carbon disulfide (230 μl, 3.83 mmol) was added followed by methyl iodide (238 μl, 3.83 mmol) and the reaction was stirred at room temperature for an additional 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 column chromatography on silica gel using an elution gradient of dichloromethane: methanol: 0.88 ammonia (97: 3: 0.3 to 95: 5: 0.5) to give the title The compound was obtained as a pale yellow solid (460 mg).

  Production Examples 118 to 137:

To a solution of the appropriate protected piperidine selected from Preparation 76, 77, 80-85, and 105-116 in methanol (9-22.5 ml / mmol) is added 4M hydrochloric acid in dioxane (8-30 equivalents). In addition, the reaction 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 MgSO ₄ and evaporated under reduced pressure to give the title compound.

A = The reaction mixture is evaporated under reduced pressure and then worked up to isolate the hydrochloride salt of the title compound.
Production Examples 138 to 141:

A solution of the appropriate protected piperidine (1 equivalent) selected from Preparation 78-79 and 86-87 in 2.2 M methanolic hydrochloric acid (13 ml / mmol) was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue was azeotropically distilled 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 give the title compound.

A = The reaction mixture was evaporated under reduced pressure and azeotropically distilled with toluene. The product was triturated with ethyl acetate, filtered and dried to give the hydrochloride salt of the title compound.
Production Example 142: 4- [4- (4-Chlorophenyl) -5- (methoxymethyl) -4H-1,2,4-triazol-3-yl] piperidine

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

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

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

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

  To a solution of the compound of Preparation 95 (4.12 g, 110 mmol) in dichloromethane (50 ml) was added 4M hydrochloric acid in dioxane (13.75 ml) and the reaction 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).

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

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

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

  To a solution of the compound of Preparation 103 (846 mg, 2.16 mmol) in dioxane (10 ml) was added 4M hydrochloric acid in dioxane (5 ml) and the reaction was stirred at room temperature for 18 hours. Tlc analysis indicated that starting material remained, so additional 4M hydrochloric acid in dioxane (5ml) was added and the reaction stirred at room temperature for an additional hour. The reaction mixture was then concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (90: 10: 1). The product was azeotropically distilled with dichloromethane and ether to give the title compound as an opalescent foam.

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

A solution of the Preparation 104 compound in 4M hydrochloric acid in dioxane (20ml) 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 give the title compound.

  Production Example 148: 1- [4- (4-Chlorophenyl) -5- (methoxymethyl) -4H-1,2,4-triazol-3-yl] -1,4-diazepan

To a solution of the compound of Preparation 89 (5.45 g, 12.93 mmol) in dioxane (30 ml) was added 4M hydrochloric acid in dioxane (25 ml) and the reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and ether. The layers were separated, the aqueous phase was basified 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).

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

  The title compound was obtained as a yellow oil in 95% yield from the compound of Preparation Example 94 according to the method described in Preparation Example 148.

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

To an ice-cold solution of the compound of Preparation 93 (2.80 g, 6.63 mmol) in dichloromethane (25 ml) was added trifluoroacetic acid (25 ml) and the solution was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was redissolved in ethyl acetate and 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 on silica gel using a silica gel cartridge and an elution gradient of dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) The title compound was obtained as an oil (780 mg).

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

  Compound of Preparation Example 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) ) And stirred for 18 hours at room temperature (relative to 110 ° C.). The cooled mixture was concentrated under reduced pressure. 2M sodium hydroxide solution (10 ml) was added and the mixture was azeotropically distilled with toluene. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5 to 80: 20: 3) to give the title compound as a milky white foam ( 1.45 g).

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

  Compound of Preparation Example 1 (900 mg, 3.4 mmol), 4-chloro-2-fluoroaniline (109.1 mg, 0.75 mmol), 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 is azeotropically distilled with toluene and the crude product is purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: 0.88 ammonia (90: 10: 1 to 80: 20: 3). Purification gave the title compound as a milky white foam (985 mg).

  Production Example 153: 4- [4- (4-Chlorophenyl) -5-[(2,2,2-trifluoroethoxy) methyl] -4H-1,2,4-triazol-3-yl] piperidine

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) was added trifluoroacetic acid (2.49 g, 21.8 mmol). ) Was added and the reaction was heated at reflux for 48 hours. Tlc analysis indicated that starting material remained, so additional trifluoroacetic acid (8 ml) was added and the reaction was heated at reflux for an additional 4 hours. The cooled mixture was extracted with water and the aqueous solution was basified with potassium hydroxide and then extracted with dichloromethane (4 × 100 ml). The combined organic extracts were dried over MgSO ₄ and evaporated under reduced pressure. The crude product is purified by column chromatography using a silica gel cartridge and an elution gradient of dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 85: 15: 1.5) to give the title compound (4.34 g) was obtained.

  Production Example 154: 4- [4- (4-Chlorophenyl) -5-[(trifluoromethoxy) methyl] -4H-1,2,4-triazol-3-yl] piperidine

A solution of 1,3-dibromo-2,4-dimethylhydantoin (283 mg, 1.0 mmol) in dichloromethane (5 ml) at −78 ° C. was followed by hydrogen fluoride-pyridine (0.35 ml, 13.2 mmol) followed by A solution of Preparation 117 compound (160 mg, 0.33 mmol) in dichloromethane (1 ml) was added. The reaction was allowed to warm to room temperature over 30 minutes and then 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 is purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (90: 10: 1) as eluent to give the title compound as a yellow oil (45 mg). It was.
LCMS: m / z APCI ⁺ 361 [MH] ⁺
Production Example 155: 4- [4- (4-Chlorophenyl) -5-methyl-4H-1,2,4-triazol-3-yl] benzonitrile

4-Chloroaniline (2.1 g, 16.2 mmol) and 4- (5-methyl-1,3,4-oxadiazol-2-yl) benzonitrile in tetrahydrofuran (50 ml) (
Journal fuer Praktische Chemie, 1994: 336 (8): 678-85) (3.0 g, 16.2 mmol) is added to a suspension with trifluoroacetic acid (600 μl, 8.1 mmol) and the reaction is brought to reflux temperature. Heated for 22 hours. The cooled mixture was partitioned between ethyl acetate (300 ml) and 20% 0.88 aqueous ammonia (120 ml), 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 amount of ethyl acetate to give the title compound as a white crystalline solid (2.82 g).

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

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

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

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

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

  A solution of the ester of Preparation 90 (4 g, 10.4 mmol) and 4N sodium hydroxide (13 ml, 52 mmol) in dioxane (200 ml) was stirred at room temperature for 2 hours. The mixture was partitioned between water and ethyl acetate and the layers were separated. The aqueous layer was acidified to pH 4 using 2N hydrochloric acid and the resulting precipitate was filtered off and washed with water. This solid was triturated with ether, filtered and dried in vacuo to give the title compound as a white solid.

  Production Example 159: 1- [4- (4-chlorophenyl) -5- (2H-1,2,3-triazol-2-ylmethyl) -4H-1,2,4-triazol-3-yl] piperidine-4 -Carboxylic acid

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

  Production Example 160: 1- [4- (4-Chlorophenyl) -5-methyl-4H-1,2,4-triazol-3-yl] -4-methylpiperidine-4-carboxylic acid

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

  Production Example 161: N- (4-chlorophenyl) -2- (2H-1,2,3-triazol-2-ylacetyl) hydrazinecarbothioamide

  4-Chlorophenyl isothiocyanate (8.58 g, 50.6 mmol) was added in portions to a suspension of Preparation 18 hydrazide (7.0 g, 50.6 mmol) in ethanol (200 ml) and the mixture was allowed to cool at room temperature. Stir 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).

  Production Example 162: 4- (4-chlorophenyl) -5- (2H-1,2,3-triazol-2-ylmethyl) -2,4-dihydro-3H-1,2,4-triazole-3-thione

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

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

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

  Production Example 164: 2-{[4- (4-chlorophenyl) -5- (methylsulfonyl) -4H-1,2,4-triazol-3-yl] methyl} -2H-1,2,3-triazole

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

  Production Example 165: 4-Chloro-2-ethoxynitrobenzene

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

  Production Example 166: 4-Chloro-2-ethoxyaniline

Between the nitro compound of Preparation Example 165 (3.30 g, 16.4 mmol), iron powder (2.7 g, 49 mmol) and calcium chloride (810 mg, 7.4 mmol) in water (5 ml) and ethanol (30 ml). The mixture was heated under reflux for 3.5 hours. The cooled mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate, the layers were separated and the organic phase was further washed with brine. The solution was dried over MgSO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of pentane: ethyl acetate (100: 0 to 0: 100) to give the title compound as an oil (2.4 g). .

  Production Example 167: 1- (5-chloro-2-nitrobenzyl) pyrrolidine

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

  Production Example 168: 4-chloro-2- (pyrrolidin-1-ylmethyl) aniline

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

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

A solution of Preparation 101 compound (8.6 g, 18.6 mmol) in dioxane (50 ml) and 4M hydrochloric acid in dioxane (30 ml) was stirred at room temperature for 18 hours. The solution was evaporated under reduced pressure and the residue was partitioned between 2N sodium hydroxide solution and ethyl acetate. The remaining solid was filtered off 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 solution was dried over MgSO4 and evaporated under reduced pressure to give additional product (1.11 g).
LCMS: m / z APCI ⁺ 362 [MH] ⁺
Production Example 170: tert-butyl 4-{[2- (2H-1,2,3-triazol-2-ylacetyl) hydrazino] carbonyl} piperidine-1-carboxylate

A suspension of N-Boc-isonipecotic acid (30.0 g, 130.8 mmol) and hydrazide of Preparation 18 (18.5 g, 130.8 mmol) in dichloromethane (150 ml) in an ice bath under N _2. Cooled down. 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (25.6 g, 133.5 mmol) was added from the addition funnel and the funnel was washed with additional dichloromethane (10 ml). The resulting solution was allowed to warm to ambient temperature. When the reaction was complete, isopropanol (150 ml) was added and the homogeneous solution was concentrated in vacuo to about 165 ml, heated to about 70 ° C. and allowed to cool to ambient temperature with stirring. The resulting thick white slurry was filtered in vacuo, washed with isopropanol (15 ml and 30 ml) and dried in vacuo at 50 ° C. to give the title compound as a white solid (25.3 g (55%)). It was. The liquid from the filtration was concentrated under reduced pressure until low, and the resulting syrup was treated with water (50 ml) and stirred vigorously to obtain a thick slurry within 2 minutes. After granulating overnight, the slurry is filtered (rapid filtration) and the residue is washed with water (2 × 10 ml) and dried in vacuo at 50 ° C. to give additional product (8.5 g (18%)) )

  Examples 1-162:

Examples 1-162 described below were synthesized as libraries. The following solutions were used:
The carboxylic acid, ZCO ₂ H, was dissolved in dimethylacetamide (anhydrous) plus 3.75% triethylamine at a concentration of 0.2M.

The amine of Preparation Example 2a was dissolved in DMA (anhydrous) plus 3.75% triethylamine at a concentration of 0.2M.
HBTU was dissolved at a concentration of 0.2M in DMA (anhydrous).
(If necessary, the monomers were dissolved using NBGentle sonication in a warm water bath (temperature <40 ° C.).)
experimental method:
The reaction scale was 20-30 μM per well (experimental details are shown for a 20 μM reaction, so the scale can be adjusted within this range). The reaction was performed in a polypropylene 96-well plate.
(A) Amine solution (0.1 ml, 20 μM, 1 equivalent) was added to the wells;
(B) A carboxylic acid solution (0.15 ml, 30 μM, 1.5 eq) was added to the wells;
(C) HBTU solution (0.15 ml, 30 μM, 1.5 eq) was added to each well;
(D) A polypropylene 96-well plate was sealed with a PTFE and Rubber gasket and clamped between a pair of metal plates.
(E) The plate was heated in an oven at 60 ° C. for 6 hours and then allowed to cool in the oven overnight.
(F) When cooled, the plate was removed from the clamp and placed in Genevac to remove the solvent.
(G) The sample was redissolved in DMSO / water (9: 1) (500 μl) and any particulate material was removed by filtration.
(H) Purification was performed by RP-HPLC.

HPLC purification conditions:
Column: Phenomenex Luna C18, 10um, 150x10mm id
Temperature: ambient eluent A: 0.05% diethylamine eluent in water B: solvent in which acetonitrile sample was dissolved: 90% dimethyl sulfoxide sample in water was loaded using a Gilson Autosampler at an injection volume of 550 μl.

The Gilson 119 uv detector was monitored at 254 nm.
Collector: Set to 225 nm Dual sensitivity: 200
Peak sensitivity: 80
Peak width: 0.3 minutes
HPLC analysis conditions and mass spectrum details:
Column: Phenomenex Luna C18, 5um, 30x4.6mm id
Eluent A: 0.05% diethylamine in water Eluent B: Solvent in which acetonitrile sample was dissolved: 90% dimethyl sulfoxide sample in water was loaded with Gilson Quad Z at an injection volume of 5 μl.

detection:
Waters 2488 Dual wavelength detector UV1 (nm): 225
UV2 (nm): 255
ELSD: PolymerLabs, temperature: 75 ° C., gas flow rate: 1.2 bar mass spectrometer
Waters ZQ 2000 4 way MUX
ES + Cone Voltage: 26V Capillary: 3.85kv
ES-Cone voltage: -30V Capillary: -3.00kv
Desolvation gas: 800 l / min Source temperature: 300 ° C.
Scanning range: 160 to 1000 Da

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

A mixture of Preparation Example 10 compound (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 subjected to microwave radiation. Under heating at 170 ° C. for 20 minutes. The cooled mixture was diluted with ethyl acetate, washed with 1N sodium hydroxide solution and brine, then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) to give the title compound (234 mg).

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

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

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

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

Example 165b: {4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidine -1-yl}-(3,5-difluoro-phenyl) -methanone To a slurry of the bis salt from Preparation 12b (4.89 g, 7.12 mmol) in dichloromethane (25 ml) was added triethylamine (3.2 ml, 23 0.0 mmol) was added to give a pale yellow solution. The solution was cooled in an ice bath before 3,5-difluorobenzoyl chloride (0.95 ml, 8.09 mmol) was added. The reaction was stirred for 30 minutes before water (20 ml) was added. After stirring for an additional 20 minutes, the phases were separated and the organic phase was washed successively with aqueous citric acid, water, aqueous sodium bicarbonate and half-saturated brine. The clear dichloromethane solution was then dried over magnesium sulfate and concentrated to give a white foam. Recrystallization from ethyl acetate afforded the title compound as a white solid (2.69 g), identical to the material prepared as described in Example 165a.

  Examples 166-167:

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

  Examples 168-173:

  A suitable amine or amine salt (1 equivalent) selected from Preparation Examples 12a, 100, 118, 119, 143 and 152 in dichloromethane (16 ml / mmol) and a suitable acid chloride (W-PhCOCl) (1 .2-1.4 equivalents) and N-ethyldiisopropylamine (4 equivalents) were stirred at room temperature for 2 hours. Next, tris- (2-aminoethyl) amine polystyrene was added and the mixture was stirred for an additional hour. The mixture was then washed with 1N sodium hydroxide solution, the aqueous solution was extracted with dichloromethane (2 ×), and the combined organic solutions were concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate: methanol: 0.88 ammonia (90: 10: 1) as eluent to give the title compound.

Using 4 equivalents of A = triethylamine, the crude product was not treated with a polymer supported amine.
Instead of B = N-ethyldiisopropylamine, 10 equivalents of polymer-supported N-ethyldiisopropylamine was used.

  Examples 174-187:

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

A = ethyl acetate: methanol: 0.88 ammonia was used as the column eluent.
Instead of B = triethylamine, 2 equivalents of N-methylmorpholine were used.
Instead of C = triethylamine, 3 equivalents of N-methylmorpholine were used.

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

  The title compound was obtained as a white solid from the compound of Preparation Example 138 and isovaleryl chloride according to the method described in Examples 174 to 187.

  Examples 189-198:

  To a solution of the appropriate amine (1 equivalent) selected from the amines of Preparation Examples 122-131 in dichloromethane (4 ml / mmol) and triethylamine (1.1 equivalents), the appropriate acid chloride, ZCOCl (1 0.0 equivalents) was added. The reaction was stirred at room temperature for 1 hour. This was then diluted with water and stirred for 5 minutes, then filtered through a phase separation cartridge. The organic solution is concentrated under reduced pressure and the crude product is purified by column chromatography on silica gel using ethyl acetate: dichloromethane: methanol (100: 0: 0 to 0: 95: 5) as eluent. did. The product was azeotroped with ether to give the title compound as a white foam.

  Examples 199-201:

Appropriate acid in dichloromethane (26 ml / mmol), ZCO ₂ H (1.2 eq), 1-hydroxybenzotriazole hydrate (1.2 eq), triethylamine (2-4 eq), 1- A mixture of (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.2 eq) and a suitable amine or amine hydrochloride (1 eq) selected from Preparation Examples 2 and 143 at room temperature. Stir for 24 hours. The reaction was then diluted with 2N sodium hydroxide solution and the organic solution was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate: methanol: 0.88 ammonia (100: 0: 0 to 95: 5: 0.5) to give the title compound Got.

A = 5- (trifluoromethyl) -2-pyridinecarboxylic acid was used, which can be prepared as described in J. Org. Chem. (European) 2003: (8): 1559-1568. it can.
B = The reaction was carried out in the absence of 1-hydroxybenzotriazole hydrate and triethylamine.

  Examples 202-204:

A suitable acid, ZCO ₂ H (1.5 eq) in dichloromethane (8 ml / mmol) and O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium hexafluoro A solution of phosphate (2 equivalents), N-methylmorpholine (5 equivalents) and the appropriate amine hydrochloride (1 equivalent) selected from Preparation Examples 2 and 133 was stirred at room temperature for 24 hours. The reaction was then washed with sodium hydroxide solution and the organic solution was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) to give the title compound. .

  Examples 205-207:

A suitable acid, ZCO ₂ H (1.2 eq) in dichloromethane (7-10 ml / mmol) and O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium. A solution of hexafluorophosphate (1.2 eq), N-methylmorpholine (1.4 eq) and a suitable amine (1 eq) selected from Preparation Examples 12 and 136 is stirred at room temperature for 24 hours. did. The reaction was then partitioned between sodium hydroxide solution and dichloromethane and the layers were separated. The organic solution was washed with ammonium chloride solution and dried over MgSO ₄ which was then evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) to give the title compound. .

A = 3-difluoromethylbenzoic acid was used. This can be manufactured according to Tetrahedron 31: 1977: 391-401.
B = 4-difluoromethylbenzoic acid was used. This can be manufactured according to Tetrahedron 31: 1977: 391-401.
C = The product was further recrystallized from isopropyl alcohol and 2.8 equivalents of N-methylmorpholine was used.

  Examples 208-210:

Appropriate oxadiazole (1 equivalent) selected from Preparation Examples 66 and 67 in toluene (2.5-9.5 ml / mmol) and appropriate aniline from Preparation Examples 166 and 168 or commercially available A mixture of possible 4-chloro-2- (trifluoromethoxy) phenylamine (1.5-2.0 eq) and trifluoroacetic acid (0.5-1.0 eq) is stirred at 110 ° C. for 18 hours. Heated. The cooled mixture was partitioned between dichloromethane and sodium carbonate solution and then the layers were separated. The organic phase was dried over MgSO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) as eluent to give the title compound. .

  Examples 211-216:

  Appropriate oxadiazole (1 equivalent) selected from Preparation 66-69, 71 and 75 and aniline (1.5-2.0 equivalents) in toluene (1.0-2.5 ml / mmol) ) And trifluoroacetic acid (0.5-1.0 equivalents) was heated at 170-185 ° C. for 20 minutes under microwave radiation. The crude solution is purified by column chromatography on a silica gel cartridge using dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) as eluent to give the title compound. It was.

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 appropriate amine (HNR ⁴ R ⁵ ) (1.5 eq) in dichloromethane (2.5 ml / mmol) was selected from preparation examples 158 and 159 in dichloromethane (3.5 ml / mmol), Appropriate acid (1 equivalent), 1-hydroxybenzotriazole hydrate (1.5 equivalents), triethylamine (4 equivalents), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1 .5 equivalents) was added and the reaction was stirred at room temperature for 24 hours. The reaction was then washed with ammonium chloride solution and the organic solution was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 95: 5: 0.5) as eluent. The title compound was obtained.

A = 1-bicyclo [1.1.1] phenylamine hydrochloride (see reference J.O.C. 2001: 66 (19): 6282-6285)

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

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

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

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

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

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

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

  To a solution of the compound of Preparation 149 (150 mg, 0.47 mmol) in dichloromethane (10 ml) was added triethylamine (100 μl, 0.71 mmol), followed by benzoyl chloride (82 μl, 0.71 mmol), then The reaction 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 column chromatography on silica gel using ethyl acetate: methanol: 0.88 ammonia (95: 5: 0.5) as eluent to give the title compound as a white solid (120 mg) Got as.

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

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

  Example 228: 1- [4- (4-chlorophenyl) -5- (methoxymethyl) -4H-1,2,4-triazol-3-yl] -4- (3-fluorobenzoyl) -1,4- Diazepan

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

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

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

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

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

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

A mixture of the compound of Preparation Example 147 (97 mg, 0.35 mmol), 2-benzoyl chloride (40.4 μl, 0.32 mmol) and N-methylmorpholine (58 μl, 0.53 mmol) in dichloromethane (5 ml) was prepared. And stirred at room temperature for 18 hours. The reaction was then diluted with dichloromethane (20 ml) and 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 and the resulting solid was filtered off and then dried to give the title compound (55 mg).

  Example 232: N- {1- [4- (4-chlorophenyl) -5- (2H-1,2,3-triazol-2-ylmethyl) -4H-1,2,4-triazol-3-yl] Pyrrolidin-3-yl} -N-methylacetamide

  The title compound was obtained as a solid in 50% yield from the compounds of Preparation Examples 54 and 18 according to the method described in Preparation Example 93.

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

To a solution of the compound of Preparation 96 (700 mg, 1.9 mmol) in acetic acid (1.5 ml) was added sulfuric acid (930 mg, 95%, 9.5 mmol) and the reaction was then allowed to proceed at 100 ° C. for 3 days. Heated. 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).

  Example 234: tert-butyl 4-{[4- (4-chlorophenyl) -5- (2H-1,2,3-triazol-2-ylmethyl) -4H-1,2,4-triazol-3- Yl] oxy} piperidine-1-carboxylate

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

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

To a solution of triethylamine (300 μl, 2.0 mmol) in dichloromethane (2 ml) was added tert-butylamine hydrochloride (223 mg, 2.0 mmol) followed by the acid chloride of Preparation 157 in dichloromethane (3 ml) ( 150 mg, 0.4 mmol) was added and the reaction was stirred at room temperature for 1 hour. The mixture was then partitioned between dichloromethane and aqueous citric acid and the phases separated. The aqueous layer was further extracted with dichloromethane (2 × 25 ml) and the combined organic solution was dried over MgSO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (93: 7: 1) as eluent to give the title compound (122 mg).

  Examples 236-395:

The appropriate acid, ZCO ₂ H (0.25 ml, 0.2 M solution in N, N-dimethylformamide, 50 μmol) was neutralized with triethylamine (7 μl per salt equivalent, 50 μmol) if necessary before Treated with O- (7-azabenzotriazol-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate solution (0.1 ml, 0.525 M, 52.5 μmol). This solution was then placed in a 96 deep well polypropylene microtiter plate with triethylamine (28 μl, 0.20 mmol) and the amine from Preparation 12 (0.25 ml, 0.2 M solution in N, N-dimethylformamide, 50 μmol). The plate was sealed and stirred at 40 ° C. for 16 hours. The reaction mixture was then evaporated under reduced pressure and the residue was used with a Waters Xterra MS C18 column and acetonitrile: 10 mM ammonium bicarbonate (5:95 to 98: 2) (adjusted to pH 10 with ammonium hydroxide). And purified by HPLC to obtain the target compound.

A = 3-Isopropyl-1-methyl-1H-pyrazole-5-carboxylic acid was used; see DE 3029281.
B = 5-Bromo-2-methoxynicotinic acid was used; see EP 306251, preparation 1.
See J. Chem. Soc. 1948: 1969, using C = 5-methyl-2-phenyl-1H-imidazole-4-carboxylic acid.
See J. Med. Chem. 83:26 (2): 243 using D = 3- (1-oxo-1,3-dihydro-2H-isoindol-2-yl) propanoic acid.
See Journal of Inorganic and Nuclear medicine: 1978: 40 (6): 1103-6, using E = 1-ethylpiperidine-2-carboxylic acid.
See J. Indian Chem. Soc. (97): 74 (7): 575 using F = 3-[(pyrimidin-2-ylthio) methyl] benzoic acid.
See US 4325959, example 2 using G = 4-[(pyridin-2-ylthio) methyl] benzoic acid.
See JOC 2000: 65 (20): 6777 using H = 6-cyclohexyl-2-oxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid.
See WO 200202614 using I = 5-oxo-1-propylpyrrolidine-3-carboxylic acid.
See J. Het. Chem. 1991: 28 (2) 453, using J = 5-propylisoxazole-4-carboxylic acid.

  Examples 396-403:

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

A = 2.5 equivalents of triethylamine was used instead of polymer-supported N-ethyldiisopropylamine.
B = 2 equivalents of N-methylmorpholine was used instead of polymer supported N-ethyldiisopropylamine.

  Examples 404-405:

A suitable acid, ZCO ₂ H (1.2 eq) in dichloromethane (7-10 ml / mmol) and O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium. A solution of hexafluorophosphate (1.2 eq), N-methylmorpholine (1.4 eq) and the amine from Preparation 12a (1 eq) was stirred at room temperature for 24 hours. The reaction was partitioned between sodium hydroxide solution and dichloromethane and then the layers were separated. The organic solution was washed with ammonium chloride solution, dried over MgSO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) to give the title compound. .

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

Claims (5)

Formula (I ′):

Or a pharmaceutically acceptable salt or solvate thereof ,
In the above formula,
X represents H, CH ₃ , CH ₂ CH ₃ , CH ₂ OCH ₃ , CH ₂ OCH ₂ CH ₃ , or [1,2,3] triazol-2-ylmethyl;
Y is H, OCH ₃ , Cl, F, CF ₃ , CH ₃
Or represents CN ;
Y 'represents H, Cl, F, and _{CH 3, OCH 3, OCH 2} CH 3, OCF 3 or OCH ₂ CF _3,;
Ring A represents a piperazine ring or a piperidine ring ;
Z is — [O] _e — [CH ₂ ] _f —R ² , a phenyl ring (optionally fused to a phenyl ring or a 5- or 6-membered saturated, partially unsaturated or aromatic heterocycle; and / Or optionally substituted by one or more groups independently selected from W), or a 6-membered aromatic heterocycle (optionally fused to a phenyl ring or a 6-membered aromatic heterocycle, And / or optionally is substituted by one or more groups independently selected from W); R ² represents C ₁ -C ₆ alkyl, or C ₃ -C ₆ cycloalkyl; e represents a number selected from 0 or 1;
f represents a number selected from 0 to 6;
W represents halo, [O] _g R ³ , SO ₂ R ³ , SR ³ , SO ₂ NR ³ R ⁴ , [O] _h [CH ₂ ] _i CF ₃ , OCHF ₂ , phenyl, CN, phenoxy (optionally Is substituted by halo), OH, benzyl, NCOR ³ , benzyloxy, oxy, CONHR ³ , NSO ₂ R ³ R ⁴ , COR ³ , C ₁ -C ₆ alkylene-NCOR ³ , Het ² ;
R ³ represents hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, or C ₁ -C ₆ alkylene-O—C ₁ -C ₆ alkyl; R ⁴ represents hydrogen or C ₁ -C the expressed ₆ alkyl; i represents a number selected from 0 to 6; is h represents a number selected from 0 or 1; g represents a number selected from 0 or 1; Het ² is (A) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms. Or a 6-membered saturated, partially unsaturated or aromatic heterocycle, which is optionally substituted by R ³ and / or R ⁴ and / or an oxy group. Y is represents Cl or F, a compound of claim 1. A compound according to claim 1 or 2 , wherein Z represents a phenyl ring. 4. A compound according to any one of claims 1-3 , wherein Z is substituted by halo. 2. The compound of claim 1, selected from:
(3-Chloro-phenyl)-{4- [4- (4-chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3- Yl] -piperidin-1-yl} -methanone;
(4-Chloro-phenyl)-{4- [4- (4-chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3- Yl] -piperidin-1-yl} -methanone;
(5-Chloro-2-fluoro-phenyl)-{4- [4- (4-chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] Triazol-3-yl] -piperidin-1-yl} -methanone;
{4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl }-(3,5-difluoro-phenyl) -methanone;
{4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl }-(3-Fluoro-phenyl) -methanone;
{4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl }-(2,3-difluoro-phenyl) -methanone;
(3-Chloro-2-fluoro-phenyl)-{4- [4- (4-chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] Triazol-3-yl] -piperidin-1-yl} -methanone;
(3-Chloro-4-fluoro-phenyl)-{4- [4- (4-chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] Triazol-3-yl] -piperidin-1-yl} -methanone;
{4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl }-(4-trifluoromethyl-phenyl) -methanone;
{4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl }-(3-trifluoromethyl-phenyl) -methanone;
{4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl }-(2-trifluoromethyl-phenyl) -methanone;
(3-Chloro-5-fluoro-phenyl)-{4- [4- (4-chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] Triazol-3-yl] -piperidin-1-yl} -methanone;
{4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl }-(4-Difluoromethyl-phenyl) -methanone;
{4- [4- (4-Chloro-phenyl) -5- [1,2,3] triazol-2-ylmethyl-4H- [1,2,4] triazol-3-yl] -piperidin-1-yl }-(1H-indazol-3-yl) -methanone
Or a pharmaceutically acceptable salt or solvate thereof .