Pyrazole derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to the agent strongly inhibiting thrombocyte aggregation, it doesn't inhibit COX-1 or COX-2. The invention offers the compounds of formula (I) or their pharmaceutically acceptable salts, where residuals and groups in the specified structure of the compounds have the values denoted in the formula of the invention. The pharmaceuticals containing any of the compounds of formula (I) or their pharmaceutically acceptable salts, and phylactic and/or therapeutic agents for coronary heart disease, which contain any of the compounds of formula (I) or their pharmaceutically acceptable salts are suggested. Moreover, application of the compounds and their pharmaceutically acceptable salts for preparation of the medicine having anti-thrombotic potency, and method of the treatment of coronary heart disease are suggested.

EFFECT: production of the medicines having anti-thrombotic potency on basis of pyrazole.

12 cl, 1 tbl, 171 ex

 

The present invention relates to the derivatives of pyrazole having the activity of inhibiting platelet aggregation.

Platelets play an important role in stopping the bleeding caused by damage to a blood vessel, through coagulation with formation of blood clots. On the other hand, it is known that when the vascular endothelium is damaged or a blood vessel is narrowed, as in the case of atherosclerosis, platelets aggregate and trigger a blood clot or pitch, causing ischemic diseases such as myocardial infarction, angina, ischemic cerebrovascular disorder and peripheral vascular disease. Therefore, inhibitors of platelet aggregation is administered for the prevention and treatment of ischemic diseases. Aspirin is one such inhibitor of platelet aggregation, which is used for a long time, and actions of aspirin were shown the ART (Antiplatelet Trialist' Collaboration), in which the results of clinical trials, obtained by the introduction of aspirin 100000 patients were subjected to meta-analysis BMJ, vol. 308, pages 81-106, 1994). However, it is known that aspirin causes side effects, such as bleeding in the gastrointestinal tract or other organs, namely the so-called "caused by aspirin ulcer", and this side effect is dose-dependent and occurs when the disease incidence of approximately 1 case per 100 patients (BMJ, vol. 321, pages 1183-1187, 2000).

It is known that the inhibitory effect of aspirin on platelet aggregation based on activity to inhibit the action of cyclooxygenase. The cyclooxygenase involves the cyclooxygenase-1 (MOR-1) and cyclooxygenase-2 (MOR-2), and aspirin specifically inhibits MOR-1 at low dose, which leads to inhibition of platelet aggregation. Inhibition of MOR-1 is also induced by aspirin ulcer (Neurology, vol. 57, Suppl. 2, pages S5-S7, 2001 and Drugs Today, vol. 35, pages 251-265, 1999). In addition, it is known that non-steroidal anti-inflammatory medicines are anti-inflammatory action through selective inhibition of MOR-2.

As described above, although aspirin is effective as an inhibitor of platelet aggregation, it causes side effects in the form of gastrointestinal dysfunction attributed to MOR-1-inhibitory action, which is the mechanism of action of inhibition of platelet aggregation, and there is a significant need for new inhibitors of platelet aggregation, is not active in the inhibition of MOR-1.

Meanwhile, as derivatives of pyrazole with antithrombotic activity, were well-known compound (A) (Japan patent No. 2586713 and Chem. Pharm. Bull., vol. 45, pages 987-995, 1997) and the connection (In) (BMJ, vol. 321, pages 1183-1187, 2000).

The compound (A), however, finds the value of the IC505,3x10-6M against induced collagenase platelet aggregation and even stronger inhibitory activity finds against MOR-2 (IC502.4 x 10-7M). The situation is similar with the case of the compound (In). Activity by inhibition of platelet aggregation connection (In) is not as strong as its inhibiting activity against SOH-2. As described above, inhibition of MOR-2 can lead to anti-inflammatory activity and inhibition of MOR-2 is not necessarily favorable for connection as an inhibitor of platelet aggregation. From the point of view of the situation described above, the present invention is the provision of a strong inhibitor against platelet aggregation, which, however, did not inhibit any one of the MOR-1 and MOR-2.

The authors of the present invention have conducted extensive study on the search for such inhibitor of platelet aggregation and found that the pyrazole derivatives represented by the following formulas (I) and (II), show strong activity in the inhibition of platelet aggregation without inhibiting MOR-1 and MOR-2, and thereby completed the invention.

Accordingly, the present invention provides a compound represented by the formula (I), a salt of this compound or salt is at compound or salt:

(where Ar1represents 5 - or 6-membered aromatic heterocyclic group having 1-3 substituent; Ar2represents 5 - or 6-membered aromatic heterocyclic group which may have 1-3 substituent, or a phenyl group which may have 1-3 substituent; R1 represents a group represented by the formula (1):

(where the cyclic structure And is a 4-7-membered ring, which may be in addition to the nitrogen atom in the formula (1) one heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom; X represents a carbonyl group, thiocarbonyl group or a methylene group which may be substituted by 1 or 2 lower alkyl groups; R3 represents 1-4 groups on the cyclic structure A, and R3 is selected from the group consisting of hydrogen atom, halogen atom, hydroxyl group, lower alkoxygroup, lower alkoxycarbonyl group, carboxyl group, sulfopropyl, lower alkylsulfonyl group, a lower alkyl group which may have 1 or 2 substituent, an amino group which may have 1 or 2 substituent, carbamoyl group which may have 1 or 2 substituent, a lower acyl group, aminosulfonyl group which may have 1 or 2 C is the election agent, the carbonyl group, hydroxykynurenine group, lower alkoxycyanobiphenyl group, aranceles group which may have 1-3 substituent, 4-7-membered alicyclic heterocyclic group which may have 1 or 2 substituent, phenyl group which may have 1-3 substituent, 5 - or 6-membered aromatic heterocyclic group which may have 1-3 substituent, substituted or unsubstituted 3-6 membered pyroelectrically alkyl groups and substituted or unsubstituted 4-6 membered pyroelectrically heterocyclic group), R2 represents a hydrogen atom, halogen atom, hydroxyl group, lower alkoxygroup, a lower alkyl group which may to have 1 or 2 substituent, an amino group which may have 1 or 2 substituent, carbamoyl group which may have 1 or 2 substituent, or an acyl group which may have 1 or 2 substituent).

The present invention also provides a compound represented by the formula (II), a salt of this compound or MES compound or salt:

(where the cyclic structure is a 5-7-membered ring that may have one heteroatom or two heteroatoms, which may be the same or different from each other, with heteroatom(s) selected from nitrogen atom, oxygen atom and the volumes of sulfur, cyclic structure Ar3represents 5 - or 6-membered aromatic heterocycle, which may have 1-3 substituent, or a benzene ring which may have 1-3 substituent; Ar4represents 5 - or 6-membered aromatic heterocyclic group which may have 1-3 substituent, or a phenyl group which may have 1-3 substituent; R4 represents a group represented by the formula (2):

(where the cyclic structure is a 4-7-membered ring, which may be in addition to the nitrogen atom in the formula (2) one heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom; Y represents a carbonyl group, thiocarbonyl group or a methylene group which may be substituted by 1 or 2 lower alkyl groups; R7 represents 1-4 groups on the cyclic structure C, and R7 is selected from the group consisting of hydrogen atom, halogen atom, hydroxyl group, lower alkoxygroup, lower alkoxycarbonyl group, carboxyl group, sulfopropyl, lower alkylsulfonyl group, a lower alkyl group which may have 1 or 2 substituent, an amino group which may have 1 or 2 substituent, carbamoyl group which may have 1 or 2 substituent, a lower acyl group, aminosulfonyl the group, which may have 1 or 2 substituent, carbonyl group, hydroxykynurenine group, lower alkoxycyanobiphenyl group, aranceles group which may have 1-3 substituent, 4-7-membered alicyclic heterocyclic group which may have 1 or 2 substituent, phenyl group which may have 1-3 substituent, 5 - or 6-membered aromatic heterocyclic group which may have 1-3 substituent, substituted or unsubstituted 3-6 membered pyroelectrically alkyl groups and substituted or unsubstituted 4-6 membered pyroelectrically heterocyclic group; each of R5 and R6 is a group selected from the group consisting of hydrogen atom, halogen atom, hydroxyl group, lower alkoxygroup, an amino group which may have 1 or 2 substituent, a lower alkyl group which may have 1 or 2 substituent, or carbonyl group).

The present invention also provides a drug containing the compound represented by formula (I) or (II), a salt of this compound or MES compounds or salts.

The present invention also provides a preventive and/or therapeutic agent for ischemic diseases containing a compound represented by the formula (I) or (II), a salt of this compound or MES compounds or salts.

Present from reenie also provides a medicinal composition, containing the compound represented by formula (I) or (II), a salt of this compound or MES compounds or salts, and its farmacologicas acceptable carrier.

The present invention also provides the use of compounds represented by formula (I) or (II), a salt of this compound or MES compound or salt while receiving the drug.

The present invention also provides a method of treating ischemic disease, characterized by the introduction of an effective amount of the compound represented by formula (I) or (II), a salt of this compound or MES compounds or salts.

The compounds of formula (I) and (II) of the present invention, the salt of this compound, and a solvate of the compound or salts strongly inhibit platelet aggregation and in accordance with that inhibit thrombogenesis without inhibition of MOR-1 and MOR-2. Therefore, they are applicable as a preventive and/or therapeutic agents for ischemic diseases caused by thrombus or emboli, such as myocardial infarction, angina pectoris (chronic, stable angina, unstable angina and the like), ischemic cerebrovascular disorder (transient ischemic stroke (TIA), cerebral infarction and the like), peripheral vascular disease, embolism after replacing SOS is Yes artificial vessel, thrombotic embolism after surgery in coronary artery bypass coronary artery (CAGB), percutaneous intraluminal coronary angioplasty (RTSA), stent placement, and the like), diabetic retinopathy and nephropathy and embolism after replacement heart valve artificial, and are also applicable as a preventive and/or therapeutic agents for thrombus and embolism associated with the operation of the vessels, artificial circulation, and the like.

The preferred method of carrying out the invention

Next will be described deputies and cyclic structures of compounds represented by formula (I) and (II).

Aromatic heterocyclic group represented by Ar1or Ar4is a 5 - or 6-membered aromatic heterocyclic group, and specific examples include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl.

Examples of the substituent of the aromatic heterocyclic group Ar1or Ar4include a lower alkyl group, halogen atom, hydroxyl group, cyano, lower alkoxygroup, aralkylated, lower dialkoxy, lower alkoxycarbonyl group, carboxyl group, lower Alky sulfonyloxy group, the amino group which may have 1 or 2 substituent, carbamoyl group which may be substituted by 1 or 2 lower alkyl groups, aminosulfonyl group which may be substituted by 1 or 2 lower alkyl groups, and 4-7-membered alicyclic heterocyclic group which may have 1 or 2 substituent. These substituents will be described below.

Among the above substituents of the aromatic heterocyclic group Ar1or Ar4the lower alkyl group refers to an unbranched, branched or cyclic C1-C6-alkyl group, examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl and cyclopentylmethyl.

Examples of the halogen atom includes fluorine, chlorine and bromine.

Lowest alkoxygroup refers to alkoxygroup, which is unbranched, branched or cyclic C1-C6-alkyl group, examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentox, cyclopentyloxy.

Kalkilya group aralkylated belongs to the group formed by the above-mentioned lower alkyl group and a C6-C20-aryl group, examples of aralkylated include benzyloxy and penetrometry.

Lower dialkoxy the group belongs to dialkoxy, having an unbranched, branched or cyclic C1-C6-alkyl group, examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, pentylthio, cyclopentolate.

Lower alkoxycarbonyl group refers to alkoxycarbonyl group having an unbranched, branched or cyclic C1-C6-alkyl group, examples include methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, from n - to tert-butoxycarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexyloxycarbonyl and cyclopentanecarbonyl.

Lower alkylsulfonyl group refers to alkylsulfonyl group having an unbranched, branched or cyclic C1-C6-alkyl group, examples include methanesulfonyl, econsultancy and trifloromethyl.

Amino group which may have 1 or 2 substituent, refers to an unsubstituted amino group, amino group, substituted by 1 or 2 described above lower alkyl groups, lower alkanolamine, lowest alkoxycarbonylmethyl or raidgroup, which may be substituted by 1 or 2 described above lower alkyl groups. Examples of the amino group, substituted by 1 or 2 described above lower alkyl groups include methylamino, ethylamino, the PCC is laminitis, isopropylamino, cyclopropylamino, butylamino, isobutylamino, cyclopentylamine, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino and N-methyl-N-cyclopentylamine. Lowest alkanolamine refers to the amino group, substituted unbranched or branched C2-C6-alkanoyloxy group, examples include acetylamino, propionamido. Lowest alkoxycarbonylmethyl refers to the amino group, substituted unbranched or branched C2-C6-lower alkoxycarbonyl group, examples of it include methoxycarbonylamino, ethoxycarbonylethyl. Examples of raidgroup, which may be substituted by 1 or 2 described above lower alkyl groups include aminocarbonyl, N1-methylaminoquinoline, N1-ethylenediamino, N3-methylaminoquinoline, N1,N1-dimethylaminocarbonylmethyl, N1,N3-diethylaminoethylamine and N1-methyl-N3-ethylenediamino.

Carnemolla group which may be substituted by 1 or 2 lower alkyl groups, refers to an unsubstituted carbamoyl group or carbamoyl group, substituted by 1 or 2 described above lower alkyl groups, examples of it include methylcarbamoyl, ethylcarbitol, dimethylcarbamoyl and methylethylketon.

Aminosulfonyl group, Kotor which may be substituted by 1 or 2 lower alkyl groups, refers to unsubstituted aminosulfonyl group or aminosulfonyl group, substituted by 1 or 2 described above lower alkyl groups, examples of it include methylaminomethyl, ethylaminomethyl, propylaminosulfonyl, isopropylaminocarbonyl, from n - to tert-butylaminoethyl, cyclopropanesulfonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanesulfonyl, cyclopentylpropionyl, dimethylaminoethanol and Diethylaminoethanol.

Examples 4-7-membered alicyclic heterocyclic group, a group that may have 1 or 2 substituent include azetidine, pyrrolidine, piperidinyl, piperazinil, hexahydropyridine, hexahydropyridine, pyrazolidine, imidazolidine, homopiperazine, morpholine and thiomorpholine. Examples of the alicyclic heterocyclic group, substituted by 1 or 2 groups include 3-aminoamides-1-yl, 3-methylaminomethyl-1-yl, 3-dimethylimidazolidin-1-yl, 2-carbamoylethyl-1-yl, 2-methylcarbamoylmethyl-1-yl, 2-dimethylcarbamoyl-1-yl, 3-carbamoylation-1-yl, 3-methylcarbamoylmethyl-1-yl, 2-dimethylcarbamoyl-1-yl, 3-hydroxypyrrolidine, 3-methoxypyridine, 2-carbamoylpiperidino, 2-methylcarbamoylmethyl, 2-dimethylcarbamoyl, 3-carbamoylpiperidino, 3-metil remoisturizing, 3-dimethylcarbamoyl, 3-aminopiperidine, 4-aminopiperidine, 3-methylaminopropane, 4-methylaminopropane, 3-dimethylaminopyridine, 4-dimethylaminopyridine, 2-methylpiperidino, 3-methylpiperidino, 4-methylpiperidino, 2,2-dimethylpiperidino, 3,3-dimethylpiperidino, 4,4-dimethylpiperidine, 2-carbamoylbiphenyl, 3-carbamoylbiphenyl, 4-carbamoylbiphenyl, 2-methylcarbamoylmethyl, 3-methylcarbamoylmethyl, 4-methylcarbamoylmethyl, 2-dimethylcarbamodithioato, 3-dimethylcarbamodithioato, 4-dimethylcarbamodithioato, 4-methylpiperazine, 4-cyclopropylbenzene, 4-carbamoylbiphenyl, 2,2-dimethylmorpholine and 3.3-dimethylmorpholine.

The substituents on the aromatic heterocyclic group Ar1preferably is present in the para-position on the pyrazole ring.

Examples of the substituents of the phenyl group, which presents Ar4and which may have 1-3 substituent include the substituents listed above in respect of the aromatic heterocyclic group Ar4. 5 - or 6-membered aromatic geterotsiklicheskikh group represented by Ar4include also the unsubstituted compounds.

Aromatic heterocyclic group Ar2represents 5 - or 6-membered aromatic heterocyclic group or phenyl group, and these gr is PPI can have 1-3 substituent. Examples of the aromatic heterocyclic group include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl.

Aromatic heterocyclic ring Ar3represents 5 - or 6-membered aromatic heterocyclic ring or a benzene ring, and the rings have 1-3 substituent. Examples of the aromatic heterocyclic ring include a pyridine ring, the ring pyridazine, a pyrimidine ring, the ring pyrazine, furan ring, thiophene ring, pyrrole ring, imidazole ring, triazole ring, ring oxazole, isoxazol ring, a thiazole ring and a pyrazole ring.

Examples of the substituent of the aromatic heterocyclic group Ar2or aromatic heterocyclic group Ar3include the substituents listed above in relation to Ar1and Ar4.

When the aromatic heterocyclic group Ar1has a substituent in the para-position on the pyrazole ring, preferably Ar2that is an aromatic heterocyclic group or phenyl group is unsubstituted or has a substituent in the meta position with respect to the pyrazole ring.

Each of the cyclic structures a and C is a 4-7-membered ring, which m which may have as its structural atom and a nitrogen atom, shown in formulas (1) and (2), one heteroatom selected from nitrogen atom, oxygen atom and sulfur atom, where the heteroatom can be nitrogen atom or another atom. Examples 4-7-membered rings include a saturated heterocyclic ring such as the ring of azetidine ring pyrrolidine, ring of imidazolidine ring pyrazoline, a piperidine ring, a piperazine ring, the ring of the research, the ring thiomorpholine, ring hexahydropyridine, ring hexahydropirimidine series, ring homopiperazine and ring azepane; and unsaturated heterocyclic rings such as pyrrole ring, ring dihydropyrrole, ring, imidazole ring dihydroimidazole, a pyrazole ring, a ring of dihydropyridines, ring dihydropyrimidine and ring dihydropyridine.

The cyclic structure is a 5-7-membered ring that may have one heteroatom or two heteroatoms that are the same or different from each other, with heteroatom(s) selected from nitrogen atom, oxygen atom and sulfur atom. For example, when the cyclic structure is condensed with Ar3and a pyrazole ring, it can be formed by a ring of 1,4-dihydroindeno[1,2-c]pyrazole ring, 1,4-dihydro-4-oxoindole[1,2-c]pyrazole ring, 4,5-dihydro-1H-benzo[b]indazole, ring 1,4-dihydrobromide[4,3-c]pyrazole or similar rings.

The substituents R2, R3, R5, R6 and R7 are described below.

Examples of the halogen atom includes fluorine, chlorine and bromine.

Lowest alkoxygroup refers to alkoxygroup having an unbranched, branched or cyclic C1-C6-alkyl group, examples include methoxy, ethoxy, propoxy, isopropoxy, from n - to tert-butoxy, cyclobutylamine, cyclopentyloxy, cyclohexyloxy, cyclopentyloxy.

Lower alkoxycarbonyl group refers to alkoxycarbonyl group having an unbranched, branched or cyclic C1-C6-alkyl group, examples include methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, from n - to tert-butoxycarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexyloxycarbonyl and cyclopentanecarbonyl.

Lower alkylsulfonyl group refers to sulfonyloxy group having an unbranched, branched or cyclic C1-C6-alkyl group, examples include methylsulphonyl, ethylsulfonyl, propylsulfonyl, isopropylphenyl, from n - to tert-butylsulfonyl, cyclopropanesulfonyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and cyclopentylmethyl.

Lower alkyl group which may have 1 or 2 substituent, refers to an unbranched, Razvitie the Noi or cyclic C1-C6-alkyl group, which may have one Deputy or two substituent which may be the same or different from each other, and the substituent(s) selected from the group consisting of a hydroxyl group; halogen atom; a carboxyl group; sulfopropyl; an unbranched, branched or cyclic C1-C3-alkoxygroup; alkoxycarbonyl group having an unbranched, branched or cyclic C1-C3-alkyl group; amino group which may be substituted by one or two unbranched, branched or cyclic C1-C3-alkyl groups; carbamoyl group which may be substituted by one or two unbranched branched or cyclic C1-C3-alkyl groups; and raidgroup, which may be substituted by one or two unbranched, branched or cyclic C1-C3-alkyl groups.

Specific examples include methyl, ethyl, propyl, isopropyl, n - up tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-foretel, 3-forprofit, 2-forprofit, 2-forciblepoppy, 2-chloroethyl, 3-chloropropyl, 2-chloropropyl, trifluoromethyl, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 2-carboxypropyl, sulfoethyl, 2-sulfoethyl 1 is sulfoethyl-sulfopropyl, 2-sulfopropyl, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxyphenyl, 2-methoxyethyl, 3-methoxypropyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-propoxycarbonyl, aminomethyl, 2-amino-ethyl, 1-amino-ethyl, 3-aminopropyl, 2-aminopropyl, methylaminomethyl, 2-(methylamino)ethyl, 1-(methylamino)ethyl, 3-(methylamino)propyl, 2-(methylamino)propyl, dimethylaminomethyl, 2-(dimethylamino)ethyl, 1-(dimethylamino)ethyl, 3-(dimethylamino)propyl, 2-(dimethylamino)propyl, 2-(methylethylamine)ethyl, 1-(methylethylamine)ethyl, carbamoylmethyl, methylcarbamoylmethyl, ethylcarboxylate, dimethylcarbamoyl, methylaminomethyl, carbamoylethyl, methylcarbamoylmethyl, ethylcarboxylate, dimethylcarbamoyl, methylethylcarbinol, carbamoylmethyl, 2-carbamoylethyl, freedomites, N3-methyluridine, N3-ethyluracil, N3,N3-dimethylaminomethyl, N3-methyl-N3-ethyleneimine, 2-(ureido)ethyl, 2-(N3-methylurea)ethyl, 2-(N3-ethylurea)ethyl, 2-(N3,N3-dimethylurea)ethyl, 2-(N3-methyl-N3-ethylurea)ethyl, 3-(ureido)propyl, 2-(ureido)cyclopropyl, N1-methyluridine, N1-ethyluracil, N1,N1-dimethylaminomethyl, N1-methyl-N1-ethyleneimine, 2-(ureido)ethyl, 2-(N1-methylurea)ethyl, 2-(N1-ethylurea)ethyl, 2-(N1,N3-dimethylurea)ethyl, 2-(N1-methyl-N1-ethylurea)ethyl, N1,N3-dimethylaminomethyl, N1-methyl-N3-ailuridae is, 2-(N3-methyl-N1-ethyl)braidouts, 2-(N1,N3-diethylurea)ethyl, 1-carbarnoyl-2-hydroxyethyl, 1,2-decarbamylated.

Amino group which may have 1 or 2 substituent, refers to an amino group which may be substituted by one or two unbranched, branched or cyclic C1-C6-alkyl groups, and examples include unsubstituted amino, methylamino, ethylamino, propylamino, isopropylamino, from n - to tert-butylamino, pentylamine, hexylamine, cyclopropylamino, cyclobutylamine, cyclopentylamine, cyclohexylamine, cyclopropanemethylamine, cyclopentylamine, dimethylamino, methylethylamine, diethylamine, methylpropylamine, methylisobutylketone, methylcyclopropane, methylcyclopentadiene and methyl-tert-butoxycarbonylamino.

Carnemolla group which may have 1 or 2 substituent, refers to carbamoyl group which may be substituted by one or two unbranched, branched or cyclic C1-C6-alkyl groups, and examples include unsubstituted carbarnoyl, methylcarbamoyl, ethylcarbitol, propellerblades, isopropylcarbamate, from n - to tert-butylcarbamoyl, intercalator, exaltabitur, cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl, cyclopropylmethanol, cyclopentanecarbonyl, di is ethylcarbitol, methylethylketon, diethylcarbamoyl, methylpropylketone, methylisobutylcarbinol, methylcyclopentanol and methylcyclopentadienyl.

The lower acyl refers to an acyl group having an unbranched, branched or cyclic C1-C6-alkyl group, and examples include formyl, acetyl, propionyl, n - and isobutyryl, pivaloyl, cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl, cyclopropanecarbonyl, cyclobutanecarbonyl and cyclopentanecarbonyl.

Aminosulfonyl group which may have 1 or 2 substituent, refers to aminosulfonyl group which may be substituted by one or two C1-C3 alkyl groups, and examples include unsubstituted aminosulfonyl, aminosulfonyl, methylaminomethyl, ethylaminomethyl, propylaminosulfonyl, isopropylaminocarbonyl, cyclopropanesulfonyl, dimethylaminomethyl, diethylaminomethyl, methylaminomethyl, methylpropanesulfonic, dimethylaminoethanol and Diethylaminoethanol.

Lower alkoxycyanobiphenyl group refers to aminocarbonyl group, substituted alkoxygroup having an unbranched, branched or cyclic C1-C6-alkyl group, and examples of it include methoxyaminomethyl, atoxigenic is of IMT, propoxymethyl, isopropylaminocarbonyl, from n - to tert-butoxycarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexyloxycarbonyl and cyclopentanecarbonyl.

Kalkilya group which may have 1-3 substituent, refers to Uralkaliy group, which formed an unbranched, branched or cyclic C1-C6-alkyl group and a C6-C20-aryl group which may have 1-3 substituent. The examples include benzyl and phenethyl.

Examples of the substituents aranceles groups include hydroxyl, carboxyl, sulfo, cyano and nitro. Examples of the substituents, referred to as the "phenyl group which may have 1-3 substituent"also include these groups.

Examples of 5 - or 6-membered aromatic heterocyclic group which may have 1-3 substituent include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl.

Examples of the substituents include the substituents listed above in relation to Ar1and Ar4.

Examples 4-7-membered alicyclic heterocyclic group which may have 1 or 2 substituent include azetidine, pyrrolidine, piperidinyl, piperazinil, hexahydropyridine, gexa dropyridine, pyrazolidine, imidazolidine, homopiperazine, morpholine and thiomorpholine.

Alicyclic heterocyclic group may be substituted, and examples of the substituents include a hydroxyl group, oxoprop, carboxyl group, alphagroup, a cyano, a nitro-group, the above-described halogen atom, the above-described lower alkoxygroup, alkylsulfonyl group, the above-described lower alkyl group which may have 1 or 2 substituent, the above-described amino group which may have 1 or 2 substituent, the above carbamoyl group which may have 1 or 2 substituent, the above-described lower acyl group, and the above aminosulfonyl group which may have 1 or 2 substituent.

Examples of substituted or unsubstituted 3-6 membered pyroelectrically alkyl groups include cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane.

Pyroelectricity alkyl group may be substituted, and examples of the substituents include a hydroxyl group, oxoprop, above the lower alkoxygroup, the above-described lower alkyl group which may have 1 or 2 substituent, the above-described amino group which may have 1 or 2 substituent, the above carbamoyl group which may have 1 or 2 substituent, the above is written lower acyl group, and the above aminosulfonyl group, which may have 1 or 2 substituent.

Substituted or unsubstituted 4-6 membered pyroelectricity heterocyclic group refers to spiroheterocyclic group which may have one double bond, and examples of it include azetidine, pyrrolidine, piperidine, piperazine, pyrazolidine, imidazolidine, morpholines, thiomorpholine.

Examples Deputy pyroelectrically heterocyclic group include a hydroxyl group, oxoprop, carboxyl group, the above-described lower alkoxygroup, the above-described lower alkyl group which may have 1 or 2 substituent, the above-described amino group which may have 1 or 2 substituent, the above carbamoyl group which may have 1 or 2 substituent, the above-described acyl group which may have 1 or 2 substituent, and above aminosulfonyl group which may have 1 or 2 substituent.

The compound (I) and (II) of the present invention will be described hereinafter in more detail.

Ar1in the formula (I) preferably represents a 6-membered aromatic heterocyclic group which has 1-3 substituent, more preferably pyridyloxy group having 1-3 substituent, pyridazinyl group having 1-3 substituent, or personilnya group having 1 to zamestitel, even more preferably pyridyloxy group having 1-3 substituent, or pyridazinyl group having 1-3 substituent.

Ar4in the formula (I) is preferably a 6-membered aromatic heterocyclic group which may have 1-3 substituent, or a phenyl group which may have 1-3 substituent, more preferably pyridyloxy group which may have 1-3 substituent, pyridazinyl group which may have 1-3 substituent, personilnya group which may have 1-3 substituent, or a phenyl group having 1-3 substituent.

As mentioned above, the aromatic heterocyclic group represented by Ar1or Ar4has from one to three substituents. Examples of preferred substituents include1-6alkyl group, a halogen atom, a C1-6alkoxygroup,1-6alkylamino and di(C1-6alkyl)amino group.

Ar2in the formula (I) is preferably pyridyloxy group which may have 1-3 substituent, pyridazinyl group which may have 1-3 substituent, personilnya group which may have 1-3 substituent, pyrrolidino group which may have 1-3 substituent, or a phenyl group which may have 1-3 Deputy.

Ar3in the formula (II) preferably represents 6-the certain aromatic heterocyclic ring, which may have 1-3 substituent, or a benzene ring which may have 1-3 substituent. In addition, Ar3represents preferably a pyridine ring which may have 1-3 substituent, or a benzene ring which may have 1-3 Deputy.

Each Ar1in the formula (I) and Ar4in the formula (II) preferably represents 3-pyridyl, 6-methoxy-3-pyridyl, 6-methyl-3-pyridyl, 6-ethyl-3-pyridyl, 6-chloro-3-pyridyl, 6-ethoxy-3-pyridyl, 6-isopropoxy-3-pyridyl, 6-methylamino-3-pyridyl, 6-cyclopropylamino-3-pyridyl, 5-methoxy-2-pyridyl, 6-methoxy-3-pyridazinyl, 6-methyl-3-pyridazinyl, 5-methoxy-2-pyrimidinyl, 5-methyl-2-pyrimidinyl, 2-methoxy-5-pyrimidinyl, 2-methyl-5-pyrimidinyl, 5-methoxy-2-pyrazinyl or 5-methoxy-2-pyrazinyl. Among them, 6-methoxy-3-pyridyl, 6-methyl-3-pyridyl, 5-methoxy-2-pyridyl, 6-methoxy-3-pyridazinyl, 6-methyl-3-pyridazinyl, 5-methoxy-2-pyrimidinyl, 5-methyl-2-pyrimidinyl, 5-methoxy-2-pyrazinyl, 5-methyl-2-pyrazinyl are more preferred. Of them, more preferred are 6-methoxy-3-pyridyl, 6-methyl-3-pyridyl, 5-methoxy-2-pyridyl, 6-methoxy-3-pyridazinyl.

Ar2represents preferably phenyl, 2-forfinal, 2-chlorophenyl, 2-were, 2-methoxyphenyl, 2-hydroxyphenyl, 3-forfinal, 3-chlorophenyl, 3-were, 3-methoxyphenyl, 3-hydroxyphenyl, 4-forfinal, 4-chlorophenyl, 4-methylphe the sludge, 4-ethylphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 4-triptoreline, 4-benzyloxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-methoxy-2-pyridyl, 6-methyl-2-pyridyl, 6-methoxy-3-pyridyl, 6-methyl-2-pyridyl, 6-methoxy-2-pyridyl, 6-methyl-2-pyridyl, 3-methoxy-2-pyridyl, 3-methyl-2-pyridyl, 3-fluoro-2-pyridyl, 4-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 6-fluoro-2-pyridyl, 4-methyl-2-pyridyl, 4-ethyl-2-pyridyl, 4-methoxy-2-pyridyl, 4-ethoxy-2-pyridyl, 4-cyano-2-pyridyl, 4-carbarnoyl-2-pyridyl, 4-pyrrolidinyl-2-pyridyl, 4-methylthio-2-pyridyl, 4-methanesulfonyl-2-pyridyl, 4-carboxy-2-pyridyl, 6-methoxy-3-pyridazinyl, 6-methyl-3-pyridazinyl, 5-methoxy-2-pyrimidinyl, 5-methyl-2-pyrimidinyl, 5-methoxy-2-pyrazinyl, 5-methyl-2-pyrazinyl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, 1-methylpyrrole-2-yl, 1-methylpyrrole-3-yl, 1-acylpyrrole-2-yl or 1-acylpyrrole-3-yl. Among them, more preferred are phenyl, 2-forfinal, 2-chlorophenyl, 2-were, 2-methoxyphenyl, 2-hydroxyphenyl, 3-forfinal, 3-chlorophenyl, 3-were, 3-methoxyphenyl, 3-hydroxyphenyl, 4-forfinal, 4-chlorophenyl, 4-were, 4-methoxyphenyl, 4-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-methoxy-3-pyridyl, 6-methyl-3-pyridyl, 6-methoxy-2-pyridyl, 6-methyl-2-pyridyl, 3-fluoro-2-pyridyl, 4-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 6-fluoro-2-pyridyl, 4-methyl-2-pyridyl, 4-ethyl-2-pyridyl, 4-methoxy-2-pyridyl, 4-cyano-2-pyridyl, 4-carbarnoyl-2-pyridyl, 4-pyrrolidinyl-2-pyridyl, 3-methoxy-2-pyrid the l, 3-methyl-2-pyridyl, 6-methoxy-3-pyridazinyl, 6-methyl-3-pyridazinyl, 5-methoxy-2-pyrimidinyl, 5-methyl-2-pyrimidinyl, 5-methoxy-2-pyrazinyl, 5-methyl-2-pyrazinyl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, 1-methylpyrrole-2-yl, 1-methylpyrrole-3-yl, 1-acylpyrrole-2-yl and 1-acylpyrrole-3-yl.

Ar3is preferably a benzene ring or a pyridine ring, more preferably a benzene ring.

As already indicated above, R1 is a group represented by the following formula (1):

and X represents a carbonyl group, thiocarbonyl group or a methylene group which may be substituted by 1 or 2 lower alkyl groups. The group represented by X preferably represents a carbonyl group or a methylene group which may be substituted by 1 or 2 lower alkyl groups, more preferably a carbonyl group.

As already indicated above, R4 is a group represented by the following formula (2):

and Y represents a carbonyl group, thiocarbonyl group or a methylene group which may be substituted by 1 or 2 lower alkyl groups. The group represented by Y preferably represents a carbonyl group or a methylene group which may be zames is 1 or 2 lower alkyl groups, more preferably a carbonyl group.

Examples of cyclic structures a and C in the above formulas (1) and (2) include saturated heterocyclic ring such as the ring of azetidine ring pyrrolidine, ring of imidazolidine ring pyrazoline, a piperidine ring, a piperazine ring, the ring of the research, the ring thiomorpholine, ring hexahydropyridine, ring hexahydropirimidine series, ring homopiperazine and ring azepane; and unsaturated heterocyclic rings such as pyrrole ring, ring dihydropyrrole, ring, imidazole ring dihydroimidazole, a pyrazole ring, a ring of dihydropyridines, ring dihydropyrimidine and ring dihydropyrazine. Of them, preferred are saturated rings such as the ring of azetidine ring pyrrolidine, ring of imidazolidine ring pyrazoline, a piperidine ring, a piperazine ring, the ring of the research, the ring thiomorpholine, ring hexahydropyridine, ring hexahydropirimidine series, ring homopiperazine and ring azepane.

Typical substituents represented by the following formula:

in formulas (1) or (2)include the following placeholders:

azetidin-1-yl, 3-oxoazetidin-1-yl, 2-ecosanitation-1-yl, 3-aminoamides-1-yl, 3-methylaminomethyl-1-yl, 3-dimethylimidazolidin-1-yl, 2-methylaziridine-1-yl, 3-methyl shall lidin-1-yl, 2.2-dimethylamide-1-yl, 3,3-dimethylamide-1-yl, 2,2-dimethyl-3-dimethylimidazolidin-1-yl, 3-dimethylaminomethylene-1-yl, 3-methoxyisatin-1-yl, 2-hydroxymethylamino-1-yl, 3-hydroxymethylation-1-yl, 3-hydroxyazetidine-1-yl, 2-carboxyamide-1-yl, 3-carboxyamide-1-yl, 2-carbamoylethyl-1-yl, 2-methylcarbamoylmethyl-1-yl, 2-dimethylcarbamoyl-1-yl, 3-carbamoylation-1-yl, 3-methylcarbamoylmethyl-1-yl, 3-dimethylcarbamoyl-1-yl, pyrrolidino, 2-oxopyrrolidin, 3-oxopyrrolidin, 2,5-dioxopyrimidine, 3-aminopyrrolidine, 3-methylaminopropyl, 2-dimethylaminopyridine, 3-dimethylaminopyridine, 2-methylpyrrolidine, 3-methylpyrrolidine, 2,2-dimethylpyrimidine, 3,3-dimethylpiperidino, 2,2-dimethyl-3-dimethylaminopyridine, 2-hydroxyethylpyrrolidine, 3-hydroxyethylpyrrolidine, 3-methoxypyridine, 2-methoxypyridine, 3-methoxypyridine, 2-carboxyethylidene, 3-carboxyamide, 2-carbamoylpiperidino, 2-methylcarbamoylmethyl, 2-dimethylcarbamoyl, 3-carbamoylpiperidino, 3-methylcarbamoylmethyl, 3-dimethylcarbamoyl, imidazolidin-1-yl, 3-methylimidazolidine-1-yl, 2-Oxymetazoline-1-yl, 4-Oxymetazoline-1-yl, 3-methyl-2-Oxymetazoline-1-yl, 3-methyl-4-Oxymetazoline-1-yl, 2,2-dimethylimidazole-1-yl, pyrazolidine-1-yl, 2-methylpiperidin-1-yl, 3-coperation-1-yl, 3,5-dioxopiperidin-1-yl, piperidino, 2-oxopiperidine, 3-oxopiperidine, 4-oxopiperidine, 3-hydroxypiperidine, 4-hydroxypiperidine, 2-hydroxylaminopurine, 3-hydroxylaminopurine, 4-hydroxylaminopurine, 2-methoxypiperidine, 3-methoxypiperidine, 4-methoxypiperidine, 2-methoxykynuramine, 3-methoxykynuramine, 4-methoxykynuramine, 3-aminopiperidine, 4-aminopiperidine, 3-methylaminopropane, 4-methylaminopropane, 3-dimethylaminopyridine, 4-dimethylaminopyridine, 2-methylpiperidino, 3-methylpiperidino, 4-methylpiperidino, 2,2-dimethylpiperidino, 3,3-dimethylpiperidino, 4,4-dimethylpiperidine, 4-ftorpirimidinu, 4-chloropyridine, 3,3-ceftobiprole, 4,4-ceftobiprole, 3,3-dichlorobenzidine, 4,4-dichloropyridine, 2-hydroxyethylpiperazine, 3-hydroxyethylpiperazine, 4-hydroxyethylpiperazine, 2-carboxypeptidase, 3-carboxypeptidase, 4-carboxypeptidase, 2-carbamoylbiphenyl, 3-carbamoylbiphenyl, 4-carbamoylbiphenyl, 2-methylcarbamoylmethyl, 3-methylcarbamoylmethyl, 4-methylcarbamoylmethyl, 2-dimethylcarbamodithioato, 3-dimethylcarbamodithioato, 4-dimethylcarbamodithioato, 2-carboxymethylamino, 3-carboxymethylamino, 4-carboxymethylamino, 2-methoxypiperidine, 3-methoxypiperidine, 4-methoxypiperidine, 2-aminomethylpyridine,3-aminomethylpyridine, 4-aminomethylpyridine, 2-methylaminopropane, 3-methylaminopropane, 4-methylaminoacetaldehyde, 2-dimethylaminopyridine, 3-dimethylaminopyridine, 4-dimethylaminopyridine, 2-AMINOETHYLPIPERAZINE, 3-AMINOETHYLPIPERAZINE, 4-AMINOETHYLPIPERAZINE, 2-methylaminoacetaldehyde, 3-methylenedianiline, 4-methylaminoanthraquinone, 2-dimethylaminopyridine, 3-dimethylaminopyridine, 4-dimethylaminopyridine, piperazine derivatives, 2-oxopiperidine, 3 oxopiperidine, 2-oxo-4-methylpiperazine, 3-oxo-4-methylpiperazine, 4-formylpiperazine, 2,3-dioxopiperazinyl, 3,5-dioxopiperazinyl, 2,6-dioxopiperidin, 2,3-dioxo-4-methylpiperazine, 3,5-dioxo-4-methylpiperazine, 2,6-dioxo-4-methylpiperazine, 2-methylpiperazine, 3 methylpiperazine, 4-methylpiperazine, 2-ethylpiperazine, 3 ethylpiperazine, 4-ethylpiperazine, 2-isopropylpiperazine, 3 isopropylpiperazine, 4-isopropylpiperazine, 2-cyclopropylbenzene, 3 cyclopropylbenzene, 4-cyclopropylbenzene, 4-cyclobutylmethyl, 2-cyclopropanemethanol, 3 cyclopropanemethylamine, 2,2-dimethylpiperazine, 3,3-dimethylpiperazine, 2,3-dimethylpiperazine, 2,4-dimethylpiperazine, 3,4-dimethylpiperazine, 3,5-dimethylpiperazine, 2,6-dimethylpiperazine, 2-ethyl-4-methylpiperazine, 3-ethyl-4-methylpiperazine, 2-isopropyl-4-methylpiperazine, 3-isopropyl-4-methylpiperazin is but 2-cyclopropyl-4-methylpiperazine, 3-cyclopropyl-4-methylpiperazine, 3-methyl-4-benzylpiperazine, 4-phenylpiperazine, 4-(2-pyridyl)piperazine derivatives, 1,2,6-trimethylpyrazine, 3,4,5-trimethylpyrazine, 2,2,4-trimethylpyrazine, 3,3,4-trimethylpyrazine, 3,3,4-trimethyl-5-oxopiperidine, 2,2,4-trimethyl-3-oxopiperidine, 2-cyclopropylamino-4-methylpiperazine, 3 cyclopropane-4-methylpiperazine, 2-cyclopropylamino-4-methyl-3-oxopiperidine, 3 cyclopropane-4-methyl-5-oxopiperidine, 4-acetylpiperidine, 4-acetyl-3-cyclopropanecarbonitrile, 2-hydroxyethylpiperazine, 3 hydroxyethylpiperazine, 2-methoxypyrazine, 3 methoxypyrazine, 2-hydroxyethylpiperazine, 3 hydroxyethylpiperazine, 4-hydroxyethylpiperazine, 2-hydroxymethyl-4-methylpiperazine, 3-hydroxymethyl-4-methylpiperazine, 2-methoxymethyl-4-methylpiperazine, 3-methoxymethyl-4-methylpiperazine, 2-hydroxyethyl-4-methylpiperazine, 3-hydroxyethyl-4-methylpiperazine, 2-methoxyethyl-4-methylpiperazine, 3-methoxyethyl-4-methylpiperazine, 2-carbamoylbiphenyl, 3 carbamoylbiphenyl, 4-carbamoylbiphenyl, 2-methylcarbamoylmethyl, 3 methylcarbamoylmethyl, 4-methylcarbamoylmethyl, 2-dimethylcarbamodithioato, 3 dimethylcarbamodithioato, 4-dimethylcarbamodithioato, 2-carbamoyltransferase, 3 carbamoyltransferase, 4-carbamoyltransferase, 2-methylcarbamoyl is rilpivirine, 3 methylcarbamoylmethyl, 4-methylcarbamoylmethyl, 2-dimethylcarbamodithioato, 3 dimethylcarbamodithioato, 2-carbarnoyl-4-methylpiperazine, 3-carbarnoyl-4-methylpiperazine, 4-carbamoylbiphenyl, 2-methylcarbamoyl-4-methylpiperazine, 3-methylcarbamoyl-4-methylpiperazine, 4-methylcarbamoylmethyl, 2-dimethylcarbamoyl-4-methylpiperazine, 3-dimethylcarbamoyl-4-methylpiperazine, 4-dimethylcarbamodithioato, 2-carbamoylmethyl-4-methylpiperazine, 3-carbamoylmethyl-4-methylpiperazine, 4-carbamoyltransferase, 2-methylcarbamoylmethyl-4 methylpiperazine, 3-methylcarbamoylmethyl-4-methylpiperazine, 4-methylcarbamoylmethyl, 2-dimethylcarbamoyl-4-methylpiperazine, 3-dimethylcarbamoyl-4-methylpiperazine, 2-carboxypeptidase, 3 carboxypeptidase, 2-methoxycarbonylamino, 3 methoxycarbonylamino, 2-ethoxycarbonylpyrimidine, 3 ethoxycarbonylpyrimidine, 2-carboxymethylamino, 3 carboxymethylamino, 4-carboxymethylamino, 2-carboxyethylpyrrole, 3 carboxyethylpyrrole, 4-carboxyethylpyrrole, 4-carboxy-tert-butylpiperazine, 2-methoxycarbonylmethylene, 3 methoxycarbonylmethylene, 2-methoxycarbonylmethylene, 3 methoxycarbonylmethylene, 4-methoxycarbonylmethylene, 2-ethoxycarbonylpyrimidine, 3-ethoxycarbonylmethylene is about, 4 ethoxycarbonylpyrimidine, 2-carboxy-4-methylpiperazine, 3-carboxy-4-methylpiperazine, 2-carboxymethyl-4-methylpiperazine, 3-carboxymethyl-4-methylpiperazine, 2-methoxycarbonylmethyl-4-methylpiperazine, 3-methoxycarbonylmethyl-4-methylpiperazine, 2-methoxycarbonylmethyl-4-methylpiperazine, 3-methoxycarbonylmethyl-4-methylpiperazine, 2-ethoxycarbonylmethyl-4-methylpiperazine, 3-ethoxycarbonylmethyl-4-methylpiperazine, 2-AMINOETHYLPIPERAZINE, 3 AMINOETHYLPIPERAZINE, 2-methylaminopropane, 3 methylaminopropane, 2 dimethylaminomethylphenol, 3 dimethylaminopyridine, 2-AMINOETHYLPIPERAZINE, 3 AMINOETHYLPIPERAZINE, 4-AMINOETHYLPIPERAZINE, 2-methylaminopropane, 3 methylaminopropane, 4-methylaminopropane, 2-diethylaminoethylamine, 3 dimethylaminopyridine, 4-dimethylaminopyridine, 2-aminomethyl-4-methylpiperazine, 3-aminomethyl-4-methylpiperazine, 2-methylaminomethyl-4-methylpiperazine, 3-methylaminomethyl-4-methylpiperazine, 2-dimethylaminomethyl-4-methylpiperazine, 3-dimethylaminomethyl-4-methylpiperazine, 2-amino-ethyl-4-methylpiperazine, 3-amino-ethyl-4-methylpiperazine, 2-methylaminomethyl-4-methylpiperazine, 3-methylaminomethyl-4-methylpiperazine, 2-dimethylaminoethyl-4-methylpiperazine, 3-dimethylaminoethyl-4-methylpiperazine, 4-methysulfonylmethane, 4-aminoantipyrine, 4-(azeti the Jn-1-yl)piperazine derivatives, 4 pyrrolidinedione, 4-piperidinemethanol, morpholino, 2-methylmorpholine, 3 methylmorpholine, 2-ethylmorpholino, 3 ethylmorpholine, 2-cyclopropanecarbonyl, 3 cyclopropanecarbonyl, 2,2-dimethylmorpholine, 3,3-dimethylmorpholine, 2-hydroxymethylpropane, 3 hydroxymethylpropane, 2-methoxyethylamine, 3 methoxyethylamine, 2-hydroxyethylimino, 3 hydroxyethylimino, 2-methoxyethylamine, 3 methoxyethylamine, 2-carbamylcholine, 3 carbamylcholine, 2-methylcarbamoylmethyl, 3 methylcarbamoylmethyl, 2-dimethylcarbamoyl, 3 dimethylcarbamoyl, 2-carbamylcholine, 3 carbamylcholine, 2-methylcarbamoylmethyl, 3 methylcarbamoylmethyl, 2-dimethylcarbamodithioato, 3 dimethylcarbamodithioato, 2-carbamylcholine, 3 carbamylcholine, 2-methylcarbamoylmethyl, 3 methylcarbamoylmethyl, 2-dimethylcarbamodithioato, 3 dimethylcarbamodithioato, 2-carboxynaphthalene, 3 carboxymaltose, 2-methoxycarbonylethyl, 3 methoxycarbonylmethyl, 2-carboxymethylamino, 3 carboxymethylamino, 2-methoxycarbonylmethylene, 3 methoxycarbonylmethylene, 2-ethoxycarbonylmethylene, 3 ethoxycarbonylmethylene, 2-aminomethylpropanol, 3 aminomethylpropanol, 2-methylaminomethyl is Olya, 3 methylaminoethanol, 2-dimethylaminomethylphenol, 3 dimethylaminomethylphenol, 2-aminoethylamino, 3 aminoethylamino, 2-methylaminoethanol, 3 methylaminoethanol, 2-diethylaminoethylamine, 3 diethylaminoethylamine, thiomorpholine, 3 Osotimehin, 1,1-dioxothiazolidine, 2-methylthiophene, 3 methylthiophene, 2-ethylthiophene, 3 ethylthiophene, 2-cyclopropanemethanol, 3 cyclopropanemethylamine, 2,2-dimethylmorpholine, 3,3-dimethylmorpholine, 2-hydroxymethylcytosine, 3 hydroxymethylcytosine, 2-methoxyethylamine, 3 methoxyethylamine, 2-hydroxyethylimino, 3-hydroxyethylimino, 2-methoxyacetophenone, 3 methoxyacetophenone, 2-carbamylcholine, 3 carbamylcholine, 2-methylcarbamoylmethyl, 3 methylcarbamoylmethyl, 2-dimethylcarbamodithioato, 3 dimethylcarbamodithioato, 2-carbamoyltransferase, 3 carbamoyltransferase, 2-methylcarbamoylmethyl, 3 methylcarbamoylmethyl, 2-dimethylcarbamodithioato, 3 dimethylcarbamodithioato, 2-carbamoyltransferase, 3 carbamoyltransferase, 2-methylcarbamoylmethyl, 3 methylcarbamoylmethyl, 2-dimethylcarbamodithioato, 3-dimethylcarbamodithioato is but 2 carboxymyoglobin, 3 carboxymyoglobin, 2-methoxycarbonylamino, 3 methoxycarbonylamino, 2-carboxymethylcysteine, 3 carboxymethylcysteine, 2-ethoxycarbonylpyrimidine, 3 methoxycarbonylmethylene, 2-ethoxycarbonylpyrimidine, 3 ethoxycarbonylpyrimidine, 2-aminoethylethanolamine, 3 aminoethylethanolamine, 2-methylaminomethyl, 3 methylaminomethyl, 2-dimethylaminoacetonitrile, 3 dimethylaminoacetonitrile, 2-aminoethylethanolamine, 3 aminoethylethanolamine, 2-methylaminoacetaldehyde, 3 methylaminoacetaldehyde, 2-dimethylaminoacetonitrile, 3 dimethylaminoacetonitrile, hexahydropyridine-1-yl, 2-acetylglucosaminidase-1-silt, 2-vormingukirjeldused-1-yl, 3-oxohexanoate-1-yl, 6-oxohexanoate-1-yl, 4-aminohexanoate-1-yl, 4-methylaminoacetaldehyde-1-yl, 4-dimethylaminohydrolase-1-yl, 2-methylhexahydrophthalic-1-yl, 3-methylhexahydrophthalic-1-yl, 4-methylhexahydrophthalic-1-yl, 2,3-dimethyltetrahydrofuran-1-yl, 3,3-dimethyltetrahydrofuran-1-yl, 4,4-dimethyloxazolidine-1-yl, 3-hydroxymethylcytosine-1-yl, 4-hydroxymethylcytosine-1-yl, 5-hydroxymethylcytosine-1-yl, 6-hydroxymethylcytosine-1-yl, 2-to remorsecapade-1-yl, 3-carbamoylaspartate-1-yl, 4-carbamoylaspartate-1-yl, 5-carbamoylaspartate-1-yl, 6-carbamoylaspartate-1-yl, 2-methylcarbamoylmethyl-1-yl, 3-methylcarbamoylmethyl-1-yl, 4-methylcarbamoylmethyl-1-yl, 5-methylcarbamoylmethyl-1-yl, 6-methylcarbamoylmethyl-1-yl, 2-dimethylcarbamodithioato-1-yl, 3-dimethylcarbamodithioato-1-yl, 4-dimethylcarbamodithioato-1-yl, 5-dimethylcarbamodithioato-1-yl, 6-dimethylcarbamodithioato-1-yl, 3-carboxylesterase-1-yl, 4-carboxylesterase-1-yl, 5-carboxylesterase-1-yl, 6-carboxylesterase-1-yl, 2-karboksimetiltselljulozy-1-yl, 3-karboksimetiltselljulozy-1-yl, 4-karboksimetiltselljulozy-1-yl, 5-karboksimetiltselljulozy-1-yl, 6-karboksimetiltselljulozy-1-yl, 3-methoxycarbonylaminophenyl-1-yl, 4-methoxycarbonylaminophenyl-1-yl, 5-methoxycarbonylaminophenyl-1-yl, 6-methoxycarbonylaminophenyl-1-yl, 2-methoxycarbonylmethyluridine-1-yl, 3-methoxycarbonylmethyluridine-1-yl, 4-methoxycarbonylmethyluridine-1-yl, 5-methoxycarbonylmethyluridine-1-yl, 6-methoxycarbonyl talexandridis-1-yl, 3-ethoxymethylencyanoacetate-1-yl, 4-ethoxymethylencyanoacetate-1-yl, 5-ethoxymethylencyanoacetate-1-yl, 6-ethoxymethylencyanoacetate-1-yl, 2-AMINOETHYLPIPERAZINE-1-yl, 3-aminomethylpyridine-1-yl, 4-aminomethylpyridine-1-yl, 5-aminomethylpyridine-1-yl, 6-AMINOETHYLPIPERAZINE-1-yl, 2-methylaminoacetaldehyde-1-yl, 3-methylaminoacetaldehyde-1-yl, 4-methylaminoacetaldehyde-1-yl, 5-methylaminoacetaldehyde-1-yl, 6-methylaminoacetaldehyde-1-yl, 3-aminomethylpyridine-1-yl, 4-aminomethylpyridine-1-yl, 5-aminomethylpyridine-1-yl, 6-aminomethylpyridine-1-yl, 3-methylaminoacetaldehyde-1-yl, 4-methylaminoacetaldehyde-1-yl, 5-methylaminoacetaldehyde-1-yl, 6-methylaminoacetaldehyde-1-yl, 3-dimethylaminoethylmethacrylate-1-yl, 4-dimethylaminoethylmethacrylate-1-yl, 5-dimethylaminoethylmethacrylate-1-yl, 6-dimethylaminoethylmethacrylate-1-yl, 2-dimethylaminoethylmethacrylate-1-yl, 3-dimethylaminoethylmethacrylate-1-yl, 4-dimethylaminoethylmethacrylate-1-yl, 5-dimethylaminoethylmethacrylate-1-yl, 6-dimethylaminoethylmethacrylate-1-yl, hexahydropirimidine series-1-yl, 2-oxog cagedreamed-1-yl, 4-oxohexanoate-1-yl, 5-oxohexanoate-1-yl, 6-oxohexanoate-1-yl, 2-methylhexahydrophthalic-1-yl, 3-methylhexahydrophthalic-1-yl, 4-methylhexahydrophthalic-1-yl, 4-methylhexahydrophthalic-1-yl, 2,2-dimethyloxazolidine-1-yl, 4,4-dimethyloxazolidine-1-yl, 5,5-dimethyloxazolidine-1-yl, 6,6-dimethyloxazolidine-1-yl, 2-hydroxymethylcytosine-1-yl, 4-hydroxymethylcytosine-1-yl, 5-hydroxymethylcytosine-1-yl, 6-hydroxymethylcytosine-1-yl, 2-carboxymethylaminomethyl-1-yl, 4-carboxymethylaminomethyl-1-yl, 5-carboxymethylaminomethyl-1-yl, 6-carboxymethylaminomethyl-1-yl, 2-carbamoilaziridin-1-yl, 3-carbamoilaziridin-1-yl, 4-carbamoilaziridin-1-yl, 5-carbamoilaziridin-1-yl, 6-carbamoilaziridin-1-yl, 2-methylcarbamoylmethyl-1-yl, 3-methylcarbamoylmethyl-1-yl, 4-methylcarbamoylmethyl-1-yl, 5-methylcarbamoylmethyl-1-yl, 6-methylcarbamoylmethyl-1-yl, 2-dimethylcyclohexylamine-1-yl, 3-dimethylcyclohexylamine-1-yl, 4-dimethylcyclohexylamine-1-yl, 5-dimethylcyclohexylamine-1-yl, 6-methylcarbamoylmethyl-1-yl, 2-carboxymethyloxime is kidin-1-yl, 3-carboxymethylcysteine-1-yl, 4-carboxymethylcysteine-1-yl, 5-carboxymethylcysteine-1-yl, 6-carboxymethylcysteine-1-yl, 2-methoxycarbonylmethylene-1-yl, 3-methoxycarbonylmethylene-1-yl, 4-methoxycarbonylmethylene-1-yl, 5-methoxycarbonylmethylene-1-yl, 6-methoxycarbonylmethylene-1-yl, 3-methoxymethamphetamine-1-yl, 4-methoxymethamphetamine-1-yl, 5-methoxymethamphetamine-1-yl, 6-methoxymethamphetamine-1-yl, 2-aminomethylpyrimidine-1-yl, 3-aminomethylpyrimidine-1-yl, 4-aminomethylpyrimidine-1-yl, 5-aminomethylpyrimidine-1-yl, 6-aminomethylpyrimidine-1-yl, 2-methylaminoacetaldehyde-1-yl, 3-methylaminoacetaldehyde-1-yl, 4-methylaminoacetaldehyde-1-yl, 5-methylaminoacetaldehyde-1-yl, 6-methylaminoacetaldehyde-1-yl, 2-dimethylaminoethylmethacrylate-1-yl, 3-dimethylaminoethylmethacrylate-1-yl, 4-dimethylaminoethylmethacrylate-1-yl, 5-dimethylaminoethylmethacrylate-1-yl, 6-dimethylaminoethylmethacrylate-1-yl, homopiperazine, 2-oklahomapersonal, 3 oklahomapersonal, 5-oklahomapersonal, 6-oklahomapersonal, 7 oklahomapersonal, 2-ACS is-4-methylhomopiperazine, 3-oxo-4-methylhomopiperazine, 5-oxo-4-methylhomopiperazine, 6-oxo-4-methylhomopiperazine, 7-oxo-4-methylhomopiperazine, 2,3-dioxopiperidin, 2,7-dioxopiperidin, 3,5-dioxopiperidin, 3,7-dioxopiperidin, 2,3-dioxo-4-methylhomopiperazine, 2,7-dioxo-4-methylhomopiperazine, 3,5-dioxo-4-methylhomopiperazine, 3,7-dioxo-4-methylhomopiperazine, 2-methylhomopiperazine, 3 methylhomopiperazine, 4-methylhomopiperazine, 5-methylhomopiperazine, 6-methylhomopiperazine, 7 methylhomopiperazine, 2-acylhomoserine, 3 acylhomoserine, 4-acylhomoserine, 5-acylhomoserine, 6-acylhomoserine, 7 acylhomoserine, 4-cyclopropylamino, 2-cyclopropanecarbonitrile, 3 cyclopropanecarbonitrile, 5-cyclopropanecarbonitrile, 6-cyclopropanecarbonitrile, 7 cyclopropanecarbonitrile, 2-cyclopropylamino-4-methylhomopiperazine, 3 cyclopropane-4-methylhomopiperazine, 5-cyclopropylamino-4-methylhomopiperazine, 6-cyclopropylamino-4-methylhomopiperazine, 7 cyclopropane-4-methylhomopiperazine, 2-cyclopropylamino-4-methyl-3 oklahomapersonal, 2-cyclopropylamino-4-methyl-5-oklahomapersonal, 2-cyclopropylamino-4-methyl-7-oklahomapersonal, 3 cyclopropylamino-4-methyl-2-oklahomapersonal, 3 cyclopropylamino-4-methyl-5-oklahomapersonal, 3 cyclopropylamino-4-methyl-7-occulomotor is of a casino, 5-cyclopropylamino-4-methyl-2-oklahomapersonal, 5-cyclopropylamino-4-methyl-3-oklahomapersonal, 5-cyclopropylamino-4-methyl-7-oklahomapersonal, 6-cyclopropylamino-4-methyl-2-oklahomapersonal, 6-cyclopropylamino-4-methyl-3-oklahomapersonal, 6-cyclopropylamino-4-methyl-5-oklahomapersonal, 6-cyclopropylamino-4-methyl-7-oklahomapersonal, 7 cyclopropane-4-methyl-2-oklahomapersonal, 7 cyclopropane-4-methyl-3-oklahomapersonal, 7 cyclopropane-4-methyl-5-oklahomapersonal, 2,2-dimethylpiperidino, 3,3-dimethylpiperidino, 5,5-dimethylpiperidino, 6,6-dimethylpiperidine, 7,7-dimethylpiperidino, 2,3-dimethylpiperidino, 2,4-dimethylpiperidino, 3,4-dimethylpiperidine, 3,5-dimethylpiperidino, 3,4,5-trimethylpyrazine, 2-hydroxyethylpiperazine, 3 hydroxyethylpiperazine, 5-hydroxyethylpiperazine, 6-hydroxyethylpiperazine, 7 hydroxyethylpiperazine, 2-hydroxymethyl-4-methylhomopiperazine, 3-hydroxymethyl-4-methylhomopiperazine, 5-hydroxymethyl-4 methylhomopiperazine, 6-hydroxymethyl-4-methylhomopiperazine, 7-hydroxymethyl-4-methylhomopiperazine, 2-methoxymethamphetamine, 3 methoxymethamphetamine, 5-methoxymethamphetamine, 6-methoxymethamphetamine, 7 methoxymethamphetamine, 2-methoxymethyl-4-methylhomopiperazine, 3-methoxymethyl-4-metil is meperidine, 5-methoxymethyl-4-methylhomopiperazine, 6-methoxymethyl-4-methylhomopiperazine, 7-methoxymethyl-4-methylhomopiperazine, 2-hydroxyethylpiperazine, 3 hydroxyethylpiperazine, 4-hydroxyethylpiperazine, 5-hydroxyethylpiperazine, 6-hydroxyethylpiperazine, 7 hydroxyethylpiperazine, 2-hydroxyethyl-4-methylhomopiperazine, 3-hydroxyethyl-4-methylhomopiperazine, 5-hydroxyethyl-4-methylhomopiperazine, 6-hydroxyethyl-4-methylhomopiperazine, 7-hydroxyethyl-4-methylhomopiperazine, 2-methoxyethylamine, 3 methoxymethamphetamine, 4-methoxymethamphetamine, 5-methoxymethamphetamine, 6-methoxymethamphetamine, 7 methoxyethylamine, 2-methoxyethyl-4-methylhomopiperazine, 3-methoxyethyl-4-methylhomopiperazine, 5-methoxyethyl-4-methylhomopiperazine, 6-methoxyethyl-4-methylhomopiperazine, 7-methoxyethyl-4-methylhomopiperazine, 2-carbamoylaspartate, 3 carbamoylaspartate, 4-carbamoylaspartate, 5-carbamoylaspartate, 6-carbamoylaspartate, 7 carbamoylaspartate, 2-carbarnoyl-4-methylhomopiperazine, 3-carbarnoyl-4-methylhomopiperazine, 4-carbarnoyl-4-methylhomopiperazine, 5-carbarnoyl-4-methylhomopiperazine, 6-carbarnoyl-4-methylhomopiperazine, 7-carbarnoyl-4-methylhomopiperazine, 2-methylcarbamoylmethyl, 3 methylcarbamoylmethyl, 4-methylcarbamoylmethyl is about, 5-methylcarbamoylmethyl, 6-methylcarbamoylmethyl, 7 methylcarbamoylmethyl, 2-methylcarbamoyl-4-methylhomopiperazine, 3-methylcarbamoyl-4-methylhomopiperazine, 5-methylcarbamoyl-4-methylhomopiperazine, 6-methylcarbamoyl-4-methylhomopiperazine, 7-methylcarbamoyl-4-methylhomopiperazine, 2-dimethylcarbamodithioato, 3 dimethylcarbamodithioato, 4-dimethylcarbamodithioato, 5-dimethylcarbamodithioato, 6-dimethylcarbamodithioato, 7 dimethylcarbamodithioato, 2-dimethylcarbamoyl-4-methylhomopiperazine, 3-dimethylcarbamoyl-4-methylhomopiperazine, 5-dimethylcarbamoyl-4-methylhomopiperazine, 6-dimethylcarbamoyl-4-methylhomopiperazine, 7-dimethylcarbamoyl-4-methylhomopiperazine, 2-carboxypropylbetaine, 3 carboxypropylbetaine, 5-carboxypropylbetaine, 6-carboxypropylbetaine, 7 carboxypropylbetaine, 2-carboxy-4-methylhomopiperazine, 3-carboxy-4-methylhomopiperazine, 5-carboxy-4-methylhomopiperazine, 6-carboxy-4-methylhomopiperazine, 7-carboxy-4-methylhomopiperazine, 2-carboxymethylamino, 3 carboxymethylamino, 4-carboxymethylamino, 5-carboxymethylamino, 6-carboxymethylamino, 7 carboxymethylamino, 2-carboxymethyl-4-methylhomopiperazine, 3-carboxymethyl-4-methylhomopiperazine, 5-carboxymethyl-4-Metalcamp is peraino, 6-carboxymethyl-4-methylhomopiperazine, 7-carboxymethyl-4-methylhomopiperazine, 2-methoxycarbonylaminophenyl, 3 methoxycarbonylaminophenyl, 4-methoxycarbonylaminophenyl, 5-ethoxycarbonylpyrimidine, 6-methoxycarbonylaminophenyl, 7 methoxycarbonylaminophenyl, 2-methoxycarbonylmethyl-4-methylhomopiperazine, 3-methoxycarbonylmethyl-4-methylhomopiperazine, 5-methoxycarbonylmethyl-4-methylhomopiperazine, 6-methoxycarbonylmethyl-4-methylhomopiperazine, 7-methoxycarbonylmethyl-4-methylhomopiperazine, 2-ethoxycarbonylpyrimidine, 3 ethoxycarbonylpyrimidine, 4-ethoxycarbonylpyrimidine, 5-ethoxycarbonylpyrimidine, 6-ethoxycarbonylpyrimidine, 7 ethoxycarbonylpyrimidine, 2-ethoxycarbonylmethyl-4-methylhomopiperazine, 3-ethoxycarbonylmethyl-4-methylhomopiperazine, 5-ethoxycarbonylmethyl-4-methylhomopiperazine, 6-ethoxycarbonylmethyl-4-methylhomopiperazine, 7-ethoxycarbonylmethyl-4-methylhomopiperazine, 2-carbamoyltransferase, 3 carbamoyltransferase, 4-carbamoyltransferase, 5-carbamoyltransferase, 6-carbamoyltransferase, 7 carbamoyltransferase, 2-carbamoylmethyl-4-methylhomopiperazine, 3-carbamoylmethyl-4-methylhomopiperazine, 5-carbamoylmethyl-4-mergemedia is Asino, 6-carbamoylmethyl-4-methylhomopiperazine, 7-carbamoylmethyl-4-methylhomopiperazine, 2-methylcarbamoylmethyl, 3 methylcarbamoylmethyl, 4-methylcarbamoylmethyl, 5-methylcarbamoylmethyl, 6-methylcarbamoylmethyl, 7 methylcarbamoylmethyl, 2-methylcarbamoylmethyl-4-methylhomopiperazine, 3-methylcarbamoylmethyl-4-methylhomopiperazine, 5-methylcarbamoyl-4-methylhomopiperazine, 6-methylcarbamoyl-4-methylhomopiperazine, 7-methylcarbamoyl-4-methylhomopiperazine, 2-dimethylcarbamodithioato, 3 dimethylcarbamodithioato, 4-dimethylcarbamodithioato, 5-dimethylcarbamodithioato, 6-dimethylcarbamodithioato, 7 dimethylcarbamodithioato, 2-dimethylcarbamoyl-4-methylhomopiperazine, 3-dimethylcarbamoyl-4-methylhomopiperazine, 5-dimethylcarbamoyl-4-methylhomopiperazine, 6-dimethylcarbamoyl-4-methylhomopiperazine, 7-dimethylcarbamoyl-4-methylhomopiperazine, 2-AMINOETHYLPIPERAZINE, 3 AMINOETHYLPIPERAZINE, 5-AMINOETHYLPIPERAZINE, 6-AMINOETHYLPIPERAZINE, 7 AMINOETHYLPIPERAZINE, 2-aminomethyl-4-methylhomopiperazine, 3-aminomethyl-4-methylhomopiperazine, 5-aminomethyl-4-methylhomopiperazine, 6-aminomethyl-4-methylhomopiperazine, 7-aminomethyl-4 methylhomopiperazine, 2-methylamine is telemetering, 3 methylenediphosphonate, 4-methylenediphosphonate, 5-methylenediphosphonate, 6-methylenediphosphonate, 7 methylenediphosphonate, 2-methylaminomethyl-4-methylhomopiperazine, 3-methylaminomethyl-4-methylhomopiperazine, 5-methylaminomethyl-4-methylhomopiperazine, 6-methylaminomethyl-4-methylhomopiperazine, 7-methylaminomethyl-4-methylhomopiperazine, 2-dimethylaminoethylacrylate, 3 dimethylaminoethylacrylate, 4-dimethylaminoethylacrylate, 5-dimethylaminoethylacrylate, 6-dimethylaminoethylacrylate, 7 dimethylaminoethylacrylate, 2-dimethylaminomethyl-4-methylhomopiperazine, 3-dimethylaminomethyl-4-methylhomopiperazine, 5-dimethylaminomethyl-4-methylhomopiperazine, 6-dimethylaminomethyl-4-methylhomopiperazine, 7-dimethylaminomethyl-4-methylhomopiperazine, 2-AMINOETHYLPIPERAZINE, 3 AMINOETHYLPIPERAZINE, 4-AMINOETHYLPIPERAZINE, 5-AMINOETHYLPIPERAZINE, 6-AMINOETHYLPIPERAZINE, 7 AMINOETHYLPIPERAZINE, 2-amino-ethyl-4-methylhomopiperazine, 3-amino-ethyl-4-methylhomopiperazine, 5-amino-ethyl-4-methylhomopiperazine, 6-amino-ethyl-4-methylhomopiperazine, 7-amino-ethyl-4-methylhomopiperazine, 2-metilaminoantipirina, 3 metilaminoantipirina, 4-metilaminoantipirina, 5-metilaminoantipirina, 6-metilaminoantipirina, 7-meth is AMINOETHYLPIPERAZINE, 2-methylaminomethyl-4-methylhomopiperazine, 3-methylaminomethyl-4-methylhomopiperazine, 5-methylaminomethyl-4-methylhomopiperazine, 6-methylaminomethyl-4-methylhomopiperazine, 7-methylaminomethyl-4-methylhomopiperazine, 2-diethylaminoethylamine, 3 dimethylaminoethylacrylate, 4-dimethylaminoethylacrylate, 5-dimethylaminoethylacrylate, 6-dimethylaminoethylacrylate, 7 dimethylaminoethylacrylate, 2-dimethylaminoethyl-4-methylhomopiperazine, 3-dimethylaminoethyl-4-methylhomopiperazine, 5-dimethylaminoethyl-4-methylhomopiperazine, 6-dimethylaminoethyl-4-methylhomopiperazine, 7-dimethylaminoethyl-4 methylhomopiperazine, 4-methanesulfonylaminoethyl, 4-methanesulfonylaminoethyl, 4-(azetidin-1-yl)homopiperazine, 4-pyrrolopyrazine, 4-piperidineacetate, 1,4-oxazepan-4-yl, Spiro[azetidine-3,2'-1'-methylaziridine]-1-yl, Spiro[piperidine-4,2'-1'-methylaziridine]-1-yl, Spiro[piperidine-2,3'-1'-methylaziridine]-1-yl, Spiro[piperidine-2,3'-1'-methylpyrrolidine]-1-yl, Spiro[morpholine-3,3'-1'-methylaziridine]-4-yl, Spiro[morpholine-3,3'-1'-methylpyrrolidine]-4-yl, Spiro[piperazine-3-cyclopropane]-1-yl, Spiro[4-methylpiperazin-3-cyclopropane]-1-yl.

Of them, preferred are the following groups:

azetidin-1-yl, 3-dimethylimidazolidin-1-yl, 2-methylaziridine-1-yl, 3-methylaziridine-1-yl, 2,2-dimethylamide-1-yl, 3,3-dimethylamide-1-yl, 2,2-is imethyl-3-dimethylimidazolidin-1-yl, 2-hydroxymethylamino-1-yl, 3-hydroxymethylation-1-yl, 2-carbamoylethyl-1-yl, 2-methylcarbamoylmethyl-1-yl, 2-dimethylcarbamoyl-1-yl, pyrrolidino, 2-oxopyrrolidin, 2-dimethylaminopyridine, 3-dimethylaminopyridine, 2,5-dioxopyrimidine, 2-methylpyrrolidine, 3-methylpyrrolidine, 2,2-dimethylpyrimidine, 3,3-dimethylpiperidine, 2-hydroxyethylpyrrolidine, 3-hydroxyethylpyrrolidine, 3-methoxypyridine, 2-methoxypyridine, 3-methoxypyridine, 2-carbamoylpiperidino, 2-methylcarbamoylmethyl, 2-dimethylcarbamoyl, 2-Oxymetazoline-1-yl, 4-Oxymetazoline-1-yl, 3-methyl-2-Oxymetazoline-1-yl, 3-methyl-4-Oxymetazoline-1-yl, 2-methylpiperidin-1-yl, 3-oxopyrrolidin-1-yl, 3,5-dioxopiperidin-1-yl, piperidino, 2-oxopiperidine, 3-oxopiperidine, 4-oxopiperidine, 2-hydroxylaminopurine, 3-hydroxylaminopurine, 4-hydroxylaminopurine, 2-methoxypiperidine, 3-methoxypiperidine, 4-methoxypiperidine, 2-methoxykynuramine, 3-methoxykynuramine, 4-methoxykynuramine, 2-methylpiperidino, 3-methylpiperidino, 4-methylpiperidino, 2,2-dimethylpiperidino, 3,3-dimethylpiperidino, 4,4-dimethylpiperidine, 4-ftorpirimidinu, 4-chloropyridine, 3,3-ceftobiprole, 4,4-ceftobiprole, 3,3-dichlorobenzidine, 4,4-dichloropyridine, 2-hydroxyethylpiperazine, 2-carbamoyl piperidino, 2-methylcarbamoylmethyl, 2-dimethylcarbamodithioato, 2-carboxymethylamino, 2-methoxypiperidine, 2-aminomethylpyridine, 2-methylaminoacetaldehyde, 2-dimethylaminopyridine, 2-AMINOETHYLPIPERAZINE, 2-methylaminoacetaldehyde, 2-dimethylaminopyridine, 2-oxo-4-methylpiperazine, 3-oxo-4-methylpiperazine, 4-formylpiperazine, 2,3-dioxo-4-methylpiperazine, 3,5-dioxo-4-methylpiperazine, 2,6-dioxo-4-methylpiperazine, 4-methylpiperazine, 4-ethylpiperazine, 4-isopropylpiperazine, 2,4-dimethylpiperazine, 3,4-dimethylpiperazine, 2-ethyl-4-methylpiperazine, 3-ethyl-4-methylpiperazine, 2-isopropyl-4-methylpiperazine, 3-isopropyl-4-methylpiperazine, 2-cyclopropyl-4-methylpiperazine, 3-cyclopropyl-4-methylpiperazine, 3,4,5-trimethylpyrazine, 2,2,4-trimethylpyrazine, 3,3,4-trimethylpyrazine, 3,3,4-trimethyl-5-oxopiperidine, 2,2,4-trimethyl-3-oxopiperidine, 2-cyclopropylamino-4-methylpiperazine, 3 cyclopropane-4-methylpiperazine, 2-cyclopropane-4-methyl-3-oxopiperidine, 3 cyclopropylamino-4-methyl-5-oxopiperidine, 4-acetyl-3-cyclopropanecarbonitrile, 2-hydroxymethyl-4-methylpiperazine, 3-geochemical-4-methylpiperazine, 2-methoxymethyl-4-methylpiperazine, 3-methoxymethyl-4-methylpiperazine, 2-gadoxetic-4-methylpiperazine, 3-hydroxyethyl-4-methylpiperazine, 2-methoxyethyl-4-methylpiperazine, 3-methoxyethyl-4-methylpiperazine, 2-CT is email-4-methylpiperazine, 3-carbarnoyl-4-methylpiperazine, 4-carbamoylbiphenyl, 2-methylcarbamoyl-4-methylpiperazine, 3-methylcarbamoyl-4-methylpiperazine, 4-methylcarbamoylmethyl, 2-dimethylcarbamoyl-4-methylpiperazine, 3-dimethylcarbamoyl-4-methylpiperazine, 4-dimethylcarbamodithioato, 2-carbamoylmethyl-4-methylpiperazine, 3-carbamoylmethyl-4-methylpiperazine, 4-carbamoyltransferase, 2-methylcarbamoylmethyl-4-methylpiperazine, 3-methylcarbamoylmethyl-4-methylpiperazine, 4-methylcarbamoylmethyl, 2-dimethylcarbamoyl-4-methylpiperazine, 3-dimethylcarbamoyl-4-methylpiperazine, 2-carboxy-4-methylpiperazine, 2-carboxymethyl-4-methylpiperazine, 2-methoxycarbonylmethyl-4-methylpiperazine, 3-methoxycarbonylmethyl-4-methylpiperazine, 2-ethoxycarbonylmethyl-4-methylpiperazine, 3-ethoxycarbonylmethyl-4-methylpiperazine, 2-aminomethyl-4-methylpiperazine, 2-methylaminomethyl-4-methylpiperazine, 2-dimethylaminomethyl-4-methylpiperazine, 2-amino-ethyl-4-methylpiperazine, 2-methylaminomethyl-4-methylpiperazine, 2-dimethylaminoethyl-4 methylpiperazine, morpholine, 2-methylmorpholine, 3 methylmorpholine, 2-ethylmorpholino, 3 ethylmorpholine, 2-cyclopropanecarbonyl, 3 cyclopropanecarbonyl, 2,2-dimethylmorpholine, 3,3-dimethylmorpholine, 3 hydroxymethylpropane, 3 methoxyethylamine, 3 hydroxyethylimino, 3 methoxyethylamine, 3 carbamylcholine, 3-methylcarbamoyl is morpholino, 3 dimethylcarbamoyl, 3 carbamylcholine, 3 methylcarbamoylmethyl, 3 dimethylcarbamodithioato, 3 carbamylcholine, 3 methylcarbamoylmethyl, 3 dimethylcarbamodithioato, 3 methoxycarbonylamino, 3 methoxycarbonylmethylene, 3 ethoxycarbonylmethylene, 3 aminomethylpropanol, 3 methylaminopropane, 3 dimethylaminomethylphenol, 3 aminoethylamino, 3 methylaminoethanol, 3 diethylaminoethylamine, thiomorpholine, 3 Osotimehin, 1,1-dioxothiazolidine, 2-methylthiophene, 3 methylthiophene, 2-ethylthiophene, 3 ethylthiophene, 2-cyclopropanemethanol, 3 cyclopropanemethylamine, 2,2-dimethylmorpholine, 3,3-dimethylmorpholine, 3 hydroxymethylcytosine, 3 methoxyethylamine, 3 hydroxyethylimino, 3 methoxyacetophenone, 3 carbamylcholine, 3 methylcarbamoylmethyl, 3 dimethylcarbamodithioato, 3 carbamoyltransferase, 3 methylcarbamoylmethyl, 3 dimethylcarbamodithioato, 3 carbamoyltransferase, 3 methylcarbamoylmethyl, 3 dimethylcarbamodithioato, 3 methoxycarbonylamino 3 methoxycarbonylmethylene, 3 ethoxycarbonylpyrimidine, 2-acetylglucosaminidase-1-yl, 2-vormingukirjeldused-1-yl, 3-okage saitopiordede-1-yl, 6-oxohexanoate-1-yl, 2,3-dimethyltetrahydrofuran-1-yl, 3-hydroxymethylcytosine-1-yl, 5-hydroxymethylcytosine-1-yl, 6-hydroxymethylcytosine-1-yl, 2-carbamoylaspartate-1-yl, 2-methylcarbamoylmethyl-1-yl, 2-dimethylcarbamodithioato-1-yl, 2-oxohexanoate-1-yl, 4-oxohexanoate-1-yl, 6-oxohexanoate-1-yl, 2-methylhexahydrophthalic-1-yl, 3-methylhexahydrophthalic-1-yl, 3-carbamoilaziridin-1-yl, 3-methylcarbamoylmethyl-1-yl, 3-dimethylcyclohexylamine-1-yl, 2-oxo-4-methylhomopiperazine, 3-oxo-4-methylhomopiperazine, 5-oxo-4-methylhomopiperazine, 6-oxo-4-methylhomopiperazine, 7-oxo-4-methylhomopiperazine, 2,3-dioxopiperidin, 2,7-dioxopiperidin, 3,5-dioxopiperidin, 3,7-dioxopiperidin, 2,3-dioxo-4-methylhomopiperazine, 2,7-dioxo-4-methylhomopiperazine, 3,5-dioxo-4-methylhomopiperazine, 3,7-dioxo-4-methylhomopiperazine, 4-methylhomopiperazine, 4-acylhomoserine, 4-cyclopropylamino, 2-cyclopropanecarbonitrile, 3 cyclopropanecarbonitrile, 5-cyclopropanecarbonitrile, 6-cyclopropanecarbonitrile, 7 cyclopropanecarbonitrile, 2,4-dimethylpiperidino, 3,4-dimethylpiperidine, 3,4,5-trimethylpyrazine, 2-hydroxymet the l-4 methylhomopiperazine, 7-hydroxymethyl-4-methylhomopiperazine, 2-methoxymethyl-4-methylhomopiperazine, 3-methoxymethyl-4-methylhomopiperazine, 5-methoxymethyl-4-methylhomopiperazine, 6-methoxymethyl-4-methylhomopiperazine, 7-methoxymethyl-4-methylhomopiperazine, 2-hydroxyethyl-4-methylhomopiperazine, 7-hydroxyethyl-4-methylhomopiperazine, 2-methoxyethyl-4-methylhomopiperazine, 3-methoxyethyl-4-methylhomopiperazine, 5-methoxyethyl-4-methylhomopiperazine, 6-methoxyethyl-4-methylhomopiperazine, 7-methoxyethyl-4 methylhomopiperazine, 2-carbarnoyl-4-methylhomopiperazine, 7-carbarnoyl-4-methylhomopiperazine, 2-methylcarbamoyl-4-methylhomopiperazine, 7-methylcarbamoyl-4-methylhomopiperazine, 2-dimethylcarbamodithioato, 7 dimethylcarbamodithioato, 2-carboxypropylbetaine, 7 carboxypropylbetaine, 2-carboxy-4-methylhomopiperazine, 7-carboxy-4-methylhomopiperazine, 2-carboxymethyl-4-methylhomopiperazine, 7-carboxymethyl-4-methylhomopiperazine and 1,4-oxazepan-4-yl.

Among them, particularly preferred groups are the following groups:

Azetidin-1-yl, 3-dimethylimidazolidin-1-yl, 2,2-dimethyl-3-dimethylimidazolidin-1-yl, 2-hydroxymethylamino-1-yl, 2-carbamoylethyl-1-yl, 2-methylcarbamoylmethyl-1-yl, 2-dimethylcarbamoyl-1-yl, pyrrolidino, 2-oxopyrrolidin, 2,5-dioxopyrimidine, 2-methylpyrrolidine, 3-methylpyrrolidine, 2,2-dimethylpyrrole is about, 3,3-dimethylpiperidine, 2-dimethylaminopyridine, 3-dimethylaminopyridine, 2-hydroxyethylpyrrolidine, 3-methoxypyridine, 2-carbamoylpiperidino, 2-methylcarbamoylmethyl, 2-dimethylcarbamoyl, 3-methyl-2-Oxymetazoline-1-yl, 3-methyl-4-Oxymetazoline-1-yl, piperidino, 2-oxopiperidine, 2-methoxypiperidine, 3-methoxypiperidine, 4-methoxypiperidine, 2-hydroxyethylpiperazine, 2-carbamoylbiphenyl, 2-methylcarbamoylmethyl, 2-dimethylcarbamodithioato, 2-methoxypiperidine, 2-aminomethylpyridine, 2-methylaminoacetaldehyde, 2-dimethylaminopyridine, 2-AMINOETHYLPIPERAZINE, 2-methylaminoacetaldehyde, 2-dimethylaminopyridine, 4-ftorpirimidinu, 3,3-ceftobiprole, 4,4-ceftobiprole, 2-oxo-4-methylpiperazine, 3-oxo-4-methylpiperazine, 4-formylpiperazine, 2,3-dioxopiperazinyl, 3,5-dioxopiperazinyl, 2,6-dioxopiperidin, 4-methylpiperazine, 4-ethylpiperazine, 4-isopropylpiperazine, 4-cyclopropylbenzene, 2,4-dimethylpiperazine, 3,4-dimethylpiperazine, 2-methyl-4-methylpiperazine, 3-methyl-4-methylpiperazine, 3,4,5-trimethylpyrazine, 2,2,4-trimethylpyrazine, 3,3,4-trimethylpyrazine, 3,3,4-trimethyl-5-oxopiperidine, 2,2,4-trimethyl-3-oxopiperidine, 2-cyclopropylamino-4-methylpiperazine, 3 cyclopropane-4-methylpiperazine, 2-cyclopropylamino-4-methyl-3-oxopiperidine, 3-cycle is proposera-4-methyl-5-oxopiperidine, 4-acetyl-3-cyclopropanecarbonitrile, 2-hydroxymethyl-4-methylpiperazine, 3-hydroxymethyl-4-methylpiperazine, 2-methoxymethyl-4-methylpiperazine, 3-methoxymethyl-4-methylpiperazine, 2-hydroxyethyl-4-methylpiperazine, 3-hydroxyethyl-4-methylpiperazine, 2-methoxyethyl-4-methylpiperazine, 3-methoxyethyl-4-methylpiperazine, 2-carbarnoyl-4-methylpiperazine, 2-methylcarbamoyl-4-methylpiperazine, 2-dimethylcarbamoyl-4-methylpiperazine, 2-carbamoylmethyl-4 methylpiperazine, 2-methylcarbamoylmethyl-4-methylpiperazine, 2-dimethylcarbamoyl-4-methylpiperazine, 2-methoxycarbonylmethyl-4-methylpiperazine, 2-ethoxycarbonylmethyl-4-methylpiperazine, 2-aminomethyl-4-methylpiperazine, 2-methylaminomethyl-4-methylpiperazine, 2-dimethylaminomethyl-4-methylpiperazine, 2-amino-ethyl-4-methylpiperazine, 2-methylaminomethyl-4-methylpiperazine, 2-dimethylaminoethyl-4-methylpiperazine, morpholine, 2-cyclopropanecarbonyl, 3 cyclopropanecarbonyl, 2,2-dimethylmorpholine, 3,3-dimethylmorpholine, 3 hydroxymethylpropane, 3 methoxyethylamine, 3 hydroxyethylimino, 3 methoxyethylamine, 3 carbamylcholine, 3 methylcarbamoylmethyl, 3 dimethylcarbamoyl, 3 aminomethylpropanol, 3 methylaminopropane, 3 dimethylaminomethylphenol, 3 aminoethylamino, 3 methylaminoethanol, 3 diethylaminoethylamine, thiomorpholine, 3 Osotimehin, 1,1-di is katiemorgan, 3 hydroxymethylcytosine, 3 hydroxyethylimino, 2-acetylglucosaminidase-1-yl, 2-vormingukirjeldused-1-yl, 3-oxohexanoate-1-yl, 2-methylhexahydrophthalic-1-yl, 2-carbamoylaspartate-1-yl, 2-oxohexanoate-1-yl, 4-oxohexanoate-1-yl, 3-methylhexahydrophthalic-1-yl, 6-hydroxymethylcytosine-1-yl, 2-oxo-4-methylhomopiperazine, 3-oxo-4-methylhomopiperazine, 5-oxo-4 methylhomopiperazine, 7-oxo-4-methylhomopiperazine, 2,3-dioxopiperidin, 2,7-dioxopiperidin, 3,5-dioxopiperidin, 3,7-dioxopiperidin, 4-methylhomopiperazine, 4-acylhomoserine, 4-cyclopropylamino, 2-cyclopropylamino-4-methylhomopiperazine, 3 cyclopropane-4-methylhomopiperazine, 5-cyclopropylamino-4-methylhomopiperazine, 7 cyclopropane-4-methylhomopiperazine and 1,4-oxazepan-4-yl.

Even more preferred examples include 3-dimethylimidazolidin-1-yl, 2,2-dimethyl-3-dimethylimidazolidin-1-yl, 2-hydroxymethylamino-1-yl, 2-carbamoylethyl-1-yl, 2-oxopyrrolidin, 2-hydroxyethylpyrrolidine, 2-carbamoylpiperidino, 2-hydroxyethylpiperazine, 2-carbamoylbiphenyl, 2-methylcarbamoylmethyl, 2-dimethylcarbamodithioato, 3-oxo-4-methylpiperazine, 4-methylpiperazine, 4-ethylpiperazine, 4-isopropylpiperazine, 4-cyclopropylbenzene, 2,4-dimethy is the piperazine derivatives, 3,4-dimethylpiperazine, 3-cyclopropyl-4-methylpiperazine, 3,4,5-trimethylpyrazine, 2,2,4-trimethylpyrazine, 3,3,4-trimethylpyrazine, 2-cyclopropylamino-4-methylpiperazine, morpholine, 3 carbamylcholine, 1,1-dioxothiazolidine, 2-methylhexahydrophthalic-1-yl, 3-methylhexahydrophthalic-1-yl, 3-oxo-4-methylhomopiperazine, 5-oxo-4-methylhomopiperazine, 4-methylhomopiperazine, 4-acylhomoserine, 4-cyclopropylamino, 1,4-oxazepan-4-yl, piperidino, 4-methoxypiperidine, thiomorpholine, 4,4-ceftobiprole, 3,3-ceftobiprole, 4-ftorpirimidinu, 2-dimethylaminopyridine, 3-dimethylaminopyridine, 3-methyl-4-Oxymetazoline-1-yl, 3-methoxypyridine, 2-acetylglucosaminidase-1-yl and 2-carbamoylaspartate-1-yl.

All of the compounds (I) and (II) of the present invention is not necessarily form a salt. However, when the compound (I) or (II) has a carboxyl group, an amino group or a similar group, and/or when Ar1, Ar2, Ar3or Ar4represents a pyridine ring or a similar ring, the compound may form a salt, and in some cases, the salt may form the MES. Examples of salts include salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid and nitric acid; organic acid salts such as methanol the background acid, p-toluensulfonate acid, fumaric acid and triperoxonane acid, and salts of alkali metal ions or alkaline earth metal ions such as sodium ion, potassium ion or calcium ion.

MES of the present compound (I) or (II) and MES salt of the present compound (I) or (II) includes a solvate formed by joining of the solvent used in the process of crystallization, and the solvate formed by absorption of moisture in the air. Examples of the solvent include lower alcohols such as methanol and ethanol; other organic solvents, such as acetone and acetonitrile, and water.

The compound (I) of the present invention can be obtained through the following ways:

(where Ar1, Ar2and R2 have the same meanings as described above, and R10 represents a methyl group or ethyl group).

Specifically, the compound (3) and dialkylated dissolved or suspended in a suitable solvent such as N,N-dimethylformamide and to the solution was added sodium hydride in a stream of argon at a temperature of from -20 to 20°and the mixture is stirred, whereby receive connection (4).

In the alternative case, the compound (4) can be obtained by treating compound (3) dialkylanilines in the presence of sodium alkoxide (metox is Yes or ethoxide) in a solution of alcohol (methanol or ethanol). The reaction temperature is preferably from -10 to 100°C.

The compound (4) is dissolved in alcohol (methanol or ethanol) and to the solution at room temperature add hydrazine derivative (6) or its salt. To the mixture is added a suitable amount of acetic acid and the mixture is refluxed, while receiving the connection (7) and isomer provisions (8) as a by-product. Compound (7) can be easily isolated and cleaned by column chromatography on silica gel.

In the reaction of formation of the pyrazole ring instead of acetic acid before boiling under reflux by heating can be added a suitable amount of triethylamine or concentrated hydrochloric acid. In some cases, the compound (7) can be obtained without adding any reagent from acetic acid, triethylamine and concentrated hydrochloric acid.

A derivative of hydrazine (6) or its salt used in the above reaction of formation of the pyrazole ring can be obtained by dissolving an aromatic amine (5) in concentrated hydrochloric acid, is added to the solution under ice cooling sodium nitrite with the formation of diazocompounds and processing of diazocompounds chloride tin (II). The reaction temperature is predpochtitelno -10 to 20° C.

A derivative of hydrazine (6) may be commercially available product in the form of a derivative of hydrazine. In the alternative case, the hydrazine derivative (6) can be obtained by the interaction of halogenated compounds Ar1with hydrazine, as described in the reference examples, or by a similar method.

Aromatic amine (5) may be commercially available product. In the alternative case, the aromatic amine (5) may be obtained by the method described in reference examples, or similar method.

When the thus obtained compound (7) is treated in the following way:

(where R2, R3, R10, Ar1, Ar2and the structure of the ring a have the same meanings as described above), can be obtained compound (I) of the present invention.

Specifically, the compound (7) hydrolyzing the usual way with the formation of carboxylic acid (9) and carboxylic acid (9) is condensed with the amine derivative (10), thus obtaining the compound (I) of the present invention.

The above hydrolysis reaction can be carried out in the presence of a base or a Lewis acid. Examples of bases include hydroxide of an alkali metal (e.g. lithium, sodium or potassium). Examples of the Lewis acid include tribromide boron. The reaction temperature preferably with the hat from -20 to 100° S, more preferably from -5 to 50°C.

When the compound (7) has as a substituent Ar1halogen atom such as chlorine or bromine, Deputy Ar1may be replaced by a methoxy group by dissolving the compound (7) in methanol and adding sodium methoxide to the solution followed by boiling under reflux by heating or by dissolving the compound (7) in a solvent mixture of methanol and toluene, and the addition of sodium methoxide as catalyst, such as copper bromide (I), followed by boiling under reflux by heating. Thus, it can be obtained compound (7)having as the substituent Ar1the methoxy group (R10 represents methyl).

The method of condensation described above can be carried out according to the method commonly used for the synthesis of peptides. Examples of the method of peptide synthesis include the azide method, acid chloride method, the acid, acid anhydride, the way DCC (dicyclohexylcarbodiimide), an active way of ester, the method carbodiimide, the way DCC/HOBT (1-hydroxybenzotriazole), a method using water-soluble carbodiimide and the way of using diethylthiophosphate. These methods are described, for example, M. Bodanszky, Y.S. Klausner, and M.A. Ondetti, "Peptide Synthesis", A Wiley-interscience publication, New York, 1976; G.R. Pettit, "Synthetic Peptides", Elsevier Scientific Publication Company, New York, 1976;and Japanese Society of Chemistry ed. "Lectures on Experimental Chemistry 4th ed., vol. 22, Organic Synthesis IV, Maruzen Publishing, 1991. Examples of the solvent used in the condensation reaction include N,N-dimethylformamide, pyridine, chloroform, methylene chloride, tetrahydrofuran, dioxane, acetonitrile or a mixture of such solvents. The reaction temperature is preferably -20 to 50°S, more preferably from -10 to 30°C. amine Derivative (10) can be commercially acceptable product or can be obtained according to the method described in the documentary sources or reference sample, or similar method.

When the amine derivative (10)used in the condensation reaction described above has a functional group such as hydroxyl group, amino group or carboxyl group, the functional group may be protected in advance with the use of suitable protective groups. Examples of typical protective group for a hydroxyl group include tert-boutelou group and benzyl group. Examples of typical protective groups for amino include trifluoracetyl group, tert-butoxycarbonyl group and benzyloxycarbonyl group. When the functional group is a carboxyl group, amine derivative (10) can be transformed into a methyl ether or tert-butyl methyl ether before the condensation reaction. Such protective groups can b is to be removed in suitable conditions, which can vary depending on the type of the protective group.

The compound (II) of the present invention can be obtained in the following way:

(where Ar3, Ar4, R5, R6, structure of rings Ar3and the structure of rings have the same meanings as described above, and R10 represents a methyl group or ethyl group).

Specifically, a commercially available compound (11) and dialkylated dissolved or suspended in a suitable solvent, for example N,N-dimethylformamide, and the solution in a stream of argon at a temperature of from -20 to 20°add sodium hydride, followed by stirring, thus obtaining the compound (12).

In the alternative case, the compound (12) can be obtained by treating compound (11) and diethyloxalate bis(trimethylsilyl)amidon lithium in an inert solvent, such as tetrahydrofuran. The reaction temperature is preferably from -78 to 50°C.

Then the compound (12) is dissolved in ethanol and to the solution at room temperature add hydrazine derivative (14) or its salt. To the mixture is added a suitable amount of acetic acid and the mixture is then refluxed by heating, thus obtaining the compound (15).

In the reaction of formation of the pyrazole ring instead of acetic acid may be added prior to the pacinian under reflux by heating the appropriate amount of triethylamine. In some cases, the compound (15) can be obtained without adding any reagent of acetic acid and triethylamine.

A derivative of hydrazine (14) or its salt used in the above reaction of formation of the pyrazole ring can be obtained by dissolving an aromatic amine (13) in concentrated hydrochloric acid by adding sodium nitrite to the solution under ice cooling with the formation of diazocompounds and processing of diazocompounds chloride tin (II). The reaction temperature is preferably -10 to 20°C.

In the alternative case, the hydrazine derivative (14) may be commercially available product in the form of a derivative of hydrazine. In the alternative case, the hydrazine derivative (14) can be obtained by the interaction of halogenated compounds Ar1with hydrazine, as described in the reference examples, or similar method.

Aromatic amine (13) may be commercially available product. In the alternative case, the aromatic amine (13) can be obtained according to the method described in reference examples, or similar method.

When the thus obtained compound (15) is treated in the following way:

(where R5, R6, R7, R10, Ar4the structure of the ring Ar3and the structure of rings b and C have the same meanings as op is Sana above), can be obtained the compound (II) of the present invention.

Specifically, the compound (15) hydrolyzing by the method known per se, with the formation of the carboxylic acid (16), and carboxylic acid (16) condensed with the amine derivative (17), thus obtaining the compound (II) of the present invention.

The above hydrolysis reaction and the condensation reaction can be carried out in conditions similar to the conditions described in obtaining the compound (I).

In the alternative case, the compound (I) of the present invention can be obtained in the following way:

(where R2, R3, R10, Ar1, Ar2and the structure of the ring a have the same meanings as described above, and Z represents the group released).

Specifically, the ester (7) restore with the formation of alcohol (18) and alcohol (18) is converted into a compound (19), has released the group Z (such as p-toluensulfonate, methysulfonylmethane, triftormetilfullerenov, chlorine atom, bromine atom or iodine atom). The compound (19) is subjected to interaction with the amine derivative (10), thus obtaining the compound (I) of the present invention.

The reduction of ester (7) in the alcohol (18) can be carried out, for example, by treatment of ester (7) aluminiumhydride, laibor what idream or similar compound in an inert solvent, such as tetrahydrofuran, at temperatures from -78 to 50°C, preferably from -20 to 30°C.

The alcohol (18) can be obtained by treatment of carboxylic acid (9) in an inert solvent, such as tetrahydrofuran, aluminiumhydride, complex, borane-tetrahydrofuran or similar compound at a temperature of from -78 to 50°C, preferably at a temperature of from -20 to 30°C.

Then the alcohol compound (18) can be converted into the compound (19) as follows. When the group Z is methysulfonylmethane, an alcohol compound (18) is subjected to interaction with methanesulfonamide in the presence of a base, such as pyridine, at a temperature of from -50 to 50°C. When the group Z is a p-toluensulfonate, triftormetilfullerenov or similar group, into a compound (19) can be carried out in similar conditions. When Z represents a chlorine atom or a bromine atom, an alcohol compound (18) turn in chlorinated (19) or bromo derivatives (19) through the use of thionyl chloride, tiniversity or similar connection. When the group Z is an iodine atom or a similar group thus obtained chloro - or bromo derivatives (19) is treated with sodium iodide, thus gaining imprisone (19). The conditions and reagents used in this is x reactions, can be determined appropriately on the basis of General knowledge of organic chemistry.

The conversion from the compound (19) in the compound (I) of the present invention can be carried out by interaction of the compound (19) with the amine (10) in a suitable solvent, such as tetrahydrofuran or N,N-dimethylformamide, using a base such as triethylamine or diisopropylethylamine, or inorganic bases such as potassium carbonate, or using such bases as sodium hydride. The reaction temperature, which varies depending on the type of group Z is preferably between -79 and 100°C.

In the above reaction, in some cases, functional groups need to be protected. Protective groups and conditions used for removal of the protective groups can be determined appropriately on the basis of General knowledge of organic chemistry.

The compound (I) of the present invention, obtained according to any one of the above three methods, can be converted into another compound (I) of the present invention by means of chemical modifications on the basis of General knowledge of organic chemistry.

The compound (I) and (II) of the present invention, their salts or solvate and a solvate salts possess strong activity against platelet aggregation, they are effective in models of thrombosis induced by p is som with high shear. Therefore, the compound (I) and (II) of the present invention, their salts or solvate and a solvate salts are suitable for humans and other animals as a preventive and/or therapeutic agents for ischemic diseases caused by thrombus or emboli, such as myocardial infarction, angina pectoris (chronic, stable angina, unstable angina and the like), ischemic cerebrovascular disorder (transient ischemic stroke (TIA), cerebral infarction and the like), peripheral vascular disease, embolism after replacing the artificial vessel vessel thrombotic embolism after surgery in coronary artery (bypass coronary artery (CAGB), percutaneous intraluminal coronary angioplasty (RTSA), stent placement, and the like), diabetic retinopathy and nephropathy and embolism after replacement heart valve artificial, and is also applicable as a preventive and/or therapeutic agents for thrombus and embolism associated with the operation of the vessels, artificial circulation, and the like.

When the compound (I) or (II) of the present invention, the salt of such compounds or MES compound or salt is used as a drug, daily dose for an adult patient, which ismene the Xia depending on age, gender, the patient's symptoms and the like, is preferably from 0.1 mg to 1 g, more preferably from 5 mg to 500 mg of the Drug can be injected once a day or several times a day in divided manner. If necessary, the compound/salt/MES can be entered in a dose exceeding the above-mentioned daily dose.

No particular limitation is imposed on the route of administration and pharmaceutical form of the medicinal product containing the compound (I) or (II) of the present invention, the salt of such compounds or MES compounds or salts, and the drug can be introduced by any route and in any desired dosage form. Dosage form may be determined appropriately depending on the route of administration. The drug can be obtained in the usual way of obtaining drugs by the inclusion of the desired pharmacologically acceptable carrier.

Examples of oral preparations include solid preparations such as tablets, powders, granules, pills and capsules, and liquid preparations such as solution, syrup, elixir, suspension and emulsion.

The injection can be obtained by filling the container with a solution of the compound (I) and (II), salts of such compounds or MES compounds or salts. Solid preparation obtained is output, for example, freeze-drying of this solution can also be used as injection after re-hydration before use.

Upon receipt of such a medicinal product choose one or more pharmaceutically acceptable additives, in accordance with the need for the drug may be included, among other additives, binder, disintegrator, a stimulator of dissolution, a lubricating agent, a filler, excipient and similar additives.

[Example]

Next will be described the methods of obtaining the typical compounds of the present invention. In addition, you will be given descriptions of specific tests carried out to demonstrate the obtained compounds strong inhibiting platelet aggregation without inhibiting MOR-1 and MOR-2.

[Reference example 1] Hydrochloride 5-hydrazino-2-methoxypyridine

A solution of sodium nitrite (3,795 g) in water (20 ml) is added dropwise to 5-amino-2-methoxypyridine (6,21 g) in concentrated hydrochloric acid (50 ml) over a period of 60 minutes under ice cooling and the resulting mixture is stirred at constant temperature for 30 minutes. To the reaction mixture dropwise added chloride dihydrate tin (II) (39.5 g) in concentrated hydrochloric acid (3 ml) at an internal temperature of approximately 10° C for 30 minutes, followed by stirring for 2 hours at room temperature. Under ice cooling, the reaction mixture was partitioned between sodium hydroxide (75 g) in water and diethyl ether. The aqueous layer was extracted with diethyl ether twice. Then the aqueous layer was saturated with sodium chloride, followed by extraction with diethyl ether. The organic layers are combined and dried over anhydrous sodium sulfate, followed by filtration. To the filtrate was added 1 M HCl in ethanol (50 ml) and the mixture is stirred. The solid, which precipitated, collected by filtration, washed with diethyl ether and dried, thereby obtaining specified in the header connection (5,02 g, 57%).

1H-NMR (400 MHz, DMSO-d6) δ: 3,81 (3H, s), PC 6.82 (1H, d, J=8,8 Hz), EUR 7.57 (1H, DD, J=8,8, 2,9 Hz), of 7.97 (1H, d, J=2,9 Hz), 8,55-9,20 (1H, usher.), 10,13-10,50 (3H, usher.).

MC (ESI) m/z 140 (M+H)+.

[Referential example 2] 5-Hydrazino-2-methoxypyridine

Sodium nitrite (3,795 g) in water (20 ml) is added dropwise to 5-amino-2-methoxypyridine (6,207 g) in concentrated hydrochloric acid (50 ml) for 80 minutes under ice cooling, followed by stirring at constant temperature for 30 minutes. To the reaction mixture at an internal temperature of approximately 10°C for 60 minutes added dropwise a chloride dihydrate tin (II) (395 g) in concentrated hydrochloric acid (30 ml) followed by stirring at room temperature for 12.5 hours. Under ice cooling to the reaction mixture is added sodium hydroxide (54 g) in water (200 ml) and chloroform. After removal of insoluble substances in the mixture formed by filtering the reaction mixture evenly. The aqueous layer was extracted twice with chloroform. The organic layers are combined and dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, thereby obtaining specified in the title compound as crystals (to 4.23 g, 60%).

1H-NMR (400 MHz, CDCl3) δ: 3,50-3,68 (2H, usher.), 3,88 (3H, s), a 4.86-to 5.03 (1H, usher.), of 6.66 (1H, d, J=8,8 Hz), 7,20 (1H, DD, J=8,8, 2,9 Hz), to 7.77 (1H, d, J=2,9 Hz).

MC (ESI) m/z 140 (M+H)+.

[Referential example 3] Ethyl ester 5-(4-chlorophenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

1) Ethyl ester of 4-(4-chlorophenyl)-2,4-dioxaborinane acid

Sodium hydride (used after washing with pentane and then drying; 0,474 g) are added to 4'-chloroacetophenone (1,535 g) in N,N-dimethylformamide (25 ml) at 0°C, followed by stirring at room temperature for 0.5 hours. To the reaction mixture add diethyloxalate (2,6 ml) followed by stirring at room temperature for 17 hours. The reaction mixture was partitioned between water and diethyl ether. The aqueous layer was acidified to pH 3 1 M water chloritoid is one acid followed by extraction with diethyl ether. Then the aqueous layer was additionally extracted with diethyl ether. The organic layer was washed with saturated salt solution and dried with anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, thus obtaining the ethyl ester of 4-(4-chlorophenyl)-2,4-dioxaborinane acid (1,952 g, 77%).

1H-NMR (400 MHz, CDCl3) δ: of 1.41 (3H, t, J=7,0 Hz), and 4.40 (2H, q, J=7.0 Hz), 7,03 (1H, s)of 7.48 (2H, d-like, J=8.6 Hz), 7,94 (2H, d-like, J=8.6 Hz).

MC (ESI) m/z: 255 (M+H)+.

2) Specified in the header of the connection

A derivative of hydrazine (0,250 g)obtained from referential example 2, are added to a solution obtained above ethyl ester of 4-(4-chlorophenyl)-2,4-dioxaborinane acid (0.930 g)dissolved in ethanol (20 ml)at room temperature. The mixture is refluxed under heating for 12 hours and then cooled in air. The solvent is evaporated under reduced pressure and the residue distributed between water and chloroform. Then the aqueous layer was extracted with chloroform. The organic layer was washed with saturated salt solution and dried with anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure and the residue purified column chromatography on silica gel (hexane-ethyl acetate: 17-50%), while receiving specified in the title compound in the form of oily what about the substance (0,543 g, 85%).

1H-NMR (400 MHz, CDCl3) δ: of 1.42 (3H, t, J=7,1 Hz), of 3.94 (3H, s), of 4.45 (2H, q, J=7,1 Hz), to 6.75 (1H, d, J=8,8 Hz), 7,03 (1H, s), to 7.15 (2H, d-like, J=8,3 Hz), 7,32 (2H, d-like, J=8,3 Hz), EUR 7.57 (1H, DD, J=8,8, 2,9 Hz), 8,08 (1H, d, J=2,9 Hz).

MC (FAB) m/z: 358 (M+H)+.

[Reference example 4] 5-(4-Chlorophenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

The monohydrate of lithium hydroxide (68,4 mg) is added to ethyl ether pyrazole-3-carboxylic acid (0,543 g), described in step 2) of referential example 3, in a mixture of tetrahydrofuran (6 ml) - water (2 ml) - methanol (1.5 ml) followed by stirring at room temperature for 2 hours. The solvent is evaporated under reduced pressure and the residue partitioned between water and diethyl ether. The aqueous layer was acidified to pH 3 1 M aqueous hydrochloric acid, followed by stirring at 0°C. the Resulting solid is collected by filtration. The solid is washed sequentially with water, isopropyl alcohol and diethyl ether. Then the solid is dried, thus obtaining specified in the title compound in the form of solids (0,240 g, 48%).

1H-NMR (400 MHz, CDCl3) δ: of 3.95 (3H, s), 6,77 (1H, d, J=8,8 Hz), to 7.09 (1H, s), 7,17 (2H, d-like, J=8.6 Hz), 7,34 (2H, d-like, J=8.6 Hz), 7,56 (1H, DD, J=8,8, 2,9 Hz), of 8.09 (1H, d, J=2,9 Hz).

MC (ESI) m/z: 330 (M+H)+.

[Reference example 5] Ethyl e is Il-5-(4-ethylphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

1) Ethyl ester of 4-(4-ethylphenyl)-2,4-dioxaborinane acid

In a manner analogous to the method described in stage 1) of reference example 3, ethyl ester of 4-(4-ethylphenyl)-2,4-dioxaborinane acid (2,577 g, 97%) are obtained with the use of 4'-ethylacetophenone (1,599 g) and diethyloxalate (2,9 ml).

1H-NMR (400 MHz, CDCl3) δ: of 1.27 (3H, t, J=7.5 Hz), of 1.41 (3H, t-like, J=7,4 Hz), 2,73 (2H, q, J=7.4 Hz), 4,30-4,50 (2H, m), 7,05 (1H, s), 7,32 (2H, d-like, J=7,1 Hz), 7,92 (2H, d-like, J=7,1 Hz).

MC (ESI) m/z: 249 (M+H)+.

2) Specified in the header of the connection

In a manner analogous to the method described in step 2) of referential example 3, specified in the title compound obtained as an oily substance (0,589 g, 83%) using the result of the above ethyl ester 4-(4-ethylphenyl)-2,4-dioxaborinane acid (1,012 g) and 5-hydrazino-2-methoxypyridine (0,280 g)obtained in reference example 2.

1H-NMR (400 MHz, CDCl3) δ: 1,22 (3H, t, J=7,6 Hz)of 1.41 (3H, t, J=7.0 Hz), 2.63 in (2H, q, J=7,6 Hz)to 3.92 (3H, s), of 4.44 (2H, q, J=7.0 Hz), was 6.73 (1H, d, J=8,8 Hz), 7,01 (1H, s), 7,08-7,20 (4H, m), EUR 7.57 (1H, DD, J=8,8, 2,7 Hz)to 8.12 (1H, d, J=2.7 Hz).

MS (FAB) m/z: 352 (M+H)+.

[Reference example 6] 5-(4-Ethylphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 4, is specified in the header connection receive in the de solids (0,457 g, 84%) using ethyl ether pyrazole-3-carboxylic acid (0,589 g)obtained in step 2) of referential example 5.

1H-NMR (400 MHz, CDCl3) δ: of 1.23 (3H, t, J=7,6 Hz)of 2.64 (2H, q, J=7,6 Hz), of 3.94 (3H, s), of 6.75 (1H, d, J=8,8 Hz), 7,07 (1H, s), 7,10-7,20 (5H, m), 7,60 (1H, DD, J=8,8, 2.7 Hz), 8,15 (1H, d, J=2.7 Hz), and 10.20 (1H, usher.).

MS (FAB) m/z: 324 (M+H)+.

[Referential example 7] Ethyl ester 1-(6-methoxy-3-pyridyl)-5-(3-were)pyrazole-3-carboxylic acid

1) Ethyl ester of 4-(3-were)-2,4-dioxaborinane acid

In a manner analogous to the method described in stage 1) of reference example 3, ethyl ester 4-(3-were)-2,4-dioxaborinane acid (2,71 g, quantitative yield) are obtained using 3'-methylacetophenone (1,557 g) and diethyloxalate (3.1 ml).

1H-NMR (400 MHz, CDCl3) δ: of 1.41 (3H, t, J=7,1 Hz), 2,43 (3H, s), and 4.40 (2H, q, J=7,1 Hz), 7,06 (1H, s), 7,35-7,45 (2H, m), 7,75-of 7.82 (2H, m).

MS (ESI) m/z: 235 (M+H)+.

2) Specified in the header of the connection

Hydrochloride 5-hydrazino-2-methoxypyridine (0,380 g)obtained in reference example 1, and triethylamine (0,30 ml) was added to a solution of the above ethyl ester 4-(3-were)-2,4-dioxaborinane acid (1,014 registered g)dissolved in ethanol (20 ml)at room temperature. The resulting mixture is refluxed under heating for 14 hours and then cooled in air. The solution is tel evaporated under reduced pressure and the residue partitioned between chloroform and water. The aqueous layer was extracted with chloroform. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure and the residue is subjected to column chromatography on silica gel (hexane-ethyl acetate: 20%), while receiving specified in the title compound as an oily substance (0,451 g, 62%).

1H-NMR (400 MHz, CDCl3) δ: of 1.42 (3H, t, J=7,1 Hz), is 2.30 (3H, s)to 3.92 (3H, s), of 4.45 (2H, q, J=7,1 Hz), 6,68-6,76 (1H, m), 6,92-of 7.25 (4H, m), 7,02 (1H, s), 7,53-to 7.61 (1H, m), 8,08-of 8.15 (1H, m).

MS (FAB) m/z: 338 (M+H)+.

[Referential example 8] 1-(6-Methoxy-3-pyridyl)-5-(3-were)pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 4, is listed in the title compound obtained as a solid (0,353 g, 86%) using ethyl ether pyrazole-3-carboxylic acid (0,451 g)obtained in step 2) of referential example 7.

1H-NMR (400 MHz, CDCl3) δ: 2,31 (3H, s), of 3.94 (3H, s), 6,74 (1H, d, J=8,8 Hz), of 6.96 (1H, d-like, J=7,3 Hz), 7,05-of 7.25 (4H, m), 7,60 (1H, DD, J=8,8, 2.7 Hz), 8,14 (1H, d, J=2.7 Hz), 9,65 (1H, usher.).

[Referential example 9] Ethyl ester 1-(6-methoxy-3-pyridyl)-5-(2-were)pyrazole-3-carboxylic acid

1) Ethyl ester of 4-(2-were)-2,4-dioxaborinane acid

By the way, analogion the m method, described in stage 1) of reference example 3, ethyl ester 4-(2-were)-2,4-dioxaborinane acid obtained as an oily substance (2,54 g, 95%) with the use of 2'-methylacetophenone (1,543 g) and diethyloxalate (3.1 ml).

1H-NMR (400 MHz, CDCl3) δ: of 1.39 (3H, t-like, J=7,1 Hz)to 2.55 (3H, s), to 4.38 (2H, q-like, J=7,1 Hz), 6,83 (1H, s), 7,20-7,30 (2H, m), 7,41 (1H, t-like, J=7,6 Hz), a 7.62 (1H, d-like, J=7,6 Hz).

LC-MS m/z: 235 (M+H)+.

2) Specified in the header of the connection

In a manner analogous to the method described in step 2) of referential example 7, is listed in the title compound obtained as an oily substance (0,542 g, 69%) using the above ethyl ester 4-(2-were)-2,4-dioxaborinane acid (1,074 g) hydrochloride and 5-hydrazino-2-methoxypyridine (0,407 g)obtained in reference example 1.

1H-NMR (400 MHz, CDCl3) δ: of 1.42 (3H, t, J=7,1 Hz), 2,04 (3H, s), 3,86 (3H, s), of 4.45 (2H, q, J=7,1 Hz), of 6.65 (1H, d, J=8,8 Hz)6,94 (1H, s), 7,10-to 7.35 (4H, m), 7,56 (1H, DD, J=8,8, 2.2 Hz), 8,01 (1H, d, J=2.2 Hz).

MS (FAB) m/z: 338 (M+H)+.

[Referential example 10] (6-Methoxy-3-pyridyl)-5-(2-were)pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 4, is listed in the title compound obtained as a solid (0,479 g, 96%) using ethyl ether pyrazole-3-carboxylic acid (0,542 g), obtained what about in stage 2) of reference example 9.

1H-NMR (400 MHz, CDCl3) δ: of 2.06 (3H, s), 3,91 (3H, s), of 6.68 (1H, d, J=9.0 Hz), 7,00 (1H, s), 7,15-7,38 (4H, m), 7,50-of 7.60 (1H, m), 8,03 (1H, d, J=2.5 Hz).

MS (ESI) m/z: 310 (M+H)+.

[Reference example 11] Ethyl ester 5-(3-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

1) Ethyl ester of 4-(3-forfinal)-2,4-dioxaborinane acid

In a manner analogous to the method described in stage 1) of reference example 3, ethyl ester 4-(3-forfinal)-2,4-dioxaborinane acid obtained as a solid substance (of 2.26 g, 86%) using 3'-fortetienne (1,530 g) and diethyloxalate (3.0 ml).

1H-NMR (400 MHz, CDCl3) δ: of 1.39 (3H, t, J=7,1 Hz), to 4.38 (2H, q, J=7,1 Hz), 7,01 (1H, s), 7,20-to 7.32 (1H, m), 7,40-7,50 (1H, m), 7,60-to 7.68 (1H, m), 7,70-to 7.77 (1H, m).

MS (ESI) m/z: 239 (M+H)+.

2) Specified in the header of the connection

In a manner analogous to the method described in step 2) of referential example 7, is listed in the title compound obtained as an oily substance (0,362 g, 52%) using the above ethyl ester 4-(3-forfinal)-2,4-dioxaborinane acid (0,978 g) hydrochloride and 5-hydrazino-2-methoxypyridine (0,385 g)obtained in reference example 1.

1H-NMR (400 MHz, CDCl3) δ: of 1.42 (3H, t, J=7,1 Hz), of 3.94 (3H, s), of 4.45 (2H, q, J=7,1 Hz), 6,76 (1H, d, J=8,8 Hz), 6,92-7,10 (3H, m), 7,06 (1H, s), 7,58 (1H, DD, J=8,8, 2,9 Hz), of 8.09 (1H, d, J=2,9 Hz).

MS (FAB) m/z: 342 (M+H)+.

[Reference primer] 5-(3-Forfinal)-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 4, is specified in the header connection (0,302 g, 91%) was obtained as a solid substance with the use of ethyl ether pyrazole-3-carboxylic acid (0,362 g)obtained in step 2) of referential example 11.

1H-NMR (400 MHz, CDCl3) δ: of 3.95 (3H, s), is 6.78 (1H, d, J=8,8 Hz), 6,93 for 7.12 (3H, m), 7,12 (1H, s), 7,28-7,38 (1H, m), 7,60 (1H, DD, J=8,8, 2.7 Hz), to 8.12 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 314 (M+H)+.

[Reference example 13] Ethyl ester 5-(4-benzyloxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

1) Ethyl ester of 4-(4-benzyloxyphenyl)-2,4-dioxaborinane acid

In a manner analogous to the method described in stage 1) of reference example 3, ethyl ester of 4-(4-benzyloxyphenyl)-2,4-dioxaborinane acid (3,18 g, quantitative yield) obtained as an oily substance using 4'-benzyloxyacetophenone (2,07 g) and diethyloxalate (2.5 ml).

MS (ESI) m/z: 327 (M+N)+.

2) Specified in the header of the connection

In a manner analogous to the method described in step 2) of referential example 3, specified in the header connection (1,026 g, 35%) was obtained as a solid substance using the above ethyl ester 4-(4-benzyloxyphenyl)-2,4-dioxaborinane acid (3,21 g) and 5-hydrazino-2-methoxypyridine (0,952 g)obtained in the SS is Lochem example 2.

1H-NMR (400 MHz, CDCl3) δ: of 1.42 (3H, t, J=7,3 Hz), of 3.94 (3H, s), of 4.44 (2H, q, J=7,3 Hz), of 5.05 (2H, s), of 6.73 (1H, d, J=8,8 Hz), 6,92 (2H, d-like, J=8.6 Hz), 6,97 (1H, s), 7,13 (2H, d-like, J=8.6 Hz), 7,30-7,46 (5H, m), 7,56 (1H, DD, J=8,8, 2.7 Hz), 8,10 (1H, d, J=2.7 Hz).

MS (FAB) m/z: 430 (M+H)+.

[Referential example 14] 5-(4-Benzyloxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 4, is specified in the header connection (0,973 g, quantitative yield) obtained as an oily substance, using ethyl ester 5-(4-benzyloxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid (0,991 g)obtained in reference example 13.

1H-NMR (400 MHz, CDCl3) δ: of 3.94 (3H, s), of 5.05 (2H, s), 6,74 (1H, d, J=8,8 Hz), 6,93 (2H, d-like, J=8,8 Hz), 7,02 (1H, s), 7,12 (2H, d-like, J=8,8 Hz), 7,30 was 7.45 (5H, m), 7,56 (1H, DD, J=8,8, 2.7 Hz), to 8.12 (1H, d, J=2.7 Hz).

MS (FAB) m/z: 402 (M+H)+.

[Referential example 15] 4-Methoxypyridine-2-carbonitrile

In the atmosphere of argon triethylamine (17,8 ml) are added to the N-oxide of 4-methoxypyridine (8.0 g) in acetonitrile (160 ml) at room temperature. To the mixture are added dropwise trimethylsilylacetamide (24,1 ml) followed by stirring the mixture for 20 minutes. After that, the mixture was stirred at 95°C for 14 hours and then cooled in air. The solvent is evaporated under reduced davlantes partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer is dried over anhydrous sodium hydrosulphate, followed by filtration. The solvent is evaporated under reduced pressure and the residue purified column chromatography on silica gel (hexane-ethyl acetate), obtaining mentioned in the title compound as a solid (1,57 g, 18%).

1H-NMR (400 MHz, CDCl3) δ: 3,91 (3H, s), 7,00-7,02 (1H, m), 7,22 (1H, d, J=2.4 Hz), 8,51 (1H, d, J=6.0 Hz).

MS (EI) m/z 134 (M+).

[Referential example 16] 1-(4-Methoxy-2-pyridyl)alanon

In the atmosphere of argon 0.93 M methylmagnesium in tetrahydrofuran (13,8 ml) is added dropwise to 4-methoxypyridine-2-carbonitrile (1.56 g) in tetrahydrofuran (31 ml) at -78°C, followed by stirring for 15 minutes. Then the reaction mixture was stirred at 0°C for 15 minutes and then at room temperature for 5 hours. To the reaction mixture dropwise add water. The resulting mixture is distributed between water and ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure and the residue purified column chromatography on silica gel (hexane-ethyl acetate), obtaining mentioned in the title compound as a solid (1,30 g, 73%).

1H-NMR (400 MHz, CDCl3) δ: of 2.72 (3H, s), 3,91 3H, C), 6,97-6,99 (1H, m), EUR 7.57-7,58 (1H, m), 8,48-and 8.50 (1H, m).

MS (ESI) m/z: 152 (M+H)+.

[Reference example 17] Ethyl ester of 4-(4-methoxy-2-pyridyl)-2,4-dioxaborinane acid

In a manner analogous to the method described in stage 1) of reference example 3, specified in the title compound obtained as a solid (0,713 g, 33%) using 1-(4-methoxy-2-pyridyl)ethanone (1.28 g) and diethyloxalate (2.30 ml).

1H-NMR (400 MHz, CDCl3) δ: 1,39 was 1.43 (3H, m), of 3.96 (3H, s), 4,37 was 4.42 (2H, m), 7.03 is-7,05 (1H, m), 7,72 (1H, d, J=2,8 Hz), 8,02 (1H, s), and 8.50 (1H, d, J=5.6 Hz).

MS (EI) m/z: 251 (M+).

[Referential example 18] Ethyl ester 1-(6-methoxy-3-pyridyl)-5-(4-methoxy-2-pyridyl)pyrazole-3-carboxylic acid

In a manner analogous to the method described in step 2) of referential example 3, specified in the title compound obtained as a solid (0,473 g, 49%) with the use of ethyl ester of 4-(4-methoxy-2-pyridyl)-2,4-dioxaborinane acid (0,691 g)obtained in reference example 17, and 5-hydrazino-2-methoxypyridine (0,383 g)obtained in reference example 2.

1H-NMR (400 MHz, CDCl3) δ: 1,41-of 1.44 (3H, m), 3,82 (3H, s), of 3.95 (3H, s), 4,43-4,48 (2H, m), 6.75 in-is 6.78 (2H, m), 6.89 in (1H, d, J=2.4 Hz), 7,25 (1H, s), to 7.68 (1H, DD, J=8,8, 2.4 Hz), 8,11 (1H, d, J=2.4 Hz), with 8.33 (1H, d, J=5,6 Hz).

MS (FAB) m/z: 355 (M+H)+.

[Reference example 19] 1-(6-methoxy-3-pyridyl)-5-(4-methoxy-2-pyridyl)Piras the l-3-carboxylic acid

1 N. Aqueous sodium hydroxide solution (2,23 ml) is added to ethyl ether 1-(6-methoxy-3-pyridyl)-5-(4-methoxy-2-pyridyl)pyrazole-3-carboxylic acid (0,416 g)obtained in reference example 18, a mixture of methanol (6.3 ml) and tetrahydrofuran (6.3 ml) at room temperature, followed by stirring for 5 hours. The reaction mixture is neutralized 1 N. aqueous solution of hydrochloric acid (2,23 ml) and then partitioned between water and chloroform. Then the aqueous layer was extracted with chloroform twice. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, thus obtaining specified in the title compound in the form of solids (0,353 g, 92%).

1H-NMR (400 MHz, DMSO-d6) δ: 3,86 (3H, s)to 3.89 (3H, s), to 6.88 (1H, d, J=8,8 Hz), 6,93 (1H, DD, J=5,6, 2.7 Hz), 7,29 (1H, d, J=5.6 Hz), 7,37 (1H, s), 7,69-7,72 (1H, m)to 8.14 (1H, d, J=2,8 Hz), 8,24 (1H, d, J=5.6 Hz), of 13.05 (1H, usher.).

MS (FAB) m/z: 327 (M+H)+.

[Referential example 20] 2-Bromo-6-methoxypyridine

In the atmosphere of argon sodium methoxide (1,82 g) are added to 2,6-dibromopyridine (8.0 g) in toluene (120 ml) followed by stirring at 120°C for 13 hours. Then to the mixture is added sodium methoxide (0,728 g), followed by stirring at 120°C for 6 hours. The mixture is cooled in air. The reaction mixture R is opredelyaut between water and ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (hexane-ethyl acetate), obtaining mentioned in the title compound as an oily substance (5,64 g, 89%).

1H-NMR (400 MHz, CDCl3) δ: 3,93 (3H, s), 6, 68 (1H, d, J=8.0 Hz), 7,05 (1H, d, J=7,2 Hz), 7,39-7,42 (1H, m).

[Referential example 21] 6-Methoxypyridine-2-carbonitrile

The copper cyanide (I) (2,68 g) are added to 2-bromo-6-methoxypyridine (5,62 g) in N,N-dimethylformamide (112 ml) at room temperature, followed by stirring at 165°C for 15 hours. The resulting mixture is cooled in air. To the mixture are added water and ethyl acetate. Insoluble substance is formed in the mixture, is filtered by alicom. The filtrate is partitioned between water and ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure. The residue is subjected to column chromatography on silica gel (hexane-ethyl acetate), obtaining mentioned in the title compound as a solid (1.78 g, 44%).

1H-NMR (400 MHz, CDCl3) δ: of 3.96 (3H, s), 6,95-6,98 (1H, m), 7,29-7,31 (1H, m), of 7.64-to 7.67 (1H, m).

MS (EI) m/z 134 (M+).

[Referential example 22] 1-(6-Methoxy-2-pyridyl)alanon

In a manner analogous to the method described in reference example 16, is listed in the title compound obtained as a solid (0,819 g, 42%) using 6-methoxypyridine-2-carbonitrile (1,75 g).

1H-NMR (400 MHz, CDCl3) δ: of 2.68 (3H, s), of 4.00 (3H, s), 6,92-6,94 (1H, m), 7,62-7,72 (2H, m).

MS (ESI) m/z: 152 (M+H)+.

[Reference example 23] Ethyl ester 4-(6-methoxy-2-pyridyl)-2,4-dioxaborinane acid

In a manner analogous to the method described in stage 1) of reference example 3, specified in the title compound obtained as an oily substance (1,16 g, 87%) using 1-(6-methoxy-2-pyridyl)ethanone (0,80 g) and diethyloxalate (1,44 ml).

1H-NMR (400 MHz, CDCl3) δ: 1,40 was 1.43 (3H, m), a 4.03 (3H, s), to 4.38-4,43 (2H, m), 6,95-6,98 (1H, m), 7,63 (1H, m), 7,74-7,76 (1H, m), 8,02 (1H, s).

MS (EI) m/z: 251 (M+).

[Reference example 24] Ethyl ester 1-(6-methoxy-3-pyridyl)-5-(6-methoxy-2-pyridyl)pyrazole-3-carboxylic acid

In a manner analogous to the method described in step 2) of referential example 3, specified in the title compound obtained as an oily substance (0,740 g, 46%) with the use of ethyl ester of 4-(6-methoxy-2-pyridyl)-2,4-dioxaborinane acid (1,15 g)obtained in reference example 23, and 5-hydrazino-2-methoxypyridine (0,637 g)obtained in reference example 2.

1H-NMR(400 MHz, CDCl3) δ: 1,41-of 1.45 (3H, m), 3.43 points (3H, s), of 3.95 (3H, s), of 4.44 figure-4.49 (2H, m), 6,64 is 6.67 (1H, m), 6,77-6,79 (1H, m), 7,08-7,10 (1H, m), 7,27 (1H, s), 7,56-of 7.60 (1H, m), of 7.64-7,66 (1H, m), 8,16-8,17 (1H, m).

MS (EI) m/z: 354 (M+).

[Reference example 25] 1-(6-Methoxy-3-pyridyl)-5-(6-methoxy-2-pyridyl)pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 19, is listed in the title compound obtained as a solid (0,584 g 91%) using ethyl ether derivative of pyrazole-3-carboxylic acid (0,694 g)obtained in reference broadcast 24.

1H-NMR (400 MHz, CDCl3) δ: 3,44 (3H, s), of 3.96 (3H, s), 6,66-6,69 (1H, m), to 6.80 (1H, d, J=8,8 Hz), 7,10 for 7.12 (1H, m), 7,33 (1H, s), EUR 7.57-to 7.61 (1H, m), 7,66-to 7.68 (1H, m), 8,19 (1H, m).

MS (FAB) m/z: 327 (M+1)+.

[Referential example 26] 6-Methylpyridin-2-carbonitril

In a manner analogous to the method described in reference example 21, is listed in the title compound obtained as a solid (2,81 g, 41%) using 2-bromo-6-picoline (9,87 g) and copper cyanide (I) (5,14 g).

1H-NMR (400 MHz, CDCl3) δ: 2,62 (3H, s), 7,39 (1H, d, J=8.0 Hz), 7,52 (1H, d, J=7,6 Hz), 7,70-7,74 (1H, m).

MS (EI) m/z: 118 (M+).

[Referential example 27] 1-(6-Methyl-2-pyridyl)alanon

In a manner analogous to the method described in reference example 16, is listed in the title compound obtained as an oily material (1.04 g, 33%) primenenie 6-methylpyridin-2-carbonitrile (2,80 g) and 0.93 M of methylacrylamide in tetrahydrofuran (28,0 ml).

1H-NMR (400 MHz, CDCl3) δ: 2,62 (3H, s), a 2.71 (3H, s), 7,30-to 7.32 (1H, m), 7.68 per-7,71 (1H, m), 7,82-a 7.85 (1H, m).

MS (FAB) m/z 136 (M+H)+.

[Reference example 28] Ethyl ester 4-(6-methyl-2-pyridyl)-2,4-dioxaborinane acid

In a manner analogous to the method described in stage 1) of reference example 3, specified in the title compound obtained as an oily substance (0,443 g, 25%) using 1-(6-methyl-2-pyridyl)ethanone (1,03 g) and diethyloxalate (2,07 ml).

1H-NMR (400 MHz, CDCl3) δ: of 1.42 (3H, t, J=7.2 Hz), to 2.67 (3H, s)to 4.41 (2H, q, J=7.2 Hz), 7,39 (1H, d, J=7,6 Hz), 7,49 (1H, usher.), 7,79-7,83 (1H, m), of 8.00 (1H, d, J=7,6 Hz).

MS (EI) m/z: 235 (M+).

[Referential example 29] Ethyl ester 1-(6-methoxy-3-pyridyl)-5-(6-methyl-2-pyridyl)pyrazole-3-carboxylic acid

In a manner analogous to the method described in step 2) of referential example 3, specified in the title compound obtained as an oily substance (0,491 g, 79%) using ethyl ester 4-(6-methyl-2-pyridyl)-2,4-dioxaborinane acid (0,431 g)obtained in reference example 28, and 5-hydrazino-2-methoxypyridine (0,255 g)obtained in reference example 2.

1H-NMR (400 MHz, CDCl3) δ: 1,41-of 1.44 (3H, m), is 2.41 (3H, s), of 3.95 (3H, s), 4,43-4,48 (2H, m), 6.75 in-6,77 (1H, m), 7,07-7,14 (2H, m), 7,27 (1H, s), 7,53-EUR 7.57 (1H, m), 7,66-of 7.69 (1H, m), 8,10-8,11 (1H, m).

MS (FAB) m/z: 339 (M+).

[Reference example 30] 1-(-Methoxy-3-pyridyl)-5-(6-methyl-2-pyridyl)pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 19, is listed in the title compound obtained as a solid (0,342 g, 84%) using ethyl ether pyrazole-3-carboxylic acid (0,444 g)obtained in reference example 29.

1H-NMR (400 MHz, DMSO-d6) δ: of 2.25 (3H, s), 3,90 (3H, s), make 6.90 (1H, d, J=8,8 Hz), 7,20 (1H, d, J=7,6 Hz), 7,32 (1H, s), 7,46 (1H, d, J=7,6 Hz), 7,71 to 7.75 (2H, m)to 8.14 (1H, d, J=2.4 Hz), of 13.05 (1H, usher.).

MS (FAB) m/z: 311 (M+H)+.

[Reference example 31] Ethyl ester 4-(2-pyridyl)-2,4-dioxaborinane acid

In a manner analogous to the method described in stage 1) of reference example 3, specified in the title compound obtained as a solid (1.12 g, 41%) using 2-acetylpyridine (1.39 ml) and diethyloxalate (3,36 ml).

1H-NMR (400 MHz, SDS3)δ: 1,40 was 1.43 (3H, m), of 4.38-4,43 (2H, m), 7,51-rate of 7.54 (1H, m), a 7.62 (1H, s), 7,89-to 7.93 (1H, m), 8,18 (1H, d, J=8.0 Hz), 8,73 (1H, d, J=4.4 Hz).

MS (EI) m/z: 221 (M+).

[Referential example 32] Ethyl ester 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid

1) Ethyl ester 5-hydroxy-1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)-4,5-dihydropyrazol-3-carboxylic acid

Ethyl ester of 4-(2-pyridyl)-2,4-dioxaborinane acid (1.10 g)obtained in reference example 31, and 5-hydrazino-2-methoxypyridine (0,692 g), the scientists in the reference example 2, dissolved in ethanol (22 ml). The resulting mixture is refluxed under heating for 14 hours with subsequent cooling in air. The solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (hexane-ethyl acetate), followed by purification column chromatography on silica gel (toluene-acetone), thus obtaining the ethyl ester of 5-hydroxy-1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)-4,5-dihydropyrazol-3-carboxylic acid as a solid (0,575 g, 34%).

1H-NMR (400 MHz, CDCl3) δ: 1,37-of 1.40 (3H, m), 3,47-of 3.64 (2H, m), 3,81 (3H, s), 4,35-and 4.40 (2H, m), 6,57-6,59 (1H, m), 6,85 (1H, m), 7,34-7,38 (1H, m), 7,45-of 7.48 (1H, m), 7,52-to 7.59 (2H, m), 7,79-7,83 (1H, m), 8,55-to 8.57 (1H, m).

2) Specified in the header of the connection

The result of the above ethyl ester 5-hydroxy-1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)-4,5-dihydropyrazol-3-carboxylic acid (0,546 g) dissolved in ethanol (11 ml). To the resulting mixture are added acetic acid (0,456 ml) followed by stirring at 105°C for 4 hours. The mixture is cooled in air. Then the reaction mixture is distributed using saturated aqueous sodium hydrogen carbonate solution, water and ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure. The residue is purified by column chrom is adopted on silica gel (hexane-ethyl acetate), while receiving specified in the title compound in the form of solids (0,516 g, 100%).

1H-NMR (400 MHz, CDCl3) δ: of 1.43 (3H, t, J=7.2 Hz), of 3.95 (3H, s), to 4.46 (2H, q, J=7.2 Hz), 6,76-of 6.78 (1H, m), 7,22-7,28 (2H, m), 7,35-7,37 (1H, m), 7,66-7,71 (2H, m), 8,11 (1H, m), charged 8.52-8,54 (1H, m).

MS (FAB) m/z: 325 (M+H)+.

[Referential example 33] 1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 19, is listed in the title compound obtained as a solid (0,344 g, 86%) using ethyl ether pyrazole-3-carboxylic acid (0,438 g)obtained in step 2) of referential example 32.

1H-NMR (400 MHz, DMSO-d6) δ: to 3.89 (3H, s), 6.89 in (1H, d, J=8,8 Hz), 7,33-7,37 (2H, m), to 7.67-7,73 (2H, m), a 7.85-7,89 (1H, m)to 8.14 (1H, d, J=2.4 Hz), 8,44-8,46 (1H, m), 13,06 (1H, usher.).

MS (FAB) m/z: 297 (M+H)+.

[Referential example 34] Ethyl ester of 4-(4-were)-2,4-dioxaborinane acid

In a manner analogous to the method described in stage 1) of reference example 3, specified in the title compound obtained as an oily substance (1.68 g, 64%) with the use of 4'-methylacetophenone (1.50 g) and diethyloxalate (3.04 from ml).

1H-NMR (400 MHz, CDCl3) δ: 1,40 was 1.43 (3H, m), is 2.44 (3H, s), 4,37-4,43 (2H, m), 7,06 (1H, s), 7,30-to 7.32 (2H, m), 7,89-to $ 7.91 (2H, m).

MS (EI) m/z: 234 (M+).

[Referential example 35] Ethyl ester 1-(6-what ethoxy-3-pyridyl)-5-(4-were)pyrazole-3-carboxylic acid

In a manner analogous to the method described in step 2) of referential example 3, specified in the title compound obtained as an oily substance (1.52 g, 63%) with the use of ethyl ester of 4-(4-were)-2,4-dioxaborinane acid (1,67 g)obtained in reference example 34, and 5-hydrazino-2-methoxypyridine (0,992 g)obtained in reference example 2.

1H-NMR (400 MHz, CDCl3) δ: 1,41-of 1.44 (3H, m)to 2.35 (3H, s), of 3.94 (3H, s), 4,43-4,48 (2H, m), 6,72 to 6.75 (1H, m), 7,01 (1H, s), 7,09-to 7.15 (4H, m), 7,56-to 7.59 (1H, m), 8,11 (1H, m).

MS (EI) m/z: 337 (M+).

[Referential example 36] 1-(6-Methoxy-3-pyridyl)-5-(4-were)pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 19, is listed in the title compound obtained as an amorphous product (1.24 g, 90%) using ethyl ether pyrazole-3-carboxylic acid (1.50 g)obtained in reference example 35.

1H-NMR (400 MHz, CDCl3) δ: a 2.36 (3H, s), of 3.95 (3H, s), of 6.75 (1H, d, J=8,8 Hz), 7,07 (1H, s), 7,11-7,16 (4H, m), to 7.59 (1H, DD, J=8,8, 2,8 Hz), 8,13 (1H, d, J=2,8 Hz).

MS (EI) m/z: 309 (M+).

[Referential example 37] Ethyl ester 4-(2-forfinal)-2,4-dioxaborinane acid

In a manner analogous to the method described in stage 1) of reference example 3, specified in the title compound obtained as a solid prophetic the STV (0,256 g, 37%) with the use of 2'-fortetienne (0.40 g) and diethyloxalate.

1H-NMR (400 MHz, CDCl3) δ: 1,39 was 1.43 (3H, m), 4,37-4,43 (2H, m), of 6.96-to 7.32 (3H, m), 7,54-to 7.59 (1H, m), of 7.90-to 7.99 (1H, m).

MS (FAB) m/z: 239 (M+H)+.

[Reference example 38] Ethyl ester 5-(2-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

In a manner analogous to the method described in step 2) of referential example 7, is listed in the title compound obtained as an oily substance (0,231 g, 65%) using ethyl ester 4-(2-forfinal)-2,4-dioxaborinane acid (0,248 g)obtained in reference example 37, hydrochloride and 5-hydrazino-2-methoxypyridine (0,219 g)obtained in reference example 1.

1H-NMR (400 MHz, CDCl3) δ: 1,41-of 1.45 (3H, m), 3,91 (3H, 3), 4,43-4,48 (2H, m), of 6.71-6.73 x (1H, m), 7.03 is-7,41 (5H, m), 7,60-7,63 (1H, m), 8,04-of 8.06 (1H, m).

MS (EI) m/z: 341 (M+).

[Referential example 39] 5-(2-Forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 19, is listed in the title compound obtained as an amorphous product (0,199 g, 98%) using ethyl ether pyrazole-3-carboxylic acid (0,222 g)obtained in reference example 38.

1H-NMR (400 MHz, CDCl3) δ: 3,93 (3H, s), of 6.75 (1H, d, J=8,8 Hz), 7.03 is-the 7.43 (5H, m), 7,63 (1H, DD, J=8,8, 2,8 Hz), 8,07 (1H, d, J=2,8 Hz).

MS (EI) m/z: 33 (M +).

[Referential example 40] Ethyl ester 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid

In a manner analogous to the method described in stage 1) of reference example 3, ethyl ester of 4-phenyl-2,4-dioxaborinane acid obtained as an oily substance (22,96 g, quantitative yield) using acetophenone (9,85 g) and diethyloxalate (23,97 g). Then, in a manner analogous to the method described in step 2) of referential example 3, specified in the title compound obtained as an oily substance (16,37 g, 61%) using the result of the above ethyl ester of 4-phenyl-2,4-dioxaborinane acid and 5-hydrazino-2-methoxypyridine (is 11.39 g)obtained in reference example 2.

1H-NMR (400 MHz, CDCl3) δ: of 1.42 (3H, t, J=7.0 Hz), 3,93 (3H, s), of 4.45 (2H, q, J=7.0 Hz), was 6.73 (1H, d, J=8,8 Hz),? 7.04 baby mortality (1H, s), 7,19-7,26 (2H, m), 7,30-7,37 (3H, m), EUR 7.57 (1H, DD, J=8,8, and 2.6 Hz), 8,11 (1H, d, J=2,6 Hz).

MS (ESI) m/z: 324 (M+H)+.

[Referential example 41] 1-(6-Methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid

In a manner analogous to the method described in reference example 19, is listed in the title compound obtained as crystals (13,88 g, 92%) using ethyl ether pyrazole-3-carboxylic acid (16,37 g)obtained in reference example 40.

1H-NMR (400 MHz, CDCl3) δ: of 3.94 (3H, s), of 6.75 (1H, d, J=8 Hz), 7,10 (1H, s), 7,21-7,27 (2H, m), 7,32-7,39 (3H, m), 7,58 (1H, DD, J=8,8, 2,6 Hz)to 8.12 (1H, d, J=2,6 Hz).

MS (ESI) m/z: 296 (M+H)+.

[Referential example 42] Ethyl ester 1-(6-chloro-3-pyridazinyl)-5-phenylpyrazol-3-carboxylic acid

In a manner analogous to the method described in step 2) of referential example 3, specified in the title compound obtained as an amorphous product (1,93 g, 65%) using 3-chloro-6-hydrazinopyridazine (1.31 g) and ethyl ester of 4-phenyl-2,4-dioxaborinane acid (2.20 g)obtained in a manner analogous to the method described in reference example 40.

1H-NMR (400 MHz, CDCl3) δ: of 1.43 (3H, t, J=7.0 Hz), to 4.46 (2H, q, J=7.0 Hz),? 7.04 baby mortality (1H, s), 7,29-7,39 (5H, m), of 7.64 (1H, d, J=9,l Hz), of 8.06 (1H, d, J=9.1 Hz).

LC-MS m/z: 329 (M+H)+.

[Referential example 43] 1-(6-Methoxy-3-pyridazinyl)-5-phenylpyrazol-3-carboxylic acid

Ethyl ester pyrazole-3-carboxylic acid (329 mg)obtained in reference example 42, dissolved in methanol (10 ml). To the resulting mixture is added 28% sodium methoxide in methanol (0.6 ml), followed by boiling under reflux under heating for 2 hours. The mixture is cooled in air. To the reaction mixture are added tetrahydrofuran (5 ml) and water (5 ml) followed by stirring at room temperature for 30 minutes. Then to the reaction mixture add 1 N. water is hydrochloric acid solution (4 ml). The resulting mixture is distributed between water and ethyl acetate. The organic layer is successively washed with water and saturated salt solution. Then the organic layer is dried over anhydrous magnesium sulfate, followed by filtration. The solvent is evaporated under reduced pressure. To the residue is added ether. The resulting solid is collected by filtration and then dried, thus obtaining specified in the title compound as a solid (218 mg, 74%).

1H-NMR (400 MHz, DMSO-d6) δ: a 4.03 (3H, s), 7,12 (1H, s), 7,28-7,31 (2H, m), 7,37-7,40 (3H, m), 7,51 (1H, d, J=9,2 Hz), 8,01 (1H, d, J=9,2 Hz), of 13.18 (1H, usher.).

LC-MS m/z: 297 (M+H)+.

[Reference example 44] Ethyl ester 5-(4-methoxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

4-Methoxyacetophenone (300 mg) is dissolved in N,N-dimethylformamide (4 ml). To the resulting mixture at 0°With added 60% sodium hydride, followed by stirring at room temperature for 0.5 hours. Under ice cooling to the reaction mixture add diethyloxalate (542 μl), followed by stirring at room temperature for 14 hours. To the reaction mixture hydrochloride 5-hydrazino-2-methoxypyridine (406 mg)obtained in reference example 1, followed by stirring at 80°C for 3 hours. The mixture is cooled down, the Reaction mixture was partitioned between water and ethyl acetate. The organic layer is successively washed with water and saturated salt solution. Then the organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure. The residue is subjected to column chromatography on silica gel (hexane-ethyl acetate), obtaining mentioned in the title compound as an oily substance (517 mg, 73%).

1H-NMR (400 MHz, CDCl3) δ: of 1.42 (3H, t, J=7.0 Hz), 3,80 (3H, s), 3,93 (3H, s), of 4.44 (2H, q, J=7.0 Hz), was 6.73 (1H, d, J=8,8 Hz), at 6.84 (2H, d-like, J=8,8 Hz), 6,97 (1H, s), 7,13 (2H, d-like, J=8,8 Hz), 7,56 (1H, DD, J=8,8 with 2.7 Hz), 8,10 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 354 (M+H)+.

[Referential example 45] 5-(4-Methoxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

Ethyl ester derivative of pyrazole-3-carboxylic acid (515 mg)obtained in reference example 44, was dissolved in methanol (10 ml). To the resulting mixture was added 1 M aqueous sodium hydroxide solution (3,64 ml), followed by boiling under reflux by heating for 1 hour. The reaction solvent is evaporated under reduced pressure. The residue is distributed between water and ethyl acetate. The aqueous layer was acidified with 1 M aqueous solution of hydrochloric acid (4.5 ml). Then the aqueous layer was extracted with ethyl acetate. The organic layer is successively washed with water is the first and saturated salt solution. Then the organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, thus obtaining specified in the title compound as crystals (453 mg, 95%).

1H-NMR (400 MHz, CDCl3) δ: 3,81 (3H, s), of 3.95 (3H, s), of 6.75 (1H, d, J=8,8 Hz)6,86 (2H, d-like, J=8,8 Hz), 7,03 (1H, s), to 7.15 (2H, d-like, J=8,8 Hz), EUR 7.57 (1H, DD, J=8,8, 2.7 Hz), to 8.12 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 326 (M+H)+.

[Referential example 46] Ethyl ester 5-(3-methoxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 44, indicated in the title compound obtained as an oily substance (495 mg, 70%) using 3-methoxyacetophenone (300 mg), diethyloxalate (542 μl) and hydrochloride 5-hydrazino-2-methoxypyridine (406 mg)obtained in reference example 1.

1H-NMR (400 MHz, CDCl3) δ: of 1.42 (3H, t, J=7,1 Hz), and 3.72 (3H, s), 3,93 (3H, s), of 4.45 (2H, q, J=7.0 Hz), was 6.73 (1H, d, J=8,8 Hz), 6.73 x-to 6.80 (2H, m), 6,85-6,91 (1H, m), 7,03 (1H, s), 7,20-7,27 (1H, m), 7,58 (1H, DD, J=8,8, 2.7 Hz), 8,11 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 354 (M+H)+.

[Referential example 47] 5-(3-Methoxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 45, indicated in the title compound obtained as Cristallo is (427 mg, 94%) using ethyl ether derivative of pyrazole-3-carboxylic acid (490 mg)obtained in reference example 46.

1H-NMR (400 MHz, CDCl3) δ: 3,74 (3H, s), of 3.94 (3H, s), of 6.75 (1H, d, J=8,8 Hz), 6.75 in-PC 6.82 (2H, m), 6,88-6,93 (1H, m), to 7.09 (1H, s), 7,22-7,29 (1H, m), 7,58 (1H, DD, J=8,8, 2.7 Hz), 8,13 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 326 (M+H).

[Referential example 48] Ethyl ester 5-(2-methoxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 44, indicated in the title compound obtained as crystals (476 mg, 67%) using 2-methoxyacetophenone (300 mg), diethyloxalate (542 μl) and hydrochloride 5-hydrazino-2-methoxypyridine (421 mg)obtained in reference example 1.

1H-NMR (400 MHz, CDCl3) δ: of 1.41 (3H, t, J=7,1 Hz), 3,49 (3H, s)to 3.89 (3H, s), of 4.44 (2H, q, J=7,1 Hz), to 6.67 (1H, d, J=8,8 Hz), for 6.81 (1H, d, J=8,3 Hz), 6,95-7,01 (1H, m), 6,97 (1H, s), 7,22-7,29 (1H, m), 7,33-7,40 (1H, m,), 7,58 (1H, DD, J=8,8, 2.7 Hz), 8,03 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 354 (M+H)+.

[Referential example 49] 5-(2-Methoxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 45, indicated in the title compound obtained as a solid (454 mg, quantitative yield) using ethyl ether derivative of pyrazole-3-carboxylic acid (473 mg), receive the frame in the reference example 48.

1H-NMR (400 MHz, CDCl3) δ: 3,50 (3H, s), 3,91 (3H, s)6,70 (1H, d, J=8,8 Hz), 6,83 (1H, d, J=8,3 Hz), 6,97-7,03 (1H, m),? 7.04 baby mortality (1H, s), 7.23 percent-7,30 (1H, m), 7,35-7,42 (1H, m), 7,58 (1H, DD, J=8,8, 2.7 GHz), with 8.05 (1H, d, J=2.7 GHz).

MS (ESI) m/z: 326 (M+H)+.

[Referential example 50] Ethyl ester 5-[4-(trifluoromethyl)phenyl]-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 44, indicated in the title compound obtained as an oily substance (332 mg, 42%) with the use of 4'-(trifluoromethyl)acetophenone (376 mg), diethyloxalate (542 μl) and hydrochloride 5-hydrazino-2-methoxypyridine (421 mg)obtained in reference example 1.

1H-NMR (400 MHz, CDCl3) δ: of 1.43 (3H, t, J=7,1 Hz), of 3.94 (3H, s), to 4.46 (2H, q, J=7,1 Hz), 6, 77 (1H, d, J=8,8 Hz), 7,10 (1H, s), 7,34 (2H, d, J=8.0 Hz), 7,56-to 7.64 (3H, m), 8,07 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 392 (M+H)+.

[Referential example 51] 5-[4-(Trifluoromethyl)phenyl]-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 45, indicated in the title compound obtained as crystals (309 mg, quantitative yield) using ethyl ether derivative of pyrazole-3-carboxylic acid (332 mg)obtained in reference example 50.

1H-NMR (400 MHz, CDCl3) δ: of 3.96 (3H, s), 6,79 (1H, d, J=8,8 Hz), to 7.15 (1H, s), 7,37 (2H, d, J=8.5 Hz), 7,58 (1H, DD, J=8,8, 2.7 Hz), a 7.62 (2H, d, J=8.5 Hz), of 8.09 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 364 (M+H)+.

[Referential example 52] 3-Hydrazinopyridazine

Sodium nitrite (4,28 g) in water (20 ml) is added dropwise to 3-aminopyridine (5,15 g) in concentrated hydrochloric acid at an internal temperature of 0 to 5°With over a period of 30 minutes, followed by stirring for 5 minutes. The reaction mixture is added dropwise to the chloride dihydrate tin (II) (43,68 g) in concentrated hydrochloric acid (30 ml) at an internal temperature of 0-10°With over a period of 1 hour, followed by stirring for 0.5 hours. The resulting solid is collected by filtration. Then the solid substance was washed with diethyl ether and then dried under reduced pressure, thus obtaining specified in the header connection (16,38 g, quantitative yield).

1H-NMR (400 MHz, DMSO-d6) δ: to 7.93 (1H, DD, J=8,8, 5.6 Hz), of 8.09 (1H, DD, J=8,8, 2.7 Hz), 8,43 (1H, d, J=5.6 Hz), 8,51 (1H, d-like, J=2.7 Hz).

MS (ESI) m/z: 109 (M)+.

[Referential example 53] Ethyl ester 4-methyl-5-phenyl-1-(3-pyridyl)pyrazole-3-carboxylic acid

1) Ethyl ester of 3-methyl-4-phenyl-2,4-dioxaborinane acid

Propiophenone (4.0 g) in diethyl ether (5 ml) is added to 1.0 M bis(trimethylsilyl)amide lithium in tetrahydrofuran (30 ml) at -78°to follow them by stirring for 30 minutes. To the reaction mixture add diethyloxalate (4.35 g) in diethyl ether (5 ml) followed by stirring for 10 minutes. The resulting mixture is additionally stirred at room temperature for 16 hours. The resulting solid is collected by filtration. Then the solid substance was washed with diethyl ether and then dried, thus obtaining lithium salt of ethyl ester of 3-methyl-4-phenyl-2,4-dioxaborinane acid in the form of solids (3,23 g, 47%).

MS (FAB) m/z: 235 (M+N)+.

2) Specified in the header of the connection

The result of the above lithium salt of ethyl ester of 3-methyl-4-phenyl-2,4-dioxaborinane acid (1,502 g) dissolved in ethanol (30 ml). To the resulting mixture was added 1 M HCl in ethanol (8 ml) and 3-hydrazinopyridazine (1,977 g)obtained in reference example 52, followed by boiling under reflux for 2.5 hours. The mixture is cooled in air. The reaction mixture is alkalinized to pH 10 with an aqueous solution of sodium hydroxide. The mixture is partitioned between chloroform and water. The aqueous layer was extracted with chloroform. The organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (chloroform-acetone), while et is m specified in the title compound as an oily substance (1,428 g, 34%).

1H-NMR (400 MHz, CDCl3) δ: of 1.44 (3H, t, J=7,1 Hz), 2,32 (3H, s), 4,47 (2H, q, J=7,1 Hz), 7,13-7,20 (2H, m), 7,22-7,30 (1H, m), 7,35-7,42 (3H, m), 7,60-to 7.68 (1H, m), 8,46 are 8.53 (2H, m).

MS (FAB) m/z: 308 (M+H)+.

[Referential example 54] 4-Methyl-5-phenyl-1-(3-pyridyl)pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 45, indicated in the title compound obtained as a solid (0,892 g, 69%) using ethyl ether derivative of pyrazole-3-carboxylic acid (1,428 g)obtained in reference example 53.

1H-NMR (400 MHz, DMSO-d6) δ: of 2.20 (3H, s), 7,20-7,30 (2H, m), 7,37-to 7.50 (m, 4H), 7,66-7,74 (1H, m), to 8.41 (1H, d, J=2.7 Hz), charged 8.52 (1H, d-like, J=4,7 Hz), 12,91 (1H, usher.).

LC-MS m/z: 280 (M+H)+.

[Referential example 55] Ethyl ester 4-methyl-1,5-diphenylphenol-3-carboxylic acid

In a manner analogous to the method described in stage 2) of reference example 53, indicated in the title compound obtained as an oily substance (1,897 g, 62%) using the lithium salt of ethyl ester of 3-methyl-4-phenyl-2,4-dioxaborinane acid (3.04 from g)obtained in stage 1) of reference example 53, and phenylhydrazone (1,671 g).

1H-NMR (400 MHz, CDCl3) δ: of 1.43 (3H, t, J=7,3 Hz), 2,32 (3H, s), to 4.46 (2H, q, J=7,3 Hz), 7,10-to 7.18 (2H, m), 7,20-7,31 (5H, m), 7,32-7,40 (3H, m)

MS (FAB) m/z: 307 (M+H)+.

[Reference example 56] 4-IU the Il-1,5-diphenylphenol-3-carboxylic acid

In a manner analogous to the method described in reference example 4, is listed in the title compound obtained as a solid (1,38 g, 80%) using ethyl ether derivative of pyrazole-3-carboxylic acid (1,897 g)obtained in reference example 55.

1H-NMR (400 MHz, DMSO-d6) δ: of 2.20 (3H, s), 7,15-of 7.25 (4H, m), 7,30 was 7.45 (6H, m), 12,80 (H, OSiR.).

MS (FAB) m/z: 279 (M+H)+.

[Referential example 57] α-Peracetate

A suspension of potassium fluoride (3,091 g) and 18-crown-6-ether (0,341 g) in acetonitrile (25 ml) was stirred at 55°C for 1 hour. To the reaction mixture add α-bromoacetophenone (5,12 g), followed by stirring for 20 hours. Then to the reaction mixture is added diethyl ether, and then the insoluble substance is formed, is removed by filtration. For distribution of the filtrate add water. The organic layer is successively washed with water and saturated salt solution. Then the organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, thus obtaining the remainder. Repeat the same procedure for the reaction, thus obtaining the remainder. Residues are combined and purified column chromatography on silica gel (hexane-ethyl acetate), thus obtaining specified in the header connect the tion in the form of oily substance (4.7 g, 45%).

1H-NMR (400 MHz, CDCl3) δ: of 5.53 (2H, d, J=47,0 Hz), 7,50 (2H, t-like, J=7.9 Hz), a 7.62 (1H, t-like, J=7.9 Hz), 7,89 (2H, d-like, J=7.9 Hz).

MS (ESI) m/z: 139 (M+H)+.

[Referential example 58] Ethyl ester of 4-fluoro-1,5-diphenylphenol-3-carboxylic acid

1) Ethyl ester of 3-fluoro-4-phenyl-2,4-dioxaborinane acid

1.0 M bis(trimethylsilyl)amide lithium in tetrahydrofuran (13 ml) is added dropwise to α-fortetienne (1.64 g) in tetrahydrofuran (35 ml) at -78°C, followed by stirring for 45 minutes. To the reaction mixture add diethyloxalate (1.77 ml), followed by stirring for 30 minutes. The mixture is additionally stirred at 0°C for 1 hour. The resulting mixture is neutralized 1 M aqueous solution of hydrochloric acid. The reaction mixture is distributed between water and chloroform. Then the aqueous layer was extracted with chloroform. The organic layers are combined, washed with saturated salt solution and then dried over anhydrous sodium sulfate. The mixture is filtered and the solvent is evaporated under reduced pressure, thus obtaining the ethyl ester of 3-fluoro-4-phenyl-2,4-dioxaborinane acid as an oily substance (0,753 g, 27%).

2) Specified in the header of the connection

In a manner analogous to the method described in step 2) of referential example 5, specified in the header connection receive (0,208 g, 15%) using the above lithium salt of ethyl ester of 3-fluoro-4-phenyl-2,4-dioxaborinane acid (0,753 g) and phenylhydrazine (0,350 g).

1H-NMR (400 MHz, CDCl3) δ: of 1.27 (3H, t, J=7,1 Hz), 4,30 (2H, q, J=7,1 Hz), 7,33-7,52 (8H, m), to 7.93 (2H, d-like, J=7,4 Hz).

MS (FAB) m/z: 311 (M+H)+.

[Referential example 59] 4-Fluoro-1,5-diphenylphenol-3-carboxylic acid

In a manner analogous to the method described in reference example 4, is listed in the title compound obtained as a solid (0,169 g, 90%) using ethyl ether derivative of pyrazole-3-carboxylic acid (0,208 g)obtained in reference example 58.

1H-NMR (400 MHz, DMSO-d6) δ: was 7.45 (1H, t-like, J=7,6 Hz), of 7.48-of 7.60 (7H, m), 7,83 (1H, d-like, J=7,3 Hz).

[Referential example 60] Ethyl ester of 1,4-dihydro-1-(6-methoxy-3-pyridyl)indeno[1,2-c]pyrazole-3-carboxylic acid

60% sodium Hydride (400 mg) are added to 1-indanone (661 mg) in N,N-dimethylformamide(10 ml) at 0°C, followed by stirring at room temperature for 0.5 hours. To the reaction mixture at 0°With add diethyloxalate (1,36 ml) followed by stirring at room temperature for 16 hours. The reaction mixture was acidified with 1 M aqueous solution of hydrochloric acid is you (11 ml). The mixture is then partitioned between water and ethyl acetate. The organic layer is successively washed with water and saturated salt solution and then dried over anhydrous sodium sulfate. The mixture is filtered and the solvent is evaporated under reduced pressure, thus obtaining the ethyl ester of 2-oxo-2-(1-oxonian-2-yl)acetic acid as an oily substance (1,441 g, quantitative yield). To the above ethyl ether, 2-oxo-2-(1-oxonian-2-yl)acetic acid in ethanol (25 ml) is added 5-hydrazino-2-methoxypyridine (696 mg)obtained in reference example 2, followed by boiling under reflux by heating for 16 hours. Then the resulting mixture is cooled in air. The reaction solvent is evaporated under reduced pressure. The residue is distributed between water and ethyl acetate. The organic layer is successively washed with water and saturated salt solution and dried over anhydrous sodium sulfate. The mixture is filtered and the solvent is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (hexane-ethyl acetate), obtaining mentioned in the title compound as crystals (890 mg, 53%).

1H-NMR (400 MHz, CDCl3) δ: of 1.45 (3H, t, J=7.0 Hz), a-3.84 (2H, s), Android 4.04 (3H, s), 4,47 (2H, q, J=7.0 Hz), 6,93 (1H, d, J=8,8 Hz), 7,27-7,34 (2H, m), of 7.36-7,41 (1H, m), EUR 7.57 (1H, d, J=6,GC), of 7.96 (1H, DD, J=8,8, 2,9 Hz), 8,54 (1H, d, J=2,9 Hz).

MS (ESI) m/z: 336 (M+H)+.

[Referential example 61] 1,4-Dihydro-1-(6-methoxy-3-pyridyl)indeno[1,2-c]pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 45, indicated in the title compound obtained as crystals (791 mg, 97%) using ethyl ether 1,4-dihydro-1-(6-methoxy-3-pyridyl)indeno[1,2-c]pyrazole-3-carboxylic acid (890 mg)obtained in reference example 60.

1H-NMR (400 MHz, CDCl3) δ: to 3.89 (2H, s), of 4.05 (3H, s), to 6.95 (1H, d, J=8,8 Hz), 7,28 and 7.36 (2H, m), 7,38-7,42 (1H, m), 7,58 (1H, d, J=6.6 Hz), of 7.96 (1H, DD, J=8,8, and 2.6 Hz), 8,56 (1H, d, J=2,6 Hz).

MS (ESI) m/z: 308 (M+H)+.

[Reference example 62] Ethyl ester 2-oxo-2-(1-oxonian-2-yl)acetic acid

In a manner analogous to the method described in stage 1) of reference example 3, specified in the title compound obtained as crystals (3,39 g, 97%) with the use of 1-indanone (1,982 g) and diethyloxalate (4,07 ml).

1H-NMR (400 MHz, CDCl3) δ: of 1.43 (3H, t, J=7,0 Hz)to 3.99 (2H, s), 4,42 (2H, q, J=7.0 Hz), 7,44 (1H, DD, J=7,3, 7,1 Hz), 7,55 (1H, d, J=7,3 Hz), to 7.64 (1H, DD, J=7,3, 7,1 Hz), 7,87 (1H, d, J=7,3 Hz).

MS (ESI) m/z: 233 (M+H)+.

[Referential example 63] Ethyl ester of 1,4-dihydro-1-(6-methyl-3-pyridyl)indeno[1,2-c]pyrazole-3-carboxylic acid

5-tert-Butoxycarbonylamino-2-meth is pyridin (625 mg) in concentrated hydrochloric acid (3 ml) was stirred at room temperature for 50 minutes. Under ice cooling to the reaction mixture over a period of 10 minutes are added dropwise sodium chloride, sodium nitrite (228 mg) in water (1 ml) followed by stirring for 10 minutes. To the reaction mixture over a period of 10 minutes added dropwise a chloride dihydrate tin (II) in concentrated hydrochloric acid (1.6 ml) followed by stirring for 3 hours under ice cooling. To the reaction mixture are added ethyl ester 2-oxo-2-(1-oxonian-2-yl)acetic acid (696 mg)obtained in reference example 62, in ethanol (20 ml). The resulting mixture is refluxed under heating for 39 hours. Under ice cooling, the reaction mixture was alkalinized with an aqueous solution of sodium hydroxide. Then the resulting mixture is distributed between ethyl acetate and water. The organic layer is successively washed with water and saturated salt solution and dried over anhydrous sodium sulfate. The mixture is filtered and the solvent is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (chloroform-acetone), thus obtaining specified in the title compound as crystals (340 mg, 35%).

1H-NMR (400 MHz, CDCl3) δ: of 1.46 (3H, t, J=7.0 Hz), 2,69 (3H, s), 3,85 (2H, s), 4,48 (2H, q, J=7.0 C), 7,24-to 7.35 (2H, m), 7,37 (1H, d, J=8,3 Hz), 7,46 (1H, DD, J=6,8, 1.3 Hz), 7,58 (1H, d, J=7,3 G is), of 8.00 (1H, DD, J=8,3, 2.4 Hz), of 8.92 (1H, d, J=2,4 Hz).

MS (ESI) m/z: 320 (M+H)+.

[Referential example 64] 1,4-Dihydro-1-(6-methyl-3-pyridyl)indeno[1,2-c]pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 45, indicated in the title compound obtained as a solid (287 mg, 95%) using ethyl ether 1,4-dihydro-1-(2-methylpiperid-5-yl)indeno[1,2-c]pyrazole-3-carboxylic acid (331 mg)obtained in reference example 63.

1H-NMR (400 MHz, DMSO-d6) δ: 2,62 (3H, s), 3,81 (2H, s), 7,31-7,39 (3H, m), 7,56 (1H, d, J=8.1 Hz), 7,60-to 7.68 (1H, m), 8,10 (1H, DD, J=8,1, 2.4 Hz), cent to 8.85 (1H, d, J=2.4 Hz), 13,02-13,16 (1H, usher.).

MS (ESI) m/z: 292 (M+H)+.

[Referential example 65] 5-Nitro-2-vinylpyridine

In the atmosphere of argon tributyl(vinyl)tin (6,658 g) and tetrakis(triphenylphosphine)palladium (0) (1,155 g) are added to 2-chloro-5-nitropyridine (3,171 g) and 2,6-di-tert-butyl-p-cresol (44 mg) in tetrahydrofuran (40 ml), followed by boiling under reflux with heating for 14 hours. The resulting mixture is cooled in air. Then to the reaction mixture at room temperature, add ethyl acetate and sodium fluoride (2,52 g) in water (60 ml), followed by stirring at room temperature for 7 hours. Insoluble substance is formed in the mixture, is filtered off. For distribution of the organic layer EXT is make water. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (hexane-ethyl acetate), obtaining mentioned in the title compound as crystals (1,519 g, 50%).

1H-NMR (400 MHz, CDCl3) δ: 5,74 (1H, DD, J=10,8, 1.0 Hz), 6,45 (1H, DD, J=17.4 years, 1.0 Hz), make 6.90 (1H, DD, J=17.4 years, and 10.8 Hz), 7,47 (1H, d, J=8,8 Hz), 8,43 (1H, DD, J=8,8, 2.4 Hz), 9,38 (1H, d, J=2,4 Hz).

MS (ESI) m/z: 151 (M+H)+.

[Reference example 66] 5-Amino-2-ethylpyridine

10% palladium on coal (50% water, 90 mg) are added to 5-nitro-2-vinylpyridine (450 mg) in ethanol (30 ml), followed by stirring in an atmosphere of hydrogen at room temperature for 15 hours. The catalyst removed from the reaction mixture by filtration. Then the solvent is evaporated under reduced pressure, thus obtaining specified in the title compound as an oily substance (359 mg, 98%).

1H-NMR (400 MHz, CDCl3) δ: of 1.25 (3H, t, J=7.5 Hz), 2,71 (2H, q, J=7.5 Hz), 3,32-of 3.78 (2H, usher.), 6,91-6,98 (2H, m), 8,02-with 8.05 (1H, m).

MS (ESI) m/z: 123 (M+H)+.

[Reference example 67] Ethyl ester 1-(6-ethyl-3-pyridyl)-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic acid

Sodium nitrite (228 mg) in water (1 ml) is added dropwise to 5-amino-2-ethylpyridine(359 mg) in concentrated hydrochloric acid (3 ml) while cooling the mixture with ice / sodium chloride over a period of 10 minutes, followed by stirring at constant temperature for 10 minutes. To the reaction mixture over a period of 10 minutes added dropwise a chloride dihydrate tin (II) (2.37 g) in concentrated hydrochloric acid (1.6 ml) followed by stirring under ice cooling for 3 hours. To the reaction mixture are added ethyl ester 2-oxo-2-(1-oxonian-2-yl)acetic acid (696 mg)obtained in reference example 62, in ethanol (20 ml). The resulting mixture is refluxed under heating for 39 hours. Under ice cooling, the reaction mixture was alkalinized using aqueous sodium hydroxide solution. The resulting mixture is distributed between ethyl acetate and water. The organic layer is successively washed with water and saturated salt solution and then dried over anhydrous sodium sulfate. The mixture is then filtered. The solvent is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (chloroform-acetone), thus obtaining specified in the title compound as crystals (372 mg, 37%).

1H-NMR (400 MHz, CDCl3) δ: of 1.39 (3H, t, J=7.0 Hz), a 1.45 (3H, t, J=7,0 Hz)to 2.94 (2H, q, J=7.0 Hz), 3,85 (2H, s), 4,48 (2H, q, J=7.0 Hz), 7,25-to 7.35 (2H, m), 7,38 (1H, d, J=8,3 Hz), 7,46 (1H, DD, J=6.3, in the 1.7 Hz), 7,58 (1H, d, J=6.8 Hz), 8,02 (1H, DD, J=8,3, 2.4 Hz), to 8.94 (1H, d, J=2,4 Hz).

MS (ESI) m/z: 334 (M+H)+.

[Referential example 68] 1-(6-Ethyl-3-pyridyl)-1,4-dihydroindeno[1,2-c]pyrazole-3-CT is about acid

In a manner analogous to the method described in reference example 45, indicated in the title compound obtained as crystals (302 mg, 91%) using ethyl ester 1-(6-ethyl-3-pyridyl)-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic acid (360 mg)obtained in reference example 67.

1H-NMR (400 MHz, DMSO-d6) δ: of 1.33 (3H, t, J=7.5 Hz), only 2.91 (2H, q, J=7.5 Hz), 3,81 (2H, s), 7,32-7,40 (3H, m), EUR 7.57 (1H, d, J=8,3 Hz), 7,62-of 7.69 (1H, m), 8,13 (1H, DD, J=8,3, 2.4 Hz), 8,89 (1H, d, J=2.4 Hz), of 13.05-13,13 (1H, user.).

MS (ESI) m/z: 306 (M+H)+.

[Referential example 69] Ethyl ester of 1,4-dihydro-(2-methoxyphenyl-5-yl)-4-oxoindole[1,2-c]pyrazole-3-carboxylic acid

1.1 M bis(trimethylsilyl)amide lithium in hexane (3 ml) in hexane (3 ml) is added dropwise to 1,3-indandione (438 mg) in tetrahydrofuran (15 ml) in an argon atmosphere at -78°With over a period of 10 minutes, followed by stirring for 45 minutes. To the reaction mixture add ethylchloride (450 mg) in tetrahydrofuran (3 ml) followed by stirring at 0°C for 2 hours. Then the solvent is evaporated under reduced pressure. The residue is dissolved in ethanol (15 ml). To the resulting mixture add 5-hydrazino-2-methoxypyridine (417 mg)obtained in reference example 2, followed by boiling under heating for 14 hours. The mixture is cooled the air. The reaction solvent is evaporated under reduced pressure. The residue is distributed between water and ethyl acetate. The organic layer is successively washed with 5% aqueous citric acid solution, water, saturated aqueous sodium bicarbonate, water and saturated salt solution. Then the organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (hexane-ethyl acetate), obtaining mentioned in the title compound as an oily material (22 mg, 2%).

1H-NMR (400 MHz, CDCl3) δ: of 1.47 (3H, t, J=7.0 Hz), Android 4.04 (3H, s), of 4.49 (2H, q, J=7.0 Hz), 6,94 (1H, d, J=8,8 Hz), 7,08-to 7.15 (1H, m), 7,32-7,40 (2H, m), 7,63-7,71 (1H, m), to 7.93 (1H, DD, J=8,8, 2,9 Hz), 8,51 (1H, d, J=2,9 Hz).

MS (ESI) m/z: 350 (M+H)+.

[Referential example 70] 1,4-Dihydro-1-(6-methoxy-3-pyridyl)-4-oxoindole[1,2-c]pyrazole-3-carboxylic acid

In a manner analogous to the method described in reference example 45, indicated in the title compound obtained as a solid (16 mg, 80%) using ethyl ether 1,4-dihydro-(6-methoxy-3-pyridyl)-4-oxoindole[1,2-c]pyrazole-3-carboxylic acid (22 mg)obtained in reference example 69.

1H-NMR (400 MHz, CDCl3) δ: of 4.05 (3H, s), of 6.96 (1H, d, J=8,8 Hz), 7,15-7,20 (1H, m), of 7.36-the 7.43 (2H, m), to 7.67-7,3 (1H, m), 7,95 (1H, DD, J=8,8, 2.7 Hz), charged 8.52 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 322 (M+H)+.

[Referential example 71] Ethyl ester of 4,5-dihydro-1-(6-methoxy-3-pyridyl)-1H-benzo[g]indazole-3-carboxylic acid

In an argon atmosphere and cooled at -78°1.1 M bis(trimethylsilyl)amide lithium in hexane (5 ml) is added dropwise to α-tetralone (731 mg) in tetrahydrofuran (10 ml) over a period of 10 minutes and the resulting mixture is stirred for 0.5 hour. To the reaction mixture add diethyloxalate (1,461 g) in tetrahydrofuran (5 ml) followed by stirring at 0°C for 2 hours and then at room temperature for 14 hours. The reaction mixture is acidified by addition of an aqueous 1 M hydrochloric acid (10 ml). The resulting mixture is distributed between water and ethyl acetate. The organic layer is successively washed with water and saturated salt solution and then dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, thus obtaining the ethyl ester of 2-(1,2,3,4-tetrahydro-1-oxonation-2-yl)-2-octoxynol acid as an oily product (1,516 g, quantitative yield). Thus obtained ethyl ester is dissolved in ethanol (20 ml) and the resulting solution was added 5-hydrazino-2-methoxypyridine (696 mg)obtained in sulochna example 2. The mixture is refluxed under heating for 18 hours and then cooled in air. The solvent is evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic layer is successively washed with 5% aqueous citric acid and saturated salt solution and then dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure and the residue purified by column chromatography on silica gel (hexane-ethyl acetate), obtaining mentioned in the title compound as an oily product (1,093 g, 62%).

1H-NMR (400 MHz, CDCl3) δ: of 1.42 (3H, t, J=7,1 Hz), 2,96-3,13 (4H, m)to 4.01 (3H, s), of 4.44 (2H, q, J=7.0 Hz), 6,77 (1H, d-like, J=7,1 Hz), 6,85 (1H, d, J=8,8 Hz), 7,00-7,06 (1H, m), 7,15-7,21 (1H, m), 7,30 (1H, d-like, J=a 7.6 Hz), of 7.70 (1H, DD, J=8,8, 2.7 GHz), with 8.33 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 350 (M+H)+.

[Reference example 72] 4,5-Dihydro-1-(6-methoxy-3-pyridyl)-1H-benzo[g]indazole-3-carboxylic acid

The General procedure of reference example 45 is repeated through the use of the ethyl ester of 4,5-dihydro-1-(6-methoxy-3-pyridyl)-1H-benzo[g]indazole-3-carboxylic acid (1,015 g)obtained in reference example 71, while receiving specified in the title compound in the form of crystals (745 mg, 79%).

1H-NMR (400 MHz, DMSO-d6) δ: 2,96 (4H,s), of 3.96 (3H, s), of 6.68 (1H, d, J=7,6 Hz), 7,03 (1H, d, J=8,8 Hz), was 7.08 (1H, DD, J=7,6, 7,6 Hz), 7,21 (1H, DD, J=7,6, 7,6 Hz), was 7.36 (1H, d, J=7,6 Hz), of 7.90 (1H, DD, J=8,8, 2.7 Hz), at 8.36 (1H, d, J=2.7 Hz), 12,92 (1H with).

MS (ESI) m/z: 322 (M+H)+.

[Reference example 73] Ethyl ester of 1,4-dihydro-1-(6-methoxy-3-pyridyl)chromeno[4,3-c]pyrazole-3-carboxylic acid

In an argon atmosphere and cooled at -78°1.1 M bis(timeteller)amide lithium in hexane (3 ml) is added dropwise to 4-chromanone (444 mg) in tetrahydrofuran (10 ml) over a period of 10 minutes and the resulting mixture is stirred for 0.5 hour. To the reaction mixture add diethyloxalate (877 mg) in tetrahydrofuran (3 ml) followed by stirring at 0°C for 2 hours. The reaction mixture is acidified by addition of an aqueous 1 M hydrochloric acid (6 ml) with subsequent distribution between water and ethyl acetate. The organic layer is successively washed with water and saturated salt solution and then dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, thus obtaining the ethyl ester of 2-oxo-2-(4-exogamy-3-yl)acetic acid in the form of semi-solid substances (855 mg, quantitative yield). Thus obtained ethyl ester is dissolved in ethanol (30 ml) and the resulting solution was added 5-hydrazino-2-methoxypyridine (417 mg), the scientists in the reference example 2. The mixture is refluxed under heating for 14 hours and then cooled in air. The reaction solvent is evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic layer is successively washed with water and saturated salt solution and then dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure and then the residue purified by column chromatography on silica gel (hexane-ethyl acetate). The resulting crystals are recrystallized from a mixture of ethyl acetate-hexane, thus obtaining specified in the title compound in the form of crystals (267 mg). The solvent in the filtrate is evaporated under reduced pressure and then the residue is purified by thin-layer chromatography on silica gel (hexane-ethyl acetate), obtaining mentioned in the title compound (28 mg). This compound is combined with the crystals obtained above, getting in the end specified in the title compound (295 mg, 27%).

1H-NMR (400 MHz, CDCl3) δ: of 1.42 (3H, t, J=7,1 Hz), a 4.03 (3H, s), of 4.44 (2H, q, J=7.0 Hz), of 5.55 (2H, s), 6,72-to 6.80 (2H, m), to 6.88 (1H, d, J=8,8 Hz), 7,01 (1H, d-like, J=8,8 Hz), 7,16-7,22 (1H, m), of 7.70 (1H, DD, J=8,8, 2.7 GHz), a 8.34 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 352 (M+H)+.

[Reference example 74] 1,4-Dihydro-1-(6-methoxy-3-pyridyl)chromeno[4,3-c]pyrazole-3-carboxylic acid

The General procedure of reference example 45 is repeated through the use of ethyl ether 1,4-dihydro-1-(2-methoxyphenyl-5-yl)chromeno[4,3-c]pyrazole-3-carboxylic acid (265 mg)obtained in reference example 73, while receiving specified in the title compound in the form of crystals (226 mg, 93%).

1H-NMR (400 MHz, DMSO-d6) δ: of 3.97 (3H, s), of 5.48 (2H, s), to 6.67 (1H, DD, J=7,8, 1.3 Hz), at 6.84 (1H, DD, J=7,8, and 7.8 Hz), 7,02 (1H, d, J=8,3 Hz), 7,06 (1H, d, J=8,8 Hz), 7,22 (1H, DD, J=8,3, a 7.6 Hz), of 7.97 (1H, DD, J=8,8, 2.7 Hz), 8,43 (1H, d, J=2.7 Hz), 13,26 (1H, users).

MS (ESI) m/z: 324 (M+H)+.

[Reference example 75] [1-(6-Methoxy-3-pyridyl)-5-phenylpyrazol-3-yl]methanol

In an argon atmosphere under ice cooling 1.08 M complex, borane-tetrahydrofuran in tetrahydrofuran (9,2 ml) is added dropwise to 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (1,181 g)obtained in reference example 41, in tetrahydrofuran (20 ml) over a period of 10 minutes and the resulting mixture was stirred at room temperature for 7 hours. To the reaction mixture are added water and ethyl acetate, followed by stirring, and the precipitated insoluble substance is removed by filtration and then separated from the organic layer. The organic layer is successively washed with water and saturated salt solution and then dried over anhydrous sodium sulfate, followed by filtering the. The solvent is evaporated under reduced pressure and the residue purified by column chromatography on silica gel (hexane-ethyl acetate), obtaining mentioned in the title compound as an oily product (682 mg, 60%).

1H-NMR (400 MHz, CDCl3) δ: to 3.92 (3H, s), rate 4.79 (2H, s), of 6.52 (1H, s), 6,72 (1H, d, J=8.5 Hz), 7.18 in-7,27 (2H, m), 7,29-7,37 (3H, m), 7,52 (1H, DD, J=8,5, 2.7 Hz), 8,07 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 282 (M+H)+.

[Referential example 76] [1-(6-Methoxy-3-pyridyl)-5-phenylpyrazol-3-yl]methylmethanesulfonate

[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazol-3-yl]methanol (112 mg)obtained in reference example 75, dissolved in methylene chloride (4 ml). To the solution at room temperature is added triethylamine (61 μl) and methanesulfonamide (34 μl), followed by stirring for 15 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic layer is successively washed with water and saturated salt solution and then dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, thus obtaining specified in the title compound as an oily product (138 mg, 96%).

MS (ESI) m/z: 360 (M+N)+.

[Reference example 77] tert-Butyl ether 2-(2-hydroxyethyl)piperidine-1-carboxylic acid

2-Piperi inethanol (1,292 g) and triethylamine (1,393 ml) dissolved in methylene chloride (40 ml). To the resulting solution at room temperature add di-tert-BUTYLCARBAMATE (2,182 g) in methylene chloride (40 ml) followed by stirring for 1 hour. The residue obtained by removal by evaporation of the reaction solvent under reduced pressure, partitioned between water and ethyl acetate. The organic layer is successively washed with 5% aqueous citric acid, water and saturated salt solution and then dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, thus obtaining specified in the title compound as an oily product (2,182 g, 95%).

1H-NMR (400 MHz, CDCl3) δ: 1,33-of 1.81 (7H, m), for 1.49 (9H, s), 1,88 is 2.00 (1H, osirm), 2,63-by 2.73 (1H, m), 3.25 to 3,47 (1H, usher.), 3,56-3,66 (1H, osirm), 3,75-4,08 (2H, usher.), 4,35-of 4.54 (1H, usher.).

[Reference example 78] 2-(N-tert-Butoxycarbonylamino-2-yl)ethylmethanesulfonate

tert-Butyl ether 2-(2-hydroxyethyl)piperidine-1-carboxylic acid (229 mg)obtained in reference example 77, and triethylamine (209 μl) dissolved in methylene chloride (5 ml). To the resulting solution at room temperature add methanesulfonanilide (116 μl), followed by stirring for 30 minutes. The residue obtained by evaporation of the reaction solvent under reduced pressure, the distribution is jut between water and methylene chloride. The organic layer is successively washed with water and saturated salt solution and then dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, thus obtaining specified in the title compound in the form of crystals (288 mg, 93%).

1H-NMR (400 MHz, CDCl3) δ: 1,34 is 1.70 ( 6H, m)of 1.46 (9H, s), 1,75 is 1.86 (1H, m), 2,16-of 2.27 (1H, m), 2.71 to of 2.81 (1H, osirm), a 3.01 (3H, s), 3,92-4,08 (1H, usher.), 4,20 (2H, t, J=6.8 Hz), 4,34-4,48 (1H, usher.).

[Referential example 79] tert-Butyl ether 2-(2-azidoethyl)piperidine-1-carboxylic acid

Sodium azide (325 mg) is added to mesilate (288 mg)obtained in reference example 78, N,N-dimethylformamide (10 ml) and the resulting mixture was stirred at 80°C for 15 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer is successively washed with water and saturated salt solution and then dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, thus obtaining specified in the title compound as an oily product (217 mg, 91%).

1H-NMR (400 MHz, CDCl3) δ: 1,32 is 1.70 (7H, m)of 1.46 (9H, s), 1,98-of 2.09 (1H, m), 2,68 is 2.80 (1H, ushort), 3,22-and 3.31 (2H, t), 3,91-4.09 to (1H, usher.), 4,28-4,39 (1H, usher.).

[Referential example 80] 2-(2-Azidoethyl)piperidine

triftoruksusnoi acid (1 ml) are added to the azide compound (215 mg), obtained in reference example 79, in methylene chloride (3 ml) at room temperature and the resulting mixture is stirred for 30 minutes. The residue obtained by evaporation of the reaction solvent under reduced pressure, dispense with the use of saturated aqueous sodium bicarbonate and methylene chloride. The aqueous layer was extracted with methylene chloride and the organic layers combined and dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, thus obtaining specified in the title compound as an oily product (62 mg). The aqueous layer from the process distribution is saturated with sodium chloride and the mixture is extracted twice with chloroform. The organic layers are combined and dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, thus obtaining specified in the title compound as an oily product (39 mg). Total yield specified in the connection header is 101 mg (77%).

1H-NMR (400 MHz, CDCl3) δ: 1,04-1,17 (1H, m), 1,30-1,45 (2H, m), 1,53-1,71 (5H, m), 1,75 is 1.86 (1H, m), 2,56-2,69 (2H, m), 3,02-3,11 (1H, m), 3,32-3,44 (2H, m).

MS (ESI) m/z: 155 (M+H)+.

[Referential example 81] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl)-2-(2-azidoethyl)piperidine

1-(6-M the toxi-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (191 mg), obtained in reference example 41, 2-(2-azidoethyl)piperidine (100 mg)obtained in reference example 80, 1-hydroxybenzotriazole (88 mg) and triethylamine (316 μl) dissolved in methylene chloride (10 ml). To the resulting mixture at room temperature add the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (186 mg), followed by stirring for 14 hours. The residue obtained by removal by evaporation of the reaction solvent under reduced pressure, partitioned between water and ethyl acetate. The organic layer is successively washed with water and saturated salt solution and then dried over anhydrous sodium sulfate, followed by filtration. The residue obtained by removal by evaporation of the solvent under reduced pressure, purified by thin-layer chromatography on silica gel (hexane-ethyl acetate), obtaining mentioned in the title compound as an oily product (227 mg, 81%).

1H-NMR (400 MHz, CDCl3[as a mixture of two isomers] δ: 1,51-1,87 (7H, m), 2,13-of 2.28 (1H, usher.), was 2.76-2,89 (0,5H, osirm), 3,13-3,27 (0,5H, osirm), 3,30-to 3.49 (2H, m), of 3.94 (3H, s), 4,67 and 4,70 (1H, users), 4,99-5,19 (1H, osirm), of 6.71 (1H, d, J=8,8 Hz), 6,86 and 6,88 (each 0,5H, each users), 7,20-7,27 (2H, m), 7,30-7,37 (3H, m), of 7.48 (1H, DD, J=8,8, 2.7 Hz), to 8.12 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 432 (M+H)+.

[Referential example 82] tert-Butyl ether 3-methylpiperazin-1-carboxylic acids of the Sabbath.

2-Methylpiperazin (3,19 g) are added to 2-(tert-BUTYLCARBAMATE)-2-phenylacetonitrile (7,87 g) in tetrahydrofuran (100 ml) at 0°C, followed by stirring for 2 hours. The residue obtained by removal by evaporation of the reaction solvent under reduced pressure, purified column chromatography on silica gel (chloroform-7 N. a mixture of ammonia/methanol), while receiving specified in the title compound as an oily product (5,70 g, 89%).

1H-NMR (400 MHz, CDCl3) δ: of 1.05 (3H, d, J=6,4 Hz)of 1.46 (9H, s), is 2.40 (1H, usher.), 2,65-2,84 (3H, m), 2,90-of 3.00 (1H, usher.), of 3.94 (2H, usher.).

MS (ESI) m/z: 201 (M+H)+.

[Referential example 83] tert-Butyl ether 3,4-dimethylpiperazine-1-carboxylic acid

tert-Butyl ether 3-methylpiperazin-1-carboxylic acid (5,70 g)obtained in reference example 82, dissolved in methanol (100 ml). To the resulting solution was added 10% palladium on coal (0,59 g), 35% aqueous formaldehyde solution (9.7 ml) and 1 M HCl in ethanol (31,3 ml) at room temperature, followed by stirring in an atmosphere of hydrogen for 15 hours. After a flush of the system with nitrogen, the insoluble substance is filtered off and the solvent of the filtrate is evaporated under reduced pressure. To the residue is added a mixture of chloroform-methanol (9%) and the resulting mixture Podlachia the t addition of aqueous sodium hydroxide with subsequent distribution. The aqueous layer was extracted with a mixture of chloroform-methanol (9%). The organic layers are combined and washed with saturated salt solution and then dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure and the residue purified by column chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound as an oily product (3,10 g, 51%).

1H-NMR (400 MHz, CDCl3) δ: was 1.04 (3H, d, J=6.3 Hz), of 1.46 (9H, s), 1,95-of 2.20 (2H, m), of 2.28 (3H, s), 2,50-2,78 (2H, usher.), 2,90 was 3.05 (1H, usher.), 3,88 (1H, usher.).

MS (ESI) m/z: 215 (M+H)+.

[Referential example 84] Salt triperoxonane acid and 1,2-dimethylpiperazine

Triperoxonane acid (15 ml) is added to tert-butyl ether, 3,4-dimethylpiperazine-1-carboxylic acid (3,10 g)obtained in reference example 83, in methylene chloride (30 ml) at room temperature, followed by stirring for 1 hour. The residue obtained by removal by evaporation of the reaction solvent under reduced pressure, crystallized from a mixture of chloroform-ether and the crystals are filtered, thus obtaining specified in the header connection (2,756 g, 56%).

1H-NMR (400 MHz, DMSO-d6) δ: 1,24 (3H, d, J=6.4 Hz), 2,30-3,70 (10H, usher.).

MS (ESI) m/z: 115 (M+H)+.

[Referential example 85] Salt triperoxonane acid and 1-benzyl-2-ethylpiperazine

1) N-Benzylamine

tert-Butyl ether 3-methylpiperazin-1-carboxylic acid (0,530 g)obtained in reference example 82, dissolved in ethanol (10 ml). To the resulting solution at room temperature is added benzaldehyde (0,405 ml), acetic acid (0,230 ml) and cyanoborohydride sodium (0,164 g) at room temperature, followed by stirring for 19 hours. When cooled at 0°mix dispense with the use of saturated aqueous sodium bicarbonate and chloroform. The aqueous layer was extracted with chloroform. The organic layers are combined and washed with saturated salt solution and then dried over sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure and the residue purified by column chromatography on silica gel (chloroform-acetone), thus obtaining N-benzylamine in the form of an oily product (0,547 g, 71%).

1H-NMR (400 MHz, CDCl3) δ: of 1.12 (3H, d, J=6,1 Hz)of 1.44 (9H, s)2,07 (1H, usher.), 2,35-2,47 (1H, m), 2,56-2,69 (1H, m), 2,97 is 3.23 (2H, m), 3,57-the 3.65 (1H, m), 3,90-4,01 (1H, m), 4,69 (2H, s), 7,15 was 7.45 (5H, m).

LC-MS m/z: 291 (M+H).

2) Specified in the header of the connection

Triperoxonane acid (1.5 ml) are added to the result of the above N-benzylamine (0,547 g) in methylene chloride (10 ml) at room temperature, followed by stirring for 2 hours. The reaction solvent is evaporated at Pont the leaders introduce pressure and to the residue is added toluene and subsequent azeotropic evaporation under reduced pressure. The residue is crystallized from a mixture of chloroform-diethyl ether and the crystals are filtered and then dried, thus obtaining specified in the header connection (0,610 g, 55%).

1H-NMR (400 MHz, DMSO-d6) δ: of 1.35 (3H, d, J=6.3 Hz), 2,5-4,5 (9H, m), 7,30-of 7.60 (5H, m), of 9.00 (1H, usher.).

MS (ESI) m/z: 191 (M+H).

[Reference example 86] (4'-Benzyloxy)acetophenone

Potassium carbonate (6,15 g) and benzylbromide (2,75 ml) are added to 4'-hydroxyacetophenone (3.00 g) in N,N-dimethylformamide (60 ml) at room temperature. The resulting mixture was stirred at 80°C for 3 hours and then cooled in air. The mixture is partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers are combined and washed with saturated salt solution and then dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, thus obtaining specified in the title compound in the form of solids (4,49 g, 90%).

1H-NMR (400 MHz, CDCl3) δ: to 2.55 (3H, s)to 5.13 (2H, s)to 7.00 (2H, d-like, J=9.1 Hz), 7,30 is 7.50 (5H, m), to 7.93 (2H, d-like, J=9,l Hz).

MS (FAB) m/z: 227 (M+H)+.

[Reference example 87] tert-Butyl ether 3,5-dimethylpiperazine-1-carboxylic acid

CIS-2,6-Dimethylpiperazine (5,08 g) are added to 2-(tert-butoxycarbonylamino)-2-phenylacetonitrile (11,35 g) in tetrahydrofuran (150 ml) at 0°followed the m by stirring for 2 hours. The reaction solvent is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (chloroform-7 n a mixture of ammonia/methanol), while receiving specified in the header connection (15,36 g, 72%).

1H-NMR (400 MHz, CDCl3) δ: of 1.16 (6H, d, J=6.5 Hz), of 1.47 (9H, s)of 2.50 (2H, usher.), 2,90 (2H, usher.), as 4.02 (2H, usher.).

MS (ESI) m/z: 214 (M+H)+.

[Reference example 88] tert-Butyl ether 3,4,5-trimethylpyrazine-1-carboxylic acid

tert-Butyl ester 3,5-dimethylpiperazine-1-carboxylic acid (3,g)obtained in reference example 87, dissolved in methanol (50 ml). To the resulting solution at room temperature, add 10% palladium on coal (0,504 g), 35% aqueous formalin (of 1.85 ml) and 1 M HCl in ethanol (15,4 ml) and the mixture is stirred in hydrogen atmosphere for 19 hours. To the mixture is added 10% palladium on coal (0.95 g), 35% aqueous formaldehyde solution (1.8 ml) and 1 M HCl-ethanol (15 ml), followed by stirring in a hydrogen atmosphere for 23 hours. After you flush the system with nitrogen, the resulting mixture is neutralized by adding aqueous sodium hydroxide and the insoluble material removed by filtration. The filtrate is dried to dryness under reduced pressure. The residue is purified column chromatography on silica gel (chloroform-7 n ammonia/methanol), while receiving specified in the title compound in the form of an oily product is (2.28 g, 65%).

1H-NMR (400 MHz, CDCl3) δ: a 1.08 (6H, d, J=6,1 Hz)of 1.45 (9H, s), 2.00 in of 2.20 (2H, m), of 2.25 (3H, s), 2,60 (2H, usher.), of 3.85 (2H, usher.).

MS (FAB) m/z: 229 (M+H)+.

[Referential example 89] Salt triperoxonane acid and 1,2,6-trimethylpyrazine

The General procedure of reference example 84 is repeated using tert-butyl ester 3,4,5-dimethylpiperazine-1-carboxylic acid (2.28 g)obtained in reference example 88, while receiving specified in the title compound in the form of solids (3,579 g, quantitative yield).

1H-NMR (400 MHz, DMSO-d6) δ: of 1.28 (6H, d, J=6, 6 Hz), 2,71 (3H, usher.), 2,90-of 3.60 (6H, usher.).

MS (ESI) m/z: 128 (M+H)+.

[Referential example 90] tert-Butyl ether 4-methyl-3-oxopiperidin-1-carboxylic acid

1) tert-Butyl ether 3-oxopiperidin-1-carboxylic acid

The triethylamine (3.9 ml) and di-tert-BUTYLCARBAMATE (of 6.31 g) are added to 2-oxopiperidine (2,61 g) in a mixture of tetrahydrofuran (40 ml) and methanol (50 ml) at room temperature, followed by stirring for 3 hours. The solvent is evaporated under reduced pressure. To the residue is added diethyl ether and the precipitated solid substance produce by filtration, thus obtaining tert-butyl ether 3-oxopiperidin-1-carboxylic acid (4,54 g, 87%).

1H-NMR (400 MHz, DMSO-d6) δ: of 1.40 (9H, s)and 3.15 (2H, usher.), of 3.45 (2H, usher.), 3,81 (2H, usher.), 8,03 (1H, usher.).

LC-MS m/z: 20 (M+H) +.

2) Specified in the header of the connection

To tert-butyl ether 3-oxopiperidin-1-carboxylic acid (0,303 g) in N,N-dimethylformamide (12 ml) is added sodium hydride (washed with pentane and dried, 44,3 mg) at 0°C, followed by stirring for 10 minutes. To the reaction mixture add methyliodide (0,141 ml) and the resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers are combined and washed with saturated salt solution and then dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, thus obtaining specified in the title compound as an oily product (0,308 g, 95%).

1H-NMR (400 MHz, CDCl3) δ: of 1.46 (9H, s)to 2.99 (3H, s)to 3.34 (2H, t-like, J=5.3 Hz), the 3.65 (2H, t-like, J=5.3 Hz), 4,07 (2H, s).

MS (FAB) m/z: 215 (M+H)+.

[Referential example 91] Salt 1-methylpiperazin-2-she triperoxonane acid

The General procedure of reference example 84 is repeated using tert-butyl ester 3-oxopiperidin-1-carboxylic acid (0,308 g)obtained in reference example 90, while receiving specified in the header connection (0,485 g, quantitative yield).

1H-NMR (400 MHz, CDCl3CD3OD (15:1)) δ: 2,98 (3H, s), 39 (2H, t-like, J=6,1 Hz), of 3.54 (2H, t-like, J=6,1 Hz), and 3.72 (2H, s).

MS (EI) m/z: 114 (M)+.

[Reference example 92] tert-Butyl ether 2-(2-dimethylaminoethyl)piperidine-1-carboxylic acid

Under ice cooling 2 M dimethylamine in methanol (5 ml) is added to the methanesulfonate (292 mg)obtained in reference example 78, in methanol (5 ml) and the resulting mixture was stirred at room temperature for 87 hours. The solvent is evaporated under reduced pressure and the residue distributed between water and chloroform. The aqueous layer was extracted with chloroform. The organic layers are combined and dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, thus obtaining specified in the title compound as an oily product (172 mg, 70%).

MS (ESI) m/z: 257 (M+H)+.

[Reference example 93] Ethyl ester 2-(piperidine-2-yl)acetic acid

The oxide of platinum (IV) (15 mg) is added to a mixture of ethyl ester of 2-(2-pyridyl)acetic acid (1,652 g) in water (1.25 ml) and concentrated hydrochloric acid (1.25 ml) in methanol (15 ml) and the resulting mixture is stirred in hydrogen atmosphere at room temperature for 15 hours. The catalyst is filtered off. The solvent is evaporated under reduced pressure IR residue add ethanol and then the solvent mixture is evaporated again under reduced pressure. To the residue is added a small amount of water, diethyl ether (about 100 ml) and excess potassium carbonate and the resulting mixture is stirred with subsequent filtering. The solvent of the filtrate is evaporated under reduced pressure, thus obtaining specified in the title compound as an oily product (1,322 g, 77%).

1H-NMR (400 MHz, CDCl3) δ: 1,08-of 1.23 (1H, m), 1,25 (3H, t, J=7.0 Hz), 1,29 to 1.47 (2H, m), 1,53-to 1.67 (2H, m), 1,73-to 1.82 (1H, m), 2,30-to 2.40 (2H, m), 2,60-a 2.71 (1H, m), 2,84-2, 94 (1H, m), 2,98-is 3.08 (1H, m), 4,13 (3H, t, J=7,0 Hz).

MS (ESI) m/z: 172 (M+H)+.

[Referential example 94] tert-Butyl ether 1-isopropylpiperazine-4-carboxylic acid

Acetone (1,47 ml) and 10% palladium on coal (50% moisture, 186 mg) is added to tert-butyl ether piperazine-1-carboxylic acid (UAH 1,862 g) in methanol (20 ml) and the resulting mixture is stirred in hydrogen atmosphere at room temperature for 10 hours. To the mixture acetone (1,47 ml) and the mixture is stirred in hydrogen atmosphere at room temperature for 36 hours. The catalyst is filtered off. The solvent is evaporated under reduced pressure, thus obtaining specified in the title compound as an oily product (2,253 g, 98%).

1H-NMR (400 MHz, CDCl3) δ: of 1.03 ( 6H, d, J=6.6 Hz), a 1.45 (9H, s), a 2.45 (4H, t, J=5,1 Hz), 2,68 (1H, septet, J=6.6 Hz), 3,42 (4H, t, J=5,1 Hz).

MS (ESI) m/z: 229 (M+H)+.

[Referential example the 95] Hydrochloride 1-isopropylpiperazine

1 M HCl in ethanol (40 ml) is added to tert-butyl ether, 1-isopropylpiperazine-4-carboxylic acid (2,253 g)obtained in reference example 94, and the resulting mixture was stirred at room temperature for 17 hours and then refluxed under heating for 1 hour. The solvent is evaporated under reduced pressure. To the residue is added ethanol and the insoluble solid substance produce by filtration, thus obtaining specified in the header connection (824 mg, 41%).

1H-NMR (400 MHz, DMSO-d6) δ: of 1.29 (6H, d, J=6.3 Hz), 3,26-3,63 (9H, usher.), for 9.47-10,02 (2H, usher.), 11,60-12,00 (1H, usher.).

MS (ESI) m/z: 129 (M+H)+.

[Referential example 96] tert-Butyl ester 1-(2-methoxyethyl)piperazine-4-carboxylic acid

2-Bromatology simple ether (0,94 ml) is added dropwise to a suspension of tert-butyl methyl ether piperazine-4-carboxylic acid (1,87 g) and potassium carbonate (1,38 g) in N,N-dimethylformamide (20 ml) at room temperature and the resulting mixture was stirred at 60°C for 24 hours. The reaction mixture is distributed using a mixture of ice-water and ethyl acetate. The organic layer is successively washed with water and saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is evaporated under reduced pressure. The residue is purified by number the night chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound as an oily product (1.39 g, 57%).

1H-NMR (400 MHz, CDCl3) δ: of 1.46 (9H, s), 2,42 at 2.45 (4H, m), 2,58 (2H, t, J=5.6 Hz), to 3.36 (3H, s), 3,44-3,47 (4H, m), 3,51 (2H, t, J=5.6 Hz).

MS (ESI) m/z: 245 (M+H)+.

[Referential example 97] Hydrochloride 1-(2-methoxyethyl)piperazine

tert-Butyl ester 1-(2-methoxyethyl)piperazine-4-carboxylic acid (1.39 g)obtained in reference example 96, dissolved in a mixture of 4 N. HCl-dioxane (20 ml). The resulting solution was stirred at room temperature for 3 hours. The solvent of the reaction mixture is evaporated under reduced pressure and to the residue is added ethanol and the solvent is then formed mixture is evaporated. To the residue is added ethanol and ether and the precipitated solid substance produce by filtration, thus obtaining specified in the title compound (900 mg, 74%).

1H-NMR (400 MHz, DMSO-d6) δ: 3,36-to 3.38 (2H, m), of 3.45 (8H, usher.), to 3.73 is 3.76 (2H, m), 10,00 (2H, usher.).

LC-MS m/z: 145 (M+H)+.

[Reference example 98] tert-Butyl ether 1-cyclopropylmethyl-4-carboxylic acid

tert-Butyl ether piperazine-1-carboxylic acid (1,87 g), [(1-amoxicilpin)oxy]trimethylsilane (8,05 ml) and acetic acid (5,72 g) dissolved in methanol (60 ml). To the resulting solution add cyanoborohydride sodium (1,89 g) at room temperature with subsequent paramasivan is eaten within 5 days. To the residue obtained by removal by evaporation of the reaction solvent under reduced pressure, add diethyl ether and the insoluble matter is filtered off. The filtrate is distributed by the addition of aqueous 1 n sodium hydroxide. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel(hexane-ethyl acetate), obtaining mentioned in the title compound as a solid (1,62 g, 71%).

1H-NMR (400 MHz, CDCl3) δ: 0,41-0,48 (4H, m)of 1.46 (9H, s), 2,54-of 2.56 (4H, m), 3,37-3,44 (4H, m).

MS (ESI) m/z: 2 68 (M+MeCN)+.

[Referential example 99] Hydrochloride 1-cyclopropylbenzene

The General procedure of reference example 97 was repeated using tert-butyl ester 1-cyclopropylmethyl-4-carboxylic acid (1,61 g, 7,11 mmol)obtained in reference example 98, while receiving specified in the title compound in the form of a solid substance (of 1.30 g, 93%).

1H-NMR (400 MHz, DMSO-d6) δ: 0,79 is 0.81 (2H, m), 1.14 in (2H, users), 3,52 (8H, users), 9,94 (2H, usher.).

LC-MS m/z: 127 (M+H).

[Reference example 100] 1-Benzhydrylamine-3-one

Under ice cooling pyridylsulfonyl acid (19.7 g) in dimethyls is levoxine (84 ml) is added dropwise to 1-benzhydrylamine-3-Olu (4,79 g) in triethylamine (27.9 ml) and the resulting mixture was stirred at 50° C for 40 minutes. The reaction mixture was partitioned between a mixture of ice-water and ethyl acetate. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (hexane-ethyl acetate), obtaining mentioned in the title compound as a solid (2.85 g, 60%).

1H-NMR (400 MHz, CDCl3) δ: of 4.00 (4H, s), 4,59 (1H, s), 7,19-7,49 (10H, m).

[Referential example 101] (1-Benzhydrylamine-3-yl)dimethylamine

5% palladium on coal (1.5 g) is added to 1-benzhydrylamine-3-ONU (1.50 g)obtained in reference example 100, and 40% aqueous dimethylamine (4 ml) in methanol (30 ml). The resulting mixture is subjected to catalytic recovery in an atmosphere of hydrogen overnight. The catalyst is filtered off and then the solvent of the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound as a solid (1.55 g, 92%).

1H-NMR (400 MHz, CDCl3) δ: of 2.08 (6H, s), 2,80-2,87 (3H, m), 3,36-of 3.42 (2H, m), 4,37 (1H, s), 7,15-7,41 (10H, m).

MS (ESI) m/z: 267 (M+H)+.

[Referential example 102] Hydrochloride azetidin-ultimatemenu

20% palladium hydroxide on coal (533 mg) are added to (1-benzhydrylamine-3-yl)dimethylamine (533 ml)obtained in reference example 101, in ethanol (15 ml) and the resulting mixture is subjected to catalytic recovery in an atmosphere of hydrogen for 18 hours. The catalyst is filtered off and then the filtrate is added a mixture of 1 N. HCl-ethanol (4 ml). The solvent is evaporated under reduced pressure. To the residue is added ether and the precipitated solid substance produce by filtration, thus obtaining specified in the title compound (300 mg, 87%).

1H-NMR (400 MHz, DMSO-d6) δ: 2,70 (6H, m), 4,05-4,10 (2H, m), 4,25-or 4.31 (1H, m), of 4.38-4,43 (2H, m).

LC-MS m/z: 101 (M+H)+.

[Reference example 103] (1-Benzhydrylamine-3-yl)methanesulfonate

While cooling with ice methanesulfonanilide (0.68 ml) is added dropwise to 1-benzhydrylamine-3-Olu (1.50 g) in pyridine (12 ml), followed by stirring at room temperature over night. To the reaction mixture is added a mixture of ice-water and the precipitated material are filtered, thus obtaining specified in the title compound (890 mg, 45%).

LC-MS m/z: 318 (M+N)+.

[Reference example 104] 3-Azido-1-benzhydrylamine

Methanesulfonate (890 mg)obtained in reference example 103, RAS is varaut in a mixture of N,N-dimethylformamide (17,8 ml) and water (1.8 ml). To the resulting solution was added sodium azide (237 mg), followed by stirring at 70°C for 3 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer is successively washed with water and saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (hexane-ethyl acetate), obtaining mentioned in the title compound as an oily product (635 mg, 86%).

1H-NMR (400 MHz, CDCl3) δ: 3,01 was 3.05 (2H, m), 3,47-3,51 (2H, m), 3.96 points-to 4.01 (1H, m), 4,34 (1H, s), 7,17-7,40 (10H, m).

LC-MS m/z: 265 (M+H)+.

[Referential example 105] 3-Amino-1-benzhydrylamine

5% palladium on coal (200 mg) are added to 3-azido-1-benzhydrylamine (630 mg)obtained in reference example 104, in ethyl acetate (12 ml). The resulting mixture is subjected to catalytic recovery in an atmosphere of hydrogen for 15 hours. The catalyst is filtered off. The solvent is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound as a solid (410 mg, 65%).

1H-NMR (400 MHz, CDCl3) δ: to 1.45 (2H, ears is.), 2,62-to 2.67 (2H, m), 3,51-of 3.54 (2H, m), 3,59-3,66 (1H, m), 4,28 (1H, s), 7,16-7,40 (10H, m).

LC-MS m/z: 239 (M+H)+.

[Referential example 106] 1-Benzhydryl-3-methoxyisatin

Under ice cooling 1-benzhydrylamine-3-ol (718 mg) in tetrahydrofuran (8 ml) is added dropwise to a suspension of 60% sodium hydride (144 mg) in N,N-dimethylformamide (8 ml) and the resulting mixture is stirred for 20 minutes. To the reaction mixture add methyliodide (0,23 ml) followed by stirring at room temperature over night. The reaction mixture was partitioned between cold saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (hexane-ethyl acetate), obtaining mentioned in the title compound as an oily product (680 mg, 90%).

1H-NMR (400 MHz, CDCl3) δ: 2,89-of 2.93 (2H, m), 3,23 (3H, s), 3,47-3,51 (2H, m), 4.04 the-4,07 (1H, m), 4,35 (1H, s), 7,16-7,41 (10H, m).

LC-MS m/z: 254 (M+H)+.

[Reference example 107] Hydrochloride 3-methoxyacridine

The General procedure of reference example 102 is repeated using 1-benzhydryl-3-methoxyacridine (680 mg)obtained in reference example 106, getting PR is listed in the title compound as a solid (287 mg, 87%).

1H-NMR (400 MHz, DMSO-d6) δ: 2,17 (3H, s), 3.75 to with 3.79 (2H, m), 4,06-4,11 (2H, m), 4,21-4,27 (1H, m), 9.28 are (2H, usher.).

[Reference example 108] Hydrochloride 3-hydroxyazetidine

The General procedure of reference example 102 is repeated using 1-benzhydrylamine-3-ol (500 mg), while receiving specified in the title compound as a solid (190 mg, 83%).

1H-NMR (400 MHz, DMSO-d6) δ: of 3.73 (2H, usher.), 3,93-a 4.03 (2H, m), 4,47-4,55 (1H, m), 6,21 (1H, d, J=6.3 Hz), 9,12 (2H, usher.).

[Referential example 109] tert-Butyl ether 1-cyclobutylmethyl-4-carboxylic acid

tert-Butyl ether piperazine-4-carboxylic acid (3,74 g), cyclobutanone (3,00 ml) and acetic acid (1,15 ml) dissolved in methanol (100 ml). To the resulting solution at room temperature add cyanoborohydride sodium (1.89 g), followed by stirring for 3 hours. The solvent is evaporated under reduced pressure and the residue is distributed using ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (chloroform-methanol), while receiving specified in the header Conn is out in the form of an oily product (4,43 g, 92%).

1H-NMR (400 MHz, CDCl3) δ: of 1.46 (9H, s), 1,61-of 1.73 (2H, m), 1,82-of 1.85 (2H, m), 1,87-of 1.94 (2H, m), 2,25-of 2.27 (4H, m), 2,62-by 2.73 (1H, m), 3,42-3,44 (4H, m).

[Reference example 110] Hydrochloride 4-cyclobutylamine

The General procedure of reference example 97 was repeated using tert-butyl ester 1-cyclobutylmethyl-4-carboxylic acid (4,40 g)obtained in reference example 109, while receiving specified in the title compound in the form of solids (3,24 g, 83%).

1H-NMR (400 MHz, DMSO-d6) δ: of 1.65 and 1.80 (2H, m), 2,13-2,19 (2H, m), 2,33-to 2.42 (2H, m), 3,49 (8H, users), 3,70-to 3.73 (1H, m), 9,83 (2H, usher.), 12,38 (1H, usher.).

LC-MS m/z: 141 (M+H)+.

[Reference example 111] (1-Benzhydrylamine-3-yl)-N,N-dimethylethylamine

3-Benzhydrylamine-3-carbonitrile (880 mg) in tetrahydrofuran (10 ml) is added dropwise to a suspension of sociallyengaged (134 mg) in tetrahydrofuran (20 ml) at 0°and the resulting mixture is refluxed under heating for 40 minutes. When cooled at 0°to the reaction mixture is added dropwise water (134 ml) and 15% aqueous sodium hydroxide (134 μl) and then add water (387 μl), followed by stirring for 20 minutes. The reaction mixture is filtered and the filtrate partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers are combined and washed on the every saturated salt solution and then dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure. To the residue is added methanol (20 ml). To the mixture at room temperature add cyanoborohydride sodium (1,11 g) and 37% aqueous formaldehyde (1,48 Il), followed by stirring for 24 hours. The solvent is evaporated under reduced pressure and the residue distributed between water and chloroform. The organic layer is extracted with chloroform. The organic layers are combined and washed sequentially with saturated aqueous sodium bicarbonate and saturated salt solution and then dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure and the residue purified by column chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound as an oily product (161 mg, 16%).

1H-NMR (400 MHz, CDCl3) δ: of 2.16 (6H, s), a 2.45 (2H, d, J=6,8 Hz)to 2.67 (1H, m), is 2.74 (2H, t, J=7,6 Hz), 3,39 (2H, t, J=7,6 Hz), 4,32 (1H, s), 7,14-to 7.18 (2H, m), 7.23 percent-7,27 (4H, m), 7,38 (4H, DD, J=1,5, 8,3 Hz).

LC-MS m/z: 281 (M+H)+.

[Reference example 112] Hydrochloride 3-dimethylaminomethylene

The General procedure of reference example 102 is repeated using (1-benzhydrylamine-3-yl)-N,N-dimethylethylamine (160 mg)obtained in reference example 111, while receiving specified in the title compound as a solid (47 mg, 44%).

1 H-NMR (400 MHz, DMSO-d6) δ: to 2.67 (6H, s), 3,28 is 3.40 (3H, m), 3,85-to 3.89 (2H, m), 4,01-4,06 (2H, m).

[Reference example 113] 4-Chloropyridin-2-carbonitril

The General procedure of reference example 15 is repeated using N-oxide 4-chloropyridine (6 g) and trimethylsilylacetamide (17.5 ml), while receiving specified in the title compound in the form of a solid substance (of 5.89 g, 92%).

1H-NMR (400 MHz, CDCl3) δ: 7,54-7,56 (1H, m), 7,72 (1H, m), 8,63-8,87 (1H, m).

MS (EI) m/z: 138 (M+).

[Reference example 114] 4-Methylthiopyridine-2-carbonitril

Thiamethoxam sodium (1.01 g) are added to 4-chloropyridin-2-carbonitrile (2.00 g)obtained in reference example 113 N,N-dimethylformamide (20 ml) at 0°C, followed by stirring for 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (hexane-ethyl acetate), obtaining mentioned in the title compound as a solid (1,96 g, 90%).

1H-NMR (400 MHz, CDCl3) δ: of 2.53 (3H, s), 7,26-7,27 (1H, m), 7,45-7,46 (1H, m), 8,45-8,46 (1H, m).

MS (EI) m/z: 150 (M+).

[Reference example 115] 1-(4-Methylthio-2-pyridyl)alanon

The General procedure of reference example 16 is repeated using 4-IU is iloperidone-2-carbonitrile (1,94 g), obtained in reference example 114, while receiving specified in the title compound as a solid (1.77 g, 82%).

1H-NMR (400 MHz, CDCl3) δ: of 2.53 (3H, s), a 2.71 (3H, s), 7,25-7,27 (1H, m), 7,83-to 7.84 (1H, m), 8,44-to 8.45 (1H, m).

MS (EI) m/z: 167 (M+).

[Referential example 116] Ethyl ester of 4-(4-methylthio-2-pyridyl)-2,4-dioxaborinane acid

The General procedure of reference example 17 is repeated using 1-(4-methylthio-2-pyridyl)ethanone (1,76 g) and diethyloxalate (2,86 ml), while receiving specified in the title compound as a solid (1.64 g, 58%).

1H-NMR (400 MHz, CDCl3) δ: 1,39 was 1.43 (3H, m), of 2.56 (3H, s), 4,37 was 4.42 (2H, m), 7,30 (1H, d, J=5,2, 2.0 Hz), 7,51 (1H, usher.), of 7.97 (1H, d, J=2.0 Hz), 8,46 (1H, d, J=5,2 Hz).

MS (EI) m/z: 267 (M+).

[Reference example 117] Ethyl ester 1-(6-methoxy-3-pyridyl)-5-(4-methylthio-2-pyridyl)pyrazole-3-carboxylic acid

The General procedure of reference example 3-2) repeat with the use of ethyl ester of 4-(4-methylthio-2-pyridyl)-2,4-dioxaborinane acid (1,62 g) and 5-hydrazino-2-methoxypyridine (0,843 g)obtained in reference example 2, thus obtaining specified in the title compound in the form of solids (0,366 g, 16%).

1H-NMR (400 MHz, CDCl3) δ: of 1.43 (3H, t, J=7.2 Hz), 2,42 (3H, s), of 3.95 (3H, s), to 4.46 (2H, q, J=7.2 Hz), 6,77 (1H, d, J=8,8 Hz), 7,01-7,03 (1H, m), 7,16 (1H, d, J=1.6 Hz), 7,26 (1H, s), 7,68 (1H, is d, J=8,8, 2,8 Hz), 8,11 (1H, d, J=2,8 Hz), of 8.28 (1H, d, J=5.6 Hz).

MS (FAB) m/z: 371 (M+H)+.

[Reference example 118] 1-(6-Methoxy-3-pyridyl)-5-(4-methylthio-2-pyridyl)pyrazole-3-carboxylic acid

The General procedure of reference example 19 is repeated using ethyl ester 1-(6-methoxy-3-pyridyl)-5-(4-methylthio-2-pyridyl)pyrazole-3-carboxylic acid (0,326 g), while receiving specified in the title compound as a solid (0.312 g, quantitative yield).

1H-NMR (400 MHz, CDCl3) δ: 2,43 (3H, s), of 3.95 (3H, s), is 6.78 (1H, d, J=8,8 Hz), 7,05-7,07 (1H, m), 7,17 (1H, d, J=1.6 Hz), 7,31 (1H, s), of 7.69 (1H, d, J=8,8, 2,8 Hz), 8,13 (1H, d, J=2,8 Hz), with 8.33 (1H, d, J=5,2 Hz).

MS (FAB) m/z: 343 (M+H)+.

[Referential example 119] 1 Ventiljacija-1H-1,4-diazepin-5-he

Concentrated sulfuric acid (25 ml) are added to 1-benzyl-4-piperidone (10,14 g) in acetic acid (50 ml) at room temperature and to this mixture at 0°With over a period of 2 hours sodium azide (3,880 g) followed by stirring at 5°C for 25 hours. The reaction mixture was alkalinized by adding aqueous sodium hydroxide with subsequent distribution with the use of chloroform. The aqueous layer was extracted with chloroform. The organic layers are combined and washed with saturated salt solution and then dried over anhydrous sodium sulfate with the settlement of edusim by filtration. The solvent is evaporated under reduced pressure and then the residue purified by column chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound in the form of solids (5,081 g, 47%).

1H-NMR (400 MHz, CDCl3) δ: 2,50-2,70 (6H, m), 3,20-to 3.35 (2H, m), of 3.60 (2H, s), 6,07 (1H, usher.), 7,20-7,40 (5H, m).

MS (ESI) m/z: 205 (M+H)+.

[Reference example 120] Hydrochloride, hexahydro-1H-1,4-diazepin-5-she

1 M HCl in ethanol (7.2 ml) and 10% palladium on coal (0.34 g) are added to 1 ventiljacija-1H-1,4-diazepin-5-ONU (1,490 g) in methanol (10 ml) at room temperature and the resulting mixture is stirred in hydrogen atmosphere for 4 hours. After blowing atmospheric reactions of nitrogen insoluble substance is removed by filtration. The solvent of the filtrate is evaporated under reduced pressure and to the residue is added diethyl ether and then precipitated solid substance produce by filtration, thus obtaining specified in the header connection (1,045 g, 96%).

1H-NMR (400 MHz, CD3OD) δ: 2,75-to 2.85 (2H, m), 3.25 to 3.40 in (6H, m), 3,48 of 3.56 (2H, m).

MS (ESI) m/z: 115 (M+H)+.

[Reference example 121] Hydrochloride (2.2-dimethylamide-3-yl)dimethylamine

1)3-Bromo-3-methylbutane-2-he

The irradiation lamp temperature glow 250 watts to potassium chloride (2.1 g) and-methylbutane-2-ONU (30 ml) in water (20 ml) at 60° With add 3 drops of bromine. After bleaching mixture by irradiation lamp temperature luminescence of 100 W to the mixture at 40 to 45°C for a period of 1 hour and added dropwise bromine (7,6 ml). The resulting mixture was stirred at 40°C for 2 hours and then cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer is successively washed with water, saturated aqueous sodium bicarbonate and saturated salt solution and then dried over anhydrous calcium chloride, followed by filtration. The solvent is evaporated under reduced pressure and the residue is distilled (boiling point: 120-130° (C)obtaining 3-bromo-3-methylbutane-2-it is in the form of an oily product (5,88 g, 13%).

1H-NMR (400 MHz, CDCl3) δ: of 1.86 (6H, s), is 2.44 (3H, s).

2) 3-(Benzylamino)-3-methylbutane-2-he

To the above 3-bromo-3-methylbutane-2-ONU (5,88 g) in methanol (30 ml) add benzhydrylamine (5.0 ml) and triethylamine (7.5 ml). The resulting mixture was stirred at 70°C for 24 hours and then cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer is successively washed with saturated aqueous sodium bicarbonate and saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is evaporated under reduced is the t and the solid substance, add diethyl ether and then the insoluble matter is removed by filtration. The mother liquor is distilled to dryness under reduced pressure. The residue is purified column chromatography on silica gel (hexane-ethyl acetate), thus obtaining 3-(benzylamino)-3-methylbutane-2-it is in the form of an oily product (3.3 g, 34%).

1H-NMR (400 MHz, CDCl3) δ: of 1.18 (6H, s), is 2.09 (3H, s), was 4.76 (1H, s), 7,17 (2H, m), 7,25-7,29 (4H, m), 7,37-7,39 (4H, m).

LC-MS m/z: 268 (M+H)+.

3) 1-Benzhydryl-2,2-dimethylamide-3-one

3-(Benzylamino)-3-methylbutane-2-he (6.5 g) in acetic acid (20 ml) rinsed before saturation with gaseous HCl and to the mixture are added dropwise bromine (1.25 ml) followed by stirring the mixture for 3 hours. To the reaction mixture are added 20% aqueous sodium hydroxide and thereby the pH of the mixture regulate to 14 or higher with subsequent distribution of the mixture with the use of carbon tetrachloride. The organic layer is washed with water. The solvent is evaporated under reduced pressure and to the residue is added N,N-dimethylformamide (30 ml) and saturated aqueous sodium bicarbonate (7 ml), followed by stirring for 3 minutes. The reaction mixture was partitioned between water and carbon tetrachloride. The organic layer is washed twice with saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is evaporated under reduced pressure and the residue purified by column chromatography the on silica gel, while receiving 1-benzhydryl-2,2-dimethylamide-3-one as a solid (754 mg, 12%).

1H-NMR (400 MHz, CDCl3) δ: of 1.20 (6H, s), of 3.95 (2H, s), is 4.85 (1H, s), 7,18 (2H, m), 7,26-7,31 (4H, m), 7,52-rate of 7.54 (4H, m).

4) Specified in the header of the connection

To a suspension of 1-benzhydryl-2,2-dimethylamide-3-one (265 mg) in methanol (4 ml) is added 2 M dimethylamine in tetrahydrofuran (3 ml) and 10% palladium on coal (50% moisture, 250 mg) and the resulting mixture is stirred in hydrogen atmosphere at room temperature for 20 hours. The reaction mixture is filtered. The solvent is evaporated under reduced pressure and to the residue is added ethanol (4 ml) and to the mixture are added 20% palladium hydroxide (50% moisture, 265 mg), followed by stirring in an atmosphere of hydrogen at room temperature for 22 hours. The reaction mixture is filtered and to the filtrate add 1 N. HCl in ethanol (2.2 ml), followed by stirring for 10 minutes. The solvent of the reaction mixture is evaporated under reduced pressure and the residue utverjdayut from a mixture of diethyl ether-ethyl acetate, and the thus obtained solid substance produce by filtration, thus obtaining specified in the title compound (60 mg, 30%).

1H-NMR (400 MHz, DMSO-d6) δ: of 1.62 (3H, s), is 1.81 (3H, s), 2.57 m (6H, m)to 3.89 (2H, m)4,06 (1H, m).

LC-MS m/z: 129 (M+H)+.

[Reference example 122] Hydrochloride 4,7-diazaspiro[2,5]octane

1,04 M complex, borane-tetrahydrofuran in tetrahydrofuran (24,7 ml) is added dropwise to a 4.7-diazaspiro[2,5]Octan-5,8-dione (1.2 g) in tetrahydrofuran (30 ml) at 0°With over a period of 30 minutes and the resulting mixture is refluxed under heating for 13 hours. To the reaction mixture at 0°add methanol (4 ml) and a solution of 4 N. HCl-dioxane (8 ml) and the mixture refluxed under heating for 1 hour and then cooled in air. The precipitated solid substance produce by filtration and washed with tetrahydrofuran, while receiving the mixture of products containing specified in the title compound (1.86 g).

To the thus obtained mixture of the product (1.4 g) in water (25 ml), add triethylamine (3,16 ml) and the reaction mixture is added N-carbobenzoxy (4.7 g) in acetonitrile (15 ml), followed by stirring at room temperature for 24 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers are combined and washed sequentially with saturated aqueous sodium bicarbonate and saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is evaporated under reduced pressure and the residue purified column chromatography on silica gel (GE the San ethyl acetate), while receiving N-benzyloxycarbonylation in the form of an oily product (1.4 g).

10% palladium on coal (50% moisture, 100 mg) is added to the thus obtained oily product (1.4 g) in ethanol (10 ml) and the resulting mixture is stirred in hydrogen atmosphere at room temperature for 1.5 hours. The reaction mixture is filtered and to the filtrate at 0°add 1 N. HCl in ethanol (5,78 ml) followed by stirring for 1 hour. The solvent of the reaction mixture is evaporated under reduced pressure and the residue utverjdayut from ethanol and ethyl acetate, and the thus obtained solid substance produce by filtration, thus obtaining specified in the title compound (315 mg, 26%).

1H-NMR (400 MHz, DMSO-d6) δ: 0,96-of 1.03 (2H, m), 1.18 to to 1.21 (2H, m), 3,30 (2H, s), at 8.36 (4H, m).

LC-MS m/z: 113 (M+H)+.

[Reference example 123] 1-(6-Chloro-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid

1) Ethyl ester of 4-phenyl-2,4-dioxaborinane acid

60% sodium hydride (1.50 g) was washed with hexane and suspended in tetrahydrofuran (60 ml). Under stirring at room temperature to the reaction mixture add the acetophenone (4,20 g) and then added to the mixture diethyloxalate (5.0 ml). To the mixture is added N,N-dimethylformamide (50 ml) and the resulting mixture is stirred in the atmosphere at 60°C for 3 hours and ZAT is m cooled down. The reaction mixture was acidified with aqueous 1 N. hydrochloric acid with subsequent distribution between water and ethyl acetate. The organic layer is successively washed with water and saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, thus obtaining the ethyl ester of 4-phenyl-2,4-dioxaborinane acid as an oily product.

2) 5-(2-Chloropyridin)hydrazine

While cooling with ice to 5-amino-2-chloropyridine (5,22 g) is added concentrated hydrochloric acid (40 ml), followed by stirring. The mixture is stirred while maintaining the temperature below 5°and thereto are added dropwise sodium nitrite (3,20 g) in water (20 ml). The resulting mixture is stirred under ice cooling for 1 hour, thus obtaining a mixture of diazocompounds.

The chloride dihydrate tin (II) (40 g) is dissolved in concentrated hydrochloric acid (25 ml) and the resulting solution is stirred under ice cooling. The mixture is stirred while maintaining the temperature below 10°to the resulting solution, supported with a 10°or lower for 1 hour and added dropwise to the above mixture of diazo compounds. The precipitated product produce by filtration and washed with ether, thus obtaining the crude salt tin 5-(2-who herperidin)of hydrazine.

3) Ethyl ester of 1-(6-chloro-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid

The result of the above crude ethyl ester of 4-phenyl-2,4-dioxaborinane acid and crude 5-(2-chloropyridin)hydrazine (salt tin) in ethanol (150 ml) is refluxed for 2 hours. The solvent is evaporated under reduced pressure and the residue is dissolved in ethyl acetate. The resulting solution was sequentially washed with 30% aqueous potassium hydroxide solution, water (twice) and saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is evaporated under reduced pressure and the residue purified by column chromatography on silica gel (hexane-ethyl acetate), thus obtaining the ethyl ester of 1-(6-chloro-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid in the form of crystals (6,01 g, 52%).

1H-NMR (400 MHz, CDCl3) δ: of 1.43 (3H, t, J=7 Hz), 4, 46 (2H, q, J=7 Hz), 7,05 (1H, s), 7,21-of 7.23 (2H, m), 7,35-7,42 (4H, m), of 7.70 (1H, DD, J=9, 3 Hz), a 8.34 (1H, d, J=3 Hz).

Elemental analysis: as With17H14ClN3O2.

Calculated: C, 62,30%; N, Or 4.31%; N, 12,81%.

Found: C, 62,20%; N, 4.25 Percent; N, 12,60%.

4) Specified in the header of the connection

To ethyl ether 1-(6-chloro-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (3,01 g) is added methanol (50 ml), tetrahydrofuran (40 ml) and aqueous 1 n sodium hydroxide (20 ml) and the resulting mixture is stirred during the course is 6 hours. To the residue obtained by removal by evaporation of the reaction solvent under reduced pressure, adding water (50 ml) and aqueous 1 n sodium hydroxide (30 ml). The mixture is washed twice with ether and acidified by addition of an aqueous 1 N. hydrochloric acid. The precipitated crystals are filtered and washed with water. The crystals are dissolved in ethyl acetate and the resulting solution washed with saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, thus obtaining specified in the title compound in the form of crystals (2.66 g, 97%).

1H-NMR (400 MHz, CDCl3) δ: 7,13 (1H, s), 7,21-of 7.25 (2H, m), 7,35-7,42 (4H, m), 7,74 (1H, DD, J=9.3 Hz), scored 8.38 (1H, d, J=3 Hz).

Elemental analysis: as With15H10ClN3O2.

Calculated: C, 60,11%; N, 3.36%Of Respondents; N, 14,02%.

Found: C, 60,06%; N, 3,30%; N, At 13.84%.

[Reference example 124] [1-(6-chloro-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-1-succinimide

Chloroform (50 ml) and triethylamine (6.5 ml) is added to 1-(6-chloro-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (2,56 g). The resulting mixture is stirred while cooling with ice and add di-(N-Succinimidyl)carbonate (4,70 g), followed by stirring over night. The reaction mixture is distributed between water and chloroform. The organic layer is successively washed with saturated in denim with sodium bicarbonate, water and water of 1 N. hydrochloric acid and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is evaporated under reduced pressure and to the residue is added a mixture of ether-hexane and the precipitated powder allocate by filtration, thus obtaining specified in the title compound (3.33 g).

1H-NMR (400 MHz, CDCl3) δ: of 2.93 (4H, s), 7,20-of 7.25 (3H, m), 7,35-7,44 (4H, m), 7,71 (1H, DD, J=9 Hz, 3 Hz), 8,35 (1H, d, J=3 Hz).

[Referential example 125] 1-(6-Ethoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid

Ethyl ester of 1-(6-chloro-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (207 mg)obtained in reference example 123-3), and ataxic sodium (500 mg) is dissolved in ethanol (15 ml). The resulting solution was sealed in a tube, heated at 90°With during the night. The residue obtained by evaporation of the reaction solvent under reduced pressure, dispense with the use of 1 n sodium hydroxide (50 ml) and diethyl ether. The aqueous layer was acidified by adding 1 N. HCl and extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is evaporated under reduced pressure and the residual solid is recrystallized from a mixture of ether-hexane, thus obtaining at asanee the title compound (120 mg, 71%).

1H-NMR (400 MHz, CDCl3) δ: of 1.39 (3H, t, J=7 Hz), 4, 36 (2H, q, J=7 Hz), 6,72 (1H, d, J=9 Hz), 7,10 (1H, s), 7,22-of 7.25 (2H, m), to 7.32 and 7.36 (3H, m), 7,56 (1H, DD, J=9, 3 Hz), 8,11 (1H, d, J=3 Hz).

Elemental analysis: as With17H15N3O3.

Calculated: C, 66,01%; N, 4,89%; N, Of 13.58%.

Found: C, 65,65%; N, 4,85%; N, 13,44%.

[Reference example 126] [1-(6-Ethoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-1-succinimide

Under ice cooling for 1-(6-ethoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (110 mg)obtained in reference example 125, in chloroform (5 ml), add triethylamine (0,30 ml) and di(N-Succinimidyl)carbonate (200 mg). The resulting mixture is stirred over night and to it was added di-(N-Succinimidyl)carbonate (500 mg) followed by stirring for 7 hours. The reaction mixture is distributed between water and chloroform. The organic layer is successively washed with 10% aqueous citric acid, water, 5% aqueous potassium carbonate and water and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is evaporated under reduced pressure and the residue purified column chromatography on silica gel (hexane-ethyl acetate), obtaining mentioned in the title compound as an oily product (232 mg, quantitative yield).

1H-NMR (400 MHz, CDCl3) δ: to 1.38 (3H, t, J=7 Hz), and 2.83 (4H, s), to 4.38 (2H, q, J=7 Hz), of 6.71 (1H, d, J=9 Hz), 7,17 (1H, s), 7,21-7,26 (H, m), 7,33 and 7.36 (3H, m), 7,54 (1H, DD, J=9.3 Hz), 8,10 (1H, d, J=3 Hz).

[Reference example 127] 1-(6-Isopropoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid

The General procedure of reference example 125 is repeated using ethyl ester 1-(6-chloro-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (1,05 g)obtained in reference example 123-3), and isopropanol, thus obtaining specified in the title compound in the form of powder (840 mg, 81%).

1H-NMR (400 MHz, CDCl3) δ: of 1.34 (6H, d, J=6 Hz), 5,28 (1H, Sep, J=6 Hz), of 6.66 (1H, d, J=9 Hz), 7,10 (1H, s), 7.23 percent-7,27 (2H, m), 7,33-7,38 (3H, m), 7,53 (1H, DD, J=9.3 Hz), 8,11 (1H, d, J=3 Hz).

Elemental analysis: as With18H17N3O3.

Calculated: C, 66,86%; N, And 5.30%; N, 13,00%.

Found: C, 66,62%; H, 5.25 Percent; N, 13,03%.

[Reference example 128] [1-(6-Isopropoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-1-succinimide

The General procedure of reference example 126 is repeated using 1-(6-isopropoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (0,80 g)obtained in reference example 127, and di-(N-Succinimidyl)carbonate (1.9 grams), while receiving specified in the title compound in the form of a foamy product (1,11 g, quantitative yield).

1H-NMR (400 MHz, CDCl3) δ: of 1.33 (6H, d, J=6 Hz), 2.91 in (4H, s), 5,27 (1H, Sep, J=6 Hz), of 6.66 (1H, d, J=9 Hz), 7,17 (1H, s), 7,22-7,26 (2H, m), 7,33-7,38 (3H, m), 7,52 (1H, DD, J=9, 3 Hz), 8,11 (1H, d, J=3 Hz).

[Reference example 129] [1-(6-Methoxy-3-pyridyl)-5-f is elpirata-3-carbonyl]-1-succinimide

The General procedure of reference example 126 is repeated using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (1,00 g)obtained in reference example 41, and di-(N-Succinimidyl)carbonate (1.88 g), while receiving specified in the title compound (1.22 g, 92%).

1H-NMR (400 MHz, CDCl3) δ: of 2.93 (4H, s), of 3.94 (3H, s), of 6.75 (1H, d, J=9 Hz), 7.18 in-7,26 (3H, m), 7,34-7,39 (3H, m), EUR 7.57 (1H, DD, J=9, 3 Hz)to 8.12 (1H, d, J=3 Hz).

[Reference example 130] 1,3 .3m-Trimethylpyrazine-2,5-dione

1) Ethyl ester of N-[α,α-dimethyl-(N-fluoren-9 ylethoxy)carbamino]acetylcarnosine

To N-[(N-fluoren-9 ylethoxy)carbonyl]-α-aminoadamantane acid (976 mg) in N,N-dimethylformamide (15 ml) add diisopropylethylamine (1.25 ml) and hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (1,25 d). The resulting mixture was stirred at room temperature for 10 minutes and then there was added the hydrochloride of the ethyl ester sarcosine (553 mg), followed by stirring at room temperature for 14 hours. The solvent is evaporated under reduced pressure and the residue partitioned between chloroform and water. The aqueous layer was extracted with chloroform. The organic layers are combined and washed with saturated salt solution and then dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated, propanganda pressure and the residue purified by column chromatography on silica gel (hexane-ethyl acetate), thus the ethyl ester of N-[α,α-dimethyl-(N-fluoren-9 ylethoxy)carbamino]acetylcarnosine in the form of solids (824 mg, 67%).

1H-NMR (400 MHz, CDCl3) δ: of 1.26 (3H, t, J=7,08 Hz)to 1.59 (6H, s), 3,10 (3H, s), of 4.05 (2H, users), 4,17-is 4.21 (4H, m), 4,47 (2H, m)to 5.56 (1H, users), 7,31 (2H, t, J=EUR 7.57 Hz), 7,40 (2H, t, J=EUR 7.57 Hz), 7,60 (2H, d, J=EUR 7.57 Hz), 7,76 (2H, d, J=EUR 7.57 Hz).

2) Specified in the header of the connection

Piperidine (867 ml) is added to ethyl ether, N-[α,α-dimethyl-(N-fluoren-9 ylethoxy)carbamino]acetylcarnosine (743 mg) in N,N-dimethylformamide (20 ml) followed by stirring at room temperature for 1 hour. To the mixture is added N,N-dimethylformamide (60 ml). The resulting mixture was stirred at 80°C for 14 hours and cooled in air. The reaction solvent is evaporated under reduced pressure and the residue is dissolved in ethyl acetate and then to the resulting solution was added hexane. The precipitated crystals are filtered, thus obtaining specified in the title compound (162 mg, 59%).

1H-NMR (400 MHz, DMSO-d6) δ: of 1.30 (6H, s), 2,82 (3H, s), of 3.95 (2H, s), 8,32 (1H, users).

[Reference example 131] piperidine-2-carboxamide

N-Benzyloxypyridine-2-carboxylic acid (2.0 g), 1-hydroxybenzotriazole (1.6 g) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.3 g) is dissolved in methylene chloride (20 ml). By the way, is valemus the solution at room temperature add concentrated aqueous ammonia (3 ml) and triethylamine (2 ml) followed by stirring for 3 days. The reaction mixture is distributed between water and methylene chloride. The organic layer is dried over anhydrous magnesium sulfate, followed by filtration. The solvent is evaporated under reduced pressure. To the residue in methanol (30 ml) is added 10% palladium on coal (1 g, 50% water) and the resulting mixture is stirred in hydrogen atmosphere for 20 hours. The catalyst is removed by filtration. The solvent is evaporated under reduced pressure and the thus obtained oily product is dried, thus obtaining specified in the title compound as a solid (970 mg, quantitative yield).

MS (ESI) m/z: 128 (M+).

[Reference example 132] Methylamide piperidine-2-carboxylic acid

The General procedure of reference example 131 is repeated using N-benzyloxypyridine-2-carboxylic acid (2.0 g) and 1.0 M methylamine in tetrahydrofuran (4 ml), while receiving specified in the title compound as an oily product (970 mg, quantitative yield).

MS (ESI) m/z 142 (M+).

[Reference example 133] Dimethylamide piperidine-2-carboxylic acid

The General procedure of reference example 131 is repeated using N-benzyloxypyridine-2-carboxylic acid (6.4 g) and dimethylamine hydrochloride (2 g), while receiving specified in the header of the connection is the form of an oily product (3.8 g, quantitative yield).

MS (ESI) m/z 156 (M+).

[Reference example 134] Ethyl ester of 4-(4-forfinal)-2,4-dioxaborinane acid

The General procedure of reference example 3-1) is repeated using 4'-fortetienne (3.0 g) and diethyloxalate (5,9 ml), while receiving specified in the title compound as a solid (3.12 g, 60%).

1H-NMR (400 MHz, CDCl3) δ: of 1.41 (3H, t, J=7,1 Hz), and 4.40 (2H, q, J=7,1 Hz), 7,02 (1H, s), 7,17 (2H, t, J=8,8 Hz), 8,02 (2H, DD, J=8,8, 5,4 Hz).

MS (ESI) m/z: 239 (M+1)+.

[Reference example 135] Ethyl ester 5-(4-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid

The General procedure of reference example 3-2) is repeated using 5-hydrazino-2-methoxypyridine (1.0 g)obtained in reference example 2, ethyl ester 4-(4-forfinal)-2,4-dioxaborinane acid (1.88 g)obtained in reference example 134, while receiving specified in the title compound as an oily product (2,12 g, 86%).

1H-NMR (400 MHz, CDCl3) δ: of 1.43 (3H, t, J=7,1 Hz), of 3.94 (3H, s), to 4.46 (2H, q, J=7,1 Hz), to 6.75 (1H, d, J=8,8 Hz), 7,02 (1H, s), 7,02 (2H, t, J=8.5 Hz), 7,21 (2H, DD, J=8,5, 5,1 Hz), EUR 7.57 (1H, DD, J=8,8, 2.7 Hz), of 8.09 (1H, d, J=2.7 Hz).

MS (EI) m/z: 341 (M+).

[Reference example 136] 5-(4-Forfinal)-1-(6-methoxy-3-pietil)pyrazole-3-carboxylic acid

Water 1 N. hydroxy is sodium (1.2 l) is added to ethyl ether, 5-(4-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid (164 g) in methanol (1.6 l) and the resulting mixture was stirred at room temperature for 5 hours. The reaction solvent is removed under reduced pressure and the residue partitioned between water and diethyl ether. the pH of the aqueous layer regulate when set to 2 by adding water 1 N. hydrochloric acid (1.5 l) and the precipitated crystals are dissolved in chloroform. The resulting solution dispense with the use of saturated salt solution and the organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is evaporated under reduced pressure, and precipitated crystals of diethyl ether are filtered, thus obtaining specified in the header connection (132,0 g, 88%).

1H-NMR (400 MHz, CDCl3) δ: of 3.95 (3H, s)6,76 (1H, d, J=8,8 Hz), 7,02-to 7.09 (3H, m), 7.18 in-7,26 (2H, m), 7,56 (1H, DD, J=8,8, 2.7 Hz), of 8.09 (1H, d, J=2.7 Hz).

[Reference example 137] 1-(5-Methoxy-2-pyridyl)-5-phenylpyrazol-3-carboxylic acid

1) 5-Amino-2-chloropyridin

Concentrated hydrochloric acid (1 ml) are added to 2-chloro-5-nitropyridine (20 g) in ethanol (160 ml) and water (40 ml). Reduced iron (70,5 g) is gradually added to the resulting mixture at room temperature and the mixture was stirred at 90°C for 1 hour and then cooled in air. The reaction mixture was filtered through celite and the solvent mother liquor is removed under reduced pressure. The remainder of ciscaucasica column chromatography on silica gel (ethyl acetate-hexane), thus the derived amine as a solid (15.2 g, 94%).

1H-NMR (400 MHz, CDCl3) δ: 3,71 (2H, users), of 6.96 (1H, DD, J=8,3, 2,9 Hz), was 7.08 (1H, d, J=8,3 Hz), the 7.85 (1H, d, J=2,9 Hz).

LC-MS m/z: 129 (M+H)+.

2) 5-Acetoxy-2-chloropyridin

48% aqueous tetracarbonyl acid (40,5 ml) are added to the result of the above 5-amino-2-chloropyridine (18 g) in ethanol (360 ml) and the resulting mixture is added dropwise while cooling at -5°With tert-butylnitrite (23,5 ml) followed by stirring for 20 minutes. To the reaction mixture is added diethyl ether and the precipitated product produce by filtration, followed by drying, thus obtaining tetrafluoroborate 6-chloropyridin-3-page (32 g, quantitative yield). Thus obtained diazonium salt (32 g) in acetic anhydride (160 ml) was gradually heated to 90°and the mixture is stirred for 45 minutes and then cooled in air. The reaction solvent is removed under reduced pressure and the residue distributed between ethyl acetate and water. The organic layer is successively washed with water and saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is removed under reduced pressure and the residue purified column chromatography on silica gel (hexane-ethyl acetate)to give 5-acetoxy-2-chloropyridin as Tverdov the substance (10 g, 42%).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 7,34 (1H, d, J=8,8 Hz), 7,47 (1H, DD, J=8,8, 2,9 Hz), 8,21 (1H, d, J=2,9 Hz).

LC-MS m/z: 172 (M+H)+.

3) 2-Chloro-5-hydroxypyridine

Potassium carbonate (400 mg) are added to the result of the above 5-acetoxy-2-chloropyridine (10 g) in methanol (200 ml) followed by stirring at room temperature for 20 hours. The reaction solvent is removed under reduced pressure and the residue purified column chromatography on silica gel (ethyl acetate), thus obtaining 2-chloro-5-hydroxypyridine in the form of solids (6,86 g, 91%).

1H-NMR (400 MHz, DMSO-d6) δ: 7,24 (1H, DD, J=8,8, 2,9 Hz), 7,29 (1H, d, J=8,8 Hz), to $ 7.91 (1H, d, J=2,9 Hz), 10,22 (1H, usher.).

LC-MS m/z: 130 (M+H)+.

4) 2-Chloro-5-methoxypyridine

28% solution of sodium methoxide-methanol (2.0 ml) is added dropwise to the above 2-chloro-5-hydroxypyridine (1.30 grams) and methyliodide (1.25 ml) in N,N-dimethylformamide (26 ml), followed by stirring at room temperature for 1.5 hours. The reaction mixture is distributed using saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is removed under reduced pressure and the residue purified column chromatography on silica gel (hexane-ethyl acetate), thus obtaining 2-chloro-5-ethoxypyridine in the form of a solid (1.40 g, 98%).

1H-NMR (400 MHz, CDCl3) δ: of 3.85 (3H, s), 7,17-of 7.25 (2H, m), with 8.05 (1H, d, J=2,9 Hz).

LC-MS m/z: 144 (M+H)+.

5) 2-Hydrazino-5-methoxypyridine

The result of the above 2-chloro-5-methoxypyridine (4.0 g) in hydrazine monohydrate (30 ml) was stirred at 100°C for 24 hours and then cooled in air. The reaction solvent is removed under reduced pressure and the residue is distributed using chloroform and aqueous 1 n sodium hydroxide. The organic layer is dried over anhydrous magnesium sulfate, followed by filtration. The solvent is removed under reduced pressure, thus obtaining 2-hydrazino-5-methoxypyridine in the form of an oily product (705 mg, 18%).

LC-MS m/z: 140 (M+N)+.

6) Ethyl ester of 1-(5-methoxy-2-pyridyl)-5-phenylpyrazol-3-carboxylic acid

The result of the above 2-hydrazino-5-methoxypyridine (705 mg) and ethyl ester of 2,4-dioxo-4-phenylalkanoic acid (1.12 g)obtained in reference example 123-1), in ethanol (25 ml), refluxed under heating for 19 hours and then cooled in air. The reaction solvent is removed under reduced pressure and the residue is distributed using ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is removed, propanganda pressure and the residue purified by chromatography on silica gel (hexane-ethyl acetate), thus the ethyl ester of 1-(5-methoxy-2-pyridyl)-5-phenylpyrazol-3-carboxylic acid as an amorphous product (705 mg, 43%).

1H-NMR (400 MHz, CDCl3) δ: of 1.42 (3H, t, J=7,1 Hz), 3,88 (3H, s), of 4.45 (2H, q, J=7,1 Hz), 7,03 (1H, s), 7,22-to 7.32 (6H, m), 7,45 (1H, d, J=6.8 Hz), with 8.05 (1H, d, J=3.1 Hz).

LC-MS m/z: 324 (M+H)+.

7) Specified in the header of the connection

Aqueous 1 n sodium hydroxide (3.5 ml) is added to the result of the above ethyl ether, 1-(5-methoxy-2-pyridyl)-5-phenylpyrazol-3-carboxylic acid (700 mg) in a mixture of methanol (7 ml) and tetrahydrofuran (7 ml), followed by stirring at room temperature for 2 hours. To the reaction mixture while cooling with ice, add water 1 N. hydrochloric acid (3.6 ml). The mixture is partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is removed under reduced pressure, thus obtaining specified in the title compound as a solid (602 mg, 94%).

1H-NMR (400 MHz, CDCl3) δ: to 3.89 (3H, s), to 7.09 (1H, s), 7.23 percent-of 7.35 (6H, m), 7,46 (1H, d, J=6.9 Hz), 8,08 (1H, d, J=3.1 Hz).

LC-MS m/z: 296 (M+H)+.

[Reference example 138] 1-(5-Methoxy-2-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid

1) 5-Bromo-2-hydrazinopyridazine

Hydrazine monohydrate (10 ml) are added to a 5-dibromopyridine (10.0 g) in pyridine (100 ml) at room temperature and the resulting mixture is refluxed under heating for 13 hours and then cooled in air. The reaction solvent is removed under reduced pressure and the residue is distributed with the application of water of 0.5 n sodium hydroxide and chloroform. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure, thus obtaining 5-bromo-2-hydrazinopyridazine in the form of solids (to 7.61 g, 96%).

1H-NMR (400 MHz, DMSO-d6) δ: to 6.67 (1H, d, J=9, 0 Hz), 7,55 (1H, DD, J=9,0, 2.4 Hz), to 7.64 (1H, s), of 8.00 (1H, d, J=2,4 Hz).

EI-MS m/z: 188 (M+).

2) Ethyl ester of 1-(5-bromo-2-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid

The result of the above 5-bromo-2-hydrazinopyridazine (7,12 g) and ethyl ester of 4-(2-pyridyl)-2,4-dioxaborinane acid (scored 8.38 g)obtained in reference example 31, suspended in ethanol (126 ml). To the suspension at room temperature, add acetic acid (8,67 ml) and the mixture refluxed under heating for 12 hours and then cooled in air. The reaction mixture is distributed using saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure and the residue purified by column chromatography on silica gel (hexane-ethyl acetate), thus obtaining the derived dihydropyrazolo. To thus obtained is produced in the water dihydropyrazolo in ethanol (146 ml) at room temperature add concentrated hydrochloric acid (4.9 ml) and the resulting mixture is refluxed under heating for 3 hours and then cooled in air. The reaction mixture is distributed using saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer is dried over sodium sulfate, followed by filtration. The solvent is removed under reduced pressure and the residue purified column chromatography on silica gel (hexane-ethyl acetate), thus obtaining the ethyl ester of 1-(5 bromo-2-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid as a solid (11.6 g, 82%).

1H-NMR (400 MHz, CDCl3) δ: of 1.42 (3H, t, J=7.2 Hz), of 4.45 (2H, q, J=7.2 Hz), 7,20 (1H, s), 7.23 percent-of 7.25 (1H, m), 7,49 (1H, DD, J=7,8, 0.7 Hz), 7,72 to 7.75 (2H, m), 7,95-of 7.97 (1H, m), compared to 8.26 (1H, d, J=2.2 Hz), 8,45-8,46 (1H, m).

EI-MS m/z: 373 (M+).

3) Specified in the header of the connection

In an argon atmosphere at room temperature to the above ethyl ether, 1-(5 bromo-2-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (3.00 g) in a mixture of methanol (30 ml) and toluene (30 ml) is added sodium methoxide (1,74 g) and copper bromide (I) (0,231 g). The resulting mixture is refluxed for 47 hours and then cooled in air. To the reaction mixture are added water (50 ml) followed by stirring at room temperature for 1.5 hours. The reaction mixture is distributed with the application of water, acetic acid (10 ml) and a solvent mixture of methanol-chloroform (1:10). The organic layer is dried over anhydrous sulfate NAT the Oia with subsequent filtering. The solvent is removed under reduced pressure, thus obtaining specified in the title compound as a solid (1.68 g, 71%).

1H-NMR (400 MHz, DMSO-d6) δ: 4,17 (3H, s), 7,56-8,71 (8H, m), 13,35 (1H, s).

FAB-MS m/z: 297 (M+H)+.

[Referential example 139] 1-(6-Methoxy-2-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid

Method (A)

1) Ethyl ester of 1-(6-chloro-2-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid

3-Chloro-6-hydrazinopyridazine (1,59 g) and ethyl ester of 4-(2-pyridyl)-2,4-dioxaborinane acid (2,45 g)obtained in reference example 31, in ethanol (60 ml) is refluxed under heating for 6 hours. To the reaction mixture are added concentrated hydrochloric acid (1 ml) and the mixture refluxed under heating for 1 hour and then cooled in air. The reaction solvent is removed under reduced pressure and the residue is distributed using ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is removed under reduced pressure and the residue purified by chromatography on silica gel (ethyl acetate-hexane), thus obtaining the ethyl ester of 1-(6-chloro-2-pyridazinyl)-5-(2-pyridyl)irsol-3-carboxylic acid as a solid (1.50 g, 41%).

1H-NMR (400 MHz, CDCl3) δ: of 1.44 (3H, t, J=7.0 Hz), to 4.46 (2H, q, J=7.0 Hz), 7.23 percent (1H, s), 7.24 to 7,27 (1H, m), 7,62-the 7.65 (1H, m), of 7.69 (1H, d, J=9.0 Hz), 7,76-7,81 (1H, m), 8,10 (1H, d, J=9.0 Hz), 8,40 (1H, d, J=4,6 Hz).

LC-MS m/z: 330 (M+H)+.

2) Methyl ether 1-(6-methoxy-2-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid

A solution of 28% sodium methoxide-methanol (3 ml) are added to the result of the above ethyl ether, 1-(6-chloro-2-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (1.50 g) in methanol (45 ml) and the resulting mixture is refluxed under heating for 2 hours and then cooled in air. The reaction solvent is removed under reduced pressure and the residue is distributed using ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is dried over anhydrous magnesium sulfate, followed by filtration. The solvent is removed under reduced pressure and the residue purified by chromatography on silica gel (ethyl acetate-hexane), while receiving methyl ester 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid as a solid (480 mg, 34%).

1H-NMR (400 MHz, CDCl3) δ: 3,99 (3H, s), 4,10 (3H, s), to 7.15 (1H, d, J=9.3 Hz), 7,21-of 7.23 (1H, m), 7,24 (1H, s), 7,58-to 7.61 (1H, m), 7,73 for 7.78 (1H, m), to 7.93 (1H, d, J=9.3 Hz), 8,40-to 8.41 (1H, m).

LC-MS m/z: 312 (M+H)+.

3) Specified in the header of the connection

Aqueous 1 n sodium hydroxide (3 ml) are added to obtained which the above methyl ether 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (475 mg) in ethanol (10 ml) and tetrahydrofuran (10 ml) followed by stirring at room temperature for 20 hours. Under ice cooling, the reaction mixture was neutralized by adding aqueous 1 N. hydrochloric acid (3 ml) and then the reaction mixture is distributed using a solvent mixture of chloroform-methanol (10:1). The organic layer is dried over anhydrous magnesium sulfate, followed by filtration. The solvent is removed under reduced pressure, thus obtaining specified in the title compound as a solid (300 mg, 66%).

1H-NMR (400 MHz, DMSO-d6) δ: Android 4.04 (3H, s), 7,32-to 7.35 (1H, m), 7,41 (1H, s), 7,49 (1H, d, J=9.3 Hz), 7,80-of 7.82 (1H, m), 7,87-to $ 7.91 (1H, m), to 7.99 (1H, d, J=9.3 Hz), 8,35-at 8.36 (1H, m).

LC-MS m/z: 298 (M+H)+.

Method In

1) Methyl ester of 4-(2-pyridyl)-2,4-dioxaborinane acid

In an argon atmosphere at room temperature 2-acetylpyridine (2,56 g) in methanol (26 ml) is added to dimethyloxalate (5,00 g) and sodium methoxide (to 2.29 g) in methanol (26 ml), followed by stirring for 15 minutes. The mixture was stirred at 60°C for 45 minutes and then cooled in air. To the reaction mixture, water is added and the resulting mixture was washed with diethyl ether. The aqueous layer dispense with the use of saturated aqueous ammonium chloride and chloroform. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure, thus obtaining methyl ester 4-(2-Piri who yl)-2,4-dioxaborinane acid in the form of solids (3,44 g, 79%).

1H-NMR (400 MHz, CDCl3) δ: of 3.94 (3H, s), 7,54 is 7.50 (1H, m), of 7.64 (1H, s), 7,93-7,89 (1H, m), 8,19-8,16 (1H, m), a total of 8.74-8,72 (1H, m).

EI-MS m/z: 207 (M+).

2) Methyl ether 1-(6-chloro-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid

The result of the above methyl ester 4-(2-pyridyl)-2,4-dioxaborinane acid (4,143 g) and 3-chloro-6-hydrazinopyridazine (2,891 g) in methanol (100 ml) is refluxed under heating for 109 hours. To the reaction mixture are added concentrated hydrochloric acid (2 ml) and the mixture refluxed under heating for 6 hours and then cooled in air. The reaction mixture is distributed using saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer is successively washed with water and saturated salt solution and then dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure, thus obtaining methyl ester 1-(6-chloro-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid as a solid (3,169 g, 50%).

1H-NMR (400 MHz, CDCl3) δ: 4,00 (3H, s), 7.24 to 7,28 (1H, m), 7,24 (1H, s), to 7.64 (1H, dt, J=7,8, 1.2 Hz), of 7.70 (1H, d, J=9.0 Hz), 7,79 (1H, TD, J=7,8) and 1.7 Hz), of 8.09 (1H, d, J=9.0 Hz), scored 8.38-to 8.41 (1H, m).

ESI-MS m/z: 316 (M+H)+.

3) Methyl ester 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid

The sodium methoxide 1,530 g) are added to the result of the above methyl ether 1-(6-chloro-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (2,981 g) in methanol (190 ml) at room temperature, followed by stirring for 19 hours. To the reaction mixture add water 1 N. hydrochloric acid (19 ml). Water added to the residue obtained by evaporation of the methanol under reduced pressure. The insoluble product are filtered and dried, thus obtaining methyl ester 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid as a solid (2,571 g, 87%).

[Reference example 140] 1-(6-Methoxy-3-pyridazinyl)-5-(4-dimethylaminophenyl)pyrazole-3-carboxylic acid

1) Methyl ester of 4-(4-dimethylaminophenyl)-2,4-dioxaborinane acid

General procedure stage 1) of the method In reference example 139 repeated through use of 4'-dimethylaminoazobenzene (1,224 g), dimethyloxalate (1,771 g) and sodium methoxide (180 mg), while receiving the methyl ester of 4-(4-dimethylaminophenyl)-2,4-dioxaborinane acid in the form of solids (742 mg, 39%).

1H-NMR (400 MHz, CDCl3) δ: 3,10 (6H, s), 3,93 (3H, s), 6,69 (2H, d, J=9.0 Hz), 7,01 (1H, s), 7,92 (2H, d, J=9.0 Hz).

ESI-MS m/z: 250 (M+H)+.

2) Methyl ether 1-(6-chloro-3-pyridazinyl)-5-(4-dimethylaminophenyl)pyrazole-3-carboxylic acid

The result of the above methyl ester 4-(4-dimethylaminophenyl)-2,4-dioxaborinane acid (742 mg) and 3-chloro-6-hydrazinopyridazine (473 mg) in methanol (30 ml) is refluxed under heating for 18 hours and then cooled in air. Rest ritel reaction is removed under reduced pressure and the residue is distributed using saturated aqueous sodium bicarbonate and chloroform. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure and the residue purified column chromatography on silica gel (chloroform-methanol), while receiving methyl ester 1-(6-chloro-3-pyridazinyl)-5-(4-dimethylaminophenyl)pyrazole-3-carboxylic acid as a solid (679 mg, 63%).

1H-NMR (400 MHz, CDCl3) δ: 2,98 (6H, s), 3,98 (3H, s), of 6.65 (2H, d, J=8,8 Hz), 6,97 (1H, s), 7,16 (2H, d, J=8, 8 Hz), a 7.62 (1H, d, J=9.0 Hz), of 7.90 (1H, d, J=9.0 Hz).

ESI-MS m/z: 358 (M+H)+.

3) Specified in the header of the connection

The General procedure of reference example 137-7) again by applying the result of the above methyl ester 1-(6-chloro-3-pyridazinyl)-5-(4-dimethylaminophenyl)pyrazole-3-carboxylic acid (679 mg), while receiving specified in the title compound in the form of solids (592 mg, 91%).

1H-NMR (400 MHz, CDCl3) δ: of 2.97 (6H, s)to 4.16 (3H, s), only 6.64 (2H, d, J=8,8 Hz), 7,01 (1H, s), 7,07 (1H, d, J=9.0 Hz), to 7.15 (2H, d, J=8,8 Hz), 7,60 (1H, d, J=9.0 Hz).

ESI-MS m/z: 340 (M+H)+.

[Referential example 141] 5-(5-Chloro-2-pyridyl)-1-(6-methoxy-3-pyridazinyl)pyrazole-3-carboxylic acid

1) 2-Bromo-5-chloropyridin

Bromine (12 ml) are added to 2-amino-5-chloropyridine (5 g) in 47% Hydrobromic acid (50 ml) at 0°and to the reaction mixture are added dropwise sodium nitrite (15 g) in water (20 ml) with the latter is the missing stirring for 1 hour. The reaction mixture dispense with the use of sodium hydroxide (32 g) in water (80 ml) and ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure, thus obtaining 2-bromo-5-chloropyridin in the form of a solid (6.8 g, 91%).

1H-NMR (400 MHz, CDCl3) δ: 7,44 (1H, d, J=8,42 Hz), 7,54 (1H, m), at 8.36 (1H, s).

2) 1-(5-Chloro-2-pyridyl)alanon

When cooled at -78°From 1.56 M n-utility in hexane (27 ml) is added dropwise to 2-bromo-5-chloropyridine (6.8 g) in diethyl ether (45 ml) and then to the mixture are added dropwise N,N-dimethylacetamide (5 ml) followed by stirring for 30 minutes. The reaction mixture is distributed using saturated aqueous ammonium chloride and ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure and the residue purified column chromatography on silica gel (hexane-ethyl acetate)to give 1-(5-chloro-2-pyridyl)Etalon in the form of solids (3,26 g, 59%).

1H-NMR (400 MHz, CDCl3) δ: 2,70 (3H, s), 7,80 (1H, DD, J=8,42, 2,32 Hz), 8,00 (1H, d, J=8,42 Hz), to 8.62 (1H, d, J=2,32 Hz).

3) Ethyl ester of 4-(5-chloro-2-pyridyl)-2,4-dioxaborinane acid

Dimethyloxalate (5 g) are added to a sodium methoxide (of 2.26 g) in ethanol (100 ml) and the mixture stirred for 5 minutes. To MESI was added 1-(5-chloro-2-pyridyl)alanon (3,26 g), followed by stirring at room temperature for 45 minutes. To the reaction mixture, water is added and the resulting mixture was washed with diethyl ether. The aqueous layer was acidified with aqueous 1 N. hydrochloric acid and for distribution to the mixture chloroform. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure, thus obtaining the ethyl ester of 4-(5-chloro-2-pyridyl)-2,4-dioxaborinane acid as a solid (4.12 g, 77%).

1H-NMR (400 MHz, CDCl3) δ: of 1.42 (3H, t, J=7,08 Hz)to 4.41 (2H, q, J=7,08 Hz), to 7.64 (1H, s), 7,87 (1H, DD, J=8,42, 2,44 Hz), 8,11 (1H, d, J=8,42 Hz), 8,67 (1H, d, J=2,44 Hz).

EI-MS m/z: 256 (M+H)+.

4) Ethyl ester of 1-(6-chloro-3-pyridazinyl)-5-(5-chloro-2-pyridyl)pyrazole-3-carboxylic acid

General procedure stage 1) method As reference example 139 repeat using the above ethyl ester 4-(5-chloro-2-pyridyl)-2,4-dioxaborinane acid (1 g) and 3-chloro-6-hydrazinopyridazine (735 mg), thus obtaining the ethyl ester of 1-(6-chloro-3-pyridazinyl)-5-(5-chloro-2-pyridyl)pyrazole-3-carboxylic acid as a solid (500 mg, 35%).

1H-NMR (400 MHz, CDCl3) δ: of 1.42 (3H, t, J=3,52 Hz), 4,47 (2H, q, J=3,52 Hz), 7,28 (1H, s), 7,58 (1H, d, J=8,30 Hz), 7,76 (1H, d, J=8,30 Hz), to 7.93 (1H, d, J=9.28 are Hz), 8,11 (1H, d, J=9.28 are Hz), a 8.34 (1H, s).

5) Specified in the header of the connection

The sodium methoxide (150 mg) is added to the result of the above ethyl ether, 1-(6-chloro-3-pyridazinyl)--(5-chloro-2-pyridyl)pyrazole-3-carboxylic acid (500 mg) in methanol (10 ml) followed by stirring at room temperature for 15 hours. The reaction mixture is distributed with the application of water 1 N. hydrochloric acid and chloroform. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure, thus obtaining specified in the title compound as an amorphous product (483 mg, >100%).

1H-NMR (400 MHz, CDCl3) δ: 4,12 (3H, s), to 7.15 (1H, d, J=9.28 are Hz), 7,19 (1H, s), EUR 7.57 (1H, DD, J=8,42, 2,81 Hz), of 7.75 (1H, dt, J=8,42, 2,81 Hz), of 7.97 (1H, d, J=9.28 are Hz), 8,40 (1H, s).

EI-MS m/z: 332 (M+H)+.

[Referential example 142] 1-(5-Methoxy-2-pyrazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid

1) 5-Chloro-2-hydrazinopyridazine

5-Chloro-2-hydroxypyridine (1.84 g), synthesized from aminopyrazine by way Palamidessi et al. (J. Org. Chem., vol. 29, p. 2491-2492, 1964), was dissolved in phosphorus oxychloride (28 ml). The solution, sealed in the tube, mix in the atmosphere at 130°C for 6 hours and then cooled in air. The reaction mixture was partitioned between a mixture of ice-water and methylene chloride. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure. To the residue in ethanol (14 ml) is added hydrazine monohydrate (1.39 ml) and the resulting mixture was stirred at room temperature for 150 minutes and at 80°C for 15 minutes and then cooled on who the ear. The solvent of the reaction mixture is removed under reduced pressure and the residue is distributed with the application of water and a solvent mixture of chloroform-methanol (1:10). The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure, thus obtaining 5-chloro-2-hydrazinopyridazine in the form of solids (0,325 g, 16%).

1H-NMR (400 MHz, DMSO-d6) δ: 4,32 (2H, users), 7,92 (1H, s), to 7.99 (1H, s), 8,13 (1H, s).

EI-MS m/z: 144 (M+).

2) Methyl ether 1-(5-chloro-2-pyrazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid

General procedure stage 2) the method In reference example 139 repeated using methyl ester of 4-(2-pyridyl)-2,4-dioxaborinane acid (0,414 g)obtained in stage 1) of the method In reference example 139, and the result of the above 5-chloro-2-hydrazinopyridazine (0,289 g), thus obtaining methyl ester 1-(5-chloro-2-pyrazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid in the form of solids (is 0.260 g, 41%).

1H-NMR (400 MHz, CDCl3) δ: 4,00 (3H, s), 7,25-7,28 (2H, m), to 7.59-to 7.61 (1H, m), to 7.77-7,81 (1H, m), 8,25 is 8.25 (1H, m), 8,39-to 8.41 (1H, m), cent to 8.85-8,84 (1H, m).

FAB-MS m/z: 316 (M+H)+.

3) Specified in the header of the connection

The General procedure of reference example 137-7) repeat using the above methyl ester 1-(5-chloro-2-pyrazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (0,254 g), while receiving specified in the agolove connection in the form of solids (0,237 g, 99%).

1H-NMR (400 MHz, DMSO-d6) δ: 3,98 (3H, s), 7,29-to 7.32 (1H, m), 7,37 (1H, s), 7,74-7,87 (2H, m), 8,11 (1H, s), 8,33-to 8.34 (1H, m), charged 8.52 (1H, s), 13,15 (1H, users).

FAB-MS m/z: 298 (M+H)+.

[Referential example 143] Ethyl ester 1-(6-methyl-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid

The General procedure of reference example 3-2) is repeated using 5-hydrazino-2-methylpyridine (1.20 g)obtained in reference example 63, and ethyl ester of 4-(2-pyridyl)-2,4-dioxaborinane acid (3,48 g)obtained in reference example 31, while receiving specified in the title compound as an oily product (0,459 g, 15%).

1H-NMR (400 MHz, CDCl3) δ: of 1.43 (3H, t-like, J=7,3 Hz), 2,60 (3H, s), to 4.46 (2H, q, J=7,3 Hz), 7,20 is 7.50 (4H, m), to 7.67-7,80 (2H, m), 8,39 (1H, usher.), 8,51 (1H, usher.).

FAB-MS m/z: 309 (M+H)+.

[Referential example 144] Lithium salt of 1-(6-methoxy-3-pyridyl)-5-(3-pyridazinyl)pyrazole-3-carboxylic acid

1) Methyl ester of 4-(3-pyridazinyl)-2,4-dioxaborinane acid

In an argon atmosphere and cooled at -78°With 3-acetylpyridine (2,097 g) in tetrahydrofuran (50 ml) added dropwise 1.0 M bis(trimethylsilyl)amide lithium in tetrahydrofuran (19 ml), followed by stirring for 1 hour. To the reaction mixture is added dropwise dimethyloxalate (4,055 g) in tetrahydrofuran (35 ml) and formed with the ect stirred at 0° C for 2 hours. The reaction solvent is removed under reduced pressure. To the residue water is added and the mixture washed with diethyl ether. The aqueous layer was slightly acidified with aqueous 1 N. hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure, thus obtaining methyl ester 4-(3-pyridazinyl)-2,4-dioxaborinane acid in the form of solids (2,63 g, 73%).

1H-NMR (400 MHz, CDCl3) δ: of 3.97 (3H, s), 7,73 (1H, DD, J=8,5, 5,1 Hz), of 7.96 (1H, s), of 8.28 (1H, DD, J=8,5, 1.8 Hz), 9,38 (1H, DD, J=5,1, 1.8 Hz).

ESI-MS m/z: 209 (M+H)+.

2) Methyl ether 1-(6-methoxy-3-pyridyl)-5-(3-pyridazinyl)pyrazole-3-carboxylic acid

The General procedure of reference example 140-2) is repeated using the above methyl ester 4-(3-pyridazinyl)-2,4-dioxaborinane acid (1,086 g) and 5-hydrazino-2-methoxypyridine (726 mg)obtained in reference example 2, thus obtaining methyl ester 1-(6-methoxy-3-pyridyl)-5-(3-pyridazinyl)pyrazole-3-carboxylic acid as a solid (309 mg, 19%).

1H-NMR (400 MHz, CDCl3) δ: of 3.95 (3H, s), of 4.00 (3H, s), to 6.80 (1H, d, J=8,8 Hz), the 7.43 (1H, s), 7,51 (2H, d, J=3,4 Hz), of 7.70 (1H, DD, J=8,8, 2.7 Hz), 8,11 (1H, d, J=2.7 Hz), to 9.15 (1H, t, J=3,4 Hz).

ESI-MS m/z: 312 (M+H)+.

3) Specified in the header of the connection

The monohydrate of lithium hydroxide (42 mg) to ablaut to the above methyl ether 1-(6-methoxy-3-pyridyl)-5-(3-pyridazinyl)pyrazole-3-carboxylic acid (309 mg) in methanol (20 ml) and the resulting mixture is refluxed for 18 hours and then cooled on the air. The reaction solvent is removed under reduced pressure, thus obtaining specified in the title compound as an amorphous product (322 mg, >100%).

ESI-MS m/z: 298 (M+N)+.

[Reference example 145] 1-(6-Methoxy-3-pyridyl)-5-(4-methyl-2-pyridyl)pyrazole-3-carboxylic acid

1) 4-Methylpyridin-2-carbonitril

The General procedure of reference example 15 is repeated using N-oxide 4-methylpyridine (6,00 g), thus obtaining 4-methylpyridin-2-carbonitrile in the form of solids (4,65 g, 72%).

1H-NMR (400 MHz, CDCl3) δ: of 2.44 (3H, s), 7,33-to 7.35 (1H, m), 7,53 (1H, s), to 8.57 (1H, d, J=4,8 Hz).

EI-MS m/z: 118 (M+).

2) 1-(4-Methyl-2-pyridyl)alanon

The General procedure of reference example 16 is repeated using the above 4-methylpyridin-2-carbonitrile (4,46 g), thus obtaining 1-(4-methyl-2-pyridyl)Etalon in the form of an oily product (of 4.38 g, 86%).

1H-NMR (400 MHz, CDCl3) δ: 2,43 (3H, s), of 2.72 (3H, s), 7,28-7,29 (1H, m), 7,87 (1H, m), 8,54 (1H, d, J=5,2 Hz).

EI-MS m/z: 135 (M+).

3) Ethyl ester of 4-(4-methyl-2-pyridyl)-2,4-dioxaborinane acid

Diethyloxalate (4.42 g) are added to ethoxide sodium (2,22 g) in ethanol (22 ml) and the mixture is stirred for 10 minutes. To the mixture obtained above 1-(4-methyl-2-pyridyl)alanon (2.20 g) in ethanol (22 ml) followed by stirring at room temperature for 20 minutes. Reaktsionnoi mixture, water is added and the resulting mixture was washed with diethyl ether and then the aqueous layer dispense with the use of saturated aqueous ammonium chloride and chloroform. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure, thus obtaining the ethyl ester of 4-(4-methyl-2-pyridyl)-2,4-dioxaborinane acid as an oily product (2,84 g, 74%).

1H-NMR (400 MHz, CDCl3) δ: of 1.41 (3H, t, J=7.2 Hz), 2,47 (3H, s), and 4.40 (2H, q, J=7.2 Hz), 7,34-to 7.35 (1H, m), 7,52 (1H, usher.), 8,01 (1H, s), to 8.57 (1H, d, J=5,2 Hz).

EI-MS m/z: 235 (M+).

4) Ethyl ester of 1-(6-methoxy-3-pyridyl)-5-(4-methyl-2-pyridyl)pyrazole-3-carboxylic acid

The General procedure of reference example 138-2) repeat using the above ethyl ester of 4-(4-methyl-2-pyridyl)-2,4-dioxaborinane acid (2.83 g) and 5-hydrazino-2-methoxypyridine (1,67 g)obtained in reference example 2, thus obtaining the ethyl ester of 1-(6-methoxy-3-pyridyl)-5-(4-methyl-2-pyridyl)pyrazole-3-carboxylic acid as a solid (1.66 g, 41%).

1H-NMR (400 MHz, CDCl3) δ: of 1.43 (3H, t, J=7, 2 Hz), was 2.34 (3H, s), of 3.94 (3H, s), to 4.46 (2H, q, J=7.2 Hz), 6,76 (1H, d, J=8,8 Hz), 7,05-7,06 (1H, m), 7.23 percent-of 7.24 (2H, m), 7,66-of 7.69 (1H, m), 8,10 (1H, d, J=2,8 Hz), at 8.36 (1H, d, J=4,8 Hz).

EI-MS m/z: 338 (M+).

5) Specified in the header of the connection

The General procedure of reference example 137-7) repeat using the above ethyl ester 1-(6-methoxy-3-pyridyl)-5-(4-methyl-2-pyridyl)pyrazole-3-carboxylic acid (1.04 g), while receiving specified in the title compound in the form of TV is Gogo substances (0,944 g, 99%).

1H-NMR (400 MHz, DMSO-d6) δ: 2,43 (3H, s)to 3.89 (3H, s), 6.87 in (1H, d, J=8,8 Hz), 7,17-7,19 (1H, m), 7,30 (1H, s), to 7.59{1H, s), 7.68 per-7,71 (1H, m), 8,13 (1H, d, J=2,8 Hz), 8,27-8,30 (1H, m), 13,04 (1H, usher.).

EI-MS m/z: 310 (M+).

[Referential example 146] 1-(6-Methoxy-3-pyridyl)-5-(5-methyl-2-pyridyl)pyrazole-3-carboxylic acid

1) 1-(5-Methyl-2-pyridyl)alanon

The General procedure of reference example 141-2) is repeated using 2-bromo-5-methylpyridine (10.0 g), thus obtaining 1-(5-methyl-2-pyridyl)Etalon in the form of an oily product (of 6.71 g, 85%).

1H-NMR (400 MHz, CDCl3) δ: to 2.42 (3H, s), a 2.71 (3H, s), to 7.61-to 7.64 (1H, m), 7,95 (1H, d, J=8.0 Hz), and 8.50 (1H, m).

EI-MS m/z: 135 (M+).

2) Ethyl ester of 4-(5-methyl-2-pyridyl)-2,4-dioxaborinane acid

The General procedure of reference example 146-3) repeat using the above 1-(5-methyl-2-pyridyl)ethanone (6.7 g) and diethyloxalate (13,5 ml), thus obtaining the ethyl ester of 4-(5-methyl-2-pyridyl)-2,4-dioxolane acid in the form of solids (8,99 g, 77%).

1H-NMR (400 MHz, CDCl3) δ: of 1.41 (3H, t, J=7.2 Hz), a 2.45 (3H, s), and 4.40 (2H, q, J=7.2 Hz), 7,56 (1H, usher.), 7,69-7,71 (1H, m), 8,08 (1H, d, J=8.0 Hz), 8,54 (1H, m).

EI-MS m/z: 235 (M+).

3) Ethyl ester of 1-(6-methoxy-3-pyridyl)-5-(5-methyl-2-pyridyl)pyrazole-3-carboxylic acid

The General procedure of reference example 138-2) repeat using the above ethyl ester 4-(5-methyl-2-pyridyl)-2,dioxaborinane acid (8,98 g) and 5-hydrazino-2-methoxypyridine (5.31g), obtained in reference example 2, thus obtaining the ethyl ester of 1-(6-methoxy-3-pyridyl)-5-(5-methyl-2-pyridyl)pyrazole-3-carboxylic acid as a solid (7,31 g, 57%).

1H-NMR (400 MHz, CDCl3) δ: of 1.42 (3H, t, J=7.2 Hz), was 2.34 (3H, s), of 3.95 (3H, s), of 4.45 (2H, q, J=7.2 Hz), 6,76 (1H, d, J=8,8 Hz), 7.23 percent-7,30 (2H, m), 7,47-7,50 (1H, m), 7,66-of 7.69 (1H, m), 8,10 (1H, d, J=2.4 Hz), at 8.36 (1H, m,).

FAB-MS m/z: 339 (M+H)+.

4) Specified in the header of the connection

The General procedure of reference example 137-7) repeat using the above ethyl ester 1-(6-methoxy-3-pyridyl)-5-(5-methyl-2-pyridyl)pyrazole-3-carboxylic acid (1,00 g), while receiving specified in the title compound in the form of solids (0,789 g, 86%).

1H-NMR (400 MHz, DMSO-d6) δ: to 2.29 (3H, s)to 3.89 (3H, s), 6.87 in-6,90 (1H, m), 7,26 (1H, s), 7,55-EUR 7.57 (1H, m), to 7.67-7,72 (2H, m), 8,13 (1H, d, J=2,8 Hz), 8,30 (1H, m), 13,04 (1H, usher.).

FAB-MS m/z: 311 (M+H)+.

[Reference example 147] Ethyl ester 1-tert-butoxycarbonylmethyl-3-carboxylic acid

1) Ethyl ester of 1,4-di-tert-butoxycarbonylmethyl-3-carboxylic acid

Hydrochloride piperazine-2-carboxylic acid (5.0 g) and di-tert-butoxycarbonyl (11,8 g) dissolved in tetrahydrofuran (50 ml). To the resulting solution add triethylamine (10,7 ml) and 6 N. aqueous sodium hydroxide (1 ml) followed by stirring the mixture at room temperature for 6 the aces. The reaction mixture dispense with the use of methylene chloride. The organic layer is dried over anhydrous magnesium sulfate, followed by filtration. The solvent is removed under reduced pressure and the residue purified column chromatography on silica gel (methylene chloride-methanol), while receiving 1,4-di-tert-butoxycarbonylmethyl-3-carboxylic acid (of 5.45 g, 67%). The General procedure of reference example 81 is repeated with the use of thus obtained 1,4-di-tert-butoxycarbonylmethyl-3-carboxylic acid and ethanol (2 ml), thus obtaining the ethyl ester of 1,4-di-tert-butoxycarbonylmethyl-3-carboxylic acid (5.5 g, 62%).

ES-MS m/z: 358 (M+).

2) Specified in the header of the connection

Concentrated hydrochloric acid (5 ml) are added to the result of the above ethyl ether, 1,4-di-tert-butoxycarbonylmethyl-3-carboxylic acid (5.5 g) in ethanol (50 ml) followed by stirring at room temperature for 3 days. The solvent of the reaction mixture is removed under reduced pressure to give the hydrochloride of ethyl ether piperazine-2-carboxylic acid (3.4 g, 95.7 per cent). Under ice cooling to thus obtained the hydrochloride of ethyl ether piperazine-2-carboxylic acid (3.4 g) in tetrahydrofuran (30 ml), add triethylamine (5 ml) and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetamido is l (4.0 g), followed by stirring at room temperature for 16 hours. The reaction mixture dispense with the use of methylene chloride. The organic layer is dried over anhydrous magnesium sulfate, followed by filtration. The solvent is removed under reduced pressure and the residue purified column chromatography on silica gel (methylene chloride-methanol), while receiving specified in the title compound as an oily product (3,14 g, 49%).

1H-NMR (400 MHz, CDCl3) δ: of 1.28 (3H, t, J=7,3 Hz)of 1.47 (9H, s), 2.70 height is 2.80 (1H, m), 3.00 and is 3.15 (3H, m), 3,40 is-3.45 (1H, m), 3,68 of 3.75 (1H, m), 4,20 (2H, q, J=7,3 Hz).

EI-MS m/z: 258 (M+).

[Reference example 148] Methyl ester of (3S)-morpholine-3-carboxylic acid

1) Methyl ester (2S)-2-(N-benzyloxycarbonyl)amino-3-(2-chloroethoxy)propanoic acid

To 1-benzyl-2-methyl ether (S)-(-)-1,2-azetidinone acid (1 g) in chloroform (10 ml) was added dropwise 2-chloroethanol (3 ml) and a catalytic amount of a complex of boron TRIFLUORIDE-diethyl ether (3 drops) followed by stirring at room temperature for 4 hours. The reaction mixture is distributed between water and chloroform. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure and the residue purified column chromatography on silica gel (hexane-ethyl acetate), thus obtaining methyl ester (2S)-2-(N-benzyl shall xianbei)amino-3-(2-chloroethoxy)propanoic acid as an oily product (1,09 g, 81%).

1H-NMR (400 MHz, CDCl3) δ: of 3.56 (2H, t, J=5,74 Hz), of 3.69 (2H, m), of 3.77 (3H, s), 3,85 (1H, m), 3, 95 (1H, DD, J=9,40, 3,17 Hz), 4,51 (1H, dt, J=8,67, 3,17 Hz)to 5.13 (2H, s), 5,67 (1H, usher.), of 7.36 (5H, m).

EI-MS m/z: 316 (M+H)+.

2) Methyl ester (2S)-2-amino-3-(2-chloroethoxy)propanoic acid

5% Palladium on coal (170 mg) are added to the result of the above methyl ether (2S)-2-(N-benzyloxycarbonyl)amino-3-(2-chloroethoxy)propanoic acid (1,09 g) in methanol (15 ml) and the resulting mixture was stirred at room temperature in a hydrogen atmosphere for 16.5 hours. The reaction mixture was filtered through celite and the solvent of the filtrate is removed under reduced pressure, thus obtaining methyl ester (2S)-2-amino-3-(2-chloroethoxy)propanoic acid as an oily product (608 mg, 97%).

1H-NMR (400 MHz, CD3OD) δ: 3,62 (2H, m), 3,70 (5H, m), 3,74 (3H, s), a-3.84 (1H, m), 3,90 (1H, m).

EI-MS m/z: 182 (M+H)+.

3) Specified in the header of the connection

The triethylamine (1.2 ml) is added to the result of the above methyl ether (2S)-2-amino-3-(2-chloroethoxy)propanoic acid (726 mg) in methanol (10 ml) and the resulting mixture is refluxed for 3 hours and then cooled in air. The reaction solvent is removed under reduced pressure. To the residue is added ethyl acetate, and the insoluble matter is removed by filtration. The solvent of the filtrate is removed under reduced pressure, recip what I mentioned in the title compound as an oily product (467 mg, 80%).

1H-NMR (400 MHz, D2O) δ: 2,70 (1H, m), is 2.88 (1H, m), 3,50-3,70 (4H, m), the 3.65 (3H, s), a 3.87 (1H, DD, J=11,60, of 3.05 Hz).

[Reference example 149] Hydrochloride 1,4-oxazepan

1) 1,4-Oxazepan-5-he

Under ice cooling to a tetrahydro-4H-Piran-4-ONU (9.80 g) in concentrated hydrochloric acid (50 ml) over a period of 40 minutes, add sodium azide (17.8 g), followed by stirring for 30 minutes and then at room temperature for 16 hours. Under ice cooling to the reaction mixture to establish the pH at 8-9 add sodium carbonate with subsequent distribution of the mixture by the addition of chloroform. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is removed under reduced pressure, thus obtaining 1,4-oxazepan-5-it is in the form of a solid (5.34 g, 47,4%).

1H-NMR (400 MHz, CDCl3) δ: 2,70-to 2.74 (2H, m), 3,32-3,37 (2H, m), 3.75 to a 3.83 (4H, m), of 6.31 (1H, users),

FAB-MS m/z: 116 (M+H)+.

2) tert-Butyl methyl ether 1,4-oxazepan-4-carboxylic acid

In nitrogen atmosphere under ice cooling obtained above 1,4-oxazepan-5-he (3,041 g) added to 1.0 M of the complex of borane-tetrahydrofuran in tetrahydrofuran (40 ml) over a period of 30 minutes, followed by stirring at room temperature for 30 mi the ut. The resulting mixture is refluxed under heating for 2.5 hours and then cooled in air. To the reaction mixture add 4 N. HCl-dioxane (25 ml) and methanol (12 ml) and the mixture refluxed under heating for 1 hour and then cooled in air. To the reaction mixture is added aqueous 1 n sodium hydroxide (80 ml) and to this mixture at room temperature, di-tert-butoxycarbonyl (8,849 g) in tetrahydrofuran (25 ml) and methanol (20 ml) followed by stirring for 17 hours. The reaction mixture is distributed between water and chloroform. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure and the residue purified column chromatography on silica gel (hexane-ethyl acetate), thus obtaining tert-butyl methyl ether 1,4-oxazepan-4-carboxylic acid as an oily product (2,68 g, 50%).

1H-NMR (400 MHz, CDCl3) δ: of 1.46 (9H, s), 1,82-of 1.95 (2H, m), 3.45 points-to 3.58 (4H, m), 3,66-of 3.77 (4H, m).

3) Specified in the header of the connection

4 N. Dioxane-HCl (4.6 ml) is added to the result of the above tert-butyl ether, 1,4-oxazepan-4-carboxylic acid (0,468 g) in methylene chloride (9,2 ml) at 0°C, followed by stirring at room temperature for 0.5 hours. The reaction solvent is removed p and reduced pressure, while receiving specified in the title compound in the form of solids (to 0.263 g, 82%).

1H-NMR (400 MHz, CDCl3) δ: 2,22 is 2.33 (2H, m), 3.27 to of 3.43 (4H, m), 3,82-are 3.90 (2H, m), 3,92-4,01 (2H, m), of 9.89 (1H, usher.).

ESI-MS m/z: 102 (M+H)+.

[Reference example 150] 1-Methylhexahydrophthalic

1) Benzylidenhydrazides-1,2, in primary forms

The triethylamine (100 ml) and benzylchloride (103 ml) are added to ethylcarbazole (50.0 g) in methylene chloride (400 ml) at 0°C, followed by stirring at room temperature for 18 hours. The reaction mixture is distributed using saturated aqueous sodium bicarbonate and chloroform. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is removed under reduced pressure and the residue purified column chromatography on silica gel (hexane-ethyl acetate), thus obtaining benzylidenhydrazides-1,2, in primary forms, in the form of an oily product (31.7 g, 27.7 per cent).

1H-NMR (300 MHz, CDCl3) δ: of 1.25 (3H, t, J=7,16 Hz), of 4.12 (2H, q, J=7,16 Hz), 5,16 (2H, s), 7,28 and 7.36 (5H, m).

2) Benzylamines-1,2, in primary forms

tert-Butylhypochlorite (19.1 ml) are added to the above benzylidenhydrazides-1,2-in primary forms (31.0 g) in ethyl acetate (150 ml) at room temperature, followed by stirring for 3 h the owls. The reaction mixture is distributed using saturated aqueous sodium carbonate and water. The organic layer is dried over anhydrous magnesium sulfate, followed by filtration. The solvent is removed under reduced pressure, thus obtaining benzylation-1,2, in primary forms, in the form of an oily product (28,7 g, 93,4%).

1H-NMR (300 MHz, CDCl3) δ: of 1.39 (3H, t, J=7,16 Hz), to 4.46 (2H, q, J=7,16 Hz), 5,41 (2H, s), 7,30-7,53 (5H, m).

3) 1-Benzyl ester-2-ethyl ether 1,2,3,6-tetrahydropyrimidin-1,2-dicarboxylic acid

1,3-Butadiene (64,0 g) product obtained above in benzylation-1,2, in primary forms (28,0 g) in benzene (100 ml) at -10°C, followed by stirring at room temperature for 18 hours. The reaction solvent is removed under reduced pressure, thus obtaining 1-benzyl ester-2-ethyl ether 1,2,3,6-tetrahydropyrimidin-1,2-dicarboxylic acid having impurities, in the form of an oily product (32 g).

FAB-MS m/z: 291 (M+N)+.

4) Ethyl ester hexahydropyridine-1-carboxylic acid

In an atmosphere of hydrogen to the resulting higher 1-benzyl ether-2-ethyl ether 1,2,3,6-tetrahydropyrimidin-1,2-dicarboxylic acid (32 g) in ethanol (100 ml) is added 10% palladium on coal (3.2 g) and the resulting mixture was stirred at 40°C for 24 hours and then cooled in air. The reaction mixture is filtered and the solvent filter is the one removed under reduced pressure and the residue purified by distillation (boiling point 81° C/1 mm Hg), thus obtaining the ethyl ester hexahydropyridine-1-carboxylic acid as an oily product (5,96 g, output 2 processes: 31,1%).

1H-NMR (300 MHz, CDCl3) δ: of 1.29 (3H, t, J=7,16 Hz), of 1.65 (4H, users), of 2.92 (2H, t, J=5,69 Hz), of 3.57 (2H, t, J=5,69 Hz), 4,19 (2H, q, J=7,16 Hz).

5) Specified in the header of the connection

To a suspension of sociallyengaged (2.64 g) in diethyl ether (50 ml) over a period of 1 hour at room temperature, added dropwise obtained above ethyl ester hexahydropyridine-1-carboxylic acid (5.5 g) in diethyl ether (20 ml). The resulting mixture is refluxed under heating for 4 hours. When cooled at -10°to the reaction mixture dropwise added a 40% aqueous solution of potassium hydroxide (100 ml), then added to the mixture diethyl ether, through which the mixture is distributed. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate, followed by filtration. The solvent is removed under reduced pressure, thus obtaining specified in the title compound as an oily product (1.75 g, 50.3 per cent).

1H-NMR (300 MHz, CDCl3) δ: of 1.42 (2H, users), 1,73-of 1.81 (2H, m), of 2.38 (3H, s), 2,48 (2H, users), to 3.02 (2H, t, J=5,51 Hz).

[Reference example 151] Salt triperoxonane acid and 4-methoxypiperidine

1) Tr is t-Butyl ether 4-methoxypiperidine-1-carboxylic acid

The General procedure of reference example 106 is repeated using tert-butyl ester 4-hydroxy-1-piperazinecarboxamide acid (2.0 g), while receiving tert-butyl ether 4-methoxypiperidine-1-carboxylic acid as an oily product (1,43 g, 67%).

1H-NMR (400 MHz, CDCl3) δ: 1,39-and 1.54 (2H, m)of 1.46 (9H, s), 1,81-of 1.84 (2H, m), 3,05-of 3.12 (2H, m), 3,31-3,39 (1H, m)to 3.35 (3H, s), 3,74-of 3.77 (2H, m).

2) Specified in the header of the connection

The General procedure of reference example 85-2) is repeated using the above tert-butyl ester 4-methoxypiperidine-1-carboxylic acid (1.42 g), while receiving specified in the title compound as an oily product (2.65 g, quantitative yield).

1H-NMR (400 MHz, CDCl3) δ: 1,98-2,02 (4H, m), 3,19 is 3.23 (2H, m), 3,30-of 3.42 (2H, m), 3,37 (3H, s), 3,54-of 3.60 (1H, m).

[Reference example 152] Hydrochloride 4,4-deformability

1) N-Benzyl-4,4-ceftobiprole

In an argon atmosphere at 0°TRIFLUORIDE With diethylaminoethyl (scored 8.38 ml) is added dropwise to 1-benzyl-4-piperidone (5,00 g) in benzene (200 ml) and the resulting mixture is stirred for 30 minutes and then refluxed under heating for 18 hours. When cooled at 0°the resulting mixture is distributed using saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer is dried over b is wodnym sodium sulfate, followed by filtration. The solvent is removed under reduced pressure and the residue purified column chromatography on silica gel (hexane-ethyl acetate), thus obtaining N-benzyl-4,4-ceftobiprole in the form of an oily product (4,67 g, 84%).

1H-NMR (400 MHz, CDCl3) δ: 1,93-2,04 (4H, m), 2,53 is 2.55 (4H, m), of 3.54 (2H, s), 7.24 to 7,34 (5H, m).

EI-MS m/z: 211 (M+).

2) Specified in the header of the connection

In an argon atmosphere 1-chloroethylphosphonic (2,62 ml) is added dropwise to the resulting higher N-benzyl-4,4-ceftobiprole (of 4.66 g) in methylene chloride (93 ml) at 0°and the resulting mixture was stirred at 55°C for 2 hours and then cooled in air. The reaction solvent is removed under reduced pressure and the residue in methanol (93 ml) is refluxed under heating for 4 hours and then cooled in air. The reaction solvent is removed under reduced pressure, thus obtaining specified in the title compound as a solid (3.03 g, 87%).

FAB-MS m/z: 122 (M+N)+.

[Reference example 153] Hydrochloride 3,3-deformability

1) N-Benzyl-3,3-ceftobiprole

The General procedure of reference example 152-1) repeat using the hydrochloride of 1-benzyl-3-piperidone (4,00 g), thus obtaining N-benzyl-3,3-ceftobiprole in the form of an oily product (1,09 g, 31%).

1H-NMR (400 MHz, CDCl3) ; : 1,73-of 1.92 (4H, m), of 2.45 (2H, t, J=5.4 Hz), 2,63 (2H, t, J=11.4 in Hz)of 3.60 (2H, s), 7.24 to 7,37 (5H, m).

FAB-MS m/z: 212 (M+H)+.

2) Specified in the header of the connection

The General procedure of reference example 152-2) repeat using the above N-benzyl-3,3-deformability (1.08 g), while receiving specified in the title compound in the form of solids (0,764 g, 95%).

1H-NMR (400 MHz, D3O) δ: 1,85 is 1.91 (2H, m), 2,01-2,11 (2H, m), of 3.12 (2H, t, J=5,2 Hz), 3,40 (2H, t, J=11.5 Hz).

FAB-MS m/z: 122 (M+H)+.

[Reference example 154] Hydrochloride 4-foreveryday

1) tert-Butyl ether 4-foreperiod-N-carboxylic acids

In an argon atmosphere under cooling at -78°TRIFLUORIDE [bis-(2-methoxyethyl)amino]sulfur (7,33 ml) is added dropwise to tert-butyl ether, 4-hydroxy-1-piperidinecarboxylic acid (4,00 g) in methylene chloride (80 ml), followed by stirring for 30 minutes. The resulting mixture was stirred at 0°C for 30 minutes and then at room temperature for 2 hours. The reaction mixture is distributed using saturated aqueous sodium bicarbonate and chloroform. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure and the residue purified column chromatography on silica gel (chloroform-ethyl acetate), getting at the fact tert-butyl ether 4-foreperiod-N-carboxylic acid as an oily product (1.77 g, 44%).

1H-NMR (400 MHz, CDCl3) δ: of 1.45 (9H, s), 1,86 to 1.76 (4H, m), 3,41-of 3.54 (4H, m), 4,70-to 4.87 (1H, m).

EI-MS m/z: 203 (M+).

2) Specified in the header of the connection

The General procedure of reference example 85-2) is repeated using the above tert-butyl ester 4-foreperiod-N-carboxylic acid (1,74 g), while receiving specified in the title compound in the form of solids (0,870 g, 73%).

1H-NMR (400 MHz, DMSO-d6) δ: 2,13-of 1.92 (4H, m), 3,01-of 3.12 (4H, m), a 4.83-equal to 4.97 (1H, m).

FAB-MS m/z: 104 (M+H)+.

[Reference example 155] tert-Butyl ether (3R)-3-ethoxypyrrolidine-1-carboxylic acid

The General procedure of reference example 106 is repeated using tert-butyl ether (3R)-3-hydroxypyrrolidine-1-carboxylic acid (0,955 g) and under the conditions (of 0.47 ml), while receiving specified in the title compound as an oily product (0,899 g, 89%).

1H-NMR (400 MHz, CDCl3) δ: of 1.46 (9H, s), 1,88-2,03 (2H, m), 3.33 and-a 3.50 (4H, m)to 3.33 (3H, s)to 3.92 (1H, users).

ESI-MS m/z: 146 (M-Bu+H)+.

[Reference example 156] Hexahydropyridine

1) Dimensiony ether 1,2,3,6-tetrahydropyrimidin-1,2-dicarboxylic acid

The General procedure of reference example 151-3) repeat with the use of dimensional ether 1,2-azodicarboxylic acid (10,28 g), while receiving dimensiony ether 1,2,3,6-tetr hydropyridine-1,2-dicarboxylic acid as an oily product (to 2.57 g, 21%).

1H-NMR (400 MHz, CDCl3) δ: 3,70-of 3.85 (2H, usher.), 4,35-to 4.52 (2H, usher.), of 5.05-5.25-inch (4H, usher.), 5,78 (2H, usher.), 7,03-7,40 (10H, m).

FAB-MS m/z: 353 (M+H)+.

2) Specified in the header of the connection

The General procedure of reference example 151-4) repeat using the above dimensional ether 1,2,3,6-tetrahydropyrimidin-1,2-dicarboxylic acid (2.57 m) g), while receiving specified in the title compound as an oily product (0,629 g, quantitative yield).

1H-NMR (400 MHz, DMSO-d6) δ: 1,67-of 1.75 (2H, m), 1,96-of 2.05 (2H, m), 2,60-3,10 (4H, m).

ESI-MS m/z: 87 (M+H)+.

[Reference example 157] Hydrochloride 1-methylpiperazin-2-it

4 N. HCl-dioxane (20 ml) is added to tert-butyl ether 3-oxopiperidin-1-carboxylic acid (of 2.06 g)obtained in reference example 90, followed by stirring at room temperature for 1 hour. The reaction solvent is removed under reduced pressure, thus obtaining specified in the title compound as an oily product (1.44 g, 99%).

1H-NMR (400 MHz, DMSO-d6) δ: of 2.86 (3H, s)to 3.34 (2H, osirm), 3,50 (2H, m)to 3.64 (2H, m).

ESI-MS m/z: 115 (M+H)+.

[Reference example 158] 1-(6-Methoxy-3-pyridazinyl)-5-(4-methoxy-2-pyridyl)pyrazole-3-carboxylic acid

1) Ethyl ester of 1-(6-chloro-3-pyridazinyl)-5-(4-methoxy-2-pyridyl)pyrazole-3-carboxylic acid

Abdulmateen stage 1) method As reference example 139 repeat with the use of ethyl ester of 4-(4-methoxy-2-pyridyl)-2,4-dioxaborinane acid (4.94 g), obtained in reference example 17 and 3-chloro-6-hydrazinopyridazine (2,84 g), thus obtaining the ethyl ester of 1-(6-chloro-3-pyridazinyl)-5-(4-methoxy-2-pyridyl)pyrazole-3-carboxylic acid as a solid (2,02 g, 29%).

1H-NMR (400 MHz, CDCl3) δ: 1,41-of 1.44 (3H, m), 3,88 (3H, s), 4,43-of 4.49 (2H, m), of 6.75 (1H, DD, J=5,9, 2.4 Hz), to 7.15 (1H, d, J=2.4 Hz), 7,19 (1H, s), 7,66-to 7.68 (1H, m)/8,07 (1H, d, J=9.0 Hz), 8,19 (1H, d, J=5,9 Hz).

EI-MS m/z: 359 (M+).

2) Specified in the header of the connection

Aqueous 1 n sodium hydroxide (14 ml) is added to the result of the above ethyl ether, 1-(6-chloro-3-pyridazinyl)-5-(4-methoxy-2-pyridyl)pyrazole-3-carboxylic acid (2,01 g) in a mixture of methanol (40 ml) and tetrahydrofuran (40 ml) at room temperature, followed by stirring for 1 hour. The reaction solvent is removed under reduced pressure and to the residue water is added and the mixture washed with chloroform. The aqueous layer was partitioned between acetic acid (20 ml) and the mixture of solvents methanol-chloroform (1:5). The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure and the residue is dissolved in methanol (14 ml). In an argon atmosphere to the resulting solution at room temperature is added sodium methoxide (of 0.332 g), followed by stirring for 3 hours. The mixture is refluxed under heating in those who tell 2 hours and then cooled in air. The reaction mixture is distributed with acetic acid (10 ml), water and a solvent mixture of methanol-chloroform (1:10). The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure, thus obtaining specified in the title compound in the form of solids (0,626 g, 34%).

1H-NMR (400 MHz, DMSO-d6) δ: a 3.87 (3H, s), a 4.03 (3H, s), 6.87 in-6,89 (1H, m), 7,40 was 7.45 (3H, m), 7,92 (1H, d, J=9,3 Hz)to 8.12 (1H, d, J=5,9 Hz), to 13.09 (1H, users).

EI-MS m/z: 327 (M+).

[Reference example 159] 1-(6-Methoxy-3-pyridyl)-5-(pyrrol-2-yl)pyrazole-3-carboxylic acid

Under ice cooling to ethoxide sodium (1.63 g) in ethanol (20 ml) add diethyloxalate (3,10 ml) and 1-[1-(phenylsulfonyl)pyrrol-2-yl]-1-Etalon (2,49 g), followed by stirring at room temperature for 5 hours. To the reaction mixture hydrochloride 5-hydrazino-2-methoxypyridine (2,52 g)obtained in reference example 1, and ethanol (20 ml) and the resulting mixture is refluxed under heating for 14.5 hours and then cooled in air. The reaction solvent is removed under reduced pressure and the residue is distributed using ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted again with ethyl acetate. The organic layer are combined and then su is at over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure, the residue is purified column chromatography on silica gel (ethyl acetate-hexane), thus obtaining the ethyl ester of 1-(6-methoxy-3-pyridyl)-5-[1-(phenylsulfonyl)pyrrol-2-yl]pyrazole-3-carboxylic acid as an oily product (3.28 g, 72%). To the thus obtained ethyl ether (3.28 g) in ethanol (22 ml) is added aqueous 1 n sodium hydroxide (22 ml) followed by stirring at room temperature for 2 days. To the reaction mixture add water 1 N. hydrochloric acid and the precipitated solid substance produce by filtration, thus obtaining specified in the title compound as a solid (1.40 g, 68%).

1H-NMR (400 MHz, DMSO-d6) δ: of 3.94 (3H, s), 5,49-the 5.51 (1H, m), 5,98-6,00 (1H, m), 6.87 in-6,89 (1H, m), 6,98 (1H, DD, J=8,8, 0.5 Hz), was 7.08 (1H, s), 7,80 (1H, DD, J=8,8, 2.7 Hz), of 8.25 (1H, DD, J=2.7, and 0.5 Hz), is 11.39 (1H, users).

ESI-MS m/z: 285 (M+H)+.

[Reference example 160] 1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid

Methyl ester 1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (2.20 g)obtained in stage 3) the method In reference example 139, dissolved in a mixture solvent of methanol (30 ml) and tetrahydrofuran (30 ml) and to the solution at room temperature was added 1 N. aqueous sodium hydroxide (15 ml) followed by stirring for 2.5 hours. When cooled l is home to the reaction mixture add 1 to N. aqueous hydrochloric acid (15 ml) and the solvent mixture chloroform-methanol (10:1) to distribute the mixture. The organic layer is dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure and to the residue is added isopropyl ether and then precipitated solid substance produce by filtration, thus obtaining specified in the title compound (1.42 g, 47.6 per cent).

1H-NMR (400 MHz, DMSO-d6) δ: Android 4.04 (3H, s), 7,32-to 7.35 (1H, m), 7,41 (1H, s), 7,49 (1H, d, J=9.3 Hz), 7,80-of 7.82 (1H, m), 7,87-to $ 7.91 (1H, m), to 7.99 (1H, d, J=9.3 Hz), 8,35-at 8.36 (1H, m).

LC-MS m/z: 298 (M+H)+.

[Reference example 161] 1-(6-Methoxy-3-pyridyl)-5-(1-methylpyrrole-2-yl)pyrazole-3-carboxylic acid

When cooled at -78°With 1-(1-methylpyrrole-2-yl)-1-ethanone (1,19 ml) in tetrahydrofuran (10 ml) is added 1.0 M bis(trimethylsilyl)amide lithium in tetrahydrofuran (10.4 ml), followed by stirring the mixture for 35 minutes. To the reaction mixture add diethyloxalate (2,05 ml) and the resulting mixture was gradually brought to room temperature, followed by stirring at room temperature for 2.5 hours. To the reaction mixture is added triethylamine (1,64 ml), hydrochloride 5-hydrazino-2-methoxypyridine (2,52 g)obtained in reference example 1, and ethanol (50 ml). The mixture is refluxed at nagrevaniyu for 2.5 hours. To the mixture is added acetic acid (5 ml) and the reaction mixture is refluxed for 3 days and then cooled in air. The reaction solvent is removed under reduced pressure. The remainder is distributed using ethyl acetate and saturated aqueous sodium bicarbonate and the aqueous layer was extracted with ethyl acetate. The organic layers are combined and dried over anhydrous sodium sulfate, followed by filtration. The solvent is removed under reduced pressure and the residue purified column chromatography on silica gel (ethyl acetate-hexane), thus obtaining the ethyl ester of 1-(6-methoxy-3-pyridyl)-5-(1-methylpyrrole-2-yl)pyrazole-3-carboxylic acid as an oily product (2.70 g, 82%). To the thus obtained ethyl ether (2.70 g) in ethanol (20 ml) is added aqueous 1 n sodium hydroxide (21 ml), followed by stirring at room temperature for 26 hours. The reaction mixture is distributed with the application of water 1 N. hydrochloric acid and ethyl acetate and the aqueous layer was extracted again with ethyl acetate. The organic layers are combined and dried over anhydrous magnesium sulfate, followed by filtration. The solvent is removed under reduced pressure, thus obtaining specified in the title compound as an amorphous solid (2.57 m) g, quantitative yield). Without complement Inoi cleaning compound is subjected to subsequent interaction.

[Example 1] 1-[5-(4-Chlorophenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl)-4-methylpiperazin

1) Specified in the header of the connection

To a solution of 5-(4-chlorophenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid (0,237 g)obtained in reference example 4 in N,N-dimethylformamide (5.0 ml) at room temperature was added 1-hydroxybenzotriazole (0,110 g), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0,303 g), triethylamine (0,255 ml) and N-methylpiperazine (0,240 ml). The resulting mixture is stirred for 21 hours and partitioned between water and ethyl acetate. Then the aqueous layer was extracted with ethyl acetate. The organic layers are combined and the resulting organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (chloroform-methanol), while receiving specified in the header connection (0,261 g, 88%).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2,40-2,60 (4H, m), a-3.84 (2H, usher.), of 3.94 (3H, s), 4,11 (2H, usher.), 6,74 (1H, d-like, J=8.7 Hz), 6,91 (1H, s), 7,17 (2H, d-like, J=8,8 Hz), 7,31 (2H, d-like, J=8,8 Hz), 7,49 (1H, DD, J=8,7, 2.7 Hz), of 8.09 (1H, d-like, J=2.7 Hz).

MS (ESI) m/z: 412 (M+H)+.

2) Salt specified in the connection header with hydrochloric acid

To the solution indicated the CSOs in the connection header (0,261 g) in chloroform (1.0 ml) was added 1 M HCl in ethanol (0635 ml) followed by stirring the mixture. To the reaction mixture to precipitate add diethyl ether and pentane. Besieged thus, the solid is collected by filtration and washed with diethyl ether, followed by drying, thus obtaining salt specified in the connection header with hydrochloric acid (0,223 g, 75%).

1H-NMR (400 MHz, DMSO-d6) δ: and 2.79 (3H, s), 3.00 and-3,70 (6H, m), 3,88 (3H, s), 4,60 (1H, usher.), of 4.95 (1H, usher.), 6,92 (1H, d, J=8,8 Hz), 7,05 (1H, s), 7,32 (2H, d, J=8.5 Hz), 7,47 (2H, d, J=8.5 Hz), 7,71 (1H, DD, J=8,8, 2,9 Hz), 8,21 (1H, d, J=2,9 Hz), or 10.60 (1H, usher.).

MS (ESI) m/z: 412 (M+H)+.

[Example 2] 1-[5-(4-Ethylphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl)-4-methylpiperazin

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an oily product (0,294 g, 87%) using 5-(4-ethylphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid (0,269 g)obtained in reference example 6, and N-methylpiperazine (0,275 ml).

1H-NMR (400 MHz, CDCl3) δ: of 1.23 (3H, t, J=7.8 Hz), 2,32 (3H, s), 2,40-2,60 (4H, m)of 2.64 (2H, q, J=7.8 Hz), a-3.84 (2H, usher.), 3,93 (3H, s), of 4.12 (2H, usher.), 6,72 (1H, d, J=8.7 Hz), to 6.88 (1H, s), 7,10-7,20 (4H, m), 7,49 (1H, DD, J=8,7, 2.4 Hz), 8,13 (1H, d, J=2.4 Hz),

MS (ESI) m/z: 406 (M+H)+.

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in the Tadei 2) of example 1, salt specified in the connection header with hydrochloric acid is obtained in the form of solids (0,276 g, 81%) using the above specified in the connection header (0,294 g).

1H-NMR (400 MHz, DMSO-d6) δ: of 1.17 (3H, t, J=7, 6 Hz), 2,60 (2H, q, J=7,6 Hz), and 2.79 (3H, s), 3, 00-3,75 (6H, m), 3,88 (3H, s)and 4.65 (1H, usher.), 5,00 (1H, usher.), 6,91 (1H, d, J=9.1 Hz), 6,97 (1H, s), 7,17-7,28 (4H, m), of 7.70 (1H, DD, J=9,1, 2.7 Hz), 8,21 (1H, d, J=2.7 Hz).

LC-MS m/z: 406 (M+H)+.

Elemental analysis: as With23H27N5O2• 1,0 HCl • 1,5 H2O.

Calculated: C, 58,90; N, 6,66; Cl, 7,56; N, 14,93.

Found: C, 58,65; N, 6,51; Cl, 7,63; N, 14,84.

[Example 3] 1-[1-(6-Methoxy-3-pyridyl)-5-(3-were)pyrazole-3-carbonyl]-4-methylpiperazin

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an oily product (0,471 g, quantitative yield) using 1-(6-methoxy-3-pyridyl)-5-(3-were)pyrazole-3-carboxylic acid (0,353 g)obtained in reference example 8 and N-methylpiperazine (0,380 ml).

1H-NMR (400 MHz, CDCl3) δ: 2,31 (3H, s), of 2.33 (3H, s), 2,40-2,60 (4H, m), a-3.84 (2H, usher.), of 3.94 (3H, s), of 4.12 (2H, usher.), of 6.71 (1H, d, J=8,8 Hz), to 6.88 (1H, s), 6,97 (1H, d-like, J=7,3 Hz), 7,08-of 7.25 (3H, m), of 7.48 (1H, DD, J=8,8, 2,6 Hz)to 8.12 (1H, d, J=2,6 Hz).

MS (ESI) m/z: 392 (M+H)+.

2) Salt specified in the header connect the deposits with hydrochloric acid

In a manner analogous to the method used in step 2) of example 1, salt specified in the connection header with hydrochloric acid is obtained in the form of solids (0,356 g, 70%) using the above specified in the connection header (0,471 g).

1H-NMR (400 MHz, DMSO-d6) δ: of 2.28 (3H, s), and 2.79 (3H, s), 2.95 and-3,70 (6H, m), and 3.7 (3H, s), 4,60 (1H, usher.), at 4.99 (1H, usher.), make 6.90 (1H, d, J=8.7 Hz), 6,95-7,03 (2H, m), 7,17-7,30 (3H, m), 7,68 (1H, DD, J=8,7, 2.0 Hz), 8,19 (1H, d, J=2.0 Hz), 10,79 (1H, usher.).

LC-MS m/z: 392 (M+H)+.

[Example 4] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-were)pyrazole-3-carbonyl]-4-methylpiperazin

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an oily product (0,335 g, 86%) using 1-(6-methoxy-3-pyridyl)-5-(2-were)pyrazole-3-carboxylic acid (0,307 g)obtained in referential example 10 and N-methylpiperazine (0,330 ml).

1H-NMR (400 MHz, CDCl3) δ: 2,04 (3H, s), of 2.34 (3H, s)of 2.50 (4H, m), 3,85 (2H, usher.), the 3.89 (3H, s), 4,17 (2H, usher.), only 6.64 (1H, d, J=9.1 Hz), 6,83 (1H, s), 7,15-to 7.35 (5H, m), 7,42 (1H, DD, J=9,1, 2.7 Hz), 8,03 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 392 (M+H)+.

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 1, salt specified in the connection header with chlorine is stevedorage acid obtained as a solid (0,30 g, 81%) using the above specified in the connection header (0,335 g).

1H-NMR (400 MHz, DMSO-d6) δ: 2,04 (3H, s), 2,80 (3H, s), 3.00 and-of 3.80 (6H, m), 3,82 (3H, s), 4,60 (1H, usher.), 5,02 (1H, usher.), 6,83 (1H, d, J=9.0 Hz), 6.90 to (1H, s), 7.18 in-7,40 (4H, m), a 7.62 (1H, DD, J=9,0, 2.7 Hz), 8,07 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 392 (M+H)+.

[Example 5] 1-[5-(3-Forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazin

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an oily product (0,314 g, 83%) using 5-(3-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid (0,302 g)obtained in reference example 12, and N-methylpiperazine (0,320 ml).

1H-NMR (400 MHz, CDCl3) δ: 2,31 (3H, s), 2,40-2,60 (4H, m), 3,82 (2H, usher.), 3,93 (3H, s), 4.09 to (2H, usher.), 6,72 (1H, d, J=8,8 Hz), make 6.90 (1H, s), 6.90 to-7,10 (3H, m), 7,25-to 7.35 (1H, m), 7,47 (1H, DD, J=8,8, 2.7 Hz), 8,08 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 396 (M+H)+.

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 1, salt specified in the connection header with hydrochloric acid is obtained in the form of solids (0,282 g, 79%) using the above specified in the connection header (0,314 g).

1H-NMR (400 MHz, DMSO-d6) δ: and 2.79(3H, C)3,00-of 3.75 (6H, m), 3,88 (3H, s), 4,60 (1H, usher.), of 4.95 (1H, usher.), 6,92 (1H, d, J=8,8 Hz), 7,05-7,13 (1H, m), to 7.09 (1H, s), 7.18 in-7,30 (2H, m), 7,39-7,50 (1H, m), 7,72 (1H, DD, J=8,8, 2.7 Hz), by 8.22 (1H, d, J=2.7 Hz), 10,50 (1H, usher.).

LC-MS m/z: 396 (M+H)+.

Elemental analysis: as With21H22FN5O2•1,0 HCl•1,0 H2O.

Calculated: C, 56,06; N, The Ceiling Of 5.60; Cl, 7,88; F, 4,22; N, 15,57.

Found: C, 55,97; N, The Ceiling Of 5.60; Cl, 8,01 F, 4,20; N, 15,36.

[Example 6] 4-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl)morpholine

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (0.126 g, 66%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (0,155 g)obtained in referential example 41 and research (0,137 ml).

1H-NMR (400 MHz, CDCl3) δ: 3,65-of 4.05 (6H, m), of 3.94 (3H, s), 4,10-4,30 (2H, m), 6,72 (1H, d, J=8,8 Hz), to 6.95 (1H, s), 7,15-7,40 (5H, m), 7,47 (1H, DD, J=8,8, 2.7 Hz), to 8.12 (1H, d, J=2.7 Hz).

MS (FAB) m/z: 365 (M+H)+.

[Example 7] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-3,4-dimethylpiperidin

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an oily product (0,268 g, 84%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (0,241 g)obtained in reference example 1, and salts of 1,2-dimethylpiperazine with triperoxonane acid (0,838 g)obtained in reference example 84.

1H-NMR (400 MHz, CDCl3) δ: of 1.09 and 1.15 (3H, each d, each J=6,1 Hz), 2,10-2,40 (1,5H, m), of 2.33 (3H, s), 2,70-2,95 (2H, m), is 3.08-3,20 (1H, m), 3,45-3,60 (0,5H, m), 3,93 (3H, s), 4,45-4,85 (2H, m), of 6.71 (1H, d, J=8,8 Hz)6,91 (1H with), 7,20-of 7.60 (6H, m)to 8.12 (1H, s).

LC-MS m/z: 392 (M+H)+.

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 1, salt specified in the connection header with hydrochloric acid is obtained in the form of solids (0,173 g, 54%) using the above specified in the connection header (0,268 g).

1H-NMR (400 MHz, DMSO-d6) δ: 1,15-of 1.45 (3H, m), 2,0-4,0 (5H, m), and 2.79 (3H, s), 3,86 (3H, s), 4,60 (1H, usher.), of 4.95 (1H, usher.), 6,89 (1H, d, J=8.7 Hz), 7,00 (1H, s), 7,20 was 7.45 (5H, m), 7,68 (1H, DD, J=8,7, 2,5 Hz), 8,18 (1H, d, J=2.5 Hz).

LC-MS m/z: 392 (M+H)+.

[Example 8] 1-[4-Methyl-5-phenyl-1-(3-pyridyl)pyrazole-3-carbonyl)-4-methylpiperazin

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an oily product (0,596 g, 61%) using 4-methyl-5-phenyl-1-(3-pyridyl)pyrazole-3-carboxylic acid (0,752 g)obtained in reference example 54, and N-methylpiperazine (0,90 ml).

1H-NMR (400 MHz, CDCl 3) δ: to 2.18 (3H, s), of 2.34 (3H, s), 2,45 at 2.59 (4H, m), a 3.87 (4H, usher.), 7,15-7,30 (3H, m), 7,35-the 7.43 (3H, m), 7,51-EUR 7.57 (1H, m), of 8.47 (1H, DD, J=4,7 Hz, J=l,5 Hz), 8,49 (1H, d, J=2.2 Hz).

MS (ESI) m/z: 362 (M+H)+.

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 1, salt specified in the connection header with hydrochloric acid is obtained in the form of solids (0.565 g, 84%) using the above specified in the connection header (0,596 g).

1H-NMR (400 MHz, DMSO-d6) δ: 2,11 (3H, s), 2,82 (3H, s), 3.00 and-the 3.65 (6H, m), 4,55-4,80 (2H, m), 7,21-to 7.32 (2H, m), 7,40-to 7.50 (3H, m), 7,63-of 7.70 (1H, m), 8,48 (1H, d, J=2.4 Hz), charged 8.52 (1H, d-like, J=4,8 Hz), 10,45 (1H, usher.).

MS (ESI) m/z: 362 (M+H)+.

[Example 9] 1-[4-Methyl-1,5-diphenylphenol-3-carbonyl]-4-methylpiperazin

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an oily product (0,818 g, 90%) using 4-methyl-1,5-diphenylphenol-3-carboxylic acid (0,70 g)obtained in reference example 56, and N-methylpiperazine (0,840 ml).

1H-NMR (400 MHz, CDCl3) δ: to 2.18 (3H, s), of 2.34 (3H, s), 2,45-2,60 (4H, m), 3,80-of 3.96 (4H, m), 7,10-to 7.50 (10H, m).

MS (ESI) m/z: 361 (M+H)+.

2) Salt specified in the connection header with hydrochloric acid

By the way, Ana is ulichnym method, used in stage 2) of example 1, salt specified in the connection header with hydrochloric acid is obtained in the form of solids (0,685 g, 56%) using the above specified in the connection header (0,818 g).

1H-NMR (400 MHz, DMSO-d6) δ: 2,10 (3H, s), of 2.81 (3H, s-like), 3,00-the 3.65 (6H, m), 4,55-4,80 (2H, m), 7,16-7,30 (4H, m), 7,30 is 7.50 (6H, m), 10,57 (1H, usher.).

MS (ESI) m/z: 361 (M+H)+.

Elemental analysis: as With22H24N4O•1,1 HCl•1,0 H2O.

Calculated: C, 63,13; N, 6,53; Cl, To 9.32; N, 13,38.

Found: C, 63,32; H, 6.42 Per; Cl, 9,11; N, 13,45.

[Example 10] 1-[4-Fluoro-1,5-diphenylphenol-3-carbonyl]-4-methylpiperazin

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an oily product (0.124 g, 49%) using 4-fluoro-1,5-diphenylphenol-3-carboxylic acid (0,169 g)obtained in reference example 59, N-methylpiperazine (0,20 ml).

1H-NMR (400 MHz, CDCl3) δ: 2,08-to 2.18 (2H, m), 2,24 (3H, s), 2,32 is 2.43 (2H, m), 3,30 is-3.45 (2H, m), 3,68-3,82 (2H, m), 7,32-to 7.68 (8H, m), to 7.93 (2H, d-like, J=7,8 Hz).

MS (ESI) m/z: 365 (M+H)+.

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 1, indicated in the title compound obtained as tenagophila (to 0.108 g, 79%) using the above specified in the title compound (0.124 g).

1H-NMR (400 MHz, DMSO-d6) δ: 2,80 (3H, s), 2,80-the 3.65 (6H, m), 4,08-4,22 (1H, m), 4,40-4,55 (1H, m), 7,35-of 7.60 (8H, m), 7,86 (2H, d, J=7,4 Hz), 11,09 (1H, usher.).

MS (ESI) m/z: 365 (M+H)+.

[Example 11] 4-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-1,1-diocletianopolis

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (0,185 g, 51%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (0,250 g)obtained in reference example 41, and 1,1-dioxide thiomorpholine (0.126 g).

1H-NMR (400 MHz, CDCl3) δ: 3,17-is 3.21 (4H, m), of 3.96 (3H, s), the 4.29 (2H, m), of 4.66 (2H, m), 6,74 (1H, d, J=8,8 Hz), 7,02 (1H, s), 7,22-7,39 (5H, m), 7,42 was 7.45 (1H, m)to 8.12 (1H, d, J=2,8 Hz).

MS (EI) m/z: 412 (M+).

[Example 12] 1-[5-(4-Forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl)-4-methylpiperazin

1) Specified in the header of the connection

To a solution of ethyl ester 5-(4-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid (2.1 g)obtained in reference example 135, in methanol (20 ml) is added at 0°With 1 M aqueous sodium hydroxide (15,4 ml). The resulting mixture was stirred at room temperature for 4.5 hours and then cooled to 0°C. To the mixture is added slowly the concentration of the new hydrochloric acid, whereby pH is adjusted to 3. Then added to the mixture chloroform and formed solid is dissolved. The solvent is removed under reduced pressure and the residue partitioned between water and a mixture of solvents chloroform-methanol (9:1). The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure. The residue is dissolved in a solvent mixture of N,N-dimethylformamide (50 ml) and methylene chloride (30 ml). To the resulting mixture is added N-methylpiperazine (1,37 ml), triethylamine (3.4 ml), 1-hydroxybenzotriazole (1.66 g) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2,36 g) at room temperature. The mixture is stirred at room temperature for 62 hours and partitioned between saturated aqueous sodium bicarbonate and chloroform. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. The resulting mixture is filtered and the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (chloroform-methanol), while receiving specified in the header connection (2,421 grams of 99.5%).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2.49 USD (4H, dt, J=14,0, a 4.9 Hz), a-3.84 (2H, users), of 3.94 (3H, s), of 4.12 (2H, users), 6,74 (1H, d, J=8,8 Hz), 6.89 in (1H, s),? 7.04 baby mortality (2H, t, J=8,8 Hz), 7,2 (2H, DD, J=8,8, 5,1 Hz), of 7.48 (1H, DD, J=8,8, 2,9 Hz), 8,10 (1H, d, J=2,9 Hz).

MS (EI) m/z: 395 (M+).

2) Salt specified in the connection header with hydrochloric acid

1-[5-(4-Forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl)-4-methylpiperazine (1.12 g) was dissolved in diethyl ether (10 ml). In an argon flow of 1 M HCl in ethanol (8.5 ml) is added to the solution at room temperature. The resulting mixture is stirred at constant temperature for 4 hours. To the mixture of ethanol and then the solvent is removed under reduced pressure. To the residue is added ether and hexane, and the precipitated solid is washed with subsequent filtering. The filtered solid is recrystallized from ethanol, thus obtaining specified in the title compound as a solid (715 mg, 57%).

MS (EI) m/z: 395 (M+).

Elemental analysis: as With21H22FN5O2•1,0 HCl 0,5•N2O.

Calculated: C, 57,21; N, 5,49; N, 15,88; F, Or 4.31; Cl, 8,04.

Found: C, 57,28; N, Lower Than The 5.37; N, 16,22; F, 4,19; Cl, 8,06.

[Example 13] 4-[5-(4-Forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl)morpholine

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (0,386 g, 86%) using 5-(4-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid (0,368 is), obtained in reference example 136, and research (0,310 ml).

1H-NMR (400 MHz, CDCl3) δ: 3,70-are 3.90 (6H, m), 3,93 (3H, s), 4,18 (2H, usher.), 6,74 (1H, d, J=8,8 Hz)6,94 (1H, s),? 7.04 baby mortality (2H, t-like, J=8.6 Hz), 7.18 in-7,29 (2H, m), 7,49 (1H, DD, J=8,6 and 2.2 Hz), 8,10 (1H, d, J=2.2 Hz).

[Example 14] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl)-4-benzyl-3-methylpiperazin

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an oily product (0,462 g, quantitative yield) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (0,290 g)obtained in reference example 41, and salts of 1-benzyl-2-methylpiperazine with triperoxonane acid (0,609 g)obtained in step 2) of referential example 85.

1H-NMR (400 MHz, CDCl3) δ: of 1.16 and 1.22 (3H, each d, each J=6,1 Hz), 2.00 in 4,60 (9H, m), 3.89 and 3,91 (3H, each s), 6,65-6,74 (1H, m), 6,92 and 6,93 (1H, each s), 7,15-of 7.55 (11H, m), 8,08 and to 8.14 (1H, each d, each J=2,5 Hz).

MS (FAB) m/z: 468 (M+H)+.

[Example 15] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-3-methylpiperazin

1) Specified in the header of the connection

To a solution of 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-benzyl-3-methylpiperazine (0,459 g)obtained in example 14, in ethanol (10 ml) at room temperature was added 1 M HCl-ethanol (0,980 ml) and 10% palladium on coal (mg). The resulting mixture is stirred in hydrogen atmosphere for 5.5 hours. After replacing the atmosphere by nitrogen, the mixture was neutralized to pH 8, 1 M aqueous sodium hydroxide, followed by removal of insoluble materials by filtration. The solvent of the filtrate is removed under reduced pressure and then the residue is distributed between water and chloroform. The aqueous layer was extracted with chloroform. The organic layers are combined and washed with saturated salt solution, followed by drying over anhydrous sodium sulfate. The resulting mixture is filtered and the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound as an oily product (0,250 g, 67%).

1H-NMR (400 MHz, CDCl3) δ: of 2.51 (0,5H, t-like, J=11,0 Hz), 2,80-3,30 (4,5H, m), 3,93 (3H, s), 4,59-to 4.87 (2H, m), of 6.71 (1H, d, J=8.7 Hz), 6.90 to (1H, s), 7,20-of 7.60 (6H, m)to 8.12 (1H, s-like).

MS (ESI) m/z: 378 (M+H)+.

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 1, salt specified in the connection header with hydrochloric acid is obtained in the form of solids (0,201 g, 68%) using the above compounds (0,250 g).

1H-NMR (400 MHz, CDCl3) δ: of 1.20 to 1.34 (3H of usher.), 3,00-of 3.75 (5H, m), 4,40-a 4.53 (1H, m), 4,70-of 4.90 (1H, m)6,91 (1H, d, J=8,8 Hz), 7,01 (1H, s), 7,25 was 7.45 (5H, m), of 7.70 (1H, DD, J=8,8, 3.0 Hz), 8,18 (1H, d, J=2.7 Hz), 9,10-9,50 (2H, usher.).

MS (ESI) m/z: 378 (M+H)+.

Elemental analysis: as With21H23N5O2•1,2 N2About•1,5 HCl.

Calculated: C, 56,27; N, 6,12; Cl, 9,49; N, 15.62 Wide.

Found: C, 56,12; N, 6,00; Cl, 9,84; N, 15,45.

[Example 16] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperazine

1) tert-Butyl ester 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperazine-4-carboxylic acid

In a manner analogous to the method used in stage 1) of example 1, tert-butyl ester 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperazine-4-carboxylic acid obtained as an oily product (0,772 g, quantitative yield) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (0,407 g)obtained in referential example 41 tert-butyl ether piperazine-1-carboxylic acid.

1H-NMR (400 MHz, CDCl3) δ: 1,48 (N, C), 3,53 (4H, usher.), with 3.79 (2H, usher.), of 3.94 (3H, s), 4,10 (2H, usher.), 6,72 (1H, d, J=8,8 Hz)6,94 (1H, s), 7,20-7,40 (5H, m), 7,47 (1H, DD, J=8,8, 2.7 Hz), to 8.12 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 464 (M+N)+.

2) Specified in the header of the connection

At room temperature triperoxonane acid (2.4 ml) are added to a solution of the above tert-butyl ester 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazol the-3-carbonyl]piperazine-4-carboxylic acid (0,639 g) in methylene chloride (15 ml), followed by stirring the mixture for 0.7 hour. The reaction solvent is removed under reduced pressure and the residue partitioned between chloroform and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with chloroform. The organic layers are combined and washed with saturated salt solution, followed by drying over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound as an oily product (0,446 g, 89%).

1H-NMR (400 MHz, CDCl3) δ: 2,90-to 3.02 (4H, m), 3,80 (2H, usher.), of 3.94 (3H, s)4,07 (2H, usher.), 6,72 (1H, d-like, J=8.7 Hz), 6.90 to (1H, s), 7,20-7,38 (5H, m), of 7.48 (1H, DD, J=8,7, 2,2 Hz)to 8.12 (1H, d-like, J=2.2 Hz).

MS (FAB) m/z: 364 (M+H)+.

[Example 17] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-isopropylpiperazine

1) Specified in the header of the connection

To a solution of 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperazine (0,446 g)obtained in example 16 in N,N-dimethylformamide (7.5 ml) at room temperature add potassium carbonate (worn : 0.505 g) and Isopropylamine (0,30 ml) and the mixture was stirred at 60°C for 16 hours and then cooled in air. The reaction mixture was partitioned between water and ethyl acetate. Then the aqueous layer was extracted with ethyl acetate. Organic with the AOI are combined and washed with saturated salt solution, followed by drying over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound as an oily product (0,283 g, 57%).

1H-NMR (400 MHz, CDCl3) δ: of 1.06 (6H, d, J=6.5 Hz), 2,50-of 2.81 (5H, m), 3,83 (2H, usher.), 3,93 (3H, s), 4,10 (2H, usher.), of 6.71 (1H, d, J=8,8 Hz), make 6.90 (1H, s), 7,19-7,38 (5H, m), 7,47 (1H, DD, J=8,8, 2.7 Hz), 8,11 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 406 (M+H)+.

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 1, indicated in the title compound obtained as a solid (0,226 g, 73%) using the above specified in the connection header (0,283 g).

1H-NMR (400 MHz, DMSO-d6) δ: of 1.26 (6H, d, J=6.4 Hz), 2,95-of 3.60 (6H, m)to 3.67 (1H, usher.), 3,86 (3H, s), 4,63 (1H, usher.), to 5.03 (1H, usher.), 6,89 (1H, d, J=8,8 Hz), 7,00 (1H, s), 7,25-the 7.43 (5H, m), 7,68 (1H, DD, J=8,8, 2.7 Hz), 8,17 (1H, d, J=2.7 Hz), 10,49 (1H, usher.).

MS (ESI) m/z: 406 (M+H)+.

[Example 18] 1-[5-(4-Benzyloxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an oily product (0,802 g, 72%) using 5-(4-benzyloxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid (0.26 g), obtained in reference example 14 and N-methylpiperazine (0.765 ml).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2,42-2,60 (4H, m), a-3.84 (2H, usher.), of 3.94 (3H, s), of 4.12 (2H, usher.), 6,72 (1H, d, J=9.0 Hz), at 6.84 (1H, s), 6,93 (2H, d-like, J=8.7 Hz), to 7.15 (2H, d-like, J=8.7 Hz), 7,30 was 7.45 (5H, m), of 7.48 (1H, DD, J=9,0, 2.7 Hz), 8,13 (1H, d, J=2.7 Hz).

MS (FAB) m/z: 484 (M+H)+.

[Example 19] 1-[5-(4-Hydroxyphenyl)-1-(6-methoxy-5-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazin

1) Specified in the header of the connection

To a solution of 1-[5-(4-benzyloxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazine (0,802 g)obtained in example 18, in ethanol (15 ml) is added 10% palladium on coal (0,466 g) and 1 M HCl-ethanol (1.65 ml) and the mixture is stirred at room temperature in a hydrogen atmosphere for 24 hours. After completion of the reaction atmosphere change on the nitrogen and the mixture is neutralized aqueous sodium hydroxide. The insoluble substance was separated and the residue is washed with methanol. The solvent of the filtrate is removed under reduced pressure and the residue distributed between water and chloroform. Then the aqueous layer was extracted with chloroform. The organic layers are combined and washed with saturated salt solution, followed by drying over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (x is roform-methanol), while receiving specified in the title compound in the form of a foamy substance (0,493 g, 69%).

1H-NMR (400 MHz, CDCl3) δ: of 2.34 (3H, s), 2,45-2,60 (4H, m), 3,85 (2H, usher.), of 3.94 (3H, s), of 4.13 (2H, usher.), of 6.71 (1H, d, J=8,8 Hz), 6,77 (2H, d, J=8,8 Hz), to 6.80 (1H, s), 7,05 (2H, d, J=8,8 Hz), 7,47 (2H, DD, J=8,8, 2,2 Hz)to 8.12 (1H, d, J=2.2 Hz).

MS (ESI) m/z: 394 (M+H)+.

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 1, salt specified in the connection header with hydrochloric acid is obtained in the form of solids (0,436 g, 72%) using the above specified in the connection header (0,493 g).

1H-NMR (400 MHz, DMSO-d6) δ: 2,77 (3H, s-like), 3,00-3,70 (6H, m), 3,86 (3H, s), 4,60 (1H, usher.), equal to 4.97 (1H, usher.), to 6.75 (2H, d-like, J=6.6 Hz), 6,86 (1H, s), 6.89 in (1H, d, J=8,8 Hz), 7,66 (1H, DD, J=8,8, 2.7 Hz), 8,16 (1H, d, J=2.7 Hz), 9,85 (1H, usher.), 10,85 (1H, usher.).

MS (ESI) m/z: 394 (M+H)+.

[Example 20] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methyl-3-oxopiperidin

At room temperature, 1-hydroxybenzotriazole (0,341 g), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0,971 g), triethylamine (1,61 ml) and salt of N-methylpiperazin-2-she triperoxonane acid (1.06 g)obtained in referential example 91, added to a solution of 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (0,695 g)obtained in reference example 41, in methylene chloride (15 ml), followed by stirring the mixture for 26 hours. The reaction mixture is acidified to pH 4 1 M aqueous hydrochloric acid. The mixture is distributed between water and chloroform. Then the aqueous layer was extracted with chloroform and the organic layers combined with subsequent washing with saturated salt solution and dried over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (chloroform-acetone), thus obtaining specified in the title compound in the form of solids (0,707 g, 79%).

1H-NMR (400 MHz, CDCl3) δ: 3,40-of 3.60 (2H, m), of 3.94 (3H, s), Android 4.04 (1H, usher.), 4,25-4,50 (2H, m), a 4.83 (1H, s), of 6.73 (1H, d, J=8.7 Hz), 7.18 in-7,40 (5H, m).

MS (ESI) m/z: 392 (M+H)+.

[Example 21] 4-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-1,2,6-trimethylpyrazine

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an oily product (0,351 g, 76%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (of 0.337 g)obtained in reference example 41, and salt 1,2,6-trimethylpyrazine with triperoxonane acid (1,178 g)obtained in reference example 89.

1H-NMR (400 MHz, CDCl3) δ: of 1.09 (3H, d, J=6,1 Hz)of 1.16 (3H, d, J=6,1 Hz), 2,20-of 2.30 (2H, m), of 2.28 (3H, s), 2,65 (1H, t-like, J=13,2 Hz), 3,03 (1H, t-like, J=13,2 Hz)to 3.92 (3H, s), 4,51-br4.61 (1H, m), 4,68-rate 4.79 (1H, m), 6,69 (1H, d, J=8,8 Hz), 6,88 (1H, s), 7,17 and 7.36 (5H, m), the 7.43 (1H, DD, J=8,8, 2.7 Hz), 8,10 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 406 (M+H)+.

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 1, salt specified in the connection header with hydrochloric acid is obtained in the form of solids (0,277 g, 71%) using the above specified in the connection header (0,335 g).

1H-NMR (400 MHz, DMSO-d6) δ: 1,30-1,45 (6H, usher.), 3,86 (3H, s), to 4.62 (1H, usher.), equal to 4.97 (1H, usher.), make 6.90 (1H, d, J=8,8 Hz), 7,00 (1H, s), 7,25 is 7.50 (5H, m), of 7.69 (1H, DD, J=8,8, 2.7 Hz), 8,18 (1H, d, J=2.7 Hz), 10,61 (1H, usher.).

MS (ESI) m/z: 406 (M+H)+.

[Example 22] 4-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-2,6-dimethylpiperazine

In a manner analogous to the method used in example 20, is listed in the title compound obtained as a solid (0.312 g, 94%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (0,278 g)obtained in reference example 41, and 2,6-dimethylpiperazine (0,214 g).

1H-NMR (400 MHz, CDCl3) δ: a 1.08 (3H, d, J=6,4 Hz)to 1.14 (3H, d, J=6.4 Hz), 2,40 (1H, t-like, J=9.0 Hz), was 2.76 (1H, t-like, J=10,7 Hz), 2,85-to 3.02 (2H, m), 3,93 (3H, s), of 4.67 (1H, d-like, J=12,6 Hz), 4,76 1H, d-like, J=12,6 Hz), of 6.71 (1H, d, J=8.7 Hz), 6.89 in (1H, s), 7,20-7,37 (5H, m), 7,46 (1H, DD, J=8,7, 2,5 Hz)to 8.12 (1H, d, J=2.5 Hz).

LC-MS m/z: 392 (M+H)+.

[Example 23] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-methyl-3-oxopiperidin

In a manner analogous to the method used in example 20, is listed in the title compound obtained as foamy substance (0,213 g, 94%) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (0,171 g)obtained in reference example 33, and salts of N-methylpiperazin-2-she triperoxonane acid (0,251 g)obtained in referential example 91.

1H-NMR (400 MHz, CDCl3) δ: to 3.02 (3H, s), 3,47 (2H, usher.), of 3.95 (3H, s), Android 4.04 (1H, usher.), was 4.42 (2H, s-like), 4,84 (1H, s-like), 6,76 (1H, d, J=8,8 Hz), 7,15-7,28 (2H, m), 7,37-of 7.48 (1H, m), 7,55 to 7.75 (2H, m), 8,05-8,17 (1H, m), 8,51 (1H, d, J=4,1 Hz).

MS (FAB) m/z: 393 (M+H)+.

Elemental analysis: as With20H20N6O3•1,5 H2O.

Calculated: C, 57,27; N, Of 5.53; N, 20,04.

Found: C, 57,03; N, Of 5.06; N, 19,66.

[Example 24] 4-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-1,2,6-trimethylpyrazine

1) Specified in the header of the connection

In a manner analogous to the method used in example 20, is listed in the title compound obtained as foamy substance (0,272 g, quantitative yield) using 1-(6-methoxy-3-the feast of the deal)-5-(2-pyridyl)pyrazole-3-carboxylic acid (0,197 g), obtained in referential example 33 and salt 1,2,6-trimethylpyrazine with triperoxonane acid (0,477 g)obtained in reference example 89.

1H-NMR (400 MHz, CDCl3) δ: of 1.10 (3H, d, J=6,1 Hz)of 1.18 (3H, d, J=6,1 Hz), 2,15-of 2.30 (2H, m)to 2.29 (3H, s), 2,69 (1H, DD, J=13,0, 11.2 Hz), 3,06 (1H, DD, J=13,0, 11.2 Hz), of 3.95 (3H, s), 4,55-4,74 (2H, m), of 6.75 (1H, d, J=8,8 Hz), 7,11 (1H, s), 7,21-7,27 (1H, m), the 7.43 (1H, d, J=7.8 Hz), EUR 7.57 (1H, DD, J=8,8, 2.7 Hz), 7,63 to 7.75 (1H, m)to 8.12 (1H, d, J=2.7 Hz), 8,51 (1H, userd, J=4.4 Hz).

MS (SEI) m/z: 407 (M+H)+.

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 1, salt specified in the connection header with hydrochloric acid is obtained in the form of solids (0,222 g, 67%) using the above specified in the connection header (0,272 g).

1H-NMR (400 MHz, DMSO-d6) δ: of 1.33 (3H, usher.), of 1.39 (3H, usher.), 2,80 (3H, d, J=4.4 Hz), 2,80-of 3.80 (4H, m), a 3.87 (3H, s), with 4.64 (1H, usher.), 4,94 (1H, usher.), to 6.88 (1H, d, J=8,8 Hz), 7,26 (1H, s), 7,33-7,40 (1H, m), to 7.67 to 7.75 (2H, m), 7,88 (1H, dt, J=7,8, 1.9 Hz), to 8.20 (1H, d, J=2.7 Hz), 8,44 (1H, d-like, J=4,9 Hz), 10,23 (1H, usher.).

MS (ESI) m/z: 407 (M+H)+.

[Example 25] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-phenylpiperazin

In a manner analogous to the method used in example 20, is listed in the title compound obtained as foamy substance (0,372 g, 85%) using 1-(6-methoxy-3-PI is ideal)-5-phenylpyrazol-3-carboxylic acid (0,296 g), obtained in referential example 41 and the N-phenylpiperazine (0,305 ml).

1H-NMR (400 MHz, CDCl3) δ: 3,20-to 3.35 (4H, m), of 3.94 (3H, s)to 3.99 (2H, usher.), 4,30 (2H, usher.), 6,72 (1H, d, J=8,8 Hz), 6,82-to 7.00 (4H, m), 7,20-7,37 (7H, m), of 7.48 (1H, DD, J=8,8, 2.7 Hz), 8,13 (1H, d, J=2.7 Hz).

MS (FAB) m/z: 440 (M+H)+.

[Example 26] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-(2-pyridyl)piperazine

In a manner analogous to the method used in example 20, is listed in the title compound obtained as an amorphous product (0,393 g, 90%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (0,299 g)obtained in referential example 41 N-(pyridin-2-yl)piperazine (0,275 ml).

1H-NMR (400 MHz, CDCl3) δ: 3,60-3,70 (4H, m), 3,90-of 3.95 (2H, m), 3,93 (3H, s), 4,24 (2H, usher.), 6,62-of 6.73 (3H, m)6,94 (1H, s), 7,20-7,37 (5H, m), 7,43-7,52 (2H, m), 8,11 (1H, DD, J=2.7, and 0.8 Hz), 8,16-8,23 (1H, m).

MS (FAB) m/z: 441 (M+H)+.

[Example 27] 1-[1-(6-Methoxy-3-pyridyl)-5-(4-methoxy-2-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (0,140 g, 65%) using 1-(6-methoxy-3-pyridyl)-5-(4-methoxy-2-pyridyl)pyrazole-3-carboxylic acid (0,171 g)obtained in reference example 19, and N-methylpiperazine (0,0639 ml).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2,4-by 2.55 (4H, m), (a 3.83 (3H, s), 3,85 (2H, m), of 3.95 (3H, s) 4.09 to (2H, m), 6,74-6,77 (2H, m), to 6.95 (1H, d, J=2,8 Hz), to 7.09 (1H, s), to 7.59 (1H, DD, J=8,8, 2,8 Hz)to 8.12 (1H, d, J=2,8 Hz), 8,32 (1H, d, J=6.0 Hz).

MS (EI) m/z: 408 (M+).

[Example 28] 4-[1-(6-Methoxy-3-pyridyl)-5-(4-methoxy-2-pyridyl)pyrazole-3-carbonyl]morpholine

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (0,132 g, 62%) using 1-(6-methoxy-3-pyridyl)-5-(4-methoxy-2-pyridyl)pyrazole-3-carboxylic acid (0,171 g)obtained in reference example 19, and research (0,0502 ml).

1H-NMR (400 MHz, CDCl3) δ: of 3.73 of 3.75 (2H, m), 3,81-a-3.84 (4H, m), of 3.84 (3H, s), of 3.95 (3H, s), 4,14 (2H, m), 6,74-of 6.78 (2H, m), of 6.96 (1H, d, J=2.4 Hz), 7,13 (1H, s), EUR 7.57-of 7.60 (1H, m)to 8.12 (1H, d, J=2,8 Hz), 8,32 (1H, d, J=6.0 Hz).

MS (FAB) m/z: 396 (M+H)+.

Elemental analysis: as With20H21N5O4•0.5 N2O.

Calculated: C, 59,40; N, Of 5.48; N, 17,32.

Found: C, 59,64; N, 5,31; N, 17,19.

[Example 29] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-ethylpiperazin

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an oily product (0,265 g, quantitative yield) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (0.20 g)obtained in alocrom example 33, and N-ethylpiperazine (0,0942 ml).

1H-NMR (400 MHz, CDCl3) δ: 1,09-of 1.13 (3H, m), 2,43 is 2.55 (6H, m), 3,86 (2H, m), of 3.95 (3H, s), 4,10 (2H, m), of 6.75 (1H, d, J=8,8 Hz), 7,12 (1H, s), 7,22-of 7.25 (1H, m), 7,41 (1H, d, J=7,6 Hz), EUR 7.57-of 7.60 (1H, m), 7.68 per-7,73 (1H, m), 8,11 (1H, d, J=2,8 Hz), 8,51 (1H, d, J=4,8 Hz).

MS (EI) m/z: 392 (M+).

2) Salt specified in the connection header with hydrochloric acid

When 0°1 N. HCl-ethanol (1,27 ml) is added dropwise to the solution obtained above, specified in the connection header (0,249 g) in diethyl ether (10 ml) followed by stirring the mixture for 10 minutes. The precipitated crystals are collected by filtration followed by washing with diethyl ether and drying, thus obtaining salt specified in the connection header with hydrochloric acid in the form of solids (0,257 g, 81%).

1H-NMR (400 MHz, DMSO-d6) δ: (1,04-1,11 (3/4H, m, 0,25 EtOH)), 1,26-of 1.29 (3H, m), 3,06-and 3.72 (8H, m, (2/4H, m, 0,25 EtOH)), the 3.89 (3H, s), 4,60 (1H, m), 4,99 (1H, m), 6.89 in (1H, d, J=8,8 Hz), 7,27 (1H, s), 7,37-7,40 (1H, m,), 7,69-7,73 (2H, m), 7,88-a 7.92 (1H, m), 8,21 (1H, d, J=2,8 Hz), 8,48 (1H, d, J=4,8 Hz).

MS (EI) m/z: 392 (M+).

[Example 30] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-3,4-dimethylpiperidin

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an oily product (0,234 g, 88%) with the use of the 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (0.20 g), obtained in reference example 33, and salts of 1,2-dimethylpiperazine with triperoxonane acid (0,254 g)obtained in reference example 84.

1H-NMR (400 MHz, CDCl3) δ: 1,07-1,17 (3H, m), of 2.20 (2H, m), of 2.33 (3H, s), 2.71 to to 3.52 (3H, m), of 3.95 (3H, s), 4,50 was 4.76 (2H, m), 6,76 (1H, d, J=8,8 Hz), 7,12 (1H, m), 7.23 percent-7,27 (1H, m), 7,40-7,44 (1H, m), 7,56-to 7.61 (1H, m), 7,69-7,73 (1H, m)to 8.12 (1H, m), charged 8.52 (1H, d, J=4,8 Hz).

MS (EI) m/z: 392 (M+).

2) Salt specified in the connection header with hydrochloric acid

In a manner similar to the method used in step 2) of example 29, salt specified in the connection header with hydrochloric acid is obtained in the form of solids (0,192 g, 67%) using the above specified in the connection header (0,223 g).

1H-NMR (400 MHz, DMSO-d6) δ: 1,04-1,11 ((3/2H, m, 0.5 EtOH) ), 1,23-of 1.39 (3H, m), 2,73-to 3.89 (5H, m, (2/2H, 0.5 EtOH)), the 3.89 (3H, s), 4,58-to 4.62 (1H, m), 4,90-5,00 (1H, m), 6.89 in (1H, d, J=8,8 Hz), 7,27 (1H, s), 7,37-7,40 (1H, m), 7,69-7,74 (2H, m), 7,88-a 7.92 (1H, m), 8,21 (1H, d, J=2,8 Hz), 8,48 (1H, d, J=4,8 Hz).

MS (EI) m/z: 392 (M+).

[Example 31] 1-[1-(6-Methoxy-3-pyridyl)-5-(6-methoxy-2-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazin

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an oily product (0,217 g, 96%) using 1-(6-methoxy-3-pyridyl)-5-(6-methoxy-2-pyridyl)pyrazole-3-carbon is howling acid (0,180 g), obtained in reference example 25, N-methylpiperazine (0,0673 g).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2,46-2,52 (4H, m), 3.43 points (3H, s), 3,85 (2H, m), of 3.95 (3H, s), of 4.12 (2H, m), 6,63 of 6.66 (1H, m), 6,76-of 6.78 (1H, m), 7,10 for 7.12 (1H, m), 7,14 (1H, s), 7,56-to 7.59 (2H, m), 8,16-8,17 (1H, m,).

MS (EI) m/z: 408 (M+).

2) Salt specified in the connection header with hydrochloric acid

In a manner similar to the method used in step 2) of example 29, salt specified in the connection header with hydrochloric acid is obtained in the form of solids (0,185 g, 78%) using the above specified in the connection header (0,209 g).

1H-NMR (400 MHz, CD3OD) δ: 2,95 (3H, s), 3,30-of 3.60 (8H, m)to 3.38 (3H, s), of 3.95 (3H, s)of 6.71 (1H, d, J=8,4 Hz), to 6.88 (1H, d, J=8,8 Hz), 7,25 (1H, s), 7,29-7,30 (1H, m), 7.68 per-7,72 (2H, m), 8,16 (1H, d, J=2,8 Hz).

MS (EI) m/z: 408 (M+).

Elemental analysis: as With21H24N6O3•HCl•N2O.

Calculated: C, 54,49; N, 5,88; N, 18,15; Cl, 7,66.

Found: C, 54,46; N, 5,94; N, To 18.01; Cl, 7,75.

[Example 32] 4-[1-(6-Methoxy-3-pyridyl)-5-(6-methoxy-2-pyridyl)pyrazole-3-carbonyl]morpholine

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (0,176 g, 80%) using 1-(6-methoxy-3-pyridyl)-5-(6-methoxy-2-pyridyl)pyrazole-3-carboxylic acid (0,180 g)obtained in reference example 25, and morpholine is (0,0529 ml).

1H-NMR (400 MHz, CDCl3) δ: of 3.43 (3H, s), of 3.73-3,82 (6H, m), of 3.95 (3H, s), 4,17 (2H, m), 6, 64-6, 66 (1H, m), 6,76-of 6.78 (1H, m), 7,10-7,13 (1H, m), 7,17 (1H, s), 7,55-of 7.60 (2H, m), 8,16-8,17 (1H, m).

MS (EI) m/z: 395 (M+).

[Example 33] 1-[1-(6-Methoxy-3-pyridyl)-5-(6-methyl-2-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (0,148 g, 72%) using 1-(6-methoxy-3-pyridyl)-5-(6-methyl-2-pyridyl)pyrazole-3-carboxylic acid (rate £ 0.162 g)obtained in reference example 30, and N-methylpiperazine (0,0637 ml).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s)to 2.41 (3H, s), 2,43-2,52 (4H, m), 3,85 (2H, m), of 3.95 (3H, s)4,08 (2H, m), of 6.75 (1H, d, J=8,8 Hz), to 7.09 (1H, d, J=8.0 Hz), 7,11 (1H, s), 7,19 (1H, d, J=8.0 Hz), 7,56 to 7.62 (2H, m,), to 8.12 (1H, d, J=2,8 Hz).

MS (EI) m/z: 392 (M+).

[Example 34] 4-[1-(6-Methoxy-3-pyridyl)-5-(6-methyl-2-pyridyl)pyrazole-3-carbonyl]morpholine

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (0.156 g, 78%) using 1-(6-methoxy-3-pyridyl)-5-(6-methyl-2-pyridyl)pyrazole-3-carboxylic acid (rate £ 0.162 g)obtained in reference example 30, and research (0,050 ml).

1H-NMR (400 MHz, CDCl3) δ: is 2.40 (3H, s), 3.72 points-is 3.82 (6H, m), of 3.95 (3H, s), 4,14 (2H, m), 6,74-6,77 (1H, m), to 7.09 (1H, d, J=7,6 Hz), 7,14 (1H, s), 7,19 (1H, d, J8,0 Hz), 7,56-to 7.61 (2H, m), 8,11-to 8.12 (1H, m).

MS (EI) m/z: 379 (M+).

Elemental analysis: as With20H21N5O3•0,25 H2O.

Calculated: C, 62,57%; N, 5,64%; N, 18,24%.

Found: C, 62,61%; N, Of 5.53%; N, 17,98%.

[Example 35] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazin

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an amorphous product (0,132 g, 63%) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (0,164 g)obtained in referential example 33 and the N-methylpiperazine (0,0675 ml).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2,45 of $ 2.53 (4H, m), 3,85 (2H, m), of 3.95 (3H, s), 4.09 to (2H, m), 6,76 (1H, d, J=8,8 Hz), 7,12 (1H, s), 7,22-7,27 (1H, m), 7,42 (1H, d, J=7,6 Hz), to 7.59 (1H, DD, J=8,8, 2,8 Hz), 7,69-7,73 (1H, m)to 8.12 (1H, d, J=2,8 Hz), charged 8.52 (1H, d, J=4.4 Hz).

MS (EI) m/z: 378 (M+).

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 29, specified in the title compound obtained as a solid (is 0.135 g, 45%) using the above specified in the connection header (0,241 g).

1H-NMR (400 MHz, DMSO-d6) δ: (1,06-1,11 (3/4H, m, 0,25 EtOH)), 2,79 is 2.80 (3H, m), 3,06-3,66 (6H, m, (2/4H, m, 0,25 EtOH)), the 3.89 (3H, s), 4,60-4,63 (1H, m), 4,96-5,00 (1H, m), 6.89 in (1H, d, J=8,8 Hz), 27 (1H, C)of 7.36-7,40 (1H, m), 7,69-7,74 (2H, m), 7,88-7, 92 (1H, m), 8,21 (1H, d, J=2,8 Hz), of 8.47 (1H, d, J=4.4 Hz).

MS (EI) m/z: 378 (M+).

[Example 36] 4-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]morpholine

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (0,171 g, 83%) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (0,164 g)obtained in referential example 33 and research (0,053 ml).

1H-NMR (400 MHz, CDCl3) δ: 3,74-a 3.83 (6H, m), of 3.95 (3H, s)to 4.15 (2H, m), 6.75 in-6,77 (1H, m), 7,16 (1H, s), 7,22-7,27 (1H, m), 7,41-the 7.43 (1H, m), EUR 7.57-of 7.60 (1H, m), 7,69-7,73 (1H, m), 8,11-to 8.12 (1H, m), 8,51 are 8.53 (1H, m).

MS (EI) m/z: 365 (M+).

[Example 37] 1-[1-(6-Methoxy-3-pyridyl)-5-(4-were)pyrazole-3-carbonyl]-4-methylpiperazin

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an amorphous product (0,912 g, quantitative yield) using 1-(6-methoxy-3-pyridyl)-5-(4-were)pyrazole-3-carboxylic acid (0,70 g)obtained in reference example 36, N-methylpiperazine (0,276 ml).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s)to 2.35 (3H, s), 2,46-2,52 (4H, m), 3,85 (2H, m), of 3.95 (3H, s), 4,13 (2H, m), of 6.71-6,74 (1H, m), to 6.88 (1H, s), 7,11-7,16 (4H, m), of 7.48-7,50 (1H, m), 8,13 (1H, d, J=2,8 Hz).

MS (EI) m/z: 391 (M+)

2) Salt specified in the connection header with hydrochloric acid

In a manner similar to the method used in step 2) of example 29, salt specified in the connection header with hydrochloric acid is obtained in the form of solids (0,425 g, 75%) using the above specified in the connection header (0,493 g).

1H-NMR (400 MHz, CD3OD) δ: 2,35 (3H, s), 2,95 (3H, s), 3,39 (8H, m), 3,93 (3H, s), for 6.81-6,84 (1H, m), to 6.95 (1H, s), 7,15-of 7.25 (4H, m), 3,93 (3H, s), for 6.81-6,84 (1H, m), to 6.95 (1H, s), 7,15-of 7.25 (4H, m), to 7.61-to 7.64 (1H, m), 8,08-of 8.09 (1H, m).

MS (EI) m/z: 391 (M+).

[Example 38] 1-[5-(2-Forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazin

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an oily product (0,238 g, 97%) using 5-(2-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid (of € 0.195 g)obtained in reference example 39, and N-methylpiperazine (0,076 ml).

1H-NMR (400 MHz, CDCl3) δ: of 2.34 (3H, s), 2,47-2,52 (4H, m), 3,85 (2H, m)to 3.92 (3H, s), 4,13 (2H, m), 6,70-of 6.73 (1H, m), to 6.95 (1H, s), 7.03 is-7,41 (4H, m), 7,51-rate of 7.54 (1H, m), of 8.06 (1H, m).

MS (EI) m/z: 395 (M+).

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 29, salt specified in sagola the COC connection with hydrochloric acid obtained as a solid (0.125 g, 51%) using the above specified in the connection header (0,224 g).

1H-NMR (400 MHz, CD3OD) δ: 2,96 (3H, s), 3,41 (8H, m), 3,91 (3H, s), 6,80-PC 6.82 (1H, m), 7,03 (1H, s), 7,12-7,51 (4H, m), 7,63-the 7.65 (1H, m), of 8.06 (1H, m).

MS (EI) m/z: 395 (M+).

[Example 39] Hydrochloride 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-2-(2-amino-ethyl)piperidine

To a solution of 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-2-(2-azidoethyl)piperidine (179 mg)obtained in reference example 81, in methanol (5 ml) was added 1 M aqueous hydrochloric acid (415 μl) and 10% palladium on coal (50% moisture, 36 mg). The resulting mixture was stirred at room temperature for 10 hours in an atmosphere of hydrogen. After removal of catalyst by filtration, the solvent of the filtrate is removed under reduced pressure and the residue is dissolved in water, followed by lyophilization, while receiving specified in the title compound as a solid (172 mg, 89%).

1H-NMR (400 MHz, DMSO-d6) δ: [as a mixture of two isomers] δ: 1,31-of 1.85 (7H, osirm), and 2.14 of-2.32 (1H, osirm), 2,64-2,92 (2,5H, osirm), 3,10-3,24 (0,5H, osirm), 3,91 (3H, s), to 4.41-a 4.53 (1H, osirm), 4,75-is 4.85 (1H, osirm), 6,85-6,93 (2H, m), 7,25-to 7.32 (2H, m), 7,35-7,42 (3H, m), of 7.64-7,74 (1H, osirm), 7,80-8,00 (3H, usher.), 8,12 and 8,18 (1H, users),

MS (ESI) m/z: 406 (M+H)+.

[Example 40] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-2-(2-dimethylaminoethyl)Pipa is one

1) Specified in the header of the connection

To a solution of tert-butyl methyl ether 2-(2-dimethylaminoethyl)piperidine-1-carboxylic acid (172 mg)obtained in reference example 92, in methylene chloride (3 ml), add triperoxonane acid (1 ml). The resulting mixture was stirred at room temperature for 30 minutes. The solvent is removed under reduced pressure and the residue is dissolved in methylene chloride (10 ml). To the mixture was added 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (198 mg)obtained in reference example 41, 1-hydroxybenzotriazole (90 mg), triethylamine (467 μl) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (192 mg), followed by stirring at room temperature for 15 hours. The solvent is removed under reduced pressure and the residue partitioned between water and ethyl acetate. The organic layer is washed with water and saturated salt solution, followed by drying over anhydrous sodium sulfate. The resulting mixture is filtered and the solvent is removed under reduced pressure. The residue is purified by thin-layer chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound as an oily product (100 mg, 34%).

1H-NMR (400 MHz, CDCl3) [as a mixture of two isomers] δ: 1,50-of 1.85 (6H, m), 1,95-2,43 (10H, m), 79-2,92 (0,5H, m), 3,15-3,28 (0,5H, m), 3,93 (3H, s), 4.53-in-4,74 (1H, usher.), to 4.81-5,04 (1H, usher.), of 6.71 (1H, d, J=8,8 Hz), at 6.84 (1H, s), 7,15-7,39 (5H, m), 7,49 (1H, DD, J=8,8, 2.7 Hz), 8,11 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 434 (M+H)+.

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 29, salt specified in the connection header with hydrochloric acid obtained as a solid (109 mg, 93%) using the above specified in the title compound (100 mg).

1H-NMR (400 MHz, DMSO-d6) δ: [as a mixture of two isomers] 1,32 and 1.80 (6H, m), 1,86 is 2.01 (1H, usher.), 2,22-2,40 (1H, osirm), 2,63-2,81 (0,5H, osirm), to 2.67 and 2.70 (6N, user. C)2,86-a 3.01 (1H, osirm), 3,03-and 3.16 (1H, osirm), 3,18-3,29 (0,5H, usher.), a 3.87 (3H, s), 4,40-of 4.57 (1H, osirm), 4,73-4,82 (1H, usher.), 6,85-6,94 (2H, m), 7,25-7,33 (2H, m), 7,35-7,42 (3H, usher.), a 7.62 for 7.78 (1H, osirm), 10,08-of 10.47 (1H, usher.).

MS (ESI) m/z: 434 (M+H)+.

[Example 41] 1-[1,4-Dihydro-1-(6-methoxy-3-pyridyl)indeno[1,2-c]pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in example 20, is listed in the title compound obtained as an amorphous product (281 mg, 72%) with the use of 1,4-dihydro-1-(6-methoxy-3-pyridyl)indeno[1,2-c]pyrazole-3-carboxylic acid (307 mg)obtained in reference example 61, and N-methylpiperazine (166 μl).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2,44-of 2.56 (4H, osirm), 3,82 (2H, s), 3,80-3,90 (2H of usher.), a 4.03 (3H, s), 4,19-the 4.29 (2H, usher.), 6,93 (1H, d, J=8,8 Hz), 7.24 to to 7.32 (2H, m), 7,37-7,42 (1H, m), 7,53-7,58 (1H, m), to $ 7.91 (1H, DD, J=8,8, 2.7 Hz), 8,53 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 390 (M+H)+.

[Example 42] 1-[4,5-Dihydro-1-(6-methoxy-3-pyridyl)benzo[g]indazol-3-carbonyl]-4-methylpiperazin

1) Specified in the header of the connection

In a manner analogous to the method used in example 20, is listed in the title compound obtained as a solid (281 mg, 93%) with the use of 4,5-dihydro-1-(6-methoxy-3-pyridyl)benzo[g]indazole-3-carboxylic acid (241 mg)obtained in reference example 72, and N-methylpiperazine (125 μl).

2) Salt specified in the connection header with hydrochloric acid

In a manner similar to the method used in step 2) of example 29, salt specified in the connection header with hydrochloric acid is obtained in the form of crystals (259 mg, 83%) using the above specified in the title compound (278 mg).

1H-NMR (400 MHz, DMSO-d6) δ: and 2.79 (3H, s), 2,81-2,90 (2H, m), 2,92-of 3.00 (2H, m), 3.00 and-3,68 (6H, osirm), of 3.96 (3H, s), 4.53-in-and 4.68 (1H, usher.), 4,77-4,91 (1H, usher.), 6,74 (1H, d, J=7.8 Hz),? 7.04 baby mortality (1H, d, J=8,8 Hz), 7,10 (1H, DD, J=7,8, and 7.6 Hz), 7.23 percent (1H, DD, J=7,6, and 7.3 Hz), 7,38 (1H, d, J=7,3 Hz), 7,92 (1H, DD, J=8,8, 2.7 Hz), to 8.41 (1H, d, J=2.7 Hz), 10,81-br11.01 (1H, usher.).

MS (ESI) m/z: 404 (M+H)+.

Elemental analysis: as With23H25N5O2•HCl•0.5 N2O.

Calculated: C, 61,53; N, The 6.06; N, 15,6; Cl, of 7.90.

Found: C, 61,70; N, The 6.06; N, 15,57; Cl, 8,06.

[Example 43] 1-[1,4-Dihydro-1-(6-methoxy-3-pyridyl)chromeno[4,3-c]pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in example 20, is listed in the title compound obtained as crystals (187 mg, 76%) using 1,4-dihydro-1-(6-methoxy-3-pyridyl)chromeno[4,3-c]pyrazole-3-carboxylic acid (194 mg)obtained in reference example 74, and N-methylpiperazine (100 μl).

1H-NMR (400 MHz, CDCl3) δ: 2,32 (3H, s), 3,42-of 3.54 (4H, m), 3,76-of 3.85 (2H, usher.), a 4.03 (3H, s), 4,19-the 4.29 (2H, usher.), the 5.51 (2H, s), 6,72-to 6.80 (2H, m), 6.89 in (1H, d, J=8,8 Hz), 7,00 (1H, d-like, J=7.8 Hz), 7,12-7,20 (1H, m), 7,68 (1H, DD, J=8,8, 2.7 GHz), with 8.33 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 406 (M+H)+.

Elemental analysis: as With22H23N5O3.

Calculated: C, Age Of 65.17; H, 5,72; N, 17,27.

Found: C, 65,02; N, 5,64; N, 17,19.

[Example 44] 1-[1,4-Dihydro-1-(6-methoxy-3-pyridyl)-4-oxoindole[1,2-c]pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in example 20, is listed in the title compound obtained as an oily product (12 mg, 60%) with the use of 1,4-dihydro-1-(6-methoxy-3-pyridyl)-4-oxoindole[1,2-c]pyrazole-3-carboxylic acid (16 mg)obtained in reference example 70 and the N-methylpiperazine (11 μl).

1H-NMR (400 MHz, CDCl3) δ: of 2.34 (3H, s), 2,41-2,60 (4H, osirm), 3,69-3,3 (4H, osirm), Android 4.04 (3H, s)6,94 (1H, d, J=8,8 Hz), 7,11-7,20 (1H, m), 7,31-7,40 (2H, m), 7,60-to 7.68 (1H, m), 7,92 (1H, DD, J=8,8, 2,4 Hz)and 8.50 (1H, d, J=2,4 Hz).

MS (ESI) m/z: 404 (M+H)+.

[Example 45] 1-[1,4-Dihydro-1-(6-methyl-3-pyridyl)indeno[1,2-c]pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in example 20, is listed in the title compound obtained as crystals (108 mg, 57%) with the use of 1,4-dihydro-1-(6-methyl-3-pyridyl)indeno[1,2-c]pyrazole-3-carboxylic acid (145 mg)obtained in reference example 64, and N-methylpiperazine (66 μl).

1H-NMR (400 MHz, CDCl3) δ: of 2.34 (3H, s), 2,43-2,60 (4H, m), 2,69 (3H, s), 3,83 (2H, s), 3,78-3,93 (2H, usher.), 4,18-4,30 (2H, usher.), of 7.23-7,34 (2H, m), 7,37 (1H, d, J=8.0 Hz), 7,46 (1H, DD, J=6.3, in the 1.7 Hz), EUR 7.57 (1H, d, J=6.3 Hz), 7,94 (1H, DD, J=8.0 a, 2,4 Hz), 8,91 (1H, d, J=2,4 Hz).

MS (ESI) m/z: 374 (M+H)+.

Elemental analysis: as With22H23N5O·0,25 H2O.

Calculated: C, 69,91; N, 6,27; N, 18,53.

Found: C, 69,79; N, 6,10; N, 18,24.

[Example 46] 1-[1,4-Dihydro-1-(6-ethyl-3-pyridyl)indeno[1,2-c]pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in example 20, is listed in the title compound obtained as crystals (163 mg, 84%) with the use of 1,4-dihydro-1-(6-ethyl-3-pyridyl)-indeno[1,2-c]pyrazole-3-carboxylic acid (152 mg)obtained in reference example 68, and N-methylpiperazine (66 μl).

1N-the Mr (400 MHz, CDCl3) δ: of 1.40 (3H, t, J=7.5 Hz), was 2.34 (3H, s), 2,42-of 2.58 (4H, m), 2,96 (2H, q, J=7.0 Hz), a-3.84 (2H, s), 3,78-3,93 (2H, usher.), 4,17-4,30 (2H, usher.), 7,25-to 7.35 (2H, m), 7,38 (1H, d, J=8,3 Hz), 7,47 (1H, DD, J=6,3, 1.9 Hz), EUR 7.57 (1H, d, J=6.3 Hz), of 7.96 (1H, DD, J=8,3, 2.4 Hz), to 8.94 (1H, d, J=2,4 Hz).

MS (ESI) m/z: 388 (M+H)+.

Elemental analysis: as With23H25N5O.

Calculated: C, 71,29; N, Of 6.50; N, 18,07.

Found: C, 71,06; N, Of 6.49; N, 17,73.

[Example 47] tert-Butyl ether 4-[1-(6-methoxy-3-pyridyl)-5-(4-methylthio-2-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid

In a manner analogous to the example used in stage 1) of example 1, indicated in the title compound obtained as a solid (0,379 g, 84%) using 1-(6-methoxy-3-pyridyl)-5-(4-methylthio-2-pyridyl)pyrazole-3-carboxylic acid (0,305 g)obtained in reference example 118, and tert-butyl methyl ether piperidine-1-carboxylic acid (0,180 g).

1H-NMR (400 MHz, CDCl3) δ: to 1.48 (9H, s), is 2.44 (3H, s), 3,51-to 3.52 (4H, m), with 3.79 (2H, m), of 3.95 (3H, s)4,08 (2H, m), 6,76 (1H, d, J=8,8 Hz), 7,02? 7.04 baby mortality (1H, m), 7,13 (1H, s), 7,22 (1H, d, J=1.6 Hz), to 7.59 (1H, DD, J=8,8, 2,8 Hz)to 8.12 (1H, d, J=2.4 Hz), of 8.27 (1H, d, J=5,2 Hz).

MS (EI) m/z: 510 (M+).

[Example 48] tert-Butyl ether 4-[1-(6-methoxy-3-pyridyl)-5-(4-methylsulphonyl-2-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid

When 0°With 3-chloroperbenzoic acid (0,260 g) are added to a solution of tert-putilovo the ester 4-[1-(6-methoxy-3-pyridyl)-5-(4-methylthio-2-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid (0,366 g), obtained in example 47, in methylene chloride (7.3 ml) and the mixture is stirred for 20 minutes. The mixture is then stirred at room temperature for an additional 2 hours. When 0°to this mixture 3-chloroperbenzoic acid (0.124 g) and the resulting mixture is stirred for 2 hours. To the reaction mixture is added saturated aqueous sodium thiosulfate (10 ml) and saturated aqueous sodium bicarbonate (10 ml), followed by stirring. The reaction mixture is distributed between water and chloroform. The organic layer is dried over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound as an amorphous product (0,387 g, 99%).

1H-NMR (400 MHz, CDCl3) δ: to 1.48 (9H, s), is 3.08 (3H, s), 3,53-of 3.54 (4H, m), 3,80 (2H, m), of 3.97 (3H, s), 4.09 to (2H, m), to 6.80 (1H, d, J=8,8 Hz), 7,31 (1H, s), 7,60-7,63 (1H, m), 7,70-7,72 (1H, m), 7,94 (1H, d, J=0.8 Hz), 8,10 (1H, d, J=2.4 Hz), 8,75-8,77 (1H, m).

MS (EI) m/z: 542 (M+).

[Example 49] 1-[5-(4-Ethoxy-2-pyridyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazin

1) tert-Butyl ether 4-[5-(4-ethoxy-2-pyridyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid

In the atmosphere of argon ethoxide sodium (28.4 mg) are added to a solution of tert-bout the business ester 4-[1-(6-methoxy-3-pyridyl)-5-(4-methylsulphonyl-2-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid (0,189 g), obtained in example 48, in tetrahydrofuran (3.8 ml) at room temperature. The resulting mixture is stirred for 1 hour and then stirred for 90 minutes at 80°C. Then added to the mixture ethoxide sodium (to 85.2 mg). The mixture was stirred at 80°C for 2 hours and 20 minutes and then cooled in air. The resulting mixture is distributed between water and ethyl acetate. The organic layer is dried over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (ethyl acetate-chloroform), to thereby obtain tert-butyl ester 4-[5-(4-ethoxy-2-pyridyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid (0,139 g, 79%) as a solid.

1H-NMR (400 MHz, CDCl3) δ: 1,41-of 1.44 (3H, m)to 1.48 (9H, s), 3,51-of 3.53 (4H, m), with 3.79 (2H, m), of 3.95 (3H, s), a 4.03-4,13 (4H, m), 6.73 x-6,77 (2H, m)6,94 (1H, d, J=2.0 Hz), 7,10 (1H, s), 7,26-7,27 (1H, m), 7,58 (1H, DD, J=8,8 and 2.8 Hz), to 8.12 (1H, d, J=2,8 Hz), 8,30 (1H, d, J=5.6 Hz).

MS (EI) m/z: 508 (M+).

2) Specified in the header of the connection

At room temperature triperoxonane acid (1.4 ml) are added to a solution of the above tert-butyl ester 4-[5-(4-ethoxy-2-pyridyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid (is 0.135 g) in methylene chloride (2.7 ml) and the mixture is stirred for 30 minutes. The solvent is removed when eigendom pressure and the residue is dissolved in ethanol (2.7 ml). To the mixture is added 35% aqueous formalin solution (0,114 g), acetic acid (0,076 ml) and cyanoborohydride sodium (50.0 mg). The resulting mixture is stirred for 100 minutes at room temperature. To the mixture additionally add cyanoborohydride sodium (33.3 mg) and the mixture is stirred for 50 minutes. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and chloroform. The organic layer is dried over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (chloroform-methanol). The residue is then purified by thin-layer chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound in the form of oil product (86,9 mg, 78%).

1H-NMR (400 MHz, CDCl3) δ: 1,41-of 1.44 (3H, m), of 2.33 (3H, s), 2,44-2,52 (4H, m), 3,85 (2H, m), of 3.95 (3H, s), a 4.03-4,08 (4H, m), 6,72-6,76 (2H, m)6,94 (1H, d, J=2.4 Hz), 7,07 (1H, s), EUR 7.57-to 7.61 (1H, m), 8,12-8,13 (1H, m), 8,30 (1H, d, J=6.0 Hz).

MS (EI) m/z: 422 (M+).

[Example 50] tert-Butyl ether 4-[1-(6-methoxy-3-pyridyl)-5-[4-(pyrrolidin-1-yl)-2-pyridyl]pyrazole-3-carbonyl]piperazine-1-carboxylic acid

A solution of tert-butyl ester 4-[1-(6-methoxy-3-pyridyl)-5-(4-methylsulphonyl-2-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid (0,186 g)obtained in example 48, pyrrolidine (3,7ml) was stirred at 100° C for 17 hours and then the mixture is cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer is dried over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound in the form of solids (0,176 g, 96%).

1H-NMR (400 MHz, CDCl3) δ: to 1.48 (9H, s), 1,84-2,07 (4H, m), is 2.05 (3H, s), 3.25 to 3,51 (8H, m), with 3.79 (2H, m), of 3.94 (3H, s)4,07 (2H, m), of 6.31-6,33 (1H, m), 6,53 (1H, d, J=2.0 Hz), was 6.73 (1H, d, J=8,8 Hz), 7,05 (1H, s), 7,60 (1H, DD, J=8,8, 2,8 Hz), of 8.09 (1H, d, J=6, 0 Hz), 8,16 (1H, d, J=2,8 Hz).

MS (EI) m/z: 533 (M+).

[Example 51] 1-[1-(6-Methoxy-3-pyridyl)-5-[4-(pyrrolidin-1-yl)-2-pyridyl]pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in step 2) of example 49, indicated in the title compound obtained as a solid (70.1 mg, 50%) using tert-butyl ester 1-[1-(6-methoxy-3-pyridyl)-5-[4-(pyrrolidin-1-yl)-2-pyridyl]pyrazole-3-carbonyl]piperazine-4-carboxylic acid (0.167 g)obtained in reference example 50.

1H-NMR (400 MHz, CDCl3) δ: 1,19-of 2.05 (4H, m), of 2.33 (3H, s), 2,45-of 2.50 (4H, m), 3.25 to or 3.28 (4H, m), a-3.84 (2H, m), 3,93 (3H, s)4,08 (2H, m), of 6.31 (1H, DD, J=6,0, 2,8 Hz), 6,53 (1H, d, J=2.4 Hz), 6,72 (1H, d, J=8,8 Hz), 7,02 (1H, s), to 7.59 to 7.62 (1H, m), of 8.09 (1H, d, J=6.0 Hz), 8,16 (1H, d, J=2,8 Hz).

MS (EI) m/z: 447 (the +).

Elemental analysis: as With24H29N7O2•0,25 H2O.

Calculated: C, 63,77%; H, 6.58 Percent; N, 21,69%.

Found: C, 63,93%; H, 6.67 Per Cent; N, 21,31%.

[Example 52] Ethyl ester 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperidine-2-luxusni acid

In a manner analogous to the method used in example 20, is listed in the title compound obtained as an oily product (331 mg, 98%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (221 mg)obtained in referential example 41 ethyl ester piperidine-2-luxusni acid (154 mg)obtained in reference example 93.

1H-NMR (400 MHz, CDCl3) [as a mixture of two isomers] δ: to 1.19 and 1.26 (each 0,5x3H, each t, each J=7,0 Hz), 1,48-of 1.85 (6H, osirm), 2,64-2,95 (2,5H, m), 3,15-3,29 (0,5H, m), 3,93 (3H, s), 4,01-4,19 (2H, usher.), 4,62-of 4.75 (1H, usher.), 5,32-5,41 (1H, usher.), 6,70 (1H, d, J=8,8 Hz), 6,84 and 6,87 (each 0,5x1H, each users), 7,18-7,28 (2H, m), 7,30-7,37 (3H, m), 7,45-EUR 7.57 (1H, osirm), 8,11 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 449 (M+H)+.

[Example 53] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperidine-2-ilocana acid

To a solution of ethyl ester 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperidine-2-luxusni acid (330 mg)obtained in example 52, in methanol (4 ml) was added 1 M aqueous sodium hydroxide (1,84 ml) and the mixture re eshivot for 2 hours at room temperature. The solvent is removed under reduced pressure and the residue partitioned between water and ethyl acetate. The aqueous layer was acidified with 1 M aqueous hydrochloric acid (2 ml) followed by extraction with ethyl acetate. Thus obtained organic layer was washed with water and saturated salt solution and dried over anhydrous sodium sulfate. The resulting mixture is filtered and the solvent is removed under reduced pressure, thus obtaining specified in the title compound as an amorphous product (311 mg, 98%).

1H-NMR (400 MHz, CDCl3) δ: 1,48-1,90 (6H, osirm), to 2.67 3.00 for (2,5H, osirm), 3,12-3,28 (0,5H, usher.), to 3.92 (3H, s), 4,65-4,82 (1H, usher.), 5,23-5,43 (1H, usher.), 6,70 (1H, d, J=8,8 Hz), make 6.90 (1H, users), 7,19-7,28 (2H, m), 7,30-7,38 (3H, m), of 7.48 (1H, DD, J=8,8, 2.7 Hz), 8,13 (1H, users).

MS (ESI) m/z: 421 (M+H)+.

Elemental analysis: as With23H24N4O4•0.5 N2O.

Calculated: C, 64,32; N, By 5.87; N, Of 13.05.

Found: C, 64,11; N, 5,90; N, Was 12.75.

[Example 54] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-isopropylpiperazine

1) Specified in the header of the connection

In a manner analogous to the method used in example 20, is listed in the title compound obtained as an amorphous product (251 mg, 82%) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (222 mg)obtained in reference example is 33, and hydrochloride 1-isopropylpiperazine (181 mg)obtained in reference example 95.

1H-NMR (400 MHz, CDCl3) δ: of 1.06 (6H, d, J=6.6 Hz), of 2.56 (2H, t, J=4.9 Hz), 2,61 (2H, t, J=4.9 Hz), 2,73 (1H, septet, J=6.6 Hz), 3,83 (2H, t, J=4.9 Hz), of 3.95 (3H, s)4,07 (2H, t, J=4.9 Hz), of 6.71 (1H, DD, J=8, 8, 0, 7 Hz), 7,11 (1H, s), 7.23 percent (1H, DDD, J=7,8, a 4.9, 1.2 Hz), 7,41 (1H, DDD, J=7,8, 1,2, 1.0 Hz), to 7.59 (1H, DD, J=8,8, 2.7 Hz), of 7.70 (1H, DDD, J=7,8, and 7.8, 1.2 Hz), to 8.12 (1H, DD, J=2.7, and 0.7 Hz), 8,51 (1H, DDD, J=4,9, to 1.7, 1.0 Hz).

MS (ESI) m/z: 407 (M+H)+.

2) Salt specified in the connection header with hydrochloric acid

In a manner similar to the method used in step 2) of example 29, salt specified in the connection header with hydrochloric acid is obtained in the form of crystals (235 mg, 73%) using the above specified in the title compound (251 mg).

1H-NMR (400 MHz, DMSO-d6) δ: of 1.30 (6H, d, J=6.6 Hz), 3, 01-3,20 (2H, usher.), 3,33 of 3.56 (4H, osirm), 3,69-3,74 (1H, osirm), the 3.89 (3H, s), 4,60-to 4.73 (1H, osirm), 5,03-5,17 (1H, osirm), to 6.88 (1H, d, J=8,8 Hz), 7,27 (1H, s), 7,35-7,41 (1H, m), of 7.64-7,74 (2H, m), a 7.85-7,94 (1H, m), to 8.20 (1H, d, J=2.7 Hz), of 8.47 (1H, DD, J=4,9, 0.7 Hz), 10,84-11,04 (1H, usher.).

MS (ESI) m/z: 407 (M+H)+.

Elemental analysis: as With22H26N6O2•2 HCl•2 H2O.

Calculated: C, 51,27; N, Of 6.26; N, 16,30; Cl, 13,76.

Found: C, 51,30; N, 6,18; N, 15,97; Cl, Made 13.36.

[Example 55] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-cyclopropylbenzene

By the way, EN is a logical method, used in example 20, is listed in the title compound obtained as crystals (253 mg, 83%) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (222 mg)obtained in reference example 33, and the hydrochloride of 1-cyclopropylbenzene (179 mg)obtained in reference example 99.

1H-NMR (400 MHz, CDCl3) δ: 0,41-0,51 (4H, m), 1,60 was 1.69 (1H, m)to 2.66 (2H, t, J=4.9 Hz), a 2.71 (2H, t, J=4.9 Hz), with 3.79 (2H, ushort, J=4,9 Hz), of 3.95 (3H, s), was 4.02 (2H, ushort, J=4,9 Hz), to 6.75 (1H, d, J=8,8 Hz), 7,11 (1H, s), 7.23 percent (1H, DDD, J=7,8, a 4.9, 1.2 Hz), 7,41 (1H, d, J=7.8 Hz), to 7.59 (1H, DD, J=8,8, 2.7 Hz), 7,71 (1H, DDD, J=7,8, and 7.8, 1.7 Hz), to 8.12 (1H, d, J=2.7 Hz), charged 8.52 (1H, DDD, J=4,9, to 1.7, 1.0 Hz).

MS (ESI) m/z: 404 (M+H)+.

Elemental analysis: as With22H24N6O2.

Calculated: C, 65,33; N, 5,98; N, 20,78.

Found: C, 64,97; N, Of 5.92; N, 20,53.

[Example 56] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-2-(2-hydroxyethyl)piperidine

In a manner analogous to the method used in example 20, is listed in the title compound obtained as an amorphous product (82 mg, 39%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (148 mg)obtained in referential example 41 2-(piperidine-2-yl)ethanol (78 mg).

1H-NMR (400 MHz, CDCl3) [as a mixture of two isomers] δ: 1,53-of 1.80 (5H, m), 1,84-1,95 (0,5H, usher.), 2,04-2,13 (0,5H, m), 2,25-2,36 (0,5H, m), 2,74-2,85 (0,5H, m), 2,98-is 3.08 (0,5H, m), 3,43-3,53 (0,5H, m), 3,57-with 3.79 (2H, m), 3,92 and 3,94 (each 3H, what each) EUR 4.00-4.09 to (0,5H, m), 4,62-4,78 (1H, t), 4,88-5,04 (1H, m), 5,10-5,17 (0,5H, m), of 6.71 and 6.75 (each 0,5x1H, each d, each J=8,8 Hz), 6,88 waste and 6.96 (each 0,5x1H, each s), 7.18 in-7,27 (2H, m), 7,29-7,38 (3H, m), 7,47 and 7,51 (each 0,5x1H, each DD, each J=8,8, 2.7 Hz), 8,04 and 8,13 (each 0,5x1H, each d, each J=2.7 Hz).

MS (ESI) m/z: 407 (M+H)+.

Elemental analysis: as With23H26N4O3•0.5 N2O.

Calculated: C, 66,49; N, 6,55; N, 13,48.

Found: C, 66,68; N, 6,53; N, 13,31.

[Example 57] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperidine

In a manner analogous to the method used in example 20, is listed in the title compound obtained as crystals (137 mg, 75%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (148 mg)obtained in reference example 41, and piperidine (59 μl).

1H-NMR (400 MHz, CDCl3) δ: 1,56-of 1.75 (6H, osirm), 3,71-3, 78 (2H, usher.), the 3.89-of 3.97 (2H, usher.), 3,93 (3H, s)of 6.71 (1H, d, J=8,8 Hz), at 6.84 (1H, s), 7,21-7,27 (2H, m), 7,30-7,37 (3H, m), of 7.48 (1H, DD, J=8,8, 2.7 Hz), 8,11 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 363 (M+H)+.

Elemental analysis: as With21H22N4O2.

Calculated: C, 69,59; N, 6,12; N, 15,46.

Found: C, 69,43; N, 6,09; N, 15,20.

[Example 58] 1-[5-(4-Methoxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in example 20, is listed in the title compounds is their gain in the form of crystals (237 mg, 77%) using 5-(4-methoxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid (244 mg)obtained in reference example 45 and the N-methylpiperazine (125 μl).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2,42-of 2.54 (4H, m), 3,78-3,88 (2H, usher.), 3,81 (3H, s), of 3.94 (3H, s), 4,07-4,17 (2H, usher.), of 6.71 (1H, d, J=8,8 Hz), at 6.84 (1H, s), 6,85 (2H, d-like, J=8,8 Hz), to 7.15 (2H, d-like, J=8,8 Hz), of 7.48 (1H, DD, J=8,8, 2.7 Hz), to 8.12 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 408 (M+H)+.

Elemental analysis: as With22H25N5O3.

Calculated: C, 64,85; N, 6,18; N, 17,19.

Found: C, 64,66; N, Of 6.20; N, 17,06.

[Example 59] 1-[5-(3-Methoxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazin

1) Specified in the header of the connection

In a manner analogous to the method used in example 20, is listed in the title compound obtained as an oily product (243 mg, 79%) using 5-(3-methoxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid (244 mg)obtained in reference example 47, and N-methylpiperazine (125 μl).

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 29, salt specified in the connection header with hydrochloric acid is obtained in the form of crystals (253 mg, 92%) using the above specified in the connection header.

1H-NMR (400MHz, DMSO-d6) δ: and 2.79 (3H, s), 2,98-to 3.73 (6H, osirm), 3,70 (3H, s), 3,88 (3H, s), 4.53-in-4,70 (1H, usher.), 4,92-5,08 (1H, usher.), to 6.80 (1H, d, J=7.5 Hz), 6,85-6,98 (3H, m), 7,02 (1H, s), 7.23 percent-to 7.32 (1H, m), of 7.70 (1H, DD, J=8,8, 2.7 Hz), 8,19 (1H, d, J=2.7 Hz), 10,78-10,94 (1H, usher.).

MS (ESI) m/z: 408 (M+H)+.

Elemental analysis: as With22H25N5O3•HCl•N2O.

Calculated: C, 57,20; N, 6,11; N, 15,16; Cl, To 7.67.

Found: C, 57,12; N, 6,09; N, 15,08; Cl, 7,74.

[Example 60] 1-[5-(2-Methoxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in example 20, is listed in the title compound obtained as crystals (263 mg, 84%) using 5-(2-methoxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid (244 mg)obtained in reference example 49, and N-methylpiperazine (125 μl).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2,43-of 2.56 (4H, usher.), of 3.48 (3H, s), 3,78-to 3.92 (2H, usher.), are 3.90 (3H, s), 4,11-4,22 (2H, usher.), to 6.67 (1H, d, J=8,8 Hz), PC 6.82 (1H, d, J=8,3 Hz)6,86 (1H, s), 6,95-7,03 (1H, m), 7,27-to 7.32 (1H, m), 7,34-7,40 (1H, m), of 7.48 (1H, DD, J=8,8, 2.7 Hz), of 8.06 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 408 (M+H)+.

[Example 61] 1-[1-(6-Methoxy-3-pyridyl)-5-(4-triptoreline)pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in example 20, is listed in the title compound obtained as crystals (272 mg, 81%) using 1-(6-methoxy-3-pyridyl)--(4-triptoreline)pyrazole-3-carboxylic acid (272 mg), obtained in reference example 51, N-methylpiperazine (125 μl).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2,42-to 2.57 (4H, m), 3,79-3,91 (2H, usher.), of 3.95 (3H, s), 4,07-4,18 (2H, usher.), 6,76 (1H, d, J=8,8 Hz), 6,98 (1H, s), of 7.36 (2H, d, J=8.0 Hz), 7,49 (1H, DD, J=8,8, 2.4 Hz), 7,60 (2H, d, J=8.0 Hz), of 8.09 (1H, d, J=2,4 Hz).

MS (ESI) m/z: 446 (M+H)+.

Elemental analysis: as With22H22F3N5O2.

Calculated: C, 59,32; N, To 4.98; N, 15,72; F, 12,80.

Found: C, 58,95; N, Is 4.93; N, 15,71; F, 12,57.

[Example 62] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazin

1) Specified in the header of the connection

In a manner analogous to the method used in example 20, is listed in the title compound obtained as an oily product (6,23 g, 66%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (7,38 g)obtained in referential example 41 and N-methylpiperazine (3,32 ml).

2) Salt specified in the connection header with hydrochloric acid

To the solution obtained above, specified in the connection header (6,23 g) in methanol (200 ml) was added 1 M aqueous hydrochloric acid (17 ml), followed by stirring. The solvent is removed under reduced pressure and to the residue is added ethanol and the solvent is optionally removed under reduced pressure. The residue is crystallized from a mixture of ethanol-diethyl ether with posleduyuschimi crystals by filtration, while receiving salt specified in the connection header with hydrochloric acid in the form of crystals (5,04 g, 72%).

1H-NMR (400 MHz, DMSO-d6) δ: 2,80 (3H, s), 3.00 and-of 3.73 (6H, osirm), 3,88 (3H, s), 4.53-in-4,72 (1H, usher.), 4,94-5,10 (1H, usher.), 6,89 (1H, d, J=8,8 Hz), 7,00 (1H, s), 7,25-to 7.32 (2H, m), of 7.36-the 7.43 (3H, m), 7,68 (1H, DD, J=8,8, and 2.6 Hz), 8,18 (1H, d, J=2.6 Hz), 10,71-10,87 (1H, usher.).

MS (ESI) m/z: 378 (M+H).

Elemental analysis: as With21H23N5O2•HCl•0.5 N2O.

Calculated: C, 59,64; N, 5,96; N, 16,56%; Cl, Scored 8.38.

Found: C, 59,60; N, 6,17; N, 16,43; Cl, 8,56.

[Example 63] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazol-3-thiocarbonyl]-4-methylpiperazin

To a solution of 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazine (173 mg)obtained in example 62, in toluene (10 ml) is added 2,4-bis-(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (reagent Lawson, 222 mg). The mixture is refluxed for 14 hours under heating. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated salt solution, followed by drying over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure. The residue is purified by thin-layer chromatography on silica gel (chloroform-methanol), while receiving specified in the header is Obedinenie in the form of an amorphous product (61 mg, 33%).

1H-NMR (400 MHz, CDCl3) δ: is 2.37 (3H, s), 2,50-a 2.71 (4H, m), 3,93 (3H, s), 4.09 to-4,20 (2H, usher.), 4,42-4,55 (2H, usher.), 6,70 (1H, d, J=8,8 Hz), make 6.90 (1H, s), 7,22-7,28 (2H, m), 7,30-7,39 (3H, m), 7,47 (1H, DD, J=8,8, 2.7 Hz), 8,10 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 394 (M+H)+.

[Example 64] tert-Butyl ether 4-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperazine-1-carboxylic acid

To a solution containing methylene chloride (5 ml) of 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (295 mg)obtained in reference example 41, added tert-butyl ether piperazine-1-carboxylic acid (186 mg), 1-hydroxybenzotriazole (135 mg) and triethylamine (488 μl), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (288 mg). The resulting mixture was stirred at room temperature for 13 hours. The reaction solvent is removed under reduced pressure and to the residue is added water and ethyl acetate, thus obtaining an aqueous layer and organic layer. The organic layer is washed with water and saturated salt solution, followed by drying over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure. Thus obtained solid is recrystallized from a mixture of ethyl acetate-hexane, thus obtaining specified in the title compound as crystals (225 mg). Separately solvent obtained above water is about layer is removed under reduced pressure. The residue is purified by thin-layer chromatography on silica gel (hexane-ethyl acetate), while receiving additional specified in the title compound (154 mg). The compound obtained above and crystals combine (379 mg, 81%).

1H-NMR (400 MHz, CDCl3) δ: to 1.48 (9H, s), 3,48 is 3.57 (4H, usher.), 3,75-3,82 (2H, usher.), of 3.94 (3H, s), 4,06-to 4.14 (2H, usher.), 6,72 (1H, d, J=8,8 Hz), 6,93 (1H, s), 7,21-7,27 (2H, m), 7,31-7,38 (3H, m), 7,47 (1H, DD, J=8,8, 2.7 Hz), to 8.12 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 464 (M+H)+.

[Example 65] Hydrochloride 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperazine

To a solution of tert-butyl ester 4-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperazine-1-carboxylic acid (332 mg)obtained in example 64, in methylene chloride (2 ml), added anisole (0.4 ml) and triperoxonane acid (1.6 ml) and the mixture is stirred at room temperature for 30 minutes. The reaction solvent is removed under reduced pressure and the residue partitioned between water and diethyl ether. The aqueous layer was alkalinized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate four times. Organic layers combined with subsequent drying over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure. The residue is dissolved in a solvent mixture of diethyl ether and a small amount of methanol. To dissolve the we add a mixture of 1 M HCl-ethanol (0,78 ml) and precipitated crystals are collected by filtration. Thus obtained substance is recrystallized from methanol-diethyl ether, thus obtaining specified in the title compound (229 mg, 76%).

1H-NMR (400 MHz, DMSO-d6) δ: 3,12 is 3.23 (4H, usher.), 3,83-of 3.94 (2H, usher.), a 3.87 (3H, s), 4,23-to 4.33 (2H, usher.), 6,89 (1H, d, J=8,8 Hz), of 6.99 (1H, s), 7,26-to 7.32 (2H, m), of 7.36-7,42 (3H, m), 7,68 (1H, DD, J=8,8, 2.4 Hz), 8,17 (1H, d, J=2.4 Hz), 9,26-9,40 (2H, usher.).

MS (ESI) m/z: 364 (M+H)+.

Elemental analysis: as With20H21N5O2•HCl•N2O.

Calculated: C, 57,48; N, 5,79; N, 16,76; Cl, 8,48.

Found: C, 57,11; N, 5,70; N, 16,58; Cl, 8,81.

[Example 66] tert-Butyl ether 4-[5-(4-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid

To a solution containing methylene chloride (5 ml) of 5-(4-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid (313 mg)obtained in reference example 136 add tert-butyl ether piperidine-1-carboxylic acid (186 mg), 1-hydroxybenzotriazole (135 mg) and triethylamine (488 μl), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (288 mg) and the mixture is stirred at room temperature for 13 hours. The solvent is removed under reduced pressure. To the residue is added water and ethyl acetate, thus obtaining an aqueous layer and organic layer. The organic layer is washed with water and saturated salt solution, followed by drying over be the aqueous sodium sulfate. After filtration the solvent is removed under reduced pressure. Thus obtained solid is recrystallized from a mixture of ethyl acetate-hexane, thus obtaining specified in the title compound (241 mg). Separately solvent layer obtained above is removed under reduced pressure. The residue is purified by thin-layer chromatography on silica gel (hexane-ethyl acetate), obtaining mentioned in the title compound as crystals (170 mg). The first crystals and the last crystals unite (411 mg, 85%).

1H-NMR (400 MHz, CDCl3) δ: to 1.48 (9H, s), 3,48 is 3.57 (4H, usher.), 3,74-3,82 (2H, usher.), of 3.95 (3H, s), 4,07 is 4.13 (2H, usher.), 6,74 (1H, d, J=8,8 Hz), 6,92 (1H, s), 7,00-was 7.08 (2H, m), 7.18 in-to 7.25 (2H, m), 7,47 (1H, DD, J=8,8, 2.7 Hz), of 8.09 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 482 (M+H)+.

Elemental analysis: as With25H28FN5O4•0.5 N2O.

Calculated: C, 61,21; N, 5,96; N, Of 14.28; F, A 3.87.

Found: C, 61,41; N, USD 5.76; N, 14,18; F, 3,95.

[Example 67] Hydrochloride 1-[5-(4-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperazine

In a manner analogous to the method used in example 65, indicated in the title compound obtained as crystals (278 mg, 81%) using tert-butyl ester 4-[5-(4-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid (363 mg)obtained in example 66.

1H-NMR (400 MHz, the MCO-d 6) δ: 3,10-up 3.22 (4H, usher.), 3,82-of 3.96 (2H, usher.), 3,88 (3H, s), 4,22-4,32 (2H, usher.), make 6.90 (1H, d, J=8,8 Hz), 7,00 (1H, s), 7,20-7,28 (2H, m), 7,31-7,40 (2H, m), of 7.69 (1H, DD, J=8,8, 2.7 Hz), 8,19 (1H, d, J=2.4 Hz), of 9.30-9,43 (2H, usher.).

MS (ESI) m/z: 382 (M+H)+.

[Example 68] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methoxyacetophenone

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound (285 mg, quantitative yield) are obtained using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (200 mg)obtained in reference example 41, and the hydrochloride of 1-(2-methoxyethyl)piperazine (175 mg)obtained in referential example 97.

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 29, salt specified in the connection header with hydrochloric acid is obtained in the form of solids 255 mg, 82%) using the above specified in the title compound (285 mg).

1H-NMR (400 MHz, DMSO-d6) δ: 3,13 (2H, usher.), 3,30-of 3.32 (2H, usher.), of 3.33 (3H, s), of 3.56 (3H, usher.), 3,72-to 3.73 (3H, m), 4,58 (1H, usher.), at 4.99 (1H, usher.), make 6.90 (1H, d, J=8,8 Hz), 7,00 (1H, s), 7,29-7,31 (2H, m), 7,39-7,41 (3H, m), of 7.70 (1H, DD, J=8,8, 2.7 Hz), to 8.20 (1H, d, J=2.7 Hz), 10,85 (1H, usher.).

MS (FAB) m/z: 422 (M+H)+.

Elemental analysis: as With23H27N5 O3•HCl.

Calculated: C, 60,45; N, 6,18; N, 15,33; Cl, 7,76.

Found: C, 60,15; N, 6,14; N, 15,01; Cl, 7,63.

[Example 69] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-cyclopropylbenzene

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (180 mg, 66%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (200 mg)obtained in reference example 41, and the hydrochloride of 1-cyclopropylbenzene (160 mg)obtained in reference example 99.

1H-NMR (400 MHz, DMSO-d6) δ: 0,34-0,36 (2H, m), of 0.41 to 0.44 (2H, m), 1,64-to 1.67 (1H, m), 2,58 (4H, usher.), 3,61 (2H, usher.), a 3.87 (3H, s)to 3.89 (2H, usher.), make 6.90 (1H, d, J=8,8 Hz), 6,92 (1H, s), 7,28-to 7.32 (2H, m), 7,37-7,40 (3H, m), of 7.70 (1H, DD, J=8,8, 2.2 Hz), 8,14 (1H, d, J=2.2 Hz).

MS (EI) m/z: 403 (M+).

Elemental analysis: as With23H25N5O2.

Calculated: C, 68,47; N, Of 6.25; N, 16,36%.

Found: C, 68,45; N, Of 6.29; N, 17,23.

[Example 70] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-3-dimethylaminoacetyl

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound (185 mg, 95%) are obtained using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (150 mg)obtained in referential example 41 and hydrochloride and midin-3-ultimatemenu (106 mg), obtained in reference example 102.

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 29, salt specified in the connection header with hydrochloric acid obtained as a solid (155 mg, 74%) using the above specified in the title compound (185 mg).

1H-NMR (400 MHz, DMSO-d6) δ: of 2.75 (6H, s), 3,88 (3H, s), 4,14 (1H, usher.), 4,24-to 4.33 (2H, m), 4,70-to 4.81 (2H, m), 6.90 to (1H, d, J=8,8 Hz),? 7.04 baby mortality (1H, s), 7,29-to 7.32 (2H, m), 7,38-7,41 (3H, m), to 7.67 (1H, DD, J=8,8, 2,9 Hz), by 8.22 (1H, d, J=2,9 Hz), 11,47 (1H, usher.).

MS (EI) m/z: 377 (M+).

Elemental analysis: as With23H27N5O3•HCl•N2O.

Calculated: C, 58,40; N, 6,07; N, 16,21%; Cl, 8,21.

Found: C, 58,08; N, Of 6.02; N, 15,97; Cl, 8,23.

[Example 71] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-3-methoxyisatin

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (140 mg, 76%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (150 mg)obtained in referential example 41 and hydrochloride 3-methoxyacridine (75,6 mg)obtained in reference example 107.

1H-NMR (400 MHz, CDCl3) δ: 3,37 (3H, s), of 3.95 (3H, s), 4,08-4,11 (1H, m), 4,25-or 4.31 (1H, m), 4,36-and 4.40 (1H, m), 4,46-4,50 (1H, m), 4,78-4,82 (1H, m), of 6.71 (1H, d, J8,8 Hz), 6,92 (1H, s), 7,22-7,24 (2H, m), 7,32-to 7.35 (3H, m), 7,46 (1H, DD, J=8,8, 2,9 Hz), 8,15 (1H, d, J=2,9 Hz).

LC-MS m/z: 365 (M+H)+.

Elemental analysis: as With20H20N4O3•0,25 H2O.

Calculated: C, 65,12; N, The Ceiling Of 5.60; N, 15,19.

Found: C, 65,12; N, 5,44; N, 15,13.

[Example 72] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-3-hydroxyazetidine

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (135 mg, 76%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (150 mg)obtained in referential example 41 and hydrochloride 3-gidroksietiliden (67,0 mg)obtained in reference example 108.

1H-NMR (400 MHz, CDCl3) δ: of 3.94 (3H, s), 4,07-of 4.12 (1H, m), 4,45-4,50 (2H, m), to 4.73 (1H, usher.), a 4.86-of 4.90 (1H, m), 6,70 (1H, d, J=8,8 Hz), 7,01 (1H, s), 7,20-of 7.23 (2H, m), 7,30-7,37 (3H, m), 7,46 (1H, DD, J=8,8, 2,8 Hz)to 8.12 (1H, d, J=2,8 Hz).

LC-MS m/z: 351 (M+H)+.

Elemental analysis: as With19H18N4O3•0,25 H2O.

Calculated: C, 64,31; N, A 5.25; N, 15,79.

Found: C, 64,19; N, 5,15; N, 15,60.

[Example 73] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-cyclobutylmethyl

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound (283 mg, quantitative in the course) are obtained using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (200 mg), obtained in reference example 41, hydrochloride and 4-cyclobutylamine (173 mg)obtained in reference example 110.

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 29, salt specified in the connection header with hydrochloric acid obtained as a solid (254 mg, 83%) using the above specified in the title compound (283 mg).

1H-NMR (400 MHz, DMSO-d6) δ: 1,69-to 1.79 (2H, m), 2,17 (2H, usher.), is 2.37 (2H, usher.), only 2.91 (2H, usher.), 3,35-3,37 (3H, m), 3,66-to 3.73 (2H, m), 3,88 (3H, s), to 4.62 (1H, userd, J=13,4 Hz), to 5.03 (1H, userd, J=13,4 Hz)6,91 (1H, d, J=8,8 Hz), 7,02 (1H, s), 7,29-to 7.32 (2H, m), 7,39-7,41 (3H, m), of 7.70 (1H, DD, J=8,8, 2.7 Hz), 8,19 (1H, d, J=2.7 Hz), 10,46 (1H, usher.).

LC-MS m/z: 418 (M+H)+.

Elemental analysis: as With24H27N5O2•HCl•0,25 H2O.

Calculated: C, 62,87; N, 6,27; N, 15,28; Cl, 7,73.

Found: C, 63,05; N, Of 6.25; N, 15,05; Cl, 7,69.

[Example 74] 1-[1-(6-Methoxy-3-pyridazinyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (150 mg, 78%) using 1-(6-methoxy-3-pyridazinyl)-5-phenylpyrazol-3-carboxylic acid (150 mg)obtained in reference example 43, and N-methylpiperazine (0,068 ml).

1N-the Mr (400 MHz, DMSO-d6) δ: of 2.21 (3H, s), 2,35-of 2.38 (4H, m), 3,66 (2H, users), the 3.89 (2H, users), was 4.02 (3H, s), of 6.96 (1H, s), 7,29-7,31 (2H, m), 7,37-7,39 (3H, m), of 7.48 (1H, d, J=9.3 Hz), to 7.99 (1H, d, J=9,3 Hz).

LC-MS m/z: 379 (M+H)+.

Elemental analysis: as With20H22N6O2•0,25 H2O.

Calculated: C, 62,73; N, Of 5.92; N, 21,95.

Found: C, 62,69; N, Of 5.81; N, 21,66.

[Example 75] Hydrochloride 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-ethylpiperazine

In a manner analogous to the method used in stage 1) of example 1, 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-ethylpiperazin get using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (100 mg)obtained in referential example 41 and the N-ethylpiperazine (52 μl). In a manner analogous to the method used in step 2) of example 29, specified in the title compound obtained as a solid (111 mg, 76%) using the above product.

1H-NMR (400 MHz, DMSO-d6) δ: of 1.27 (3H, t, J=7,1 Hz), 3,05 (2H, osirm), of 3.13 (2H, osirm), to 3.33 (3H, s)to 3.33 (1H, osirm), of 3.54 (2H, osirm), 3,71 (1H, osirm), 3,88 (3H, s), 4,60 (1H, d, J=12,5 Hz), to 5.03 (1H, J=13.5 Hz), make 6.90 (1H, d, J=8,8 Hz), 7,01 (1H, s), 7,27-7,31 (2H, m), 7,38-7,41 (3H, m), of 7.70 (1H, DD, J=8,8, 2.7 Hz), 8,19 (1H, d, J=2.7 Hz), 11,13 (1H, users).

LC-MS m/z: 392 (M+H)+.

Elemental analysis: as With22H25N6O2•HCl•0,75 H2O.

Calculated: C, 59,86; N, 6,28; N $ 15.87 With; Cl, 8,03.

N is Geno: C, 59,89; N, Of 6.20; N, 15,81; Cl, 8,08.

[Example 76] Hydrochloride 1-[5-(4-forfinal)-1-(6-methoxy-3-pyridyl)-pyrazole-3-carbonyl]-4-ethylpiperazine

In a manner analogous to the method used in stage 1) of example 1, 1-[5-(4-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]-4-ethylpiperazin get using 5-(4-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid (150 mg)obtained in reference example 136, and N-ethylpiperazine (73 μl). In a manner analogous to the method used in step 2) of example 29, specified in the title compound obtained as a solid (96 mg, 45%) using the above product.

1H-NMR (400 MHz, DMSO-d6) δ: of 1.26 (3H, t, J=7,1 Hz), 3.04 from (2H, osirm), of 3.12 (2H, osirm), to 3.33 (3H, s)to 3.33 (1H, osirm), 3,53 (2H, osirm), 3,71 (1H, osirm), 3,88 (3H, s), 4,60 (1H, osirm), 5,00 (1H, osirm), 6,91 (1H, d, J=8,8 Hz), 7,02 (1H, s), of 7.25 (2H, t, J=8,8 Hz), 7,34-7,37 (2H, m), of 7.70 (1H, DD, J=8,8, 2.7 Hz), 8,21 (1H, d, J=2.7 Hz), 11,10 (1H, users).

LC-MS m/z: 410 (M+H)+.

Elemental analysis: as With22H24FN5O2•HCl•0.5 N2O.

Calculated: C, 58,08; N, USD 5.76; N, 15,39; F, 4,18; Cl, 7,79.

Found: C, 57,90; N, Of 5.82; N, 15,12; F 4,07; Cl, Of 7.64.

[Example 77] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-3-dimethylaminomethylene

In a manner analogous to the method used in stage 1) of example 1, specified in the header with the Association obtained as a solid (17 mg, 22%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (60 mg)obtained in referential example 41 and hydrochloride 3-dimethylaminopyridine (40 mg)obtained in reference example 112.

1H-NMR (400 MHz, CDCl3) δ: of 2.23 (6H, s), 2,52 (1H, DD, J=12,2, 6,8 Hz), 2,60 (1H, DD, J=12,2, 8,3 Hz), 2,86 (1H, m), 3,85 (1H, DD, J=10,3, 5.6 Hz), of 3.94 (3H, s), 4,28-to 4.33 (2H, m), 4,74 (1H, t, J=8,3 Hz), of 6.71 (1H, d, J=8,8 Hz), 7,01 (1H, s), 7,21-of 7.25 (2H, m), 7,32-to 7.35 (3H, m), 7,46 (1H, DD, J=8,8, 2.7 Hz), to 8.12 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 392 (M+H)+.

Elemental analysis: as With20H22N6O2•0.5 N2O.

Calculated: C, 65,98; N, Is 6.54; N, 17,48.

Found: C, 65,92; N, 6,36; N, 17,37.

[Example 78] tert-Butyl ether N-[1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]azetidin-3-yl]-N-methylcarbamate acid

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an amorphous product (453 mg, 96%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (300 mg)obtained in referential example 41 tert-butyl ester azetidin-3-yl-N-methylcarbamate acid (250 mg).

1H-NMR (400 MHz, CDCl3) δ: of 1.47 (9H, s), and 1.56 (9H, s), 2,95 (3H, s), of 3.95 (3H, s), 4,24 (1H, m)to 4.41 (1H, m), with 4.64 (1H, m), 4,84 (1H, m), 6,72 (1H, d, J=8,8 Hz), 7,03 (1H, s), 7,22-7,24 (2H, m), 7,33-to 7.35 (3H, m), 7,46 (1H, DD, J=8,8, 2,5 Hz), 8,13 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 464 (M+H)+.

[Note the p 79] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-3-methylimidazolidine

In a manner analogous to the method used in step 2) of example 49, indicated in the title compound obtained as a solid (255 mg, 72%) using tert-butyl ether N-[1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]azetidin-3-yl]-N-methylcarbamate acid (450 mg)obtained in example 78.

1H-NMR (400 MHz, CDCl3) δ: 3,51 (3H, s), 3,66 (1H, m)to 3.92 (1H, m), of 3.95 (3H, s), 4,32 (1H, DD, J=10,6, a 4.9 Hz), 4,39 (1H, DD, J=10,6, 7,4 Hz), 4,79 (1H, DD, J=9,5, 7,3 Hz), of 6.71 (1H, d, J=8,8 Hz), 7,02 (1H, s), 7,21-of 7.25 (2H,, m), 7,32-to 7.35 (3H, m), 7,45 (1H, DD, J=8,8, 2.7 Hz), 8,14 (1H, d, J=2.2 Hz).

MS (FAB) m/z: 364 (M+H)+.

[Example 80] tert-Butyl ether 4-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid

In a manner analogous to the method used in example 20, is listed in the title compound obtained as an amorphous product (0,407 g, quantitative yield) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (0,252 g)obtained in reference example 33, and tert-butyl methyl ether piperazine-1-carboxylic acid (0,311 g).

1H-NMR (400 MHz, CDCl3) δ: to 1.48 (9H, s), 3,52 (4H, usher.), with 3.79 (2H, usher.), of 3.94 (3H, s)4,08 (2H, usher.), to 6.75 (1H, d, J=8.7 Hz), to 7.15 (1H, s), 7,20-7,30 (1H, m), 7,42 (1H, d, J=7.8 Hz), 7,58 (1H, DD, J=8,7, and 2.6 Hz), 7,71 (1H, dt, J=7,8, 1.5 Hz), to 8.12 (1H, d, J=2.6 Hz), 8,45-8,55 (1H, m).

MS (FAB) m/z: 465 (M+H)+.

[Example 81] -[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]piperazine

1) Specified in the header of the connection

In a manner analogous to the method used in step 2) of example 49, indicated in the title compound obtained as an oily product (0,281 mg, 91%) using tert-butyl ester 4-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid (0,396 g)obtained in example 80.

1H-NMR (400 MHz, CDCl3) δ: 2,85-to 3.02 (4H, m), with 3.79 (2H, usher.), of 3.94 (3H, s), a 4.03 (2H, usher.), to 6.75 (1H, d, J=8,8 Hz), 7,11 (1H, s), 7,20-7,30 (1H, m), 7,40 (1H, d, J=7.8 Hz), to 7.59 (1H, DD, J=7,8, 2.7 Hz), of 7.70 (1H, dt, J=7,8) and 1.7 Hz), 8,11 (1H, d, J=2.7 Hz), 8,45-8,55 (1H, m).

LC-MS m/z: 365 (M+H)+.

2) Salt specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 1, salt specified in the connection header with hydrochloric acid is obtained in the form of solids (0,237 g, 69%) using the above specified in the connection header (0,281 g).

1H-NMR (400 MHz, DMSO-d6) δ: 3,18 (4H, usher.), 3,88 (3H, s)to 3.89 (2H, usher.), of 4.25 (2H, usher.), to 6.88 (1H, d, J=9.1 Hz), 7,26 (1H, s), 7,32-7,40 (1H, m), the 7.65 to 7.75 (2H, m), 7,86 (1H, dt, J=7,8, 2,5 Hz), 8,19 (1H, d, J=2.5 Hz), 8,42-and 8.50 (1H, m), 9,25 (2H, usher.).

LC-MS m/z: 365 (M+H)+.

[Example 82] 4-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-3-oxopiperidin

In a manner analogous to that of the mu in example 20, specified in the title compound obtained as a solid (210 mg, 66%) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (0,248 g)obtained in reference example 33, and piperazine-2-it (0,129 g).

1H-NMR (400 MHz, CDCl3) δ: 3,45-of 3.60 (2H, m), of 3.96 (3H, s), a 4.03 (1H, usher.), of 4.35 (2H, usher.), 4,88 (1H, usher.), 6,25-6,40 (1H, usher.), 6,72-to 6.80 (1H, usher.), 7,15-7,30 (2H, m), 7,37 to 7.75 (3H, m), 8,05-8,16 (1H, usher.), 8,51 (1H, d, J=4.4 Hz).

MS (ESI) m/z: 379 (M+H)+.

Elemental analysis: as With19H18N6O3•0,3 H2O.

Calculated: C, 59,46; N, 4,88; N, 21,90.

Found: C, 59,35; N, 4,71; N, 21,57.

[Example 83] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl] - for 3,5-dimethylpiperazine

In a manner analogous to the method used in example 20, is listed in the title compound obtained as a solid (0,142 g, 72%) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (0,150 mg)obtained in referential example 33 and 2,6-dimethylpiperazine (91,4 mg).

1H-NMR (400 MHz, CDCl3) δ: of 1.05 (3H, d, J=6,1 Hz)to 1.14 (3H, d, J=6,1 Hz), 2,40 (1H, t-like, J=a 12.7 Hz), was 2.76 (1H, t-like, J=a 12.7 Hz), 2,85-of 3.00 (2H, m), of 3.95 (3H, s), of 4.67 (2H, d-like, J=8,8 Hz), to 7.09 (1H, s), 7,20-7,30 (1H, m), 7,41 (1H, d, J=8.1 Hz), 7, 57 (1H, DD, J=8,8, 2.7 Hz), of 7.70 (1H, dt, J=8,1, 2.0 Hz), 8,11 (1H, d, J=2.7 Hz), 8,49-8,55 (1H, m).

MS (ESI) m/z: 393 (M+H)+.

[Example 84] 4-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)Piras the l-3-carbonyl]-3-dimethylaminoacetyl

In a manner analogous to the method used in example 20, is listed in the title compound obtained as a solid (0,248 g, 90%) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (0,216 mg)obtained in reference example 33, and the hydrochloride of 3-dimethylaminopyridine (0,252 g)obtained in reference example 102.

1H-NMR (400 MHz, CDCl3) δ: of 2.21 (6H, s), 3,05-of 3.25 (1H, m), of 3.96 (3H, s), 4,00-4,10 (1H, m), 4,17-to 4.28 (1H, m), 4,35-4,47 (1H, m), 4,60-4,72 (1H, m), 6,74 (1H, d, J=8,9 Hz), 7,17-7,30 (2H, m), 7,44 (1H, d, J=7,3 Hz), 7,50-of 7.60 (1H, m), to 7.67 for 7.78 (1H, m), 8,15 (1H, d, J=2,5 Hz)and 8.50 (1H, userd, J=3.5 Hz).

MS (ESI) m/z: 379 (M+H)+.

Elemental analysis: as With20H22N6O2:

Calculated: C, 63,48; N, 5,86; N, 22,21.

Found: C, 63,34; N, Of 5.84; N, 22,31.

[Example 85] Ethyl ester 1-[5-(4-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperidine-4-carboxylic acid

In a manner analogous to the method used in example 20, is listed in the title compound obtained as an oily product (262 mg, 90%) using 5-(4-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid (0.2 g)obtained in reference example 136, and ethyl ether isonipecotic acid (0.1 g).

1H-NMR (400 MHz, CDCl3) δ: of 1.27 (3H, t, J=7,3 Hz), 1,75-1,90 (2H, m), 1,90-2,10 (2H, m), 2,58-of 2.66 (1H, m), 2,98-3,10 (1H, m), 3,32-of 3.43 (1H, m), of 3.95 (3H, s), and 4.6 (2H, kV, J=7,3 Hz), to 4.52-4,60 (1H, m) 4,70-4,80 (1H, m), 6, 73 (1H, d, J=8,8 Hz), 6.87 in (1H, s), 7,02-7,26 (2H, m), of 7.48 (1H, DD, J=8,8, 2.7 Hz), of 8.09 (1H, d, J=2,GC).

MS (EI) m/z: 452 (M+).

[Example 86] 1-[5-(4-Forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperidine-4-carboxylic acid

In a manner analogous to the method used in reference example 4, is listed in the title compound obtained as an amorphous product (170 mg, 69%) using ethyl ester 1-[5-(4-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperidine-4-carboxylic acid (262 mg)obtained example 85.

1H-NMR (400 MHz, CDCl3) δ: 1,77-of 1.94 (2H, m), 2.00 in of 2.16 (2H, m), 2,65 is 2.75 (1H, m), 3,05 is 3.15 (1H, m), 3,35 is-3.45 (1H, m), of 3.95 (3H, s), 4,55-4,60 (1H, m), 4,72 was 4.76 (1H, m), 6,74 (1H, d, J=8,8 Hz), to 6.88 (1H, s), 7,02-7,07 (2H,, m), 7,19-7,24 (2H, m), of 7.48 (1H, DD, J=8,8, 2.4 Hz), 8,11 (1H, d, J=2,4 Hz).

MS (EI) m/z: 424 (M+).

Elemental analysis: as With22H21FN4O4•0,75 H2O.

Calculated: C, 60,36; N, 5,18; N, 12,80.

Found: C, 60,24; N, Free 5.01; N, 12,47.

[Example 87] Ethyl ester 1-[5-(4-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperidine-3-carboxylic acid

In a manner analogous to the method used in example 20, is listed in the title compound obtained as an oily product (280 mg, 97%) using 5-(4-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid (0.2 g), polucen is in reference example 136, and ethyl ether nicotinebuy acid (0.1 g)

1H-NMR (400 MHz, CDCl3) δ: 1,21-of 1.30 (3H, m), 2,13-of 2.20 (1H, m), 2,56 is 2.75 (1H, m), 2,94-3,10 (1H, m), 3,21-3,30 (0,HN, m), 3,42-3,50 (0,HN, m), of 3.94 (3H, s), 4,10-4,20 (2H, m), 4,47-4,55 (0,5x1H, m), 4,67-4,75 (0,5x1H, m), 4,80-is 4.93 (1H, m), of 6.73 (1H, d, J=8,8 Hz), 6.87 in (1H, s), 7,05 (2H, t, J=8,8 Hz), 7,20-7,27 (2H, m), 7,47-of 7.55 (1H, m), 8,10 (1H, d, J=2.7 Hz).

MS (EI) m/z: 452 (M+).

[Example 88] 1-[5-(4-Forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperidine-3-carboxylic acid

In a manner analogous to the method used in reference example 4, is listed in the title compound obtained as an amorphous product (150 mg, 57%) using ethyl ester 1-[5-(4-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperidine-3-carboxylic acid (280 mg)obtained in example 87.

1H-NMR (400 MHz, CDCl3) δ: of 3.94 (3H, s), of 6.73 (1H, d, J=8,8 Hz), to 6.88 (1H, s), 7,01-7,07 (2H, m), 7,20-7,26 (2H, m), of 7.48 (1H, DD, J=8,8, 2,9 Hz), 8,11 (1H, d, J=2,9 Hz).

MS (EI) m/z: 424 (M+).

Elemental analysis: as With22H21FN4O4•0,75 H2O.

Calculated: C, 60,36; N, 5,18; N, 12,80.

Found: C, 60,49; N, 5,04; N, 12,47.

[Example 89] Ethyl ester 1-[5-(4-Forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperidine-2-carboxylic acid

In a manner analogous to the method used in example 20, is listed in the title compound obtained as maslany the product (270 mg, 93%) using 5-(4-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid (0.2 g)obtained in reference example 136, and ethyl ether nicotinebuy acid (0.1 g).

1H-NMR (400 MHz, CDCl3) δ: 1,24 (0,5x3H, t, J=7,1 Hz), 1,30 (0,5x3H, t, J=7,1 Hz), 2.26 and-2,40 (1H, m), 2.95 and-3,05 (0,5x1H, m) of 3.32-3.40 in (0,5x1H, m), 3,94 (0,5x3H, C), 3,95 (0,5x3H, C), 4,19-to 4.28 (2H, m), 4,67-4,73 (0,5x1H, m), 4,80-4,85 (0,5x1H, m), 5,51 (0,5x1H, d, J=4.6 Hz), 5,81 (0,HN, d, J=4.6 Hz), of 6.71 (0,5x1H, d, J=7,1 Hz), 6,72 (0,5x1H, d, J=7,1 Hz), 6.89 in (0,5x1H, C), 6,92 (0,5x1H, C), 7,00-7,07 (2H, m), 7,17-7,21 (2H, m), 7,44 (0,5x1H, DD, J=8,8, 2.7 Hz), 7,50 (0,5x1H, DD, J=8,8, 2.7 Hz), 8,05 (0,5x1H, d, J=2.7 Hz), 8,10 (0,5x1H, d, J=2.7 Hz).

MS (EI) m/z: 452 (M+).

[Example 90] 1-[5-(4-Forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperidine-2-carboxylic acid

In a manner analogous to the method used in reference example 4, is listed in the title compound obtained as an amorphous product (130 mg, 51%) using ethyl ester 1-[5-(4-forfinal)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperidine-2-carboxylic acid (270 mg)obtained in example 89.

1H-NMR (400 MHz, CDCl3) δ: of 3.95 (3H, s), 4,67 to 4.92 (1H, m), 5,47-the 5.65 (1H, m), 6.73 x to 6.75 (1H, m), 6,91-of 7.24 (5H, m), 7,42-7,53 (1H, m), 8,08-8,11 (1H, m).

MS (EI) m/z: 424 (M+).

Elemental analysis: as With22H21FN4O4•N2O.

Calculated: C, 59,74; N, Of 5.24; N, 12,67.

Found: C, 59,85; N, 5,00; N, Of 12.26.

[Example 91] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazol the-3-carbonyl]-2-hydroxyethylpiperazine

In a manner analogous to the method used in example 20, is listed in the title compound obtained as an amorphous product (220 mg, 48%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (300 mg)obtained in referential example 41 2-hydroxyethylpiperazine (234 mg).

1H-NMR (400 MHz, CDCl3) δ: 1,55-1,90 (6H, m), 3,93 (0,5x3H, and 0 5x3H, C), 6,72 (1H, d, J=8,8 Hz), 6,92 (1H, users), 7,31 and 7.36 (3H, m) 7,46 (1H, DD, J=8,8, 2.4 Hz), of 8.09 (1H, users).

MS (FAB) m/z: 393 (M+H)+.

[Example 92] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-2-hydroxyethylpiperazine

In a manner analogous to the method used in example 20, is listed in the title compound obtained as an amorphous product (250 mg, 55%) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (300 mg)obtained in referential example 33 and 2-hydroxyethylpiperazine (234 mg).

1H-NMR (400 MHz, CDCl3) δ: 1,52-of 1.88 (6H, m), of 3.95 (3H, s), of 6.75 (1H, DD, J=8,8, 0.7 Hz), 7,12 (1H, users), 7,22-7,26 (1H, m), 7,42 (1H, d, J=8.1 Hz), EUR 7.57 (1H, DD, J=8,8, 2.7 Hz), 7,69-7,73 (1H, m), of 8.09 (1H, users), 8,51 are 8.53 (1H, m).

MS (FAB) m/z: 394 (M+H)+.

[Example 93] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperidine-2-carboxamide

In a manner analogous to the method used in example 20, is listed in the header with the Association obtained as an amorphous product (270 mg, 58%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (300 mg)obtained in referential example 41 and piperidine-2-carboxamide (131 mg)obtained in reference example 131.

1H-NMR (400 MHz, CDCl3) δ: 1,50-of 1.95 (6H, m), 2,30-2,47 (1H, m), 2,80-2.91 in (0,5x1H, m), 3.15 and of 3.28 (0,5x1H, m), of 3.94 (3H, s), 4,68-4,88 (2H, m), and 5.30-the 5.65 (2H, m), 6,40 (0,5x1H, users), 6,70-6,74 (1H, m), 6,93 (1H, d, J=14 Hz), 8,09 (0,HN, users), 8,13 (0,5x1H, users).

MS (EI) m/z: 405 (M+).

[Example 94] Methylamide 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperidine-2-carboxylic acid

In a manner analogous to the method used in example 20, is listed in the title compound obtained as an amorphous product (150 mg, 32%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (300 mg)obtained in referential example 41 and methylamide piperidine-2-carboxylic acid (145 mg)obtained in reference example 132.

1H-NMR (400 MHz, CDCl3) δ: 1,50-of 1.95 (6H, m), 2,33-2,48 (1H, m), 2,83 (0,5x3H, C)2,84 (0,5x3H, C)of 3.10-3.20 (0,5x1H, m), of 3.94 (3H, s), 4,60-4,82 (1H, m), and 5.30-of 5.40 (1H, m), 6.42 per (0,5x1H, users), 6,72 (1H, d, J=8,8 Hz), 6,92 (1H, d, J=9.0 Hz), 8,06 (0,5x1H, users), 8,14 (0,5x1H, users).

MS (EI) m/z: 419 (M+).

Elemental analysis: as With23H25N5O3•0,3 CHCl3.

Calculated: C, 61,46; N, The Ceiling Of 5.60; N, 15,38.

Found: C, 61,06; N, Of 5.68; N, 15,08.

[Example 95] Dimethylamide 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-arbonyl]piperidine-2-carboxylic acid

In a manner analogous to the method used in example 20, is listed in the title compound obtained as an amorphous product (194 mg, 42%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (300 mg)obtained in reference example 41, and dimethylamide piperidine-2-carboxylic acid (159 mg)obtained in reference example 133.

1H-NMR (400 MHz, CDCl3) δ: 1,52-2,15 (7H, m), 2,98 (3H, s), of 3.12 (3H, s), 3,55-3,70 (1H, m), of 3.94 (3H, s), 4,70-is 4.85 (1H, m), 6,72 (1H, d, J=8,8 Hz), to 6.88 (1H, s), 7,20-7,40 (4H, m), 7,49 (1H, DD, J=8,8, 2.7 Hz), 8,10-8,13 (1H, m).

MS (EI) m/z: 433 (M+).

Elemental analysis: as With24H27N5O3•0,75 H2O.

Calculated: C, 64,48; N, To 6.43; N, 15,67.

Found: C, 61,11; N, 6,09; N, 15,58.

[Example 96] 1-[1-(6-Methoxy-3-pyridyl)-5-(4-methylthio-2-pyridyl)pyrazole-3-carbonyl]piperidine

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as solid product (0,870 g, 91%) using 1-(6-methoxy-3-pyridyl)-5-(4-methylthio-2-pyridyl)pyrazole-3-carboxylic acid (0,80 g)obtained in reference example 118, and piperidine (0,254 ml).

1H-NMR (400 MHz, CDCl3) δ: 1,64 was 1.69 (6H, m), is 2.44 (3H, s), 3.75 to 3,76 (2H, m), 3,89-to 3.92 (2H, m), of 3.95 (3H, s), of 6.75 (1H, d, J=8,8 Hz), 7,02? 7.04 baby mortality (1H, m), 7,05 (1H, s), 7,22 (1H, d, J=1.6 Hz), to 7.59 to 7.62 (1H, m)to 8.12 (1H, d, J=2.4 Hz), of 8.27 (1H, d, J=5.6 Hz).

MS (EI) m/z: 09 (M +).

[Example 97] 1-[5-(4-Methanesulfonyl-2-pyridyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperidine

In a manner analogous to the method used in example 48, indicated in the title compound obtained as a solid (0.935 g, quantitative yield) using 1-[1-(6-methoxy-3-pyridyl)-5-(4-methylthio-2-pyridyl)pyrazole-3-carbonyl]piperidine (0,869 g)obtained in example 96, and 3-chloroperbenzoic acid (1.10 g).

1H-NMR (400 MHz, CDCl3) δ: 1,64 is 1.70 (6H, m), is 3.08 (3H, s), 3,76 (2H, m)to 3.92 (2H, m), of 3.96 (3H, s), to 6.80 (1H, d, J=8,8 Hz), 7,22 (1H, s), 7,63 (1H, DD, J=8,8, 2,8 Hz), 7,69-7,71 (1H, m), 7,92-to 7.93 (1H, m), 8,10 (1H, d, J=2,8 Hz), 8,76 (1H, d, J=5,2 Hz).

MS (EI) m/z: 441 (M+).

Elemental analysis: as With21H23N5O4S•0,25 H2O.

Calculated: C, 56,55%; N, 5,31%; N, 15,70%, S, 7,19%.

Found: C, 56,73%; N, Of 5.05%; N, 15,68%, S, 7,30%.

[Example 98] 1-[5-(4-Cyano-2-pyridyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperidine

To a solution of 1-[5-(4-methanesulfonyl-2-pyridyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperidine (of 0.60 g)obtained in example 97, N,N-dimethylformamide (12 ml) at room temperature add potassium cyanide (97,3 mg). The mixture was stirred at 120°for 37 hours and then the mixture is additionally added potassium cyanide (97,3 mg). The mixture is additionally stirred at 120°C for 4 hours and then cooled in air. The reaction mixture was partitioned between saturated salt solution and ethyl acetate. The organic layer is dried over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure and the residue purified column chromatography on silica gel (chloroform-ethyl acetate), obtaining mentioned in the title compound as a solid (0,441 g, 84%).

1H-NMR (400 MHz, CDCl3) δ: 1,63 is 1.70 (6H, m in), 3.75 (2H, m), 3,91 (2H, m), of 3.97 (3H, s), 6,79 (1H, d, J=8,8 Hz), 7,17 (1H, s), 7,43 was 7.45 (1H, m), 7,58-to 7.61 (1H, m), the 7.65 (1H, m), 8,10 (1H, d, J=2.4 Hz), 8,66-8,68 (1H, m).

MS (EI) m/z: 388 (M+).

[Example 99] 2-[1-(6-Methoxy-3-pyridyl)-3-(piperidine-1-carbonyl)pyrazole-5-yl]isonicotinamide acid

To a solution of 1-[5-(4-cyano-2-pyridyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperidine (0,418 g)obtained in example 98, in a mixture of methanol (8,4 ml) and tetrahydrofuran (8,4 ml) at room temperature was added 1 N. aqueous sodium hydroxide (5,38 ml). The resulting mixture was stirred at 80°C for 7 hours and then cooled in air. The reaction mixture is distributed between water and chloroform. The organic layer is neutralized to pH 6 1 N. aqueous hydrochloric acid. To the water layer to distribute add chloroform. The aqueous layer was additionally extracted with chloroform. The organic layers are combined and dried over betwedn the m sodium sulfate. After filtration the solvent is removed under reduced pressure, thus obtaining specified in the title compound in the form of solids (0,239 g, 52%).

1H-NMR (400 MHz, CDCl3) δ: of 1.73 (6H, m), a-3.84 (2H, m), of 3.95 (3H, s), 4.04 the-4,06 (2H, m), of 6.75 (1H, d, J=8,8 Hz), 7,39 (1H, s), 7,58-to 7.61 (1H, m), 7,80-of 7.82 (1H, m)to 8.14 (1H, d, J=2.4 Hz), compared to 8.26 (1H, m), 8,58 (1H, d, J=4,8 Hz).

MS (EI) m/z: 407 (M+).

[Example 100] 2-[1-(6-Methoxy-3-pyridyl)-3-(piperidine-1-carbonyl)pyrazole-5-yl]isonicotinamide

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (52,0 mg, 42%) using 2-[1-(6-methoxy-3-pyridyl)-3-(piperidine-1-carbonyl)pyrazole-5-yl]isonicotinic acid (0,120 g)obtained in example 99, and 28% aqueous ammonia (of 53.7 mg).

1H-NMR (400 MHz, DMSO-d6) δ: 1,57-of 1.66 (6H, m), 3,63 (2H, m), 3,86 (2H, m)to 3.89 (3H, s), 6.87 in (1H, d, J=8,8 Hz), 7,25 (1H, s), 7,69-7,72 (2H, m), 7,78 (1H, s), 8,15-8,17 (2H, m), 8,29-8,30 (1H, m), 8,56 (1H, d, J=4,8 Hz).

MS (EI) m/z: 406 (M+).

[Example 101 N-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-yl]methyl-2-oxopyrrolidin

At room temperature, 60% sodium hydride (26 mg) are added to a solution of 2-pyrrolidinone (55 mg) in tetrahydrofuran (5 ml) and the mixture is stirred for 30 minutes. To the reaction mixture is added N,N-dimethylformamide (2 ml) and the mixture is stirred for 30 minutes.The mixture add a solution of [1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-yl]methylmethanesulfonate (195 mg), obtained in reference example 76, in tetrahydrofuran (3 ml) followed by stirring at room temperature for 16 hours. The solvent is removed under reduced pressure and the residue partitioned between water and ethyl acetate. The organic layer is washed with water and saturated salt solution and then dried over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure. The residue is purified by thin-layer chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound as an oily product (140 mg, 74%).

1H-NMR (400 MHz, CDCl3) δ: 2,04 (2H, TT, J=7,8, and 7.1 Hz), a 2.45 (2H, t, J=7.8 Hz), of 3.48 (2H, t, J=7,1 Hz), 3,93 (3H, s), 4,56 (2H, s), 6,44 (1H, s), 6,72 (1H, d, J=8,8 Hz), 7,17-of 7.23 (2H, m), 7,28-7,34 (3H, m), 7,51 (1H, DD, J=8,8, 2.7 Hz), 8,07 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 349 (M+H)+.

[Example 102] 3-Methyl-1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-yl]methyl-2-Oxymetazoline

In a manner analogous to the method used in example 101, specified in the title compound obtained as crystals (167 mg, 77%) using 1-methylimidazolidine-2-she (71 mg) and [1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-yl]methylmethanesulfonate (214 mg)obtained in reference example 76.

1H-NMR (400 MHz, CDCl3) δ: and 2.83 (3H, s), 3,26-to 3.41 (4H, m)to 3.92 (3H, s), 4,47 (2H, s), 6.48 in (1H, s)of 6.71 (1H, d, J=8,8 Hz), 7,17-of 7.23 (2H, m), 7,27-7,33 3H, m), 7,51 (1H, DD, J=8,8, 2.7 Hz), of 8.06 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 364 (M+H)+.

Elemental analysis: as With20H21N5O2.

Calculated: C, 66,10; N, Of 5.82; N, 19,27.

Found: C, 65,76; N, 5,80; N, 18,97.

[Example 103] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazol-3-yl]methyl-2,5-dioxopiperidin

At room temperature, potassium carbonate (373 mg) are added to a solution of [1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-yl]methylmethanesulfonate (194 mg)obtained in reference example 76, and succinimide (53 mg) in N,N-dimethylformamide (5 ml). The mixture was stirred at 60°C for 16 hours and then cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer is washed with water and saturated salt solution and then dried over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure. The residue is purified by thin-layer chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound as crystals (151 mg, 75%).

1H-NMR (400 MHz, CDCl3) δ: 2,77 (4H, s), 3,91 (3H, s), to 4.81 (2H, s), 6,44 (1H, s), 6,69 (1H, d, J=8,8 Hz), 7,14-7,22 (2H, m), 7,27-7,33 (3H, m)to 7.50 (1H, DD, J=8,8, 2.7 Hz), 8,03 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 363 (M+H)+.

Elemental analysis: as With20H18N4O3•0.5 N2O.

Calculated: C, 64,68; N, 5,16; N, 15,09.

Found: C, 64,74; N, 4,96 N, 14,85.

[Example 104] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-2,2-dimethyl-3-dimethylaminoacetyl

In a manner analogous to the example used in stage 1) of example 1, indicated in the title compound obtained as a solid (48 mg, 47%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (74 g)obtained in referential example 41 and hydrochloride (2.2-dimethylamide-3-yl)dimethylamine (50 mg)obtained in reference example 121.

1H-NMR (400 MHz, CDCl3) δ: 1,67 (3H, s)to 1.70 (3H, s), and 2.14 (6H, s), 2,69 (1H, DD, J=7,9, to 15.4 Hz), of 3.94 (3H, S), is 4.21 (1H, DD, J=7,6, 10,0 Hz), 4,60 (1H, DD, J=7,8, 10,0 Hz), of 6.71 (1H, d, J=8,8 Hz), 7,00 (1H, s), 7,20-of 7.23 (2H,, m), 7,31-7,34 (3H, m), 7,42 (1H, DD, J=2.7, and an 8.8 Hz), 8,17 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 406 (M+H)+.

Elemental analysis: as With23H27N5O2•0,25 H2O.

Calculated: C, 67,38; N, 6,76; N, 17,08.

Found: C, 67,27; N, To 6.67; N, 17,03.

[Example 105] 7-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4,7-diazaspiro[2,5]Octan

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (224 mg, 71%) using 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (240 g)obtained in referential example 41 and hydrochloride 4,7-diazaspiro[2.5]octane (150 mg)obtained in saleclonidine 122.

1H-NMR (400 MHz, DMSO-d6) δ: of 0.48 (2H, m)of 0.53 (2H, m), 2,82 (2H, t, J=5,1 Hz), 3,12 (2H, s), 3,42-3,55 (2H, m), of 3.94 (3H, s), 6.87 in (2H, m), 7,29-to 7.32 (2H, m), 7,38-7,40 (3H, m), the 7.65 (1H, m)to 8.12 (1H, users).

MS (ESI) m/z: 390 (M+H)+.

Elemental analysis: as With22H23N5O2.

Calculated: C, 67,85; N, 5,95; N, 17,98.

Found: C, 67,62; N, 5,96; N, 17,94.

[Example 106] Hydrochloride of 4-methyl-7-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4,7-diazaspiro[2,5]octane

At room temperature to a solution of 7-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4,7-diazaspiro[2,5]octane (120 mg)obtained in example 105, in methanol (4 ml) add cyanoborohydride sodium (78 mg) and 37% aqueous formaldehyde solution (26 ml) and the mixture is stirred for 41.5 hours. Then to the reaction mixture add cyanoborohydride sodium (78 mg) and 37% aqueous formaldehyde solution (26 ml) and the mixture is stirred for 4 hours. The solvent is removed under reduced pressure and the residue distributed between ethyl acetate and water. The organic layer is successively washed with saturated aqueous sodium bicarbonate and saturated salt solution and then dried over anhydrous magnesium sulfate. After filtration the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (chloroform-methanol), to thereby obtain 4-methyl-7-[1-(6-methodology the C-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4,7-diazaspiro[2,5]octane. Thus obtained product is dissolved in diethyl ether (4 ml). To the solution at 0°add 1 N. HCl in ethanol (372 μl), followed by stirring for 10 minutes. The solvent is removed under reduced pressure and the residue is crystallized from a mixture of diethyl ether-hexane, thus obtaining specified in the title compound as a solid (101 mg, 74%).

1H-NMR (400 MHz, DMSO-d6) δ: 0,94 (2H, m), 1,24 (2H, m), 2,85 (3H, users), 3.25 to 3.40 in (4H, m), 3,88 (3H, s)4,06 (2H, m), to 6.88 (1H, d, J=8,8 Hz), of 6.96 (1H, s), 7,29 (2H, m), 7,38 (3H, m), to 7.67 (1H, DD, J=9,0, 2,5 Hz), 8,14 (1H with).

MS (ESI) m/z: 404 (M+H)+.

Elemental analysis: as With23H25N5O2•HCl•0,25 H2O.

Calculated: C, 62,16; N, 6,01; N, 15,76; Cl, 7,98.

Found: C, 62,17; N, 5,90; N, 15,79; Cl, 7,98.

[Example 107] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-acetylpiperidine

When 0°With triethylamine (0,205 ml) and acetylchloride (0,0447 ml) are added to a solution of the hydrochloride of 4-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]piperazine (0,185 g)obtained in example 81, in methylene chloride (5.0 ml). The mixture is stirred at room temperature for 1 hour. The reaction mixture is distributed between water and chloroform. The aqueous layer was additionally extracted with chloroform and the organic layers combined with subsequent washing with a saturated solution of salt and what uskoi over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound as an amorphous product (0,147 g, 87%).

1H-NMR (400 MHz, CDCl3) δ: 2,13 (3H, usher.), of 3.56 (2H, usher.), the 3.65-3,90 (2H, usher.), of 3.95 (3H, s), 4,06-of 4.25 (2H, m), 6,76 (1H, d, J=8.6 Hz), 7,13-7,20 (2H, m), 7,42 (1H, usher.), 7,58 (1H, usher.), 7,71 (1H, t-like, J=7.8 Hz), 8,10 (1H, usher.), 8,51 (1H, d, J=4,1 Hz).

LC-MS m/z: 407 (M+H)+.

[Example 108] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-5-oxo-1,4-diazepan

In a manner analogous to the method used in example 20, is listed in the title compound obtained as a solid (0,223 g, 76%) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (0,223 g)obtained in reference example 33, and hydrochloride of hexahydro-1H-1,4-diazepin-5-it (0,227 g)obtained in reference example 120.

1H-NMR (400 MHz, CDCl3) δ: 2,70-to 2.85 (2H, m), 3,39-to 3.49 (2H, m), a 3.87-was 4.02 (2H, m), of 3.94 (3H, s), 4,16-of 4.25 (2H, m), 6,76 (1H, d, J=8,8 Hz), 7,17 (1H, s), 7,44 (1H, d, J=7.8 Hz), of 7.48 (1H, usher.), 7,58 (1H, usher.), the 7.65 7,76 (1H, m), 8,11 (1H, d, J=2.5 Hz), 8,51 (1H, userd, J=3.0 Hz).

LC-MS m/z: 393 (M+H)+.

Elemental analysis: as With20H20N6O3.

Calculated: C, 61,22; N, 5,14; N, 21,42.

Found: C, 61,01; N, Of 5.05; N, 21,23.

[Example 109] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-p is Ridel)pyrazole-3-carbonyl]-4-methyl-5-oxo-1,4-diazepan

When 0°With sodium hydride (washed with pentane and dried to 20.4 mg) are added to a solution of 1-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-5-oxo-1,4-diazepine (0,253 g)obtained in example 108, N,N-dimethylformamide (5.0 ml) and the mixture is stirred for 15 minutes. To the reaction mixture add methyliodide (0,0602 ml) and the mixture is stirred at room temperature for 14 hours. The resulting mixture is partitioned between water and a mixture of chloroform-methanol (5%). The aqueous layer was additionally extracted with a mixture of chloroform-methanol (5%) and the organic layers combined with subsequent washing with saturated salt solution and dried over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure and the residue purified column chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound as an amorphous product (0,231 g, 88%).

1H-NMR (400 MHz, CDCl3) δ: of 2.81 (2H, usher.), 3,00-3,14 (3H, m), 3,51-3,70 (2H, m), 3,90-of 4.05 (2H, m), of 3.95 (3H, s), 4,10-4,27 (2H, m), 6,76 (1H, d, J=8,9 Hz), to 7.15 (1H, userd, J=10.0 Hz), 7,22-7,30 (1H, m), 7,45 (1H, usher.), EUR 7.57 (1H, usher.), 7,71 (1H, ushort, J=7,6 Hz), 8,10 (1H, usher.), 8,53 (1H, usher.).

LC-MS m/z: 407 (M+H)+.

[Example 110] 1-[1-(6-Chloro-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazin

At room temperature N-methylpiperid is n (1.80m) are added to a solution of 1-[1-(6-chloro-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-1-succinimide (3,20 g), obtained in reference example 124, in chloroform (30 ml) and the mixture is stirred for 2 hours. The reaction mixture is distributed between water and chloroform. The organic layer is successively washed with water, 1 N. aqueous sodium hydroxide and water and then dried over anhydrous magnesium sulfate. After filtration the solvent is removed under reduced pressure and the thus obtained solid is recrystallized from a mixture of ether-hexane, thus obtaining specified in the header connection (2,60 g, 80%).

1H-NMR (400 MHz, CDCl3) δ: of 2.34 (3H, s), 2,46-2,52 (4H, m), 3,83-3,86 (2H, m), 4,07-4,12 (2H, m), 6,92 (1H, s), 7,22-7,41 (6H, m), 7,58 (1H, DD, J=9, 3 Hz), 8,35 (1H, d, J=3 Hz).

Elemental analysis: as With20H20ClN5O.

Calculated: C, 62,91%; N, 5,28%; N, MT 18 : 34%.

Found: C, 62,67%; N, 5,22%; N, 18,29%.

[Example 111] Hydrochloride 1-[1-(6-ethoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazine

In a manner analogous to the method used in example 110, 1-[1-(6-ethoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazin get using [1-(6-ethoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-1-succinimide (232 mg)obtained in reference example 126, and N-methylpiperazine (0,14 ml). Thus obtained product is dissolved in ethanol and to the solution add 1 N. aqueous hydrochloric acid (0,07 ml) with subsequent paramashiva is receiving. The solvent is removed under reduced pressure and the residual solid is recrystallized from a mixture of ether-hexane, thus obtaining specified in the title compound (25 mg, 16%).

1H-NMR (400 MHz, CDCl3) δ: of 1.40 (3H, t, J=7 Hz), 2,82 (3H, s), 2,80 was 3.05 (2H, m), 3.45 points-of 3.80 (m, 3H), 3,98-to 4.15 (1H, m), 4,36 (2H, q, J=7 Hz), 4.75 V-4,99 (1H, m), 5,23-5,52 (1H, m), 6,70 (1H, d, J=9 Hz), of 6.99 (1H, s), 7,21-the 7.43 (6H, m), 8,08 (1H, d, J=3 Hz), 13,49 (1H, users).

Elemental analysis: as With22H26ClN5O2•0,25 H2O.

Calculated: C, 61,11%; N, 6,18%; N, 16,20%.

Found: C, 61,10%; N, 6,15%; N, 16,02%.

[Example 112] Hydrochloride 1-[1-(6-isopropoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazine

At room temperature N-methylpiperazine (of 0.64 ml) was added to a solution of [1-(6-isopropoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-1-succinimide (1,11 g)obtained in reference example 128, in methylene chloride (20 ml) and the mixture is stirred over night. The reaction mixture is partitioned between chloroform and water. The organic layer is successively washed with water, 1 N. aqueous sodium hydroxide and water and then dried over anhydrous magnesium sulfate. After filtration the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (chloroform-methanol) and get 1-[1-(6-isopropoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-m is teleperson. Thus obtained product is dissolved in ethanol and to the solution add 1 N. aqueous hydrochloric acid (2.9 ml), followed by stirring. The solvent is removed under reduced pressure. Thus obtained solid is recrystallized from a mixture of ether-ethanol, thus obtaining specified in the title compound (25 g, 16%).

1H-NMR (400 MHz, CDCl3) δ: of 1.35 (6H, d, J=6 Hz), 2,85 (3H, s), 2,80 was 3.05 (2H, m), 3,50-of 3.78 (m, 3H), 4,00-to 4.15 (1H, m), 4,85-of 4.95 (1H, m), from 5.29 (1H, Sep, J=6 Hz), 5,35-of 5.45 (1H, m), of 6.65 (1H, d, J=9 Hz), of 6.99 (1H, s), 7,22-7,42 (6H, m), 8,07 (1H, d, J=3 Hz), 13,43 (1H, users).

Elemental analysis: as With23H28ClN5O2•0,25 H2O.

Calculated: C, 61,88%; N, To 6.43%; N, 15,69%.

Found: C, 61,98%; N, 6,40%; N, 15.62 Wide%.

[Example 113] 1-[1-(6-Methylamino-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazin

To a solution of 1-[1-(6-chloro-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazine (300 mg)obtained in example 110, N,N-dimethylformamide (1.5 ml) is added a 40% solution of methylamine in methanol (0.6 ml). The mixture is stirred at 85°C for 3 days in a sealed tube and then cooled in air. The reaction mixture was partitioned between 1 N. aqueous sodium hydroxide (30 ml) and ethyl acetate. The organic layer is successively washed with water, saturated aqueous sodium bicarbonate and water and then dried over anhydrous with what LifeCam magnesium. After filtration the solvent is removed under reduced pressure and the residue is dissolved in dimethyl sulfoxide (1 ml). The solution is purified preparative high performance liquid chromatography (eluent: water-acetonitrile) followed by recrystallization from a mixture of ether-hexane, thus obtaining specified in the title compound (11.7 mg, 4%).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2,47 is 2.51 (4H, m), with 2.93 (3H, d, J=5 Hz), 3,83-3,86 (2H, m), 4.09 to to 4.14 (2H, m), 4,70 (1H, q, J=5 Hz), 6,33 (1H, d, J=9 Hz), 6.89 in (1H, s), 7,25-7,34 (6H, m), with 8.05 (1H, d, J=3 Hz).

Elemental analysis: as With21H24N6O•0,25 H2O.

Calculated: C, 66,21%; N, 6,48%; N, Representing 22.06%.

Found: C, 66,21%; N, 6,39%; N, 21,86%.

[Example 114] 1-[1-(6-Cyclopropylamino-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazin

To a solution of 1-[1-(6-chloro-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazine (200 mg)obtained in example 110, in dioxane (1.0 ml) add cyclopropylamine (1.0 ml). The mixture was stirred at 100°C for 3 days in a sealed tube and then cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer is successively washed with water and saturated aqueous sodium bicarbonate and then dried over anhydrous magnesium sulfate. After filtration the solvent is removed under reduced pressure and the residue is dissolved in Dimity is the sulfoxide (1 ml). The solution is purified preparative high performance liquid chromatography (eluent: water-acetonitrile), while receiving specified in the title compound as an oily product(19.6 mg, 9%).

MS (ESI) m/z: 403 (M+N)+.

[Example 115] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-2,2,4-trimethylpyrazine

To a solution of 1,3 .3m-trimethylpyrazine-2,5-dione (162 mg)obtained in reference example 130, in tetrahydrofuran (2 ml) add a solution of the complex of 1.0 M borane-tetrahydrofuran in tetrahydrofuran (3 ml). The mixture is refluxed under heating for 14 hours and then cooled in air. The solvent is removed under reduced pressure and to the residue was added 1 N. aqueous hydrochloric acid (4 ml). The resulting mixture is heated at 100°C for 30 minutes and then cooled in air. To the reaction mixture are added tetrahydrofuran (3 ml) and anion-exchange resin (amberlite, 3,29 g), previously washed with ethanol. The mixture is stirred at room temperature for 8 hours. The reaction mixture is filtered and the solvent is removed under reduced pressure, thus obtaining a mixture of 1,3 .3m-trimethylpyrazine and 1-fluorenylacetamide in the form of an oily product (71,0 mg). Oily mixture of 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-1-succ is of nimid (66,4 mg), obtained in reference example 129, dissolved in methylene chloride (2 ml) and the mixture was added diisopropylethylamine (185 μl). The resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated to 1 ml under reduced pressure, followed by purification preparative high performance liquid chromatography (acetonitrile-water (containing 1% formic acid, 12-50.vol.%)), while receiving specified in the title compound as an oily product (11.8 mg, 15%).

MS (FAB) m/z: 406 (M+N)+.

[Example 116] 4-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-1,2,6-trimethylpyrazine

4-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-2,6-dimethylpiperazine (29,7 mg)obtained in example 22, was dissolved in ethanol (2.0 ml). To the solution at room temperature add 35% aqueous formalin solution (0,0325 ml), acetic acid (0,0217 ml) and cyanoborohydride sodium (9,2 mg) followed by stirring for 1.5 hours. The reaction mixture is partitioned between aqueous sodium bicarbonate and chloroform at 0°C. the Aqueous layer was additionally extracted with chloroform. The organic layers are combined and washed with saturated salt solution, followed by drying over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure and the residue is dried, thus obtaining specified in zag is lowke compound (40 mg, quantitative yield).

LC-MS m/z: 406 (M+N)+.

[Example 117] 1-[1-(5-Methoxy-2-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (130 mg, 68%) using 1-(5-methoxy-2-pyridyl)-5-phenylpyrazol-3-carboxylic acid (150 mg)obtained in reference example 137, and N-methylpiperazine (0,068 ml).

1H-NMR (400 MHz, DMSO-d6) δ: of 2.20 (3H, s)to 2.35 (4H, usher.), the 3.65 (2H, usher.), a 3.87 (3H, s)to 3.92 (2H, usher.), 6,91 (1H, s), 7,21-of 7.23 (2H, m), 7,33-to 7.35 (3H, m), 7,60-7,63 (2H, m), 8,08-of 8.09 (1H, m).

LC-MS m/z: 378 (M+H)+.

Elemental analysis: as With21H23N5O2.

Calculated: C, 66,77; N, X 6.15; N, 18,63.

Found: C, 66,83; N, 6,14; N, 18,55.

[Example 118] (2S)-1-[1-(5-Methoxy-2-pyridyl)-5-phenylpyrazole-3-carbonyl]pyrrolidin-2-carboxamide

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (270 mg, 81%) using 1-(5-methoxy-2-pyridyl)-5-phenylpyrazol-3-carboxylic acid (250 mg)obtained in reference example 137, and L-prolinamide (116 mg).

1H-NMR (400 MHz, CDCl3) δ: 1,99-of 2.46 (4H, m), a 3.87 (3H, s), of 4.13 (1H, m), 4,88 (1H, usher.), to 5.35 (1H, s),? 7.04 baby mortality (1H, s), 7.23 percent-of 7.48 (7H, m), of 7.96 and 8.08 (1H, each s).

FAB-MS m/z: 392 (M+H)+.

[Example 119] 1-[1-(5-Methoxy-2-pyridyl)-5-phenylpyrazole-3-carbonyl]piperidine-2-carboxamide

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (229 mg, 66%) using 1-(5-methoxy-2-pyridyl)-5-phenylpyrazol-3-carboxylic acid (250 mg)obtained in reference example 137, and piperidine-2-carboxamide (119 mg)obtained in reference example 131.

1H-NMR (400 MHz, CDCl3) δ: 1,62 is 1.91 (6H, m), 2,28-to 2.40 (1H, m), 2,81-is 3.21 (1H, m), 3,88 (3H, s), 4,71-4,80 (1H, m), lower than the 5.37 (1H, users), 5,46 (1H, users), to 6.39 (1H, s)6,91 (1H, d, J=26,4 Hz), 7,22-7,33 (6H, m), of 8.06 (1H, d, J=9,8 Hz).

EI-MS m/z: 405 (M+).

[Example 120] 1-[1-(5-Methoxy-2-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazin

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an oily product (264 mg, 69%) using 1-(5-methoxy-2-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (300 mg)obtained in reference example 138, and N-methylpiperazine (0,247 ml).

1H-NMR (400 MHz, CDCl3) δ: 2,31 (3H, s), 2,42 is 2.51 (4H, m), a-3.84 (2H, m), 3,86 (3H, s)4,08 (2H, m), 7,06 (1H, s), 7,17-7,21 (1H, m), 7,32 (1H, DD, J=8,8, 2,9 Hz), 7,40-7,42 (1H, m), 7,55 (1H, d, J=8,8 Hz), 7,66-of 7.70 (1H, m), to 7.93 (1H, d, J=2,9 Hz), 8,44-8,46 (1H, m).

EI-MS m/z: 378 (M+).

2) With the ü specified in the connection header with hydrochloric acid

In a manner analogous to the method used in step 2) of example 29, salt specified in the connection header with hydrochloric acid obtained as a solid (187 mg, 64%) using the above specified in the title compound (254 mg).

1H-NMR (400 MHz, DMSO-d6) δ: 2,78 (3H, m), 3,10-to 3.67 (4H, m), 3,86 (3H, s), 4,60-5,32 (4H, m), 7,18 (1H, s), 7,34-7,37 (1H, m), 7,55-of 7.60 (2H, m), 7,66-to 7.68 (1H, m), 7,84-7,88 (1H, m), of 7.97 (1H, d, J=2,9 Hz), 8,43 (1H, d, J=4,9 Hz), 11,08 (1H, users).

EI-MS m/z: 378 (M+).

[Example 121] 4-[1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]morpholine

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (85 mg, 69%) using 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (100 mg)obtained in referential example 139 and the research (or 0.035 ml).

1H-NMR (400 MHz, DMSO-d6) δ: 3,62 (2H, usher.), 3,66 (4H, users), of 3.96 (2H, usher.), a 4.03 (3H, s), 7,27 (1H, s), to 7.32 and 7.36 (1H, m), 7,4 7 (1H, d, J=9.3 Hz), 7,79 (1H, d, J=7.8 Hz), 7,89 (1H, dt, J=7,8, 1.5 Hz), to 7.99 (1H, d, J=9.3 Hz), of 8.37 (1H, d, J=4.0 Hz).

LC-MS m/z: 367 (M+H)+.

Elemental analysis: as With18H18N6O3•0.5 N2O.

Calculated: C, 58,29; N, Of 5.03; N, Cushion 22.66.

Found: C, 58,59; N, 4,89; N, 22,57.

[Example 122] 1-[1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]piperidine

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (87 mg, 71%) using 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (100 mg)obtained in referential example 139, and piperidine (0,040 ml).

1H-NMR (400 MHz, DMSO-d6) δ: of 1.55 (4H, usher.), of 1.65 (2H, usher.), of 3.64 (2H, usher.), of 3.80 (2H, usher.), a 4.03 (3H, s), 7,21 (1H, s), 7,32-to 7.35 (1H, m), 7,47 (1H, d, J=9,2 Hz), to 7.77 (1H, d, J=7.8 Hz), 7,88 (1H, dt, J=7,8, 1.5 Hz), of 7.97 (1H, d, J=9,2 Hz), of 8.37 (1H, d, J=4,1 Hz).

LC-MS m/z: 365 (M+H)+.

Elemental analysis: as With19H20N6O2.

Calculated: C, 62,62; N, Of 5.53; N, 23,06.

Found: C, 62,46; N, 5,43; N, 23,01.

[Example 123] 4-[1-(6-Methoxy-3-pyridazinyl)-5-phenylpyrazole-3-carbonyl]morpholine

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (170 mg, 69%) using 1-(6-methoxy-3-pyridazinyl)-5-phenylpyrazol-3-carboxylic acid (200 mg)obtained in reference example 43, and research (0,071 ml).

1H-NMR (400 MHz, DMSO-d6) δ: 3,63 (2H, usher.), to 3.67 (4H, users), of 3.96 (2H, usher.), a 4.03 (3H, s), 7,00 (1H, s), 7,29-7,31 (3H, m), of 7.36-7,39 (2H, m), 7,49 (1H, d, J=9,2 Hz), to 7.99 (1H, d, J=9,2 Hz).

LC-MS m/z: 366 (M+N)+.

[Example 124] 1-[1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-methyl-3-oxopiperidin

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (54 mg, 43%) using 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (90 mg)obtained in referential example 139 and hydrochloride 1-methylpiperazin-2-she (57 mg)obtained in reference example 157.

1H-NMR (400 MHz, CDCl3) δ: 3,03 (3H, s), 3,47 (2H, t, J=5.8 Hz), 4,07 (1H, m), of 4.11 and 4.13 (3H, each s), and 4,40 of 4.44 (2H, each osirm), to 4.87 (1H, users), 7,14-7,24 (3H, m), to 7.59 (1H, d, J=7.8 Hz), 7,70 and 7,86 (1H, each d, J=9.0 Hz), of 7.75 (1H, TD, J=7,8) and 1.7 Hz), 8,40 (1H, s).

ESI-MS m/z: 394 (M+H)+.

[Example 125] 1-[1-(6-Methoxy-3-pyridazinyl)-5-phenylpyrazole-3-carbonyl]-4-methyl-3-oxopiperidin

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (125 mg, 63%) using 1-(6-methoxy-3-pyridazinyl)-5-phenylpyrazol-3-carboxylic acid (151 mg)obtained in reference example 43, and salts of 1-methylpiperazin-2-she triperoxonane acid (128 mg)obtained in referential example 91.

1H-NMR (400 MHz, DMSO-d6) δ: 2,89 (3H, s), 3.43 points (2H, users), 3,91 (1H, usher.), a 4.03 (3H, s), is 4.21 (2H, users), to 4.62 (1H, usher.), ? 7.04 baby mortality (1H, s), 7,31-7,52 (5H, m)to 7.50 (1H, d, J=9.3 Hz), of 7.96-of 8.04 (1H, m).

LC-MS m/z: 393 (M+H)+.

[Example 126] (2S)-1-[1-(6-Methoxy-3-pyridazinyl)-5-phenylpyrazol-3-to rbony]-2-hydroxyethylpyrrolidine

1-[1-(6-Methoxy-3-pyridazinyl)-5-phenylpyrazol-3-carboxylic acid (237 mg)obtained in reference example 43, dissolved in N,N-dimethylformamide (4 ml). To the solution add diphenylphosphinite (0,19 ml), triethylamine (0,245 ml) and (S)-2-pyrrolidineethanol (amount of 0.118 ml) followed by stirring at room temperature for 17 hours. The reaction mixture is distributed between water and chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate, followed by drying over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure and the residue purified column chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound in the form of solids (0,166 g, 47%).

1H-NMR (400 MHz, CDCl3) δ: 1,60-of 2.20 (4H, m), 3,55-4,60 (5H, m), of 4.12 (3H, s), a 4.83-to 4.98 (1H, m), 7,03 (1H, s), was 7.08 (1H, d, J=9,2 Hz), 7,25-7,42 (5H, m), to 7.61 (1H, d, J=9,2 Hz).

ESI-MS m/z: 380 (M+H)+.

[Example 127] 1-[1-(6-Methoxy-3-pyridazinyl)-5-phenylpyrazole-3-carbonyl]piperidine-2-carboxamide

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (213 mg, 65%) using 1-(6-methoxy-3-pyridazinyl)-5-phenylpyrazol-3-carboxylic acid (151 mg)obtained in referential example the e 43, and piperidine-2-carboxamide (154 mg)obtained in reference example 131.

1H-NMR (400 MHz, CDCl3) δ: 1,50-to 1.87 (6H, m), 2,30 is 2.43 (1H, m), 2,83-2,92 (1/2x1H, m), 3,15-3,26 (1/2x1H, m), 4,13 (3H, s), 4,70-4,78 (1H, m), 5,34-of 5.50 (1H, m), 5,52 (1/2x1H, CL), 6,36 (1/2x1H, CL), 7,05 for 7.12 (2H, m), 7,26-7,38 (5H, m), 7,50 (1/2x1H, d, J=9.3 Hz), 7,63 (1/2x1H, d, J=9,3 Hz).

ESI-MS m/z: 407 (M+H)+.

Elemental analysis: as With21H22N6O3.

Calculated: C, 62,06; N, 5,46; N, 20,68.

Found: C, 62,16; N, 5,52; N, 20,59.

[Example 128] 1-[1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]pyrrolidin

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (226 mg, 77%) using 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (250 mg)obtained in referential example 139 and pyrrolidine (0,084 ml).

1H-NMR (400 MHz, DMSO-d6) δ: of 1.85 (2H, q, J=6, 59 Hz), at 1.91 (2H, q, J=6,59 Hz), 3,53 (2H, t, J=6,59 Hz), 3,88 (2H, t, J=6,59 Hz), a 4.03 (3H, s), 7,30 (1H, s), 7,33 (1H, dt, J=4,27, 1,59 Hz), 7,47 (1H, d, J=9.28 are Hz), 7,79 (1H, d, J=7,81 Hz), 7,89 (1H, dt, J=7,81, 1,59 Hz), to 7.99 (1H, d, J=9.28 are Hz), of 8.37 (1H, d, J=4,27 Hz).

FAB-MS m/z: 351 (M+H)+.

Elemental analysis: as With18H18N6O2.

Calculated: C, 61,70; N, 5,18; N, 23,99.

Found: C, 61,42; N, Free 5.01; N, 23,87.

[Example 129] 4-[1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-1,4-oxazepan

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (77,5 mg, 25%) using 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (250 mg)obtained in referential example 139 and hydrochloride 1,4-oxazepan (363 mg)obtained in reference example 149.

1H-NMR (400 MHz, CDCl3) δ: 2,01-2,11 (2H, m), 3,79-3,91 (6H, m), 4,05-to 4.15 (2H, m), 4,11 (3H, s), 7,13 (1/2x1H, C)7,14 (1H, d, J=9.3 Hz), 7,14 (1/2x1H, C), 7,20-7,24 (1H, m), to 7.59 (1H, d, J=7.8 Hz), 7,73 for 7.78 (1H, m), 7,79 (1H, d, J=9.3 Hz), 8,40-8,43 (1H, m).

ESI-MS m/z: 381 (M+H)+.

[Example 130] 1-[1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-methoxypiperidine

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (130 mg, 39%) using 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (250 mg)obtained in referential example 139 and salt 4-methoxypiperidine with triperoxonane acid (386 mg)obtained in reference example 151.

1H-NMR (400 MHz, CDCl3) δ: 1,65-1,72 (2H, m), 1,90-1,95 (2H, m)to 3.38 (3H, s), 3,48 is 3.57 (1H, m), 3,69-3,74 (1H, m), 4,11 (3H, s), 4,22-4,24 (1H, m), 7,07 (1H, s), 7,13 (1H, d, J=9,2 Hz), 7,21-7,24 (1H, m), 7,71 (1H, d, J=8,4 Hz), 7,72-7,83 (2H, m), to 8.41-8,42 (1H, m).

EI-MS m/z: 394 (M+).

Elemental analysis: as With19H20N6O3.

p> Calculated: C, 60,90; N, 5,62; N, 21,31.

Found: C, RUR 60,72; N, 5,38; N, To 21.15.

[Example 131] 1-[1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-2-methylhexahydrophthalic

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an amorphous product (16.5 mg, 5%) using 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (251 mg)obtained in referential example 139 and 1-methylhexahydrophthalic (143 mg)obtained in reference example 150.

1H-NMR (400 MHz, CDCl3) δ: of 1.35 to 1.48 (1H, m), 1,65-2,05 (3H, m)of 2.75 (3H, s), 2,85-2,95 (1H, m), 3,10-of 3.23 (1H, m), 4,07 (3H, s), 4,42-4,60 (1H, m), 7,07 (1H, s), 7,12 (1H, d, J=9.3 Hz), 7,17-of 7.25 (1H, m), 7,52 (1H, d, J=7,8 Hz), 7,72 (1H, dt, J=7,8, 1.9 Hz), 8,03 (1H, d, J=9.3 Hz), 8,46 (1H, d, J=4,7 Hz).

ESI-MS m/z: 380 (M+H)+.

[Example 132] 1-[1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (215 mg, 71%) using 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (238 mg)obtained in referential example 139 and N-methylpiperazine (122 mg).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2.40 a-to 2.57 (4H, m), 3,81-to 3.92 (2H, m), a 4.03-4,11 (2H, m), 4,11 (3H, s), 7,10 (1H, s), 7,13 (1H, d, J=9.3 Hz), 7,22 (1H, DD, J=7,8,4,9 Hz), 7,58 (1H, d, J=7.8 Hz), of 7.75 (1H, dt, J=7,8) and 1.7 Hz), 7,80 (1H, d, J=9.3 Hz), to 8.41 (1H, d, J=4,9 Hz).

ESI-MS m/z: 380 (M+H)+.

Elemental analysis: as With19H21N7O2.

Calculated: C, 60,15; N, To 5.58; N, 25,84.

Found: C, 59,95; N, Of 5.40; N, 25,71.

[Example 133] 1-[1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-piperazine

1) tert-Butyl ester 1-[1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]piperazine-4-carboxylic acid

In a manner analogous to the method used in stage 1) of example 1, tert-butyl ester 1-[1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]piperazine-4-carboxylic acid obtained as a solid (349 mg, 94%) using 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (237 mg)obtained in referential example 139 and N-tert-butoxycarbonylamino (223 mg).

1H-NMR (400 MHz, CDCl3) δ: to 1.48 (9H, s), and 1.56 (6H, s), 3,48 is 3.57 (4H, m), of 3.77-3,82 (2H, m), a 4.03-4.09 to (2H, m), of 4.12 (3H, s), 7,13 (1H, 8), 7,14 (1H, d, J=9.0 Hz), 7,22 (1H, DDD, J=7, and 8.4, and 9.1 Hz), to 7.59 (1H, dt, J=7,8, the 1.1 Hz), of 7.75 (1H, dt, J=7,8, 1.8 Hz), to 7.77 (1K, d, J=9.0 Hz), to 8.41 (1H, DDD, J=4,9, 1,8, 1,1 Hz).

ESI-MS m/z: 466 (M+H)+.

2) Specified in the header of the connection

In a manner analogous to the method used in step 2) of example 16, is listed in the title compound obtained as a solid (242 mg, 88%) using the above product, tert-Buti is a new ester 1-[1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-piperazine-4-carboxylic acid (349 mg)

1H-NMR (400 MHz, CDCl3) δ: 2,86-of 3.06 (4H, m), 3,76-3,88 (2H, m), 4,00-4,08 (2H, m), 4,11 (3H, s), 7,10 (1H, s), 7,13 (1H, d, J=9.0 Hz), 7,22 (1H, DD, J=7,8, and 4.9 Hz), 7,58 (1H, d, J=7.8 Hz), of 7.75 (1H, dt, J=7,8, 1.3 Hz), 7,79 (1H, d, J=9.0 Hz), scored 8.38-to 8.45 (1H, m).

ESI-MS m/z: 366 (M+H)+.

[Example 134] 1-[1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-3-oxopiperidin

1) Hydrochloride piperidine-3-one

tert-Butyl ether 3-oxopiperidin-1-carboxylic acid (400 mg) is dissolved in methylene chloride (5 ml). To the solution was added a solution of 4 N. HCl-dioxane (3 ml) followed by stirring at room temperature for 3 hours. The reaction solvent is removed under reduced pressure to give the hydrochloride piperidine-3-one.

1H-NMR (400 MHz, CD3OD) δ: of 1.85 (2H, m), 3.04 from (2H, m), 3,66 (2H, usher.), 4,88 (2H, usher.).

2) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (53 mg, 10%) using 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (400 mg)obtained in referential example 139 and the product obtained above, hydrochloride piperidine-3-one (272 mg).

1H-NMR (400 MHz, CDCl3) δ: 2,13 (2H, usher.), of 2.58 (2H, t, J=6,47 Hz), of 3.97 (1H, usher.), of 4.12 (3H, usher.), to 4.23 (1H, usher.), 4,39 (1H, usher.), 4,74 (1H, usher.), to 7.15 (2H, m), 7,22 (1H, m), to 7.59 (1H, d, J=7,81 Hz), 7,79 (2H, m), and 8.4 (1H, d, J=3,91 Hz).

FAB-MS m/z: 379 (M+H)+.

[Example 135] 1-[1-(6-Methoxy-3-pyridazinyl)-5-(4-methoxy-2-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (226 mg, 60%) using 1-(6-methoxy-3-pyridazinyl)-5-(4-methoxy-2-pyridyl)pyrazole-3-carboxylic acid (300 mg)obtained in reference example 158, and N-methylpiperazine (0,244 ml).

1H-NMR (400 MHz, CDCl3) δ: 2,32 (3H, s), 2,42 is 2.51 (4H, m), 3,83-to 3.92 (2H, m), 3,86 (3H, s), 4,06-to 4.14 (2H, m), 4,10 (3H, s), of 6.73 (1H, DD, J=5,9, 2.4 Hz), 7,06 (1H, s), 7,10 for 7.12 (2H, m), 7,76-7,79 (1H, m), to 8.20 (1H, d, J=5,9 Hz).

EI-MS m/z: 409 (M+).

Elemental analysis: as With20H23N7O3•0,25 H2O.

Calculated: C, 58,03; N, 5,72; N, 23,69.

Found: C, 58,07; N, 5,64; N, 23,47.

[Example 136] 4-Cyclopropyl-1-[1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]piperazine

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (271 mg, 79%) using 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (250 mg)obtained in referential example 139 and the hydrochloride of 1-cyclopropylbenzene (0,284 mg)obtained in reference example 99.

1H-NMR (400 MHz, CDCl ) δ: 0,41-of 0.50 (4H, m), 1,61-to 1.67 (1H, m), 2,63-of 2.72 (4H, m), with 3.79 (2H, t, J=4,9 Hz)to 3.99 (2H, t, J=4.9 Hz), 4,10 (3H, s), was 7.08 (1H, s), 7,11-7,13 (1H, m), 7,19-of 7.23 (1H, m), 7,56-7,58 (1H, m), 7,71-7,81 (2H, m), 8,39-to 8.41 (1H, m).

EI-MS m/z: 405 (M+).

Elemental analysis: as With21H23N7O2•0,25 H2O.

Calculated: C, 61,51; N, 5,78; N, 23,92.

Found: C, 61,51; N, 5,54; N, 23,94.

[Example 137] 4-[1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-1,1-diocletianopolis

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (235 mg, 72%) using 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (250 mg)obtained in referential example 139 and thiomorpholine-1,1-dioxide (0,136 ml).

1H-NMR (400 MHz, DMSO-d6) δ: of 3.28 (4H, usher.), a 4.03 (3H, s)4,07 (2H, usher.), of 4.35 (2H, usher.), to 7.32 (1H, s), 7,34 (1H, DD, J=7,81, 4,88 Hz), 7,47 (1H, d, J=9.28 are Hz), to 7.77 (1H, d, J=7,81 Hz), 7,89 (1H, dt, J=7,81, 1,59 Hz), to 7.99 (1H, d, J=9.28 are Hz), of 8.37 (1H, d, J=4,88 Hz).

FAB-MS m/z: 415 (M+H)+.

[Example 138] 4-[1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]thiomorpholine

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (236 mg, 92%) using 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (200 mg)obtained in referential example 139, and thiomorpholine (of 0.081 ml).

1H-NMR (400 MHz, CDCl3) δ: 2,74 (4H, usher.), 4,07 (2H, m), 4,11 (3H, s)4,27 (2H, usher.), to 7.09 (1H, s), 7,14 (1H, d, J=9,16 Hz), 7.23 percent (1H, DDD, J=EUR 7.57, 4,88, 1,10 Hz), 7,58 (1H, d, J=7,81 Hz), 7,74 (1H, DD, J=EUR 7.57, 1,71 Hz), 7,78 (1H, d, J=9,16 Hz), to 8.41 (1H, d, J=4,88 Hz).

FAB-MS m/z: 383 (M+H)+.

[Example 139] 1-[1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4,4-ceftobiprole

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (574 mg, 85%) using 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (500 mg)obtained in referential example 139, hydrochloride and 4,4-deformability (398 mg)obtained in reference example 152.

1H-NMR (400 MHz, CDCl3) δ: 2,07 (4H, m)to 3.92 (2H, m), 4,11 (3H, s), 4,17 (2H, m), 7,12-to 7.15 (2H, m), 7,20-of 7.23 (1H, m), 7,58 (1H, d, J=7.8 Hz), 7,72-to 7.77 (2H, m), 8,40 (1H, d, J=4,6 Hz).

EI-MS m/z: 400 (M+).

[Example 140] 1-[1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-3,3-ceftobiprole

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (403 mg, 74%) using 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (400 mg)obtained in referential example 139 and hydrochloride 3,3-deformability (33 mg), obtained in reference example 153.

1H-NMR (400 MHz, CDCl3) δ: of 1.88 (2H, m), 2,12-of 2.09 (2H, m), with 3.79 (1H, m)4,06 (1H, m), 4,11 (3H, s), 4,30 is 4.36 (1H, m), 7,14-7,26 (3H, m), 7,60-to 7.61 (1H, m), 7,73-to 7.84 (2H, m), to 8.41 (1H, d, J=3,9 Hz).

EI-MS m/z: 400 (M+).

[Example 141] 1-[1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-foreperiod

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (403 mg, 74%) using 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (400 mg)obtained in referential example 139, hydrochloride and 4-foreveryday (207 mg)obtained in reference example 154.

1H-NMR (400 MHz, CDCl3) δ: 1,91 is 2.01 (4H, m), 3,69-and 3.72 (1H, m), 3,92-is 4.21 (3H, m), 4,11 (3H, s), a 4.86-4,99 (1H, m), 7,10 (1H, s), 7,14 (1H, d, J=9.3 Hz), 7,20-7,24 (1H, m), EUR 7.57-to 7.59 (1H, m), 7,73-7,80 (2H, m), 8,40-8,42 (1H, m).

FAB-MS m/z: 383 (M+H)+.

Elemental analysis: as With19H19FN6O2.

Calculated: C, 59,68; N, Free 5.01; N, 21,99; F, Equal To 4.97.

Found: C, 59,65; N, 4,96; N, 22,04; F, 4,91.

[Example 142] 1-[1-(6-Methoxy-3-pyridazinyl)-5-(4-dimethylaminophenyl)pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in example 20, is listed in the title compound obtained as an amorphous product (200 mg, 76%) using 1-(6-methoxy-3-pyridazinyl)-5-(4-Dima is illinoisil)pyrazole-3-carboxylic acid (203 mg), obtained in reference example 140, and N-methylpiperazine (0,067 ml).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2,43-of 2.54 (4H, m), 2,96 (6H, s), 3,82-3,88 (2H, m), 4,06-4,12 (2H, m), 4,15 (3H, s), only 6.64 (2H, d, J=8,8 Hz), for 6.81 (1H, s), 7,02 (1H, d, J=9.3 Hz), 7,16 (2H, d, J=8,8 Hz), 7,47 (1H, d, J=9,3 Hz).

ESI-MS m/z: 422 (M+H)+.

Elemental analysis: as With22H27N7O2•0,75 H2O.

Calculated: C, 60,74; N, 6,60; N, 22,54.

Found: C, 60,62; N, Of 6.68; N, 22,54.

[Example 143] 1-[5-(5-Chloro-2-pyridyl)-5-(6-methoxy-3-pyridazinyl)pyrazole-3-carbonyl]-4-methyl-3-oxopiperidin

In a manner analogous to the method used in example 20, is listed in the title compound obtained as a solid (45 mg, 7%) using 5-(5-chloro-2-pyridyl)-1-(6-methoxy-3-pyridazinyl)pyrazole-3-carboxylic acid (483 mg)obtained in reference example 141, and hydrochloride of N-methylpiperazin-2-she (440 mg)obtained in reference example 157.

1H-NMR (400 MHz, CDCl3) δ: a 3.01 (3H, s), of 3.45 (3H, m), Android 4.04 (1H, usher.), of 4.11 (3H, usher.), 4,36 (1H, usher.), 4,84 (1H, s), to 7.15 (1H, d, J=9,03 Hz), 7,16 (1H, s), 7,53 (1H, d, J=8,30 Hz), 7,71 (1,5H, DD, J=8,30, 2.20 Hz), 7,85 (0,5H, d, J=9,03 Hz), a 8.34 (1H, s).

FAB-MS m/z: 428 (M+H)+.

[Example 144] 1-[1-(5-Methoxy-2-pyrazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in stage 1) of example 1, indicated in the header is connected to the e obtained as a solid (251 mg, 61%) using 1-(5-methoxy-2-pyrazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (320 mg)obtained in reference example 142, and N-methylpiperazine (0,179 ml).

1H-NMR (400 MHz, CDCl3) δ: 2,32 (3H, s), 2,44-2,52 (4H, m), 3,85 (2H, m)to 4.01 (3H, s), 4,10 (2H, m), 7,12 (1H, s), 7,22-7,19 (1H, m), 7,52-rate of 7.54 (1H, m), 7,70 to 7.75 (1H, m), to $ 7.91 (1H, d, J=1.0 Hz), 8,40-to 8.41 (2H, m).

EI-MS m/z: 379 (M+).

[Example 145] 1-[1-(5-Methoxy-2-pyrazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-methyl-3-oxopiperidin

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (287 mg, 64%) using 1-(5-methoxy-2-pyrazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (329 mg)obtained in reference example 142, and hydrochloride of 1-methylpiperazin-2-she (333 mg)obtained in reference example 157.

1H-NMR (400 MHz, CDCl3) δ: to 3.02 (3H, s), 3,47 (2H, m), 4,01-a 4.03 (4H, m), of 4.44 (2H, m), to 4.87 (1H, m), 7,16-of 7.23 (2H, m), 7,52-rate of 7.54 (1H, m), 7,73 (1H, m), 7,92 (1H, d, J=8,8 Hz), 8,44 is 8.38 (2H, m).

FAB-MS m/z: 394 (M+H)+.

Elemental analysis: as With19H19N7O3.

Calculated: C, 56,71; N, Free 5.01; N, 24,36.

Found: C, 56,77; N, 5,16; N, 24,40.

[Example 146] 1-[1-(6-Methyl-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazin

To a solution of ethyl ester of 1-(6-methyl-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (245 mg)obtained the CSOs in reference example 143, in a mixture of tetrahydrofuran (2 ml), ethanol (0.5 ml) and water (1 ml) at room temperature add the monohydrate of lithium hydroxide (40,1 mg), followed by stirring for 1 hour. To the reaction mixture add 1 N. aqueous hydrochloric acid (0,191 ml) and the reaction solvent is removed under reduced pressure, thus obtaining lithium salt of 1-(6-methyl-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid. To the solution thus obtained lithium salt in N,N-dimethylformamide (4.0 ml) at room temperature was added 1-hydroxybenzotriazole (153 mg), the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (238 mg) and N-methylpiperazine (0,265 ml) followed by stirring for 3 days. The reaction mixture was partitioned between water and the solvent of chloroform-methanol (15:1) and the organic layer is dried over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure and the residue purified column chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound as an amorphous product (up to 66.5 mg, 25%).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2,45 is 2.55 (4H, m), 2,59 (3H, s), 3,85 (2H, usher.), 4.09 to (2H, usher.), for 7.12 (1H, s), 7,19 (1H, d, J=8,3 Hz), 7,21-7,27 (1H, m), 7,44 (1H, d-like, J=7.8 Hz), a 7.62 (1H, DD, J=8,3, 2.7 Hz), 7,72 (1H, t-like, J=7.8 Hz), 8,40 (1H, d, J=2.7 Hz), of 8.47 are 8.53 (1H, m).

ESI-MS m/z: 362 (M+H)+.

[Example 14] Hydrochloride 1-[1-(6-methoxy-3-pyridyl)-5-(3-pyridazinyl)pyrazole-3-carbonyl]-4-methylpiperazine

In a manner analogous to the method used in stage 1) of example 1, 1-[1-(6-methoxy-3-pyridyl)-5-(3-pyridazinyl)pyrazole-3-carbonyl]-4-methylpiperazin get using the lithium salt of 1-(6-methoxy-3-pyridyl)-5-(3-pyridazinyl)pyrazole-3-carboxylic acid (160 mg)obtained in referential example 144 and the N-methylpiperazine (0,088 ml). In a manner analogous to the method used in step 2) of example 29, specified in the title compound obtained as a solid (123 mg, 50%) using the above product.

1H-NMR (400 MHz, DMSO-d6) δ: of 2.81 (3H, s), 3,01-of 3.78 (6H, m), 3,90 (3H, s), 4,57-4,70 (1H, osirm), 4,93 is 5.07 (1H, osirm), of 6.90 (1H, d, J=8,8 Hz), 7,45 (1H, s), 7,75-to 7.84 (2H, m), 7,98-8,03 (1H, m), of 8.25 (1H, d, J=2.7 Hz), 9,17-of 9.21 (1H, m), 11,07-11,22 (1H, usher.).

ESI-MS m/z: 380 (M+H)+.

[Example 148] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyrazinyl)pyrazole-3-carbonyl]-4-methylpiperazin

1) Ethyl ester of 4-(2-pyrazinyl)-2,4-dioxolane acid

In a manner analogous to the method used in reference example 71, ethyl ester 4-(2-pyrazinyl)-2,4-oxomalonate acid obtained as a solid (1,83 g, 82%) using 1-(2-pyrazinyl)-1-ethanone (1.22 g) and diethyloxalate (2,05 ml). Thus obtained product is subjected to the next reaction without purification.

2) Ethyl ester of 1-(6-methoxy-3-pyridyl)-5-(2-pyrazinyl)pyrazole-3-Carbo the OIC acid

In a manner analogous to the method used in stage 2) of reference example 138, ethyl ester 1-(6-methoxy-3-pyridyl)-5-(2-pyrazinyl)pyrazole-3-carboxylic acid obtained as a solid (1,05 g, 45%) with the use of the resulting product, ethyl ester 4-(2-pyrazinyl)-2,4-oxomalonate acid (1,58 g), and hydrochloride of 5-hydrazino-2-methoxypyridine (1.50 g)obtained in reference example 1.

3) 1-(6-Methoxy-3-pyridyl)-5-(2-pyrazinyl)pyrazole-3-carboxylic acid

In a manner analogous to the method used in stage 7) of reference example 137, 1-(6-methoxy-3-pyridyl)-5-(2-pyrazinyl)pyrazole-3-carboxylic acid is obtained in the form of solids (0,883 g, 92%) with the use of the resulting product, ethyl ester 1-(6-methoxy-3-pyridyl)-5-(2-pyrazinyl)pyrazole-3-carboxylic acid (1,05 g).

4) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (145 mg, 48%) with the use of the resulting product, 1-(6-methoxy-3-pyridyl)-5-(2-pyrazinyl)pyrazole-3-carboxylic acid (0,232 g), and N-methylpiperazine (0,156 ml).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2,45 of $ 2.53 (4H, m), 3,84-a 3.87 (2H, m), of 3.97 (3H, s), 4.09 to of 4.12 (2H, m), 6,79 (1H, d, J=8,8 Hz), 7,26 (1H, d, J=2.7 Hz), 7,60 (1H, DD, J=8,8, 2.7 Hz), to 8.12 (1H, d, J=2.7 Hz), of 8.47 (1H, DD, J=2,4) and 1.7 Hz), 8,51 (1H, d, J=2.4 Hz), 8,73 (1H, d, J=1.5 Hz).

ESI-MS m/z: 380 (M+) +.

Elemental analysis: as With19H21N7O2.

Calculated: C, 60,15; N, To 5.58; N, 25,83.

Found: C, 60,00; N, 5,52; N, 25,57.

[Example 149] (2S)-1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-2-dimethylaminomethylphenol

1) (2S)-2-Dimethylaminomethylphenol

When cooled at -78°With solution sulfurylchloride (0,409 ml) in methylene chloride (30 ml) is added dropwise to a solution of (2S)-2-pyrrolidineethanol (0,498 ml) and triethylamine (1.39 ml) in methylene chloride (30 ml) over a period of 10 minutes. The temperature of the resulting mixture gradually returned to room temperature, followed by stirring the mixture for 20 hours. The reaction mixture was partitioned between 1 N. aqueous hydrochloric acid and methylene chloride and the organic layer was washed with saturated salt solution, followed by drying over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure and to the residue is added a solution of 2.0 M dimethylamine in tetrahydrofuran (25 ml), followed by stirring in a sealed tube at an internal temperature of 100°C for 14 hours and 30 minutes and then cooled in air. To this mixture triperoxonane acid (one drop). The resulting mixture was additionally stirred in a sealed tube at an internal temperature of 10° C for 21 hours and then cooled in air. The solvent is removed under normal pressure and to the residue add 2 N. aqueous sodium hydroxide (50 ml) followed by stirring at 100°C for 15 hours. The resulting mixture is cooled in air. For distribution of the mixture there was added diethyl ether and the organic layer is dried over anhydrous sodium sulfate. After filtration the solvent is removed under reduced pressure, thus obtaining (2S)-2-dimethylaminomethylphenol.

2) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (116 mg, 5.1 per cent) with the use of the resulting product, (2S)-2-dimethylaminopyridine, and 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (231 mg)obtained in reference example 33.

1H-NMR (400 MHz, CDCl3) δ: 2,03-2,11 (2H, m), 2,27-is 2.37 (1H, m), 2,48 is 2.55 (1H, m), 2,87-is 3.08 (7H, m), 3,48 (1H, d, J=12.3 Hz), 3.96 points-Android 4.04 (4H, m), 4,11-4,17 (1H, m), 4,60 with 4.65 (1H, m), 6,76 (1H, d, J=8,8 Hz), 7,21 (1H, s), 7,24-7,27 (1H, m), 7,42 (1H, d, J=7.8 Hz), 7,58 (1H, DD, J=8,8, 2.7 Hz), 7,72 (1H, DD, J=7,7, to 7.6 and 1.7 Hz), to 8.12 (1H, d, J=2.5 Hz), charged 8.52 (1H, d, J=4, 2 Hz).

ESI-MS m/z: 407 (M+H)+.

[150] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-3-dimethylaminopyridine

In a manner analogous to the method used in the article is Hai 1) of example 1, specified in the title compound obtained as a solid (250 mg, 80%) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (231 mg)obtained in reference example 33, 3-dimethylaminopyridine (0,148 ml).

1H-NMR (400 MHz, CDCl3) δ: 1,77-of 1.95 (1H, m), 2,11-of 2.21 (1H, m)to 2.29 (3H, s), 2,32 (3H, s), 2,69-2,84 (1H, m), 3.43 points (1/2x1H, DD, J=11,7, 9.0 Hz), 3,59-and 3.72 (1H, m), 3,88-of 3.97 (1H, m), of 3.96 (3H, s), 4,05 (1/HN, DD, J=12,0, the 6.8 Hz), 4,27-4,39 (1H, m), of 6.75 (1H, d, J=8,8 Hz), 7,21-of 7.25 (2H, m), 7,46 (1H, d, J=7.8 Hz), 7,56-of 7.60 (1H, m), 7,69-7,74 (1H, m), 8,12-to 8.14 (1H, m), charged 8.52-8,49 (1H, m).

ESI-MS m/z: 393 (M+H)+.

[Example 151] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-2-methyl-3-oxopyrrolidin

1) 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-3-oxopyrrolidin

In a manner analogous to the method used in stage 1) of example 1, 1-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-3-oxopyrrolidin receive in the form of a solid (141 mg, 48%) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (231 mg)obtained in reference example 33, and the hydrochloride of 3-oxadiazolidine (115 mg).

1H-NMR (400 MHz, DMSO-d6) δ: 2,70 (2H, t, J=8,4 Hz)to 3.89 (3H, s), 4,48 (2H, users), 6,89 (1H, d, J=8,8 Hz), 7,33 (1H, s), 7,37 (1H, DD, J=7,6, a 4.9 Hz), 7,71 to 7.75 (2H, m), 7,89 (1H, DDD, J=7,8, and 7.8, 1.2 Hz), 8,19 (1H, d, J=2.7 Hz), of 8.47 (1H, d, J=4.6 Hz), 11,35 (1H, users).

ESI-MS m/z: 365 (M+H)+.

2) Specified in the header is Obedinenie

60% sodium hydride (142,4 mg) are added to the above 1-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-3-oxadiazolidine (0,542 g) in N,N-dimethylformamide (5 ml) at room temperature, followed by stirring for 15 minutes. Then to the resulting mixture add methyliodide (0,828 ml) followed by stirring for 10 days. To the reaction mixture is added potassium carbonate (0,614 g) and methyliodide (0,276 ml). The resulting mixture was stirred at 60°C for 2 hours and then cooled in air. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer is dried over anhydrous sodium sulfate. The mixture is filtered and the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (ethyl acetate-hexane), while receiving specified in the title compound in the form of solids (89,8 mg, 15%).

1H-NMR (400 MHz, CDCl3) δ: of 2.93 (2H, t, J=9.6 Hz), of 3.94 (3H, s), of 3.96 (3H, s), 4,28 (2H, t, J=9.5 Hz), to 6.75 (1H, DD, J=8,8, 0.7 Hz), 7,21-7,24 (1H, m), 7,33 (1H, d, J=7.8 Hz), 7,42 (1H, s), 7,65-7,71 (2H, m), 8,11 (1H, d, J=2.7 Hz), 8,55 (1H, d, J=4, 2 Hz).

ESI-MS m/z: 379 (M+H)+.

[Example 152] 1-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazin-2-carboxamide

1) Ethyl ester 4-tert-butoxycarbonyl-1-[1-(6-methoxy-3-pyrid the l)-5-phenylpyrazole-3-carbonyl]piperazine-2-carboxylic acid

In a manner analogous to the method used in example 20, ethyl ester 4-tert-butoxycarbonyl-1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperazine-2-carboxylic acid (992 mg, 95%) was obtained as an amorphous product with the use of 1-(6-methoxy-3-pyridyl)-5-phenylpyrazol-3-carboxylic acid (540 mg)obtained in referential example 41 ethyl ester 4-tert-butoxycarbonylmethyl-2-carboxylic acid (500 mg)obtained in reference example 147.

1H-NMR (400 MHz, CDCl3) δ: 1,23 (1/2x3H, t, J=7,1 Hz), 1,31 (1/2x3H, t, J=7,1 Hz)of 1.47 (9H, s), 3,94 (1/HN, C), 3,95 (1/2x3H, C), 6,69-6,74 (1H, m), 6,72 (1/2x1H, C), 6,74 (1/HN, C), 7,22-to 7.50 (6H, m), 8,08 (1/HN, d, J=2.7 Hz), 8,13 (1/2x1H, d, J=2.7 Hz).

FAB-MS m/z: 536 (M+H)+.

2) Ethyl ester of 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazin-2-carboxylic acid

In a manner analogous to the method used in step 2) of example 16, ethyl ester 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperazine-2-carboxylic acid is obtained in application of the above ethyl ester 4-tert-butoxycarbonyl-1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperazine-2-carboxylic acid (992 mg) and triperoxonane acid (2 ml). This compound is dissolved in methylene chloride (27 ml). To the resulting mixture is added 37% aqueous formalin solution (0,36 ml) and triacetoxyborohydride sodium (1.4 g), followed by stirring at to the room temperature for 1 hour. Then to distribute the reaction mixture is added saturated aqueous solution of sodium bicarbonate. The organic layer is dried over anhydrous magnesium sulfate. The mixture is filtered and the solvent is removed under reduced pressure and then dried, thus obtaining the ethyl ester of 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazin-2-carboxylic acid as an amorphous product (702 mg, 84%).

1H-NMR (400 MHz, CDCl3) δ: 1,23 (1/2x3H, t, J=7,1 Hz), 1,30 (1/2x3H, t, J=7,1 Hz), 2.06 to 2,19 (1H, m)2,301 (1/HN, C)2,304 (1/2x3H, (C), was 2.76-2,90 (1H, m), 3.27 to 3,68 (2H, m), 3,94 (1/2x3H, C)3,94 (1/2x3H, C), 4,20-4,33 (2H, m), 4,58 (1/2x1H, d, J=13,4 Hz), 4.95 points (1/2x1H, d, J=13,4 Hz), 5,38 of 5.39 (1/2x1H, m)of 5.85 and 5.86 (1/2x1H, m), 6,72 (1H, t, J=8,3 Hz), of 6.96 (1/2x1H, C), 6,99 (1/2x1H, C), 7,22-7,51 (6H, m), 8,07 (1/2x1H, d, J=2.7 Hz), 8,14 (1/2x1H, d, J=2.7 Hz).

EI-MS m/z: 449 (M+).

3) Specified in the header of the connection

The monohydrate of lithium hydroxide (66 mg) are added to the result of the above ethyl ether, 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazin-2-carboxylic acid (702 mg) in a mixture of tetrahydrofuran (33 ml) and water (7 ml), followed by stirring at room temperature for 41 hours. The reaction mixture is neutralized using concentrated hydrochloric acid. Then to distribute the mixture methylene chloride. The organic layer is dried over anhydrous magnesium sulfate, followed by filtration. Dissolve Itel removed under reduced pressure, thus the carboxylic acid derivative. To a mixture of carboxylic acid derivative, which is obtained, add triethylamine (0.5 ml), 1-hydroxybenzotriazole (422 mg), the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (600 mg) and 28% aqueous ammonia (1.0 ml) in methylene chloride (10 ml) followed by stirring at room temperature for 1 day. For the distribution of the reaction mixture are added water. The organic layer is dried over anhydrous magnesium sulfate. The mixture is filtered and the solvent is removed under reduced pressure. The residue is purified by thin-layer chromatography on silica gel (methylene chloride-methanol), while receiving specified in the title compound as an amorphous product (430 mg, 65%).

1H-NMR (400 MHz, CDCl3) δ: 2,10-of 2.20 (2H, m), of 2.33 (3H, s), 2,75-of 2.93 (1H, m), 3,15-of 3.60 (2H, m), 3,94 (,3H, s), 4,65-5,00 (1H, m), 6,70 to 6.75 (1H, m), 6,98-7, 01 (1H, m), 7,22-7,27 (2H, m), 7,33-7,38 (3H, m), 7,33-7,47 (1H, m), 8,08 (1/2x1H, users), 8,14 (1/2Hx1H, users).

FAB-MS m/z: 421 (M+H)+.

[Example 153] (3S)-4-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]morpholine-3-carboxamide

1) Methyl ester of (3S)-4-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]morpholine-3-carboxylic acid

In a manner analogous to the method used in example 20 methyl ester (3S)-4-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]morpholine-3-ka is oil acid obtained as an amorphous product (387 mg, quantitative output) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (250 mg)obtained in reference example 33, and a methyl ether, morpholine-3-carboxylic acid (190 mg)obtained in reference example 148.

1H-NMR (400 MHz, CDCl3) δ: 3,57-was 4.02 (5H, m), 3,76 (3H, s), of 3.96 (3H, s), of 4.45 (1H, d, J=12,09 Hz), 5,00 (0,5H, m), 5.25 in (0,2H, C), of 5.89 (0,3H, s), 6,74 (1H, d, J=8,79 Hz), 7.23 percent (1H, d, J=4.52 Hz), 7,27 (1H, d, J=of 3.78 Hz), 7,46 (1H, m), to 7.59 (1H, DD, J=8,79, 2,69 Hz), 7,79 (1H, m), 8,13 (1H, DD, J=5,13, 2,69 Hz)and 8.50 (1H, d, J=4,88 Hz).

EI-MS m/z: 424 (M+H)+.

2) (3S)-4-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]morpholine-3-carboxylic acid

1 N. Aqueous sodium hydroxide solution (3 ml) is added dropwise to the above methyl ether (3S)-4-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]morpholine-3-carboxylic acid (387 mg) in tetrahydrofuran (5 ml) under ice cooling, followed by stirring at room temperature for 3 hours. The reaction mixture was partitioned between 1 N. aqueous solution of hydrochloric acid (3.5 ml) and chloroform. Then the organic layer is dried over anhydrous sodium sulfate. The mixture is filtered and the solvent is removed under reduced pressure, thus obtaining (3S)-4-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]morpholine-3-carboxylic acid as an amorphous product (338 mg, 90%).

1H-NMR (400 MHz, CDCl3δ : 3,57-of 3.80 (3H, m), 3,76 (3H, s), of 4.45 (1H, d, J=12,09 Hz), 4,93 (0,5H, m), 5.25 in (0,2H, C), 5,79 (0,3H, s)6,76 (1H, m), 7.24 to 7,78 (5H, m), 8,13 (1H, m), and 8.50 (1H, m).

EI-MS m/z: 410 (M+H)+.

3) Specified in the header of the connection

In a manner similar to the method used in example 20, is listed in the title compound obtained as an amorphous product (58 mg, 17%) using the above (3S)-4-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]morpholine-3-carboxylic acid (338 mg) and ammonium chloride (221 mg).

1H-NMR (400 MHz, CDCl3) δ: 3,23 (0,5H, m), 3,65 (2,5H, m), 3,91 (1H, m), of 3.95 (3H, s), br4.61 (1,5H, m), 4,96 (0,5H, m), 5,17 (0,5H, usher.), 5,46 (1,5H, usher.), 6,27 (0,5H, usher.), 6,76 (1,5H, usher.), 7,26 (2H, m), 7,42 (1H, m), 7,55 (1H, m), 7,73 (1H, m), of 8.09 (1H, m), 8,53 (1H, m).

FAB-MS m/z: 409 (M+H)+.

[Example 154] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-3-methyl-4-Oxymetazoline

1) 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-Oxymetazoline

In a manner analogous to the method used in stage 1) of example 1, 1-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-Oxymetazoline obtained as a solid (200 mg, 70%) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (231 mg)obtained in reference example 33, 4-imidazolinone (80,5 mg).

2) Specified in the header of the connection

In a manner analogous to the method used in stage 1) reference the example 152, specified in the title compound obtained as a solid (141 mg, 68%) using the above 1-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-Oxymetazoline (200 mg) and under the conditions (0,052 ml).

1H-NMR (400 MHz, CDCl3) δ: 2,98 (1H, s), to 3.02 (2H, s), of 3.97 (2H, s), 3,98 (1H, s), 4,29 (2/3H, s), 4,71 (4/3H, s), 5,09 (4/3H, s), the 5.45 (2/3H, s), 6,76-to 6.80 (1H, m), 7.24 to 7,27 (1H, m), 7,32 (2/3H, s), 7,33 (1/3H, s), 7,43-of 7.48 (1H, m), 7,55 (1/3H, DD, J=8,9, 2,8 Hz), 7.62mm (2/3H, DD, J=8,9, 2,8 Hz), 7,71-7,76 (1H, m), 8,08 (2/3H, d, J=2.7 Hz), 8,19 (1/3H, d, J=2.4 Hz), 8,50-8,54 (1H, m).

ESI-MS m/z: 379 (M+H)+.

[Example 155] (3R)-1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-3-ethoxypyrrolidine

1) Hydrochloride, (3R)-3-ethoxypyrrolidine

4 n HCl-dioxane (10 ml) is added to tert-butyl ether (3R)-3-ethoxypyrrolidine-1-carboxylic acid (899 mg)obtained in reference example 155, followed by stirring at room temperature for 18.5 hours. The reaction mixture was treated under reduced pressure to give the hydrochloride (3R)-3-ethoxypyrrolidine (0,637 g, quantitative yield).

2) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an oily substance (267 mg, 88%) using the above hydrochloride (3R)-3-ethoxypyrrolidine (0.20 g) and 1-(6-methoxy-3-pyrid the l)-5-(2-pyridyl)pyrazole-3-carboxylic acid (231 mg), obtained in reference example 33.

1H-NMR (400 MHz, CDCl3) δ: 1,95-to 2.18 (2H, m)to 3.34 (3H, s), 3,37 (3H, s), 3,71-4,08 (4H, m), of 3.96 (3H, s), 4,15-of 4.25 (1H, m), of 6.75 (1H, d, J=8,8 Hz), 7,21-7,27 (2H, m), 7,44-of 7.48 (1H, m), EUR 7.57-to 7.61 (1H, m), 7,69-7,74 (1H, m,), 8,13-of 8.15 (1H, m), and 8.50 (1H, d, J=3,7 Hz).

ESI-MS m/z: 380 (M+H)+.

Elemental analysis: as With20H21N5O3•0.5 N2O.

Calculated: C, 61,84; N, 5,71; N, 18,03.

Found: C, 61,69; N, The Ceiling Of 5.60; N, 17,74.

[Example 156] 1-[1-(6-Methoxy-3-pyridyl)-5-(4-methyl-2-pyridyl)pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (265 mg, 82%) using 1-(6-methoxy-3-pyridyl)-5-(4-methyl-2-pyridyl)pyrazole-3-carboxylic acid (250 mg)obtained in reference example 145 and the N-methylpiperazine (0,0983 ml).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), a 2.36 (3H, s), 2,46 is 2.51 (4H, m), 3,85 (2H, m), of 3.95 (3H, s), 4.09 to (2H, m), 6.73 x to 6.75 (1H, m), 7,05-7,07 (1H, m), was 7.08 (1H, s), 7,27-7,28 (1H, m), EUR 7.57-of 7.60 (1H, m), 8,11 (1H, d, J=2,4 Hz), at 8.36 (1H, d, J=4,8 Hz).

EI-MS m/z: 392 (M+).

Elemental analysis: as With21H24N6O2•0.5 N2O.

Calculated: C, 62,83; N, 6,28; N, 20,93.

Found: C, 63,09; N, 6,18; N, 20,67.

[Example 157] 1-[1-(6-Methoxy-3-pyridyl)-5-(4-methyl-2-pyridyl)pyrazole-3-carbonyl]-4-methyl-3-oxopiperidin

In a manner analogous to the manual, used in stage 1) of example 1, indicated in the title compound obtained as a solid (204 mg, 57%) using 1-(6-methoxy-3-pyridyl)-5-(4-methyl-2-pyridyl)pyrazole-3-carboxylic acid (250 mg)obtained in reference example 145, and salts of N-methylpiperazin-2-she triperoxonane acid (313 mg)obtained in referential example 91.

1H-NMR (400 MHz, CDCl3) δ: is 2.37 (3H, 3), 3,03 (3H, s), of 3.48 (2H, m), of 3.96 (3H, s), of 4.05 (1H, m), of 4.44 (2H, m), is 4.85 (1H, m), 6,76 (1H, d, J=8.0 Hz), 7,07 (1H, m), 7,16 (1H, m), 7,27-7,30 (1H, m), 7,56 to 7.62 (1H, m), 8,02-to 8.14 (1H, m), 8,35 (1H, d, J=4,8 Hz).

EI-MS m/z: 406 (M+).

Elemental analysis: as With21H22N6O3•0.5 N2O.

Calculated: C, 60,71; N, To 5.58; N, On 20, 23.

Found: C, 60,83; N, Of 5.55; N, 20,19.

[Example 158] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]piperidine-2-carboxamide

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (198 mg, 59%) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (231 mg)obtained in referential example 33 and piperidine-2-carboxamide (150 mg)obtained in reference example 131.

1H-NMR (400 MHz, CDCl3) δ: 1,49-of 1.88 (5H, m), a 2.36 (1H, DD, J=30,0, to 13.6 Hz), 2,80-2,87 (1/2x1H, m), 3,15-3,22 (1/2x1H, m), of 3.96 (3H, s), 4,70-rate 4.79 (1H, m), 5, 33-5,44 (2H, m), 6,37 (1/HN, users), 6,76 (1H, DD, J=8,6, a 4.9 Hz), 7,12 (1/2x1H, users), 715 (1H, d, J=15.7 Hz), 7.24 to 7,27 (1H, m), 7,42 (1H, DD, J=12,0, 7,8 Hz), 7,56 (1H, DD, J=25,6, and 8.7 Hz), 7,70 to 7.75 (1H, m), 8,11 (1H, d, J=17,4 Hz), 8,54 (1H, s).

ESI-MS m/z: 407 (M+H)+.

[Example 159] 1-[1-(6-Methoxy-3-pyridyl)-5-(5-methyl-2-pyridyl)pyrazole-3-carbonyl]-4-methyl-3-oxopiperidin

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (156 mg, 46%) using 1-(6-methoxy-3-pyridyl)-5-(5-methyl-2-pyridyl)pyrazole-3-carboxylic acid (250 mg)obtained in reference example 146, and salts of N-methylpiperazin-2-she triperoxonane acid (313 mg)obtained in referential example 91.

1H-NMR (400 MHz, CDCl3) δ: of 2.34 (3H, s), to 3.02 (3H, s), 3,47 (2H, m), of 3.96 (3H, s), Android 4.04 (1H, m), 4,43 (2H, m), 4,84 (1H, m), 6,76 (1H, d, J=8,8 Hz), to 7.15 (1H, m), 7,27 (1H, m), 7,51-7, 62 (2H, m), 8,08-8,13 (1H, m), 8,35 (1H, m).

EI-MS m/z: 406 (M+).

[Example 160] 4-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-1,4-oxazepan

In a manner analogous to the method used in example 20, is listed in the title compound obtained as a solid (215 mg, 66%) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (250 mg)obtained in referential example 33 and hydrochloride 1,4-oxazepan (173 mg)obtained in reference example 149.

1H-NMR (400 MHz, DMSO-d6) δ: to 1.86 (2H, usher.), 3,70 (6H, m), a 3.87 (H, C)of 3.96 (2H, m), 6.87 in (1H, d, J=8,67 Hz), 7,19 (1H, s), 7,35 (1H, m), 7,68 (2H, m), 7,87 (1H, t, J=7,81 Hz), 8,15 (1H, s), to 8.45 (1H, d, J=with 4.64 Hz).

FAB-MS m/z: 380 (M+H)+.

Elemental analysis: as With20H21N5O3•0.5 N2O.

Calculated: C, 61,84; N, 5,71; N, 18,03.

Found: C, 62,12; N, 5,49; N, 17,89.

[Example 161] 1-[1-(6-Methoxy-3-pyridyl)-5-(4-methoxy-2-pyridyl)pyrazole-3-carbonyl]-4-methylhomopiperazine

1) Specified in the header of the connection

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (136 mg, 42%) using 1-(6-methoxy-3-pyridyl)-5-(4-methoxy-2-pyridyl)pyrazole-3-carboxylic acid (250 mg)obtained in reference example 158, and N-methylhomopiperazine (0,105 ml).

1H-NMR (400 MHz, CDCl3) δ: 1,99-2,07 (2H, m), 2,39 (1/h, C)2,41 (1/2x3H, C), 2,61-to 2.67 (2H, m), was 2.76-2,77 (2H, m), 3,80-4,10 (10H, m), 6.73 x-6,77 (2H, m), of 6.96-6,99 (1H, m), 7,09 (1/2x1H, C), 7,11 (1/HN, C), 7,55-7,60 (1H, m), 8,13 (1H, d, J=2,8 Hz), 8,32-to 8.34 (1H, m).

EI-MS m/z: 422 (M+).

2) Salt specified in the title compound with hydrochloric acid

In a manner analogous to the method used in step 2) of example 29, salt specified in the connection header with hydrochloric acid obtained as a solid (140 mg, 82%) using the above specified in the title compound (132 mg).

1H-NMR (400 MHz, DMSO-d-sub> 6) δ: 2,14-of 2.34 (2H, m), 2,78 is 2.80 (3H, m), 3,18-3,26 (1,5H, m), 3,35-of 3.95 (5H, m), 3,88 (3H, s), 4,06-4,19 (1H, m), 4,50-4,54 (0,5H, m), 6.87 in (1H, DD, J=8,9, 3.5 Hz),? 7.04 baby mortality-7,06 (1H, m), 7,28-7,33 (2H, m), 7,70-7,72 (1H, m), to 8.20 (1H, DD, J=17.1 to be 2.7 Hz), 8,33-at 8.36 (1H, m).

EI-MS m/z: 422 (M+).

[Example 162] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]hexahydropyridine

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as an amorphous product (1,61 g, 87%) using 1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (1,495 g)obtained in referential example 33 and hexahydropyridine (0,629 g)obtained in reference example 156.

1H-NMR (400 MHz, CDCl3) δ: 1,60-1,90 (4H, m), 2.95 and-3,10 (2H, m), 3,80-3,90 (1/HN, m), 3,95 (2/3x3H, (C), 3, 97 (1/HN, C), 4,20-4,27 (2/3x1H, m)of 6.75 (1H, d, J=8,8 Hz), 7,17 (1H, s), 7,20 to 7.75 (5H, m)to 8.12 (1H, user.), and 8.5 (1H, usher.).

FAB-MS m/z: 365 (M+H)+.

[Example 163] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-2-acetylglucosaminidase

The triethylamine (0,210 ml), acetylchloride (0,0807 ml) and 4-dimethylaminopyridine (13.5 mg) are added to 1-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]hexahydropyridine (0,275 g)obtained in example 162, in methylene chloride (6.0 ml) at room temperature, followed by stirring for 20 minutes. The mixture is distributed between water and chloroform, the Organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. The mixture is filtered and the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound as an amorphous product (0,149 g, 59%).

1H-NMR (400 MHz, CDCl3) δ: 1,65-1,90 (3H, m)to 2.13 (3H, s), 2,52 (1H, usher.), 2,84-to 3.02 (2H, m), 3,93 (3H, s), 4,60-4,85 (7/HN, m), 5,20-5,40 (1/8x2H, m)6,76 (1H, d, J=8,8 Hz), 7,15-7,80 (5H, m), 8,02 (1H, usher.), 8,53 (1H, usher.).

ESI-MS m/z: 407 (M+H)+.

[Example 164] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]hexahydropyridine-2-carboxamide

Trimethylsilylacetamide (0,920 ml) are added to 1-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]hexahydropyridine (0,397 g)obtained in example 162, in 1,4-dioxane (3 ml) at room temperature, followed by stirring at an internal temperature of 110°C in a sealed tube for 4 days. The mixture is then cooled in air. After adding to the reaction mixture of methanol, the reaction solvent is removed under reduced pressure. The residue is partitioned between saturated aqueous sodium hydrogen carbonate and a mixture of solvents chloroform-methanol (20:1). The organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. The mixture is filtered and the solvent is removed under reduced on the no. The residue is purified column chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound in the form of solids (0,122 g, 25%).

1H-NMR (400 MHz, CDCl3) δ: 1,60-1,90 (4H, m), 2,84-3,13 (2H, m), 3,93 (3H, s), 4,42 (1H, d-like, J=12,4 Hz), 4,62-to 4.73 (1H, usher.), the 5.51 (2H, usher.), of 6.73 (1H, d, J=8.7 Hz), was 7.08 (1H, s), 7,20-7,26 (1H, m), 7,33 (1H, d-like, J=7.8 Hz), a 7.62 (1H, DD, J=8,8, 2.7 Hz), 7,65-7,72 (1H, m), of 8.06 (1H, d, J=2.4 Hz), 8,48-8,54 (1H, m).

ESI-MS m/z: 408 (M+H)+.

[Example 165] 1-[1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-4-formylpiperazine

In a manner analogous to the method used in example 20, is listed in the title compound obtained as a solid (0,249 g, 77%) using 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid (0,246 g)obtained in referential example 139 and N-formylpiperazine (0,185 ml).

1H-NMR (400 MHz, CDCl3) δ: 3,42-3,55 (2H, m), 3,61-and 3.72 (2H, m), 3,80-are 3.90 (2H, m), 4,10-4,24 (2H, m), of 4.12 (3H, s), 7,12-7,27 (3H, m), to 7.59 (1H, d, J=8.1 Hz), 7,70-7,81 (2H, m), 8,13 (1H, usher.), to 8.40 (1H, d, J=4,6 Hz).

ESI-MS m/z: 394 (M+H)+.

[Example 166] 1-[1-(6-Methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-2-vormingukirjeldused

4-Dimethylaminopyridine (0,142 g) and anhydrous triftormetilfullerenov acid (0,140 ml) are added to 1-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]hexage pyridazine (0,203 g), obtained in example 162, N,N-dimethylformamide (4.0 ml) at 0°C, followed by stirring for 20 minutes. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. The mixture is filtered and the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (chloroform-methanol), while receiving specified in the title compound in the form of solids (65,5 mg, 30%).

1H-NMR (400 MHz, CDCl3) δ: 1,65 is 2.00 (4H, m), 2,86-3,10 (1H, m), of 3.94 (3H, s), to 4.41-4,51 (1H, usher.), is 4.85 (1H, usher.), 6,76 (1H, d, J=8,8 Hz), 7,12-7,30 (2H, m), 7,47 (1H, d, J=8,8 Hz), 7,52-7,63 (1H, m), to 7.67-7,76 (1H, m), 8,02 (1H, usher.), a 8.34 (1H, usher.), 8,50-8,55 (1H, m).

FAB-MS m/z: 393 (M+H)+.

[Example 167] 1-[1-(6-Methoxy-3-pyridyl)-5-(pyrrol-2-yl)pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (218 mg, 76%) using 1-(6-methoxy-3-pyridyl)-5-(pyrrol-2-yl)pyrazole-3-carboxylic acid (222 mg)obtained in reference example 159 and N-methylpiperazine (0,156 ml).

1H-NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2,44-2,52 (4H, m), 3,83-of 3.85 (2H, m)to 3.99 (3H, s), 4,11-to 4.14 (2H, m), 5,91-to 5.93 (1H, m), 6,15-of 6.17 (1H, m)6,0 (1H, d, J=8,8 Hz), 6,82-6,84 (1H, m), 6,93 (1H, s), EUR 7.57 (1H, DD, J=8,8, 2.7 Hz), compared to 8.26 (1H, d, J=2.7 Hz), 8,66 (1H, users).

ESI-MS m/z: 367 (M+H)+.

Elemental analysis: as With19H22N6O2.

Calculated: C, 62,28; N, Equal To 6.05; N, 22,94.

Found: C, 62,08; N, Between 6.08; N, 22,73.

[Example 168] 4-[1-(6-Methoxy-3-pyridyl)-5-(pyrrol-2-yl)pyrazole-3-carbonyl]morpholine

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (212 mg, 76%) using 1-(6-methoxy-3-pyridyl)-5-(pyrrol-2-yl)pyrazole-3-carboxylic acid (222 mg)obtained in reference example 159, and research (0,123 ml).

1H-NMR (400 MHz, CDCl3) δ: 3,72 of 3.75 (2H, m), 3,79-a 3.83 (4H, m)to 3.99 (3H, s), 4,16-4,19 (2H, m), of 5.92-5,94 (1H, m), 6,16-6,18 (1H, m), for 6.81 (1H, d, J=8,8 Hz), 6,82-6,84 (1H, m)6,94 (1H, s), 7,56 (1H, DD, J=8,8, 2.7 Hz), of 8.25 (1H, d, J=2,4 Hz)and 8.50 (1H, users).

ESI-MS m/z: 354 (M+H)+.

[Example 168] 4-[1-(6-Methoxy-3-pyridyl)-5-(2-pyrazinyl)pyrazole-3-carbonyl]morpholine

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a solid (141 mg, 55%) using 1-(6-methoxy-3-pyridyl)-5-(2-pyrazinyl)pyrazole-3-carboxylic acid (195 mg), obtained in stage 3) of example 148, and research (0,123 ml).

1H-NMR (400 MHz, CDCl3) δ: of 3.73 is 3.76 (2H, m), 3,79-3,86 (4H, m), of 3.97 (3H, s), 4,15-4,17 (2H, m, 6,79 (1H, d, J=8,8 Hz), 7,29 (1H, s), to 7.59 (1H, DD, J=8,9, 2,8 Hz)to 8.12 (1H, d, J=2.7 Hz), of 8.47-8,48 (1H, m), 8,51 (1H, d, J=2.4 Hz), 8,73 (1H, d, J=1.5 Hz).

ESI-MS m/z: 367 (M+H)+.

[Example 170] 1-[1-(6-Methoxy-3-pyridyl)-5-(1-methylpyrrole-2-yl)pyrazole-3-carbonyl]-4-methylpiperazin

In a manner analogous to the method used in stage 1) of example 1, indicated in the title compound obtained as a viscous substance (258 mg, 81%) using 1-(6-methoxy-3-pyridyl)-5-(1-methylpyrrole-2-yl)pyrazole-3-carboxylic acid (232 mg)obtained in reference example 161, and N-methylpiperazine (0,156 ml).

1H-NMR (400 MHz, CDCl3) δ: of 2.34 (3H, s), 2,47 of $ 2.53 (4H, m), 3,39 (3H, s), 3,84-3,86 (2H, m), of 3.94 (3H, s), 4,13-4,16 (2H, m), 6,07 (1H, DD, J=3,7) and 1.7 Hz), 6,14 (1H, DD, J=3,7, 2,9 Hz), 6,69-of 6.71 (2H, m), to 6.88 (1H, 3), 7,42 (1H, DD, J=8,8, 2.7 Hz), 8,13 (1H, d, J=2.7 Hz).

ESI-MS m/z: 381 (M+H)+.

[Test example 1] the Effect on inhibition of platelet aggregation

Human blood collected in the presence of 3.13% sodium citrate as an anticoagulant in the amount of 1/10 volumes of blood. The collected blood is centrifuged at 180 g for 10 minutes to isolate from the blood of the upper layer, i.e. platelet-rich plasma (PRP). The remaining bottom layer then centrifuged at 1600 g for 10 minutes and collect depleted platelet plasma (PPP), i.e. the thus obtained upper layer. To PRP (200 μl) is added a solution (1 μl) of the compound of the invention and with whom thou didst give the opportunity to stand at 37° C for 2 minutes. Then to the resulting mixture add collagen (2 ml)to induce platelet aggregation. Percent platelet aggregation was measured using a RAM 12C (SSR Engineering). Optical transmittance PPP is used as the value reflecting the state, which has 100% coagulation. Interest aggregation of platelets, PRP is determined at several concentrations of each compound of example. From the determined values of the calculated IC50for each connection. The results are shown in table 1.

[Test example 2] Inhibiting action exerted on cyclooxygenase-1 (MOR-1) and cyclooxygenase-2 (SOH-2)

Inhibitory activity against MOR-1 and MOR-2 compounds obtained in the examples were measured using the test kit screening inhibitor MOR (product of Cayman Chemical Company, Catalog No. 560101 and 560121).

Before starting the measurement buffer reactions, heme, arachidonic acid, SnCl2the EIA buffer, washing buffer, the EIA screening prostaglandin (PG), acetylcholinesterase (AchE) screening GHG tag (conjugate chromogenic enzyme HRP) and anticigarette EIA screening GHG received ready for use.

(1) Obtaining PG fin the presence of MOR-1 and MOR-2

The reaction mixture containing the compound of examples (50 μm) and MOR-1 and MOR-2 were incubated at 37°C for 10 minutes. To the mixture add ulali arachidonic acid (10 ml) and the resulting mixture was additionally incubated at 37° C for 2 minutes. To the reaction mixture were added 1 N. hydrochloric acid (50 ml), to thereby stop the reaction. To the mixture was added a solution of SnCl2(100 μl) and the resulting mixture was stirred at room temperature for 5 minutes.

(2) Quantitative determination of PG fusing ELISA

Anticigarette (rabbit antibodies against PG f, 50 ml) was added to the wells of 96-hole tablet, which were coated with mouse antibodies against rabbit IgG). The solution obtained above containing PG fa mixture of (2000-fold dilution, 50 µl) and label AchE (50 ml) was added to a hole in that order and the mixture is incubated at room temperature for 18 hours. The wells were washed 5 times with washing buffer to remove excess label AchE and added the Ellman reagent (200 μl). After keeping the tablet in a dark room for 60 minutes was measured by the absorption at 405 nm.

(3) calculation of the inhibitory activity of the compounds of examples.

A calibration curve was obtained with the application of EIA screening GHG emissions and absorption was determined by the number of production PG f. To calculate the percentage inhibition activity of MOR-1 and MOR-2 at 50 μm of the compounds of examples. The results are shown in table 1.

Significant is the fact that when calculating the percentage inhibition of the number of products the sale of PG fin the reaction mixture not containing the compound taken as 100%.

Table 1
ConnectionThe inhibition induced by collagen platelet aggregation IC50(µm)Inhibitory effect against MOR-1 at 50 μm (% inhibition)Inhibitory effect against SOH-2 at 50 μm (% inhibition)
230,17-1,23.4
270,270,5-0.1
360,14NDND
550,035NDND
620,12-2,4-2,6
700,26NDND
1220,7514,5
1320,42,710,5
1390,0427,63,4
1400,11NDND
1440,44the 9.78,8
1480,09NDND
1600,17 NDND
1630,09NDND
1670,029NDND
1680,017NDND
ND-not determined

As clearly seen from table 1, the compounds (I) and (II) of the present invention, their salts, or their solvate, or solvate salts have a strong activity of inhibiting platelet aggregation without inhibiting as MOR-1 and MOR-2.

1. Derivatives of pyrazole represented by the formula (I)or their pharmaceutically acceptable salts

where Ar1represents pyridyloxy, pyridazinyl or personilnya group with the Deputy, selected from a lower alkyl group, halogen atom, lower alkoxygroup, an amino group which may be substituted by 1 or 2 lower alkyl groups, and C3-6cycloalkylation;

Ar2represents 5 - or 6-membered aromatic heterocyclic group selected from peredelnoj, pyridazinyl, personalni and pyrrolidino groups, which may have a Deputy, selected from a lower alkyl group, halogen atom, lower alkoxygroup, low toolcategory, ceanography, lower alkoxycarbonyl the group, carboxyl group, a lower alkylsulfonyl group, an amino group which may be substituted by 1 or 2 lower alkyl groups, carbamoyl group which may be substituted by 1 or 2 lower alkyl groups and pyrrolidinone; or

Ar2represents a phenyl group which may have a Deputy, selected from a lower alkyl group, halogen atom, hydroxyl group, lower alkoxygroup, phenyl(lower alkyl)actigraphy, an amino group which may be substituted by 1 or 2 lower alkyl groups, and triptorelin;

R1 represents a group represented by the formula (1)

where the cyclic structure And is a 4-7-membered saturated ring which may have in addition to the nitrogen atom in the formula (1) one heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom; X represents a carbonyl group, thiocarbonyl group or a methylene group;

R3 represents 1 to 3 groups on the cyclic structure And,

and R3 is selected from the group consisting of hydrogen atom, halogen atom, hydroxyl group, lower alkoxygroup, lower alkoxycarbonyl group, carboxyl group, With3-6cycloalkyl groups, lower alkyl groups, which may be Samusenko the hydroxy-group, lowest alkoxygroup, lower alkoxycarbonyl group, carboxyl group, amino group which may be substituted by 1 or 2 lower alkyl groups, amino groups which may have 1 or 2 substituent selected from lower alkyl groups and lower alkoxycarbonyl group, carbamoyl group which may be substituted by 1 or 2 lower alkyl groups, lower acyl group, a carbonyl group, phenyl group, peredelnoj group, 3-6-membered pyroelectrically alkyl groups;

R2represents a hydrogen atom or a lower alkyl group.

2. Compounds according to claim 1 or their pharmaceutically acceptable salts, where X is a carbonyl group.

3. The compound according to claim 1 or their pharmaceutically acceptable salts, where X represents a methylene group.

4. Compounds according to claim 3 or pharmaceutically acceptable salts, where Ar1represents pyridyloxy group or pyridazinyl group with Deputy defined in claim 1.

5. The compound according to claim 3 or pharmaceutically acceptable salts, where Ar2represents pyridyloxy group or pyrrolidinyl group which may have a Deputy, as defined in claim 1, or a phenyl group which may have a Deputy, as defined in claim 1.

6. The compound according to claim 2 or pharmaceutically acceptable Sol is, where the portion represented by the following formula:

is a group selected from among

3-dimethylimidazolidin-1-ilen group, 2,2-dimethyl-3-dimethylimidazolidin-1-ilen group, 2-oxopyrrolidin, 2-hydroxyethylpyrrolidine, 2-carbamoylphenoxy, 2-hydroxyethylpiperazine, 2-carbamoylphenoxy, 2-methylcarbamoylmethyl, 2-dimethylcarbamodithioato, 3-oxo-4-methylpiperazine, 4-methylpiperazine, 4-ethylpiperazine, 4-isopropylpiperazine, 4-cyclopropylbenzene, 3,4-dimethylpiperazine, 3,4,5-trimethylpyrazole, 2,2,4-trimethylpyrazine, 2-cyclopropylamino-4-methylpiperazine, morpholinopropan, 3-carbamoylphenoxy, 1,1-dioxothiazolidine, 2-methylhexahydrophthalic-1-ilen group, 5-oxo-4-methylhomopiperazine, 4-methylhomopiperazine, 4-cyclopropylmethanol, 1,4-oxazepan-4-ilen group, piperidino, 4-methoxypiperidine, thiomorpholine, 4,4-dittospyderdisallow, 3,3-dittospyderdisallow, 4-ftorpirimidinov, 2-dimethylaminomethylphenol, 3-dimethylaminopyridinium, 3-methyl-4-Oxymetazoline-1-ilen group, 3-methoxypyridine, 2-acetylglucosaminidase-1-ilen is the group of 2-carbamoylaspartate-1-ilen group.

7. Drug, possess antidromically activity containing a compound according to any one of claims 1 to 6, or its pharmaceutically acceptable salt.

8. Preventive and/or therapeutic agent for ischemic diseases, where the agent contains a compound according to any one of claims 1 to 6, or its pharmaceutically acceptable salt.

9. Pharmaceutical composition having activity of inhibiting platelet aggregation comprising as active ingredient a compound according to any one of claims 1 to 6, or its pharmaceutically acceptable salt in an effective amount and a pharmaceutically acceptable carrier.

10. The use of compounds according to any one of claims 1 to 6, or its pharmaceutically acceptable salt for the manufacture of drugs having antidromically activity.

11. The use of claim 10, where the drug is used to treat ischemic diseases.

12. A method of treating ischemic disease, comprising introducing an effective amount of a compound according to any one of claims 1 to 6, or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to the novel compounds with the common formula III: where, if X is selected from the group containing NH and S, R1, R2, R3, R4, R5, R6, R7, R8 and R9, each independently is selected from the group containing H, OH, OR', substituted or unsubstituted aryl, where substitutes independently correspond to H, OH, C1-C12alkoxy; where, if X means O, R1, R2, R3, R4, R5, R6, R7 and R8, each independently, selected from the group containing H, OH, OR', SH, SR', SOR', SO2R', OSO2R', NHR', N(R') CO2R', OC(=O)R'; and R9 independently selected from the group containing H, OR', unsubstituted or substituted with aminogroup or halogen C2-C12 alkenyl, unsubstituted C2- C12 alkenyl, unsubstituted thienyl and halogen; where each of the R' groups are independently selected from the group containing H, substituted or unsubstituted C1-C18 alkyl, substituted or unsubstituted aryl; where substitutes are independently selected from the group containing halogen, OH, CN, C1-C12 alkoxy, phenyl; and the dotted line represents the simple or double bind; or its pharmaceutically compatible salt or complex ether. Other novel lamellarin analogs are described.

EFFECT: compounds have antitumor activity.

24 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new pyranoindazoles of the formula (1): wherein R1 and R2 are chosen independently from hydrogen atom or alkyl group; R3 and R4 represent independently hydrogen atom or alkyl group; R5, R6 and R7 mean hydrogen atom; R8 and R9 mean hydrogen atom, hydroxyl, alkoxy-group, -NR10R11, -OC(=O)NR1R2, -OC(=O)-(C1-C4)-alkyl or alkylthiol; R10 and R11 mean hydrogen atom; A means -(CH2)n, C=O; B means a simple or double bond; n = 0-2; Y means nitrogen atom (N); X means carbon atom C; dotted line means the corresponding simple or double bond. Also, invention relates to a pharmaceutical composition based on compounds of the formula (1), to a method for regulating normal or enhanced intraocular pressure, method for treatment of glaucoma and method for blocking or binding serotonine receptors. Invention provides preparing new pyranoindazoles possessing the valuable pharmaceutical effect.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 4 tbl, 22 ex

FIELD: organic chemistry, pharmacy, biochemistry.

SUBSTANCE: invention relates to new substituted 2H-pyrano[2,3-c] of the general formula (1) eliciting ability to inhibit activity of protein kinase. In the general formula (1) X represents oxygen atom or group NR3; R1 represents group -C(O)R4, optionally substituted and optionally condensed azaheterocycle; R2 represents optionally substituted hydroxyl group or optionally substituted amino-group; R3 represents hydrogen atom or inert substitute meaning optionally substituted low- or non-reactive radical including such as (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C1-C7)-alkoxy-group, (C7-C12)-aralkyl, heterocyclylalkyl, (C7-C12)-alkaryl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkenyl, phenyl, aryl, (C2-C12)-alkoxyalkyl, (C2-C10)-alkylsulfinyl, (C2-C10)-alkylsulfonyl, -(CH2)-O-(C1-C7-alkyl), -(CH2)m-N(C1-C7-alkyl)n, aryloxyalkyl, heterocyclyl wherein m and n have value from 1 to 7; R4 represents optionally substituted amino-group or hydrogenated optionally substituted azaheterocycle. Also, invention relates to combinatory and focused libraries consisting of compounds of the present invention and designated for the search of compound-hits and compound-leaders prepared by screening of these libraries for using in preparing medicinal agents.

EFFECT: valuable medicinal properties of compounds.

8 cl, 2 tbl, 6 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention proposes applying derivatives of benzopyranoimidazole and benzothiopyranoimidazole as inhibitors of activity of phosphodiesterase VII, new derivatives of benzopyranoimidazole of the general formula (I)

with radical values given in the invention claim that elicit the above said activity and a pharmaceutical preparation based on thereof. Claimed derivatives elicit specific inhibition of rolipram-insensitive cAMP-phosphodiesterase (phosphodiesterase VII) in combination with good tolerance that allows their applying in asthma treatment. Indicated compounds show activity with respect to inhibition of tumor necrosis factor (TNF) producing that allows their applying for treatment of some autoimmune diseases.

EFFECT: valuable medicinal and biochemical properties of compounds.

3 cl, 2 tbl, 9 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

The invention relates to a new 1.8-fused derivative of 2-Hinayana formula (I), where A, X, R1, R2, R3, R4, R5, R6such as defined in the claims

The invention relates to derivatives of 1-arylsulfonyl, arylcarbamoyl or aristoteleion General formula I where L is selected from the group consisting of Co, CS and SO2; R1and R2independently selected from the group consisting of hydrogen, halogen, alkyl (C1-C6), haloalkyl (C1-C6), provided that when L - SO2, R1and R2at the same time do not represent hydrogen; R3independently represents 1 to 3 groups consisting of hydrogen, halogen, alkyl (C1-C6), haloalkyl (C1-C6); X is chosen from (CH2)nor Y(CH2)n-1where Y Is O or S, and n = 1, 2, 3

The invention relates to new coumadinhydrochloride acids, in which the system of pyridone condensed in the 3,4-, 6,7 - and 7,8-positions coumarin system, the General formula I

< / BR>
where R1R2= NHCH=C(CO2R6)CO., R3= NO2or NH2, R4= R5= H, R6= H or C2H5; R1R2= NHCH=C(CO2R6)CO., R3= R4= H, R5= F, R6= H or C2H5; R1R2= CO(CO2R6) = СНNH, R3= R4= R5= H, R6= H or C2H5; R1R2= R3R4= NHCH= C(CO2R6)CO., R5= H, R6= H or C2H5; R1= H or HE, R2= R5= N, R3R4= -NHCH=C(CO2R6)CO., R6= H or C2H5; R1= HE, R2= R3= N, R4R5= -CO(CO2R6) = СНNH, R6= H or C2H5; R1= R5= N, R2- CH3or CF3, R3R4= CO(CO2R6)C = CHNH, R6= H or C2H5and their pharmaceutically acceptable salts

FIELD: chemistry.

SUBSTANCE: invention relates to the new pyridine and new pyrimidine derivative, their pharmaceutically accepted salt or hydrate of the general formula (I): . The invention also relates to the pharmaceutical composition, which possesses the inhibiting activity with respect to the receptor of the growth factor of hepatocytes; to the inhibitor of the receptor of the growth factor of hepatocytes, the inhibitor of angiogenesis, the antitumor drug, the inhibitor of cancerous metastatic spreading, that contains the pharmacologically effective dose of the said compounds, its pharmaceutically acceptable salt or hydrate.

EFFECT: inhibitory activity.

27 cl, 45 tbl, 540 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new derivatives of imide indolylmaleic acid with the formula I , where Ra denotes H; C1-4alkyl or C1-4alkyl, with substituted OH, NH2, NH(C1-4 alkyl) or H(C1-4alkyl)2; Rb denotes H or C1-4alkyl; R denotes a radical of the formula (d) or (e) , where each one from R8 and R11 independently denotes OH; heterocyclic residue; NR16R17, where each from R16 and R17 independently denotes H or C1-4alkyl, or R16 and R17 together with a nitrogen atom; to which they are joined, form a heterocyclic residue; or a radical of the formula -X-RC-Y (α) where X denotes a covalent bond, O, S or NR18, where R18 denotes H or C1-4alkyl; Rc denotes C1-4alkylen or C1-4alkylen, in which one CH2 has been changed with the group CRxRy, whereby one of Rx and Ry denotes H, and the other denotes CH3, each of the Rx and Ry denote CH3 or Rx and Ry together form the group -CH2-CH2-, and Y is joined with the terminal carbon atom and is selected from OH, -NR19R20, where each one of R19 and R20 independently denotes C1-4alkyl; each one of R9, R10, R12, R13 independently denotes H, halogen, C1-4alkyl, OH, NH2, C1-4alkoxy, NH(C1-4alkyl) or N(C1-4alkyl)2 or each E denotes -N= and G denotes -CH= or E denotes -CH= and G denotes -N=, and cycle A is unsubstituted, monosubstituted, where the substitute is selected from a group containing halogen, OH, C1-4alkoxy, C1-4alkyl, NO2, NH2, NH(C1-4alkyl) or N(C1-4alkyl)2 or CN; where the heterocyclic residue is 3-8 member saturated, heterocyclic rings, containing 1-2-heteroatoms, of which one is N, and the other N or O, possibly substituted with one or more carbon atoms in the cycle and/or with a nitrogen atom in the cycle, if it is in the ring; where the substitutes of the carbon atom ring, if they exist, are selected from the group which contains C1-4alkyl, C3-C6cycloalkyl, it is optional to further substitute C1-4alkyl; , where p denotes 1, 2 or 3; and where the substitutes on the nitrogen atom ring if they exist, are selected from a group which contains C1-4alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl C1-4alkyl, phenyl, phenylC1-4alkyl, heterocyclic residue and the residue from the formula β: -R21-Y' (β) R21 - denotes C1-C4alkylen, a Y' denotes OH, NH2, NH(C1-4alkyl) or N(C1-4alkyl)2, where the heterocyclic residue is of importance, as stated above, or its pharmaceutically acceptable salts.

EFFECT: bonds possess an action, which has an inhibitory activity on proteinkinase C and can be used in a pharmaceutical composition for treatment or prophylaxis of acute or chronic rejection of allo or xenotransilants of organs or tissues.

10 cl, 7 tbl, 182 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of quinazoline of the general formula (I): and their pharmaceutically acceptable salts and in vivo hydrolyzed esters as aurorakinase inhibitors and their using, to a method for inhibition and pharmaceutical composition based on thereof, and to a method for their synthesis. In compound of the general formula (I) X represents -NR6 wherein R6 represents hydrogen atom or (C1-C6)-alkyl; R5 represents group of the formula (a): or (b): wherein * means a point for adding to group X in compound of the formula (I); R1, R2, R3 and R4 are chosen independently from hydrogen atom or -X1R9 wherein X1 represents -O-, and R9 is chosen from one of the following groups: (1) hydrogen atom or (C1-C5)-alkyl; (3) (C1-C5)-alkyl-X3R20 wherein X3 represents -O- or -NR25 wherein R25 represents hydrogen atom, (C1-C3)-alkyl or (C1-C3)-alkoxy-(C2-C3)-alkyl, and R20 represents hydrogen atom, (C1-C3)-alkyl, cyclopentyl, cyclohexyl or 5- or 6-membered saturated heterocyclic group with 1 or 2 heteroatoms that are chosen independently from nitrogen atom (N) wherein (C1-C3)-alkyl group can carry 1 or 2 substitutes that are chosen from oxo, hydroxy group, halogen atom and (C1-C4)-alkoxy group, and wherein cyclic group can carry 1 or 2 substitutes that are chosen from (C1-C4)-alkyl; (4) (C1-C5)-alkyl-X4-(C1-C5)-alkyl-X5R26 wherein X4 and X5 can be similar or different, and each means -O- or -NR31- wherein R31 represents hydrogen atom, (C1-C3)-alkyl or (C1-C3)-alkoxy-(C2-C3)-alkyl, and R26 represents hydrogen atom or (C1-C3)-alkyl; (5) R32 wherein R32 represents 5- or 6-membered saturated heterocyclic group added through carbon atom or nitrogen atom with 1 or 2 heteroatoms that are chosen independently from oxygen (O), sulfur (S) and N atoms wherein heterocyclic group can carry 1 or 2 substitutes that are chosen from hydroxy, (C1-C4)-alkyl, (C1-C4)-hydroxyalkyl, (C1-C4)-alkoxy, (C1-C4)-alkoxy-(C1-C4)-alkyl; (6) (C1-C5)-alkyl-R32 wherein R32 is given above; (18) (C1-C5)-alkyl optionally substituted with 1, 2 or 3 halogen atoms; (19) (C1-C5)-alkyl-X10-(C1-C5)-alkyl-X11R90 wherein X10 and X11 that can be similar or different each means -O- or -NR95- wherein R95 represents (C1-C5)-alkyl, (C1-C3)-alkyl substituted with 1, 2 or 3 halogen atoms, (C1-C4)-alkyl or (C1-C4)-alkoxy groups, (and wherein 2 (C1-C4)-alkoxy groups by (C1-C4)-alkyl groups alkoxy can form in common 5- or 6-membered saturated heterocyclic group that comprises 2 oxygen atoms), (C2-C5)-alkenyl, (C2-C5)-alkynyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C3)-alkyl or (C1-C3)-alkoxy-(C2-C3)-alkyl; R90 represents hydrogen atom or (C1-C3)-alkyl; (22) (C1-C5)-alkyl-R96 wherein R96 represents 5- or 6-membered heterocyclic group that can be saturated or unsaturated (added through carbon or nitrogen atom) with 1 or 2 heteroatoms that are chosen independently from N wherein heterocyclic group can carry 1 or 2 substitutes that are chosen from (C1-C4)-hydroxyalkyl, (C1-C4)-alkyl, hydroxy and (C1-C4)-alkoxy-(C1-C4)-alkyl, and wherein R60 represents hydrogen atom; R61 represents group of the subformula (k): wherein p represents 0 or 1; q represents 1; R'1 and R''1 represent independently hydrogen atom or (C1-C10)-alkyl; T represents C=O; V represents -N(R63)R64 wherein R63 represents -(CH2)q'R70 or phenyl optionally substituted with 1 or 2 groups chosen independently from halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy, trifluoromethyl, trifluoromethoxy, nitro, difluoromethyl, difluoromethoxy and cyano group; R64 represents hydrogen atom or (C1-C3)-alkyl; q' = 0; R70 represents -K-J wherein K represents a bond, and J represents phenyl optionally substituted with 1, 2 or 3 groups that are chosen from halogen atom, (C1-C3)-alkyl, cyano, (C1-C3)-alkoxy, and R62 represents hydrogen atom. Proposed compounds can be used in treatment and prophylaxis of diseases mediated by aurorakinase activity, for example, proliferative diseases, such as cancer.

EFFECT: valuable medicinal properties of compounds.

32 cl, 7 tbl, 2 sch, 147 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and/or stereomer form of compound of the formula (I), and/or physiologically compatible salt of compound of the formula (I) wherein X and M are similar or different and mean independently of one another nitrogen atom (N) or -CH; R1 and R11 are similar or different and mean independently of one another: (1.) hydrogen atom; (2.) fluorine (F), chlorine (Cl), iodine (J) or bromine (Br) atom; R2 means: (1.) heteroaryl residue of group comprising 1,3,4-oxadiazole, oxadiazolylidinedione, oxadiazolone, thiazole, and heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another: (1.1.) keto-group; (2) -C(O)-R5 wherein R5 means hydrogen atom or -(C1-C4)-alkyl, or (3.) -C(O)-N(R7)-R8 wherein R7 and R8 mean independently of one another hydrogen atom, -(C1-C4)-alkyl-OH, -O-(C1-C4)-alkyl or -(C1-C4)-alkyl; R3 means hydrogen atom or -(C1-C4)-alkyl; R4 means: (1.) heteroaryl residue of group comprising thiazole, isothiazole, pyridine, pyrazine, pyrimidine wherein heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another with -(C1-C5)-alkyl, halogen atom, trifluoromethyl, or (2.) aryl residue of group comprising phenyl. Also, invention relates to a method for preparing a medicinal agent and to using compounds based on the formula (I) possessing activity with respect to IkB kinase. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical agent.

6 cl, 67 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of indoline of the formula (I): wherein (i) R1 means hydrogen atom (H), (C1-C4)-alkyl; R2 means -A1-NR5R6 wherein each substitute R5 and R6 means independently H, (C1-C4)-alkyl; A1 means -(CH2)m, -(CH2)n-A2-(CH2)p or -(CH2CH2O)qCH2CH2 wherein m means a whole number from 2 to 10; each n and p means a whole number from 1 to 6; A2 means -CH=CH, phenylene, biphenylene, cyclohexylene or piperazinylene; q = 1, 2 or 3; (ii) R1 and R2 represent in common -A3-NR7-A4 wherein each A3 and A4 means independently -(CH2)r or -(CH2CH2O)sCH2CH2 wherein r means a whole number from 2 to 6; s = 1, 2 or 3; R7 means H, (C1-C4)-alkyl; (iii) R1 and R2 in common with nitrogen atom to which they are bound form piperidinyl that comprises a substitute of the formula: -A5-R8 at 4 position wherein A5 represents (C1-C4)-alkylene, and R8 represents piperidin-4-yl; or (iv) R1 and R2 in common with nitrogen atom to which they are bound form piperidinyl, and each R3 and R4 means independently H, or its pharmaceutically acceptable salt. Proposed compounds inhibit tyrosine kinase receptors that allow their using as components of pharmaceutical compositions for treatment. Also, invention describes methods for synthesis of compounds of the formula (I).

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical compositions.

15 cl, 1 tbl, 24 ex

FIELD: organic chemistry, medicine, oncology, pharmacy, biochemistry.

SUBSTANCE: invention relates to amide derivative represented by the following formula [1]:

in any of the following cases (A) or (B), or its salt. In the case (A) R1 represents 5-7-membered saturated cyclic group comprising 1-2 nitrogen atoms as atom forming cycle (saturated cyclic amino-group can be substituted with 1-3 similar or different substitutes chosen from group consisting of (C1-C10)-alkyl, (C1-C10)-alkoxycarbonyl), mono-(C1-C10)-alkylamino- or di-(C1-C10)-alkylamino-group; R2 represents (C1-C10)-alkyl, halogen atom, halogen-(C1-C10)-alkyl, (C1-C10)-alkoxy-group, (C1-C10)-alkoxycarbonyl, nitro-group, mono-(C1-C10)-alkylcarbamoyl, di-(C1-C10)-alkylcarbamoyl or cyano-group; R3 represents hydrogen atom, halogen atom or (C1-C10)-alkoxy-group; Het1 represents any of the following formulae: [2] , [3] , [4] , [5] , [6] , [7] and [8] ; Het2 represents pyridyl, pyrimidinyl, pyrazinyl or 1,2-dihydropyridazinyl (wherein Het2 can be substituted with 1-3 similar or different substitutes chosen from halogen atom) but except for compound wherein R1 means (i) pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl and each of them can be substituted with 1-3 similar or different substitutes chosen from group consisting of alkyl, alkoxycarbonyl, halogen atom, halogenalkyl, hydroxyalkyl, amino-, monoalkylamino-, dialkylamino-group, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl; (ii) monoalkylamino-group, or (iii) dialkylamino-group; Het1 means group of the formula [6], and Het2 means pyrazinyl or pyridyl and each of them can mean a substituted alkyl. In case the (B) R1 represents 4-methylpiperazin-1-yl, 1-pyrrolidinyl, piperidino-group, 4-ethylpiperazin-1-yl, 4-n-propylpiperazin-1-yl, cis-3,5-dimethylpiperazin-1-yl, morpholino-, dimethylamino- or diethylamino-group; R2 represents methyl, halogen atom, trifluoromethyl, methoxy-group, methoxycarbonyl, nitro-group, dimethylcarbamoyl or cyano-group; R3 represents hydrogen atom, bromine atom or methoxy-group; Het1 represents compound of the formula [6]; Het2 represents 3-pyridyl. Invention relates to a pharmaceutical composition possessing inhibitory activity with respect to BCR-ABL tyrosine kinase comprising amide derivative of the formula (I) or its salt as active component and a pharmaceutically acceptable nontoxic and inert carrier. Also, invention relates to BCR-ABL tyrosine kinase inhibitor, therapeutic agents comprising amide derivative of the formula (I) or its salt and, optionally, a pharmaceutically acceptable nontoxic and inert carrier used in treatment of chronic myelogenous leukemia, acute lymphoblast cell leukemia, acute myelogenous leukemia. Invention provides and proposes amide derivative inhibiting activity of BCR-ABL tyrosine kinase.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 2 tbl, 83 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel nitrogen-containing aromatic derivatives of the general formula (I): wherein X1 means nitrogen atom (N) or group -CR10= wherein R10 means hydrogen atom (H), halogen atom or -CN; X2 means N or group -CR11= but X1 and X2 can't mean N simultaneously; Y means oxygen atom (O) or group -NRY- wherein RY means hydrogen atom or (C1-C6)-alkyl group; R1 means phenoxy-group, group -NR12aR12b, group , group and other values; each radical among R3, R4, R5, R6 and R11 means hydrogen atom; R7 means hydrogen atom or (C1-C6)-alkyl group; R8 means hydrogen atom or (C1-C6)-alkyl group; R10 means hydrogen atom, halogen atom or cyano-group; R9 means group -NR16aR16b or group of the formula: wherein T2 means pyrrolidine, piperazine ring possibly substituted with (C1-C6)-alkyl group, or morpholine ring; R12a and R12b mean independently hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; R2 means hydrogen atom or (C1-C6)-alkyl; R16a means hydrogen atom or (C1-C6)-alkyl, and R16b means (C1-C6)-alkyl possibly substituted with phenyl, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group or di-(C1-C6)-alkylamino-group, (C3-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl possibly substituted with halogen atom, thiazolyl or piperidinyl possibly substituted with (C1-C6)-alkyl, and their salts or hydrates. Also, invention describes a pharmaceutical composition, method for treatment or prophylaxis of tumor diseases and using the novel compounds for preparing an agent useful in treatment abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method for treatment.

26 cl, 17 tbl, 221 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new compounds of general formula I , wherein one from V or X is N and another is CRa or both V and X are CRa (each CRa is independently hydrogen atom); Y is O, S; Z is N(R2)(R3); R1 is hydrogen, C1-C10-alkyl, C3-C7-cycloalkyl, etc.; R4 is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl, etc.; A is hydrogen, C1-C10-alkyl, halo-C1-C6-alkyl, etc.; B is optionally substituted 5-membered aromatic ring containing at least one nitrogen atom and 0-3 additional heteroatoms; U is -NR5; meanings of the rest substituents are as defined in specification, and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical composition and intermediates of formula I.

EFFECT: new biologically active compounds and pharmaceutical compositions based on the same having inhibition activity in relates to IKK-β enzyme.

26 cl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to azaindoleoxoacetic derivatives of piperazine of the general formula (I): wherein Q is chosen from the group consisting of the following compounds: ; -W- represents compound of the formula: . Proposed compounds possess antiviral activity both in separate using and in combination with other antiviral, anti-infectious agents, immunomodulating agents or inhibitors HIV entering. Also, invention describes a pharmaceutical composition based on compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

55 cl, 10 tbl, 169 ex

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (1): and their salts wherein values R1, k, Ar, n, j, Y, R and R2 are determined in the invention claim. Novel compounds are able to modulate activity of chemokine receptors. Also, invention relates to using indicated compounds for treatment of human immunodeficiency virus or feline immunodeficiency virus and to a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 100 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new derivatives of imide indolylmaleic acid with the formula I , where Ra denotes H; C1-4alkyl or C1-4alkyl, with substituted OH, NH2, NH(C1-4 alkyl) or H(C1-4alkyl)2; Rb denotes H or C1-4alkyl; R denotes a radical of the formula (d) or (e) , where each one from R8 and R11 independently denotes OH; heterocyclic residue; NR16R17, where each from R16 and R17 independently denotes H or C1-4alkyl, or R16 and R17 together with a nitrogen atom; to which they are joined, form a heterocyclic residue; or a radical of the formula -X-RC-Y (α) where X denotes a covalent bond, O, S or NR18, where R18 denotes H or C1-4alkyl; Rc denotes C1-4alkylen or C1-4alkylen, in which one CH2 has been changed with the group CRxRy, whereby one of Rx and Ry denotes H, and the other denotes CH3, each of the Rx and Ry denote CH3 or Rx and Ry together form the group -CH2-CH2-, and Y is joined with the terminal carbon atom and is selected from OH, -NR19R20, where each one of R19 and R20 independently denotes C1-4alkyl; each one of R9, R10, R12, R13 independently denotes H, halogen, C1-4alkyl, OH, NH2, C1-4alkoxy, NH(C1-4alkyl) or N(C1-4alkyl)2 or each E denotes -N= and G denotes -CH= or E denotes -CH= and G denotes -N=, and cycle A is unsubstituted, monosubstituted, where the substitute is selected from a group containing halogen, OH, C1-4alkoxy, C1-4alkyl, NO2, NH2, NH(C1-4alkyl) or N(C1-4alkyl)2 or CN; where the heterocyclic residue is 3-8 member saturated, heterocyclic rings, containing 1-2-heteroatoms, of which one is N, and the other N or O, possibly substituted with one or more carbon atoms in the cycle and/or with a nitrogen atom in the cycle, if it is in the ring; where the substitutes of the carbon atom ring, if they exist, are selected from the group which contains C1-4alkyl, C3-C6cycloalkyl, it is optional to further substitute C1-4alkyl; , where p denotes 1, 2 or 3; and where the substitutes on the nitrogen atom ring if they exist, are selected from a group which contains C1-4alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl C1-4alkyl, phenyl, phenylC1-4alkyl, heterocyclic residue and the residue from the formula β: -R21-Y' (β) R21 - denotes C1-C4alkylen, a Y' denotes OH, NH2, NH(C1-4alkyl) or N(C1-4alkyl)2, where the heterocyclic residue is of importance, as stated above, or its pharmaceutically acceptable salts.

EFFECT: bonds possess an action, which has an inhibitory activity on proteinkinase C and can be used in a pharmaceutical composition for treatment or prophylaxis of acute or chronic rejection of allo or xenotransilants of organs or tissues.

10 cl, 7 tbl, 182 ex

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