Derivative of n-acylanthranilic acid or its salt


FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a novel derivative of N-acylanthranilic acid, represented by the following general formula 1, or to its pharmaceutically acceptable salt, in which R1, R2, R3, X1, X2, X3, X4 and A are determined in the invention formula.

EFFECT: invention relates to an inhibitor of collagen production, a medication for treating diseases, associated with the excessive production of collagen, containing N-acylanthranilic acid derivative Formula 1.

 

The technical field to which the invention relates

The present invention relates to a derived N-acylanthranilic acid or salts thereof having inhibitory effect on collagen production.

The level of technology

Fibrogenic, which is produced extracellular matrix, including collagen as a typical example, is a mechanism of wound healing. However, if the damage is long, the process deviates from the normal, and there is increased deposition of excess extracellular matrix that leads to fibrosis. Fibrosis is observed in various organs, but the origins of producing extracellular matrix cells are the same. It is believed that such sources are endogenous fibroblasts, epithelial cells have undergone a transition from epithelial to mesenchyme, and fibroblasts (non-Patent Document 1). Fibrosis is a disease in which a functional disturbance occurs as a result of damage to the tissue due to the cause of the disease and the subsequent formation of fibers, leading to organ failure. This disease is characterized by poor prognosis.

To the present time for the treatment of fibrosis attempted suppression in sporitelny reaction, but significant effects from such treatment could not be obtained. Studies have been conducted with the aim of developing antifibrosis funds targeted effect on the regulatory factors of fibrosis, such as TGF (transforming growth factor)-β1, VEGF (factor vascular endothelial growth), PDGF (platelet growth factor) and angiotensin II (non-Patent Document 2).

Pirfenidone was used as the sole antifibrosis means for idiopathic pulmonary fibrosis. The effectiveness of pirfenidone detected in clinical trials, represented only a suppression of reducing lung capacity. In addition, pirfenidone had side effects such as photosensitivity in 87,9% of patients (non-Patent Document 3). Consequently, the use of pirfenidone is not an adequate method of therapy in terms of efficacy and safety.

A major component of the extracellular matrix, which is excessively delayed when fibrosis is collagen. Among others, the most common collagen is collagen type I. Accordingly, a substance inhibiting the production of collagen, applicable to the prevention or treatment of diseases accompanied by fibrotic lesions.

To date, data were presented that the derivative of Anthranilic acid has Inga is youdim effect on the production of matrix metalloproteinase-13 (Patent Document 1). However, it was not known that the derivative of Anthranilic acid has an inhibitory effect on collagen production.

A list of the sources cited

Patent Documents

Patent Document 1: international publication WO2006/062093, brochure

Non-patent Documents

Non-patent Document 1: Experimental Biology and Medicine, Vol. 233, pp. 109-122, 2008

Non-patent Document 2: Journal of Pathology, Vol. 214, pp. 199-210, 2008

Non-patent Document 3: Pirespa 200mg, an insert in the packaging, Vol. 1, Shionogi & Co., Ltd., prepared in October 2008

A brief description of the invention

The technical problem

There was the intention to develop a tool that has inhibitory effect on collagen production and used for the prevention, treatment and the like, and diseases associated with excessive production of collagen.

The solution

In connection with the above-mentioned circumstances, the authors of the present invention conducted a thorough investigation. In the result, the inventors found that the derived N-acylanthranilic acid represented by the following General formula [1] or its salt:

in which

R1represents an optionally protected carboxyl group or optionally protected 1H-tetrazol-5-ilen group;

R2the present is the focus of a hydrogen atom, halogen atom, a cyano, a nitro-group, optionally protected hydroxyl group, optionally protected amino, optionally protected or substituted alkylamino, optionally substituted by dialkylamino, optionally substituted alkyl group or optionally substituted alkoxygroup;

R3represents an optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted aryl group or optionally substituted heterocyclic group;

X1represents a carbonyl group;

X2represents an optionally substituted alkylenes group, optionally substituted alkynylamino group, optionally substituted alkynylamino group or Association;

X3represents an oxygen atom, a sulfur atom or a bond;

X4represents a group represented by the General formula-X5-X6or X6-X5- (assuming that the link on the left side of each General formula associated with R3), in which

X5represents an oxygen atom, a sulfur atom, optionally protected aminogroup, sulfonyloxy group, sulfonyloxy group or Association; and

X6represents an optionally substituted alkylenes group, long is correctly substituted alkynylamino group, optionally substituted alkynylamino group or Association; and

But is an optionally substituted phenyl group, optionally substituted cycloalkyl group or optionally substituted heterocyclic group,

has an inhibitory effect on the production of collagen and applicable to the prevention, treatment and the like, and diseases associated with excessive production of collagen.

Moreover, the authors present invention also found that the new derived N-acylanthranilic acid represented by the following General formula [1]or its salt:

[Formula 2]

in which

R1represents an optionally protected carboxyl group or optionally protected 1H-tetrazol-5-ilen group;

R2represents a hydrogen atom, a halogen atom, a cyano, a nitro-group, optionally protected hydroxyl group, optionally protected amino, optionally protected or substituted alkylamino, optionally substituted by dialkylamino, optionally substituted alkyl group or optionally substituted alkoxygroup;

R3represents an optionally substituted aryl group or optionally substituted heterocyclic group;

X1before the hat is a carbonyl group;

X2represents a bond;

X3represents a bond;

X4represents an oxygen atom, optionally protected aminogroup, optionally substituted alkylenes group or Association; and

A represents a group represented by the following General formula:

[Formula 3]

in which

R4represents a hydrogen atom or a protective group of a phenolic hydroxyl;

one of R5, R6, R7and R8represents a group represented by the General formula-Y-R9,

in which

R9represents a halogen atom, a cyano, a nitro-group, optionally protected hydroxyl group, optionally protected amino, optionally protected or substituted alkylamino, optionally substituted by dialkylamino, optionally substituted alkyl group, optionally substituted by alkoxygroup, optionally substituted aryl group, optionally substituted by alloctype, optionally substituted heterocyclic group, optionally substituted heterocyclic oxygraph, optionally substituted acyl group or optionally substituted alloctype;

Y represents an optionally substituted alkylenes group, neobyazatelnostyu alkynylamino group, optionally substituted alkynylamino group communication, the group represented by the General formula -(CH2)m-O-(CH2)n-,

in which m is an integer from 0 to 4; and n is an integer from 1 to 4, or the General formula -(CH2)m-NR10-(CH2)n-,

in which R10represents a hydrogen atom, optionally substituted lower alkyl group or aminosidine group; and m and n have the same aforesaid meanings, and

each of the remaining, which is the same or different, represents a hydrogen atom, halogen atom, optionally protected hydroxyl group, optionally protected amino, optionally protected or substituted alkylamino or optional substituted dialkylamino; or

each of R5and R8that is the same or different, represents a hydrogen atom, halogen atom, optionally protected hydroxyl group, optionally protected amino group, and

each R6and R7together with the carbon atoms to which they are linked, represent an optionally substituted 5-7-membered heterocyclic group, or

the group represented by the following General formula:

[Formula 4]

in which

one of the Z1, Z2/sup> , Z3, Z4and Z5represents a nitrogen atom,

one of the remaining four is a group represented by the General formula (C-R11,

in which R11represents an optionally substituted aryl group, optionally substituted nitrogen-containing 6-membered aromatic heterocyclic group, optionally substituted oxygen-containing 5-membered aromatic heterocyclic group, optionally substituted nitrogen-containing oxygen-containing 5-membered aromatic heterocyclic group or optionally substituted nitrogen-containing sulfur-containing 5-membered aromatic heterocyclic group,

each of the remaining three, which is the same or different, represents a group represented by the General formula (C-R12,

in which R12represents a hydrogen atom or halogen atom,

has an inhibitory effect on the production of collagen and applicable to the prevention, treatment and the like, and diseases associated with excessive production of collagen, and is excellent from the point of view of safety and kinetics, making thereby the present invention.

Useful effects of the invention

Because a derived N-acylanthranilic acid of the present invention or its salt possesses Inga is youdim effect on collagen production and is excellent from the point of view of safety and kinetics, it is applicable to the prevention, treatment and the like, and diseases associated with excessive production of collagen, such as pulmonary fibrosis, scleroderma, nephrosclerosis and cirrhosis of the liver.

Description of embodiments

The compound of the present invention are described in detail below.

In the present description, each term has the following meaning, unless otherwise specified.

The halogen atom means a fluorine atom, chlorine atom, bromine atom or iodine atom.

Alkyl group means an unbranched or branched C1-12alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl and octyl.

The lower alkyl group means an unbranched or branched C1-6alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl and isopentyl.

Alchemilla group means an unbranched or branched C2-12alkenylphenol group, such as vinyl, allyl, propenyl, Isopropenyl, butenyl, Isobutanol, pentanol, hexanol, heptanol and octanol.

Alchemilla group means an unbranched or branched C2-12alkylamino group, such as ethinyl, 2-PROPYNYL and 2-butynyl.

Cycloalkyl group means With3-8cycloalkyl group, such as ecoprofile, cyclobutyl, cyclopentyl and cyclohexyl.

The aryl group means a group such as phenyl or naphthyl.

Kalkilya group means ar-C1-6alkyl group, such as benzyl, diphenylmethyl, trityl, phenethyl and naphthylmethyl.

Allenova group means an unbranched or branched C1-6alkylenes group such as methylene, ethylene, propylene, butylene, hexylen.

Alkenylamine group means an unbranched or branched C2-6alkynylamino group, such as vinile, propylen, 1-butylen and 2-butylen.

Akinlana group means an unbranched or branched C2-6alkynylamino group such as ethynylene, propylen, 1-Butyrin and 2-Butyrin.

Alkoxygroup means an unbranched or branched C1-6alkoxygroup, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentylamine.

Alloctype means a group such as phenoxy or naphthoxy.

Alkoxyalkyl group means C1-6alkoxyl1-6alkyl group, such as methoxymethyl and 1-ethoxyethyl.

Aracelikarsaalyna group means ar-C1-6alkoxyl1-6alkyl group, such as benzoyloxymethyl and penetrometer.

Acyl group means, for example, formyl group, narasu Tulenol or branched C 2-12alkanoyloxy group, such as acetyl, propionyl and isovaleryl, ar-C1-6alkylcarboxylic group, such as benzylcarbamoyl, cyclic hydrocarbon carbonyl group such as benzoyl and naphtol, heterocyclic carbonyl group, such as nicotinoyl, thenoyl, pyrrolidinecarbonyl and furoyl, succinimido group, glutaryl group, Malolo group, palolo group, or an unbranched or branched α-aminoalcohol group containing an optionally protected N-end derived from amino acids (where examples of amino acids include glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine hydroxylysine, phenylalanine, tyrosine, tryptophan, Proline and hydroxyproline).

Acidalkaline group means a group such as acetylenyl, benzoylmethyl, para-nitrobenzoyl, para-bromobenzoyl, para-methoxybenzoyl or 1-benzoylethyl.

Alloctype means an unbranched or branched C2-6alkanoyloxy, such as atomic charges, propionyloxy, or Kolocep, such as benzoyloxy.

Aryloxyalkyl group means a group such as acetoxymethyl, propionyloxy or pivaloyloxymethyl.

Allyloxycarbonyl will krupoznaja unbranched or branched C 1-12allyloxycarbonyl group, such as methoxycarbonyl, etoxycarbonyl, 1,1-dimethylpropanolamine, isopropoxycarbonyl, 2-ethylhexyloxymethyl, tert-butoxycarbonyl and tert-pentyloxybenzoyl.

Aracelikarsaalyna group means ar-C1-6allyloxycarbonyl group, such as benzyloxycarbonyl and ventilatsioonil.

Aryloxyalkyl group means a group such as vinyloxycarbonyl.

Alkylamino means mono(C1-6alkyl)amino group, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamine.

Dialkylamino means di(C1-6alkyl)amino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, (ethyl)(methyl)amino, (methyl)(propyl)amino, (butyl)(methyl)amino and (methyl)(pentyl)amino.

Allylthiourea group means C1-6alkylthio1-6alkyl group, such as methylthiomethyl, ethylthiomethyl and propylthiouracil.

Aristocrata means a group such as phenylthio.

Artioukhina group means a group such as phenylsulfinyl or 2-(para-nitrobenzylidene)ethyl.

Alkylsulfonyl group means C1-6alkylsulfonyl group, such as methylsulphonyl, ethylsulfonyl and propylsulfonyl.

Arylsulfonyl group means the group is akuu as benzazolyl, pair-toluensulfonyl or naphthalenesulfonyl.

Arylsulfonyl group means a group such as para-toluensulfonate.

Alkylsulfonates means C1-6alkylsulfonates, such as methylsulfonate, ethylsulfonyl.

Arylsulfonamides means a group such as benzosulfimide or steam-toluensulfonate.

Alkylsulfonamides means C1-6alkylsulfonamides, such as methylsulfonylamino, ethylsulfonyl.

Substituted silyl group means a group such as trimethylsilyl, triethylsilyl or tributyltin.

Alkylsalicylate group means a group such as 2-(trimethylsilyl)ethyl.

Nitrogen-containing 6-membered aromatic heterocyclic group means pyridinol, personilnya, pyrimidinyl or pyridazinyl group and the like.

Oxygen-containing 5-membered aromatic heterocyclic group means fornillo group and the like.

Nitrogen-containing oxygen-containing 5-membered aromatic heterocyclic group means oxazolidinyl, oxadiazolyl or isoxazolyl group and the like.

Nitrogen-containing sulfur-containing 5-membered aromatic heterocyclic group means thiazolidine, thiadiazolyl or isothiazolinone gr the foam and the like.

Oxygen-containing heterocyclic group means a group such as 2-tetrahydropyranyl or 2-tetrahydrofuranyl.

Sulfur-containing heterocyclic group means a group such as tetrahydropyranyl.

Heterocyclic oxycarbonyl group means a group such as 2-furfurylalcohol or 8-hinolincarbonova.

Nitrogen-containing heterocyclic alkyl group means a group such as phthalimidomethyl or Succinimidyl.

Monocyclic heterocyclic group means monocyclic nitrogen-containing heterocyclic group, which as heteroatom to form a ring contains only the nitrogen atom, such as aestendrela, pyrrolidine, pyrrolidinone, pyrrolidinyl, piperideine, piperazinilnom, homopiperazine, aseanindia, deazapurine, octahydronaphthalene, imidazolidine, pyrazolidine, perederina, tetrahydropyridine, pyridinoline, piratininga, pyrimidinyl, tetrataenia, imidazolidinone, imidazolidinyl, piratininga and pyrazolidinone group; monocyclic oxygen-containing heterocyclic group, which as heteroatom to form a ring contains only the oxygen atom, such as tetrahydrofuranyl, furazilina and Pernilla group; monocyclic serosal Rasul heterocyclic group, which as heteroatom to form a ring contains only sulfur atom, such as thienyl group; monocyclic nitrogen - and oxygen-containing heterocyclic group, which as of heteroatoms to form a ring only contains the nitrogen atom and oxygen atom, such as oxazolidine, oxadiazolidine, isoxazolidine and morpholinyl group; monocyclic nitrogen - and sulfur-containing heterocyclic group, which as of heteroatoms to form a ring only contains the nitrogen atom and sulfur atom, such as thiazolidine, isothiazolinone, thiadiazolidine, thiomorpholine, 1-oxidatively and 1,1-dioxidecontaining group; monocyclic oxygen - and sulfur-containing heterocyclic group that as heteroatoms to form a ring contains only the oxygen atom and sulfur atom, such as tixanidine group; or the like.

Bicyclic heterocyclic group means a bicyclic nitrogen-containing heterocyclic group represented by condensed ring or a crosslinked ring, which as heteroatom to form a ring contains only the nitrogen atom, such as indayla, indolenine, 2-accountonline, isoindoline, indolizinyl, benzimidazolyl, benzotriazolyl, indazolinone, hin lilina, tetrahydropyrimidine, tetrahydroisoquinoline, finalizinga, izochinolina, vladimirka, naphthylidine, khinoksalinona, dihydroisoquinoline, chinadaily, indolenine, hinkleyville and 2,3-dihydrobenzofuranyl group; a bicyclic oxygen-containing heterocyclic group represented by condensed ring or a crosslinked ring, which as heteroatom to form a ring contains only the oxygen atom, such as benzofuranyl, isobenzofuranyl, romanella, romanella, thrombilia, benzo-1,3-dioxolene, benzo-1,4-dioxinlika and 2,3-dihydrobenzofuranyl group; sulfur-containing bicyclic heterocyclic group represented by condensed ring or a crosslinked ring, which as heteroatom for education the ring contains only sulfur atom, such as benzothiazoline and 2,3-dihydrobenzofuranyl group; a bicyclic nitrogen - and oxygen-containing heterocyclic group represented by condensed ring or a crosslinked ring, which forms a ring with 10 or more atoms and which as heteroatoms to form a ring contains a nitrogen atom and oxygen atom, such as benzoporphyrin and benzoporphyrin group; a bicyclic nitrogen - and sulfur-containing heterocyclic g is the SCP, presented with a condensed ring or a crosslinked ring, which as heteroatoms to form a ring contains a nitrogen atom and a sulfur atom, such as benzothiazoline and benzothiadiazole group.

Heterocyclic group means monocyclic heterocyclic group; bicyclic heterocyclic group; or tricyclic heterocyclic group, such as tenteleni, xantener, phenoxathiin, carbazolyl, β-carbolines, phenanthridines, acridines, pyrimidinyl, phenanthrolines, phenazines, phenothiazines and phenoxazines.

5-7-membered heterocyclic group means a group such as imidazolyl, triazolyl, pyrrolyl, furanyl, dioxole, dioxane, thienyl, morpholinyl, morpholinyl or thiazolyl.

The heterocyclic oxygraph means a group such as pyrrolidinyloxy, piperidinyloxy, piperidinyloxy, morpholinoethoxy, thiomorpholine, tetrahydropyranyloxy, tetrahydropyranyloxy, tetrahydropyranyloxy, pyridyloxy or pyrimidinone.

The cyclic amino group may be either saturated or unsaturated cyclic amino group. In addition, it may optionally contain in the ring one or more heteroatoms, such as nitrogen atom, oxygen atom or sulfur atom, and a carbonyl carbon atom. Moreover, it can be monocyclic bicyclic or tricyclic group. More specifically, a cyclic amino group means a saturated or unsaturated monocyclic 3-7-membered cyclic amino group containing one nitrogen atom, such as aziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolin-1-yl, pyrrol-1-yl, dihydropyridines-1-yl, tetrahydropyridine-1-yl, piperidine-1-yl, dehydroacetic-1-yl and peligrosas-1-yl; a saturated or unsaturated monocyclic 3-7-membered cyclic amino group containing two nitrogen atom, such as imidazol-1-yl, imidazolidin-1-yl, imidazolin-1-yl, pyrazolin-1-yl, piperazine-1-yl, 1,4-dihydropyridin-1-yl, 1,2-dihydropyrimidin-1-yl, permitability-1-yl and homopiperazin-1-yl; a saturated or unsaturated monocyclic 3-7-membered cyclic amino group containing three or more nitrogen atoms, such as 1,2,4-triazole-1-yl, 1,2,3-triazole-1-yl, 1,2-dihydro-1,2,4-triazine-1-yl, perhydro-S-triazine-1-yl; a saturated or unsaturated monocyclic 3-7-membered cyclic amino group containing 1 to 4 heteroatoms selected from oxygen atom and sulfur atom, and nitrogen atom, such as oxazolidin-3-yl, isoxazolidine-2-yl, morpholine-4-yl, thiazolidin-3-yl, isothiazolin-2-yl, thiomorpholine-4-yl, sometimesvalid-4-yl and 1,2,4-thiadiazoline-2-yl; a saturated or unsaturated bicyclic or tricyclic cyclic amino group, such as isoindoline-2-yl, indolin-1-yl, 1H-indazol-1-yl,1H-indol-1-yl, 1H-benzimidazole-1-yl, purine-7-yl, tetrahydroquinolin-1-yl and tetrahydroisoquinoline-2-yl; or a spiral or stapled saturated or unsaturated 5-to 12-membered cyclic amino group such as 5-azaspiro[2.4]heptane-5-yl, 2,8-diazabicyclo[4.3.0]nonan-8-yl, 3-azabicyclo[3.1.0]hexane-3-yl, 2-oxa-5,8-diazabicyclo[4.3.0]nonan-8-yl, 2,8-diazaspiro[4.4]nonan-2-yl and 7-azabicyclo[2.2.1]heptane-7-yl.

Aminosidine group includes all groups that can be used as a General aminosidine groups. Examples of such aminosidine groups include groups described in W. Greene et al., Protective Groups in Organic Synthesis, 4thedition, pp. 696-868, 2007, John Wiley & Sons, INC. Specific examples include an acyl group, allyloxycarbonyl group, aracelikarsaalyna group, aryloxyalkyl group, aracelio group, alkoxyalkyl group, kalkylarksmall group, killigrew, alkylsulfonyl group, arylsulfonyl group and a substituted silyl group.

Aminosidine group includes all groups that can be used as a General aminosidine groups. Examples of such aminosidine groups include described in W. Greene et al., Protective Groups in Organic Synthesis, 4thedition, pp. 696-868, 2007, John Wiley & Sons, INC. Specific examples include an acyl group, allyloxycarbonyl group, aracelikarsaalyna group, aryloxyalkyl group, rancilio group, alkoxyalkyl group, killigrew, alkylsulfonyl group, arylsulfonyl group and a substituted silyl group.

Hydroxylamine group includes all groups that can be used as a General hydroxylamine groups. Examples of such hydroxylamine groups include described in W. Greene et al., Protective Groups in Organic Synthesis, 4thedition, pp.16-299, 2007, John Wiley & Sons, INC. Specific examples include an acyl group, allyloxycarbonyl group, aracelikarsaalyna group, heterocyclic oxycarbonyl group, alkyl group, alkenylphenol group, aracelio group, oxygen-containing heterocyclic group, a sulfur-containing heterocyclic group, alkoxyalkyl group, kalkylarksmall group, alkylsulfonyl group, arylsulfonyl group and a substituted silyl group.

Carboxylamide group includes all groups that can be used as a General carboxylamide groups. Examples of such carboxylamide groups include described in W. Greene et al., Protective Groups in Organic Synthesis, 4thedition, pp.533-643, 2007, John Wiley & Sons, INC. Specific examples include alkyl group, aryl group, aracelio group, arylalkyl group, alltoallw group, arylsulfonyl group, oxygen-containing heterocyclic group, alkylsilanes the ilen group, aryloxyalkyl group, nitrogen-containing heterocyclic alkyl group, cycloalkyl group, alkoxyalkyl group, alkyloxyalkyl group, kalkylarksmall group, alkylthiomethyl group, alkenylphenol group and a substituted silyl group.

The protective group of a phenolic hydroxyl includes all groups that can be used as a General protective group of a phenolic hydroxyl. Examples of such protective groups, phenolic hydroxyl include described in W. Greene et al., Protective Groups in Organic Synthesis, 4thedition, pp.370-424, 2007, John Wiley & Sons, INC. Specific examples include an acyl group, alkyl group, alkenylphenol group, aracelio group, oxygen-containing heterocyclic group, a sulfur-containing heterocyclic group, alkoxyalkyl group, alkylsulfonyl group, arylsulfonyl group and a substituted silyl group.

Terazosina group includes all groups that can be used as a General tetrazolate groups. Examples of such tetrazolate groups include described in W. Greene et al., Protective Groups in Organic Synthesis, 4thedition, pp. 872-894, 2007, John Wiley & Sons, INC. Specific examples include an acyl group, allyloxycarbonyl group, aracelikarsaalyna group, aryloxyalkyl group, aracelio group, arylalkyl group, Alcock alkiline group, arylsulfonyl group and a substituted silyl group.

Examples of leaving groups include halogen atom, alkylsulfonate and arylsulfonate.

Examples of aliphatic hydrocarbons include pentane, hexane, cyclohexane.

Examples of halogenated hydrocarbons include methylene chloride, chloroform and dichloroethane.

Examples of the alcohol include methanol, ethanol, propanol, 2-propanol, butanol and 2-methyl-2-propanol.

The simple examples of the ether include diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol, dimethyl ether of diethylene glycol and diethyl ether of diethylene glycol.

Examples of the ketone include acetone, 2-butanone and 4-methyl-2-pentanone.

Examples of ester include methyl acetate, ethyl acetate, propyl and butyl acetate.

Examples of the amide include N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone.

Examples of aromatic hydrocarbons include benzene, toluene and xylene.

Examples of salts of compounds of General formula [1] include: salts of basic groups, such as the well-known amino group; or salts of acid groups, such as hydroxyl group of the phenol or carboxyl group.

Examples of salts of basic groups include: salts with mineral acids such as hydrochloric acid, Hydrobromic and sulphuric acid; the Oli with organic carboxylic acids, such as tartaric acid, formic acid, acetic acid, citric acid, trichloroacetic acid and triperoxonane acid; salts with sulfonic acids such as methanesulfonate acid, benzolsulfonat acid, para-toluensulfonate acid, mesitylenesulfonic acid and naphthalenesulfonate acid.

Examples of salts of the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine and N,N'-dibenziletilendiaminom.

Moreover, among the above-mentioned salts, preferred salts of the compounds represented by the General formula [1]include pharmacologically acceptable salt.

Alkylamino as R2and dialkylamino as R2may be optionally substituted by one or more groups selected from amino groups, hydroxyl groups, carboxyl groups and alkoxygroup.

The alkyl group as R2and alkoxygroup as R2may be optionally substituted by one or more groups selected from a halogen atom, ceanography, hydroxyl group, carboxyl group and alkoxygroup.

Cycloalkyl group as R3, cycloalkenyl group as R3, aryl group as R3, monocyclic heterocyclic group as R3, bicyclic heterocyclic group as R3and heterocyclic group as R3may be optionally substituted by one or more groups selected from a halogen atom, ceanography, nitro, acyl group, alloctype, sulfopropyl, phosphoryl group, alkylsulfonyl group, alkylsulfonamides group, acetamide group, carbamoyl group, carbonyl group, optionally protected carboxyl, amino, alkylamino and hydroxyl groups, and optionally substituted alkyl, alkenylphenol, alkenylphenol, alkoxy, aryl, alkylamino, dialkylamino, cyclic amino, Uralkaliy and heterocyclic groups.

Alkylamino as R5, R6, R7and R8and dialkylamino as R5, R6, R7and R8may be optionally substituted by one or more groups selected from amino groups, hydroxyl groups and alkoxygroup.

5-, 6 - and 7-membered heterocyclic group formed by R6and R7together with the carbon atoms to which they are linked, may be optionally substituted by one or more groups selected from a halogen atom, ceanography, nitro, acyl group, alloctype, sulfopropyl, phosphoryl group, alkylsulfonyl group, alkylsulfonamides, acetamide group, carbamoyl group, carbonyl group, optionally protected carboxyl, amino, alkylamino and hydroxyl groups, and optionally substituted alkyl, alkenylphenol, alkenylphenol, alkoxy, aryl, alkylamino, dialkylamino, cyclic amino, Uralkaliy and heterocyclic groups.

Alkylamino as R9and R9aand dialkylamino as R9and R9amay be optionally substituted by one or more groups selected from hydroxyl group, optionally protected carboxyl, amino, alkylamino groups, and optionally substituted alkyl, alkenylphenol, alkenylphenol, alkoxy, aryl, alkylamino, dialkylamino, cyclic amino, Uralkaliy and heterocyclic groups.

The alkyl group as R9and R9aand alkoxygroup as R9and R9amay be optionally substituted by one or more groups selected from a halogen atom, ceanography, hydroxyl group and alkoxygroup.

Aryl group as R9and R9a, aryloxy PPI as R 9and R9a, heterocyclic group, R9, R9aand R9band heterocyclic actigraphy as R9and R9amay be optionally substituted by one or more groups selected from a halogen atom, ceanography, nitro, acyl group, alloctype, sulfopropyl, phosphoryl group, alkylsulfonyl group, alkylsulfonamides, acetamide group, carbamoyl group, carbonyl group, optionally protected carboxyl, amino, alkylamino and hydroxyl groups, and optionally substituted alkyl, alkenylphenol, alkenylphenol, alkoxy, aryl, alkylamino, dialkylamino, cyclic amino, Uralkaliy and heterocyclic groups.

Acyl group as R9and R9aand alloctype as R9and R9amay be optionally substituted by one or more groups selected from a halogen atom, ceanography, hydroxyl group and alkoxygroup.

The lower alkyl group as R10may be optionally substituted by one or more groups selected from hydroxyl group, optionally protected carboxyl, amino, alkylamino groups, and optionally substituted alkyl, alkenylphenol, alkenylphenol, alkoxy, aryl, alkylamino, dialkylamino, cyclic amino, aranceles the heterocyclic groups.

Aryl group as R11and R11a, nitrogen-containing 6-membered aromatic heterocyclic group as R11and R11a, oxygen-containing 5-membered aromatic heterocyclic group as R11and R11a, oxygen-containing nitrogen-containing 5-membered aromatic heterocyclic group as R11sulfur-containing and nitrogen-containing 5-membered aromatic heterocyclic group as R11may be optionally substituted by one or more groups selected from a halogen atom, ceanography, nitro, acyl group, alloctype, sulfopropyl, phosphoryl group, alkylsulfonyl group, alkylsulfonamides, acetamide group, carbamoyl group, carbonyl group, optionally protected carboxyl, amino, alkylamino and hydroxyl groups, and optionally substituted alkyl, alkenylphenol, alkenylphenol, alkoxy, aryl, alkylamino, dialkylamino, cyclic amino, Uralkaliy and heterocyclic groups.

Alkylene group as X2and X6, alkenylamine group as X2and X6and alkenylamine group as X2and X6may be optionally substituted by one or more groups selected from a halogen atom and optionally substituted alkylen the th, phenyl, cyclic amino, and heterocyclic groups.

Allenova group as X4may be optionally substituted by one or more groups selected from a halogen atom, ceanography, hydroxyl group and alkoxygroup.

Allenova group as Y and Ya, alkenylamine group as Y, and akinlana group as Y may be optionally substituted by one or more groups selected from hydroxyl groups and alkoxygroup.

Phenyl group as Well, cycloalkyl group as Well, and heterocyclic group as And may be optionally substituted by one or more groups selected from a halogen atom, ceanography, nitro group, acetamide group, carbamoyl group, optionally protected carboxyl, amino and hydroxyl groups, and optionally substituted alkyl, alkoxy, phenyl, cyclic amino, and heterocyclic groups.

Examples of the substituent for the above optionally substituted alkyl, alkenylphenol, alkenylphenol, alkoxy, aryl, alkylamino, dialkylamino, cyclic amino, Uralkaliy and heterocyclic groups include a halogen atom, a cyano, a nitro-group, acyl group, alphagroup, phosphoryl group, cyclic amino group, alkylsulfonyl group, the alkyl is sulfonylamino, acetamide group, aracelio group, karbamoilnuyu group, alkyl group, alkenylphenol group, alkylamino group, alkoxygroup, aryl group, heterocyclic group and optionally protected carboxyl, amino and hydroxyl groups.

The connection represented by the General formula [1] according to the present invention, preferably includes the following compounds.

The compound in which R1represents an optionally protected carboxyl group is preferred.

The compound in which R2represents a hydrogen atom or a halogen atom is preferred, and a compound in which R2represents a hydrogen atom is most preferable.

The compound in which R3represents an optionally substituted phenyl group, optionally substituted fornillo group or optionally substituted thienyl group, is preferred, and a compound in which R3represents an optionally substituted phenyl group or optionally substituted fornillo group is most preferred.

The compound in which R3represents an optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, not necessarily samewe the ing phenyl group, optionally substituted monocyclic heterocyclic group, or optionally substituted bicyclic heterocyclic group is preferable; a compound in which R3represents an optionally substituted phenyl group or optionally substituted bicyclic heterocyclic group is more preferable; and a compound in which R3represents an optionally substituted phenyl group is more preferred.

The compound in which R4represents a hydrogen atom, is preferred.

Connection in which one of R5, R6, R7and R8represents a group represented by the General formula-Y-R9a[in which R9arepresents a halogen atom, a nitro-group, optionally protected hydroxyl group, optionally protected amino, optionally protected or substituted alkylamino, optionally substituted by dialkylamino, optionally substituted alkyl group, optionally substituted by alkoxygroup, optionally substituted aryl group, optionally substituted by alloctype, optionally substituted heterocyclic group, optionally substituted heterocyclic oxygraph, optionally substituted is cilou group or optionally substituted alloctype;

Yarepresents an optionally substituted alkylenes group communication, the group represented by the General formula-O-(CH2)n- [in which n is an integer from 1 to 4], or a group represented by the General formula NR10a-(CH2)n- [in which R10arepresents a lower alkyl group; and n has the same meaning as above]], and each of the other remaining represents a hydrogen atom, is preferred. The connection, in which each R5, R6and R8represents a hydrogen atom, and R7represents a group represented by the General formula-Yb-R9b[in which R9brepresents an optionally substituted heterocyclic group; and Ybrepresents alkylenes group, a relationship or a group represented by the General formula-O-(CH2)n- [in which n is an integer from 1 to 4]], is preferable. The connection, in which each R5, R6and R8represents a hydrogen atom, and R7represents a group represented by the General formula-Yc-R9c[in which R9crepresents a heterocyclic group which may be optionally substituted lower alkyl group; and Ycrepresents a methylene group is, bond or a group represented by the General formula-O-(CH2)2-], is even more preferred.

The compound in which X2represents an optionally substituted alkylenes group, optionally substituted alkynylamino group or communications is preferred, and a compound in which X2represents the relationship is more preferred.

The compound in which X3represents the relationship is preferred.

The compound in which X4represents an oxygen atom, optionally protected aminogroup or communication is preferred, and a compound in which X4represents the relationship is more preferred.

The compound in which X4represents an oxygen atom, alkylenes group, alkenylamine group or communications is preferred, and a compound in which X4represents the relationship is more preferred.

The compound in which Z1represents CH, Z2represents a nitrogen atom, Z3represents CH, Z4represents a group represented by the General formula (C-R11a[in which R11arepresents an optionally substituted aryl group, optionally substituted nitrogen-containing 6-membered aromatics the Yu heterocyclic group or optionally substituted oxygen-containing 5-membered aromatic heterocyclic group], and Z5represents CH, is preferred. The compound in which Z1represents CH, Z2represents a nitrogen atom, Z3represents CH, Z4represents a C-C6H5and Z5represents CH, is preferable.

The compound in which a represents an optionally substituted phenyl group or optionally substituted heterocyclic group is preferred, and a compound in which a represents an optionally substituted phenyl group or optionally substituted pyridyloxy group, is preferable.

Examples of diseases associated with excessive production of collagen include pulmonary fibrosis, scleroderma, nephrosclerosis and cirrhosis of the liver. Which one is preferable disease is pulmonary fibrosis.

Preferred examples of the compounds represented by the General formula [1] according to the present invention include the following compounds:

2-(2-hydroxy-5-(pyridin-4-yl)benzamido)-4-phenylbenzene acid,

2-(2-hydroxy-5-(pyridin-3-yl)benzamido)-4-phenylbenzene acid,

2-(2-hydroxy-5-(pyrimidine-2-yl)benzamido)-4-phenylbenzene acid,

2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-4-phenylbenzene acid,

2-(2-hydroxy-5-(1-methylpiperidin-4-yl)Besame is about)-4-phenylbenzene acid,

2-(5-(1-ethylpiperazin-4-yl)-2-hydroxybenzamide)-4-phenylbenzene acid,

2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-4-(3-were)benzoic acid,

2-(2-hydroxy-5-(morpholine-4-yl)benzamido)-4-phenylbenzene acid,

4-(3-forfinal)-2-(2-hydroxy-5-(morpholine-4-yl)benzamido)benzoic acid,

2-(2-hydroxy-5-(morpholine-4-yl)benzamido)-4-(3-methoxyphenyl)benzoic acid,

2-(2-hydroxy-5-(morpholine-4-yl)benzamido)-4-(3-were)benzoic acid,

2-(2-hydroxy-5-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)benzamido)-4-phenylbenzene acid,

2-(2-hydroxy-5-(2-(4-methylpiperazin-1-yl)ethyl)benzamido)-4-phenylbenzene acid,

2-(2-hydroxy-5-((4-methylpiperazin-1-yl)methyl)benzamido)-4-phenylbenzene acid,

2-(5-(2-(4-ethylpiperazin-1-yl)ethoxy)-2-hydroxybenzamide)-4-phenylbenzene acid,

2-(2-hydroxy-5-(2-(1-methylpiperidin-4-yl)ethoxy)benzamido)-4-phenylbenzene acid,

4-(2-(methylamino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid,

4-(2-(ethylamino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid and

4-(furan-2-yl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid.

Typical examples of the compounds of the present invention include compounds shown in Tables 1a, 1b, 1c, 2a and 2b. These compounds are new compounds. These compounds possess inhibitory action n the production of collagen and applicable to the prevention, treatment and the like, and diseases associated with excessive production of collagen.

Table 1a
R6R6
Cl
methyl
methoxy
dimethylamino
phenyl
pyridine-2-yl
pyridine-3-yl
pyridine-4-yl
pyrimidine-2-yl
pyrimidine-5-Il
furan-3-yl
1H-pyrazole-1-Il
1H-imidazol-1-yl
piperidine-1-Il
1 methylpiperidin-4-yl
morpholin-4-yl
(2-(dimethylamino)ethyl)(methyl)amino
2-(morpholine-4-yl)ethoxy
2-(4-methylpiperazin-1-yl)ethoxy

Table 1b
R7R7
Cl
Br
acetyl
methyl
methoxy
ethoxy
propoxy
isopropoxy
dimethylamino
diethylamino
phenyl
phenoxy
piperidine-1-Il
piperidine-2-Il
piperidine-3-Il
1 methylpiperidin-2-yl
1 methylpiperidin-4-yl
2 methylpiperidin-1-Il
3 methylpiperidin-1-Il
4 methylpiperidin-1-Il
1-ethylpiperazin-4-yl
1,4-oxazepan-4-yl
4-methyl-3-occupiers the n-1-Il
4-ethyl-3-oxopiperidin-1-Il
methyl(2-(pyrrolidin-1-yl)ethyl)amino
methyl(2-(piperidine-1-yl)ethyl)amino
methyl(2-(morpholine-4-yl)ethyl)amino
(2-(dimethylamino)ethyl)(methyl)amino
(2-(diethylamino)ethyl)(methyl)amino
(3-(dimethylamino)propyl)(methyl)amino
(2-(dimethylamino)ethyl)(ethyl)amino
(4-methylpiperazin-1-yl)methyl
(4-ethylpiperazin-1-yl)methyl
(4-propylpiperazine-1-yl)methyl
(4-isopropylpiperazine-1-yl)methyl
(piperidine-1-yl)methyl
(piperazine-1-yl)methyl
(morpholine-4-yl)methyl
(4-methylhomopiperazine-1-yl)methyl
(4-aminopiperidin-1-yl)methyl
(4-(methylamino)piperidine-1-yl)methyl
(4-(dimethylamino)piperidine-1-yl)methyl

1-propylpiperidine-4-yl
1-(2-hydroxyethyl)piperidine-4-yl
3-hydroxypiperidine-1-Il
4-(hydroxymethyl)piperidine-1-Il
4-(diethylamino)piperidine-1-Il
azetidin-1-Il
thiomorpholine-4-yl
morpholine-4-yl
4-methylpiperazin-1-Il
4-ethylpiperazin-1-Il
pyridine-2-yl
pyridine-3-yl
pyridine-4-yl
pyrimidine-2-yl
pyrimidine-5-Il
6-aminopyridine-2-yl
furan-2-yl
furan-3-yl
tetrahydrofuran-3-yl
1H-pyrazole-1-Il
1H-imidazol-1-yl
oxazol-5-yl
((2-dimethylamino)ethyl)(methyl)amino)methyl
2-(piperazine-1-yl)ethyl
2-(4-methylpiperazin-1-yl)ethyl
2-(4-ethylpiperazin-1-yl)ethyl
1 methylpiperidin-4-ylox the
2-(dimethylamino)ethoxy
2-(diethylamino)ethoxy
2-(morpholine-4-yl)ethoxy
2-(pyrrolidin-1-yl)ethoxy
2-(piperazine-1-yl)ethoxy
2-(thiomorpholine-4-yl)ethoxy
2-(azetidin-1-yl)ethoxy
2-(4-hydroxypiperidine-1-yl)ethoxy
2-(4-(hydroxymethyl)piperidine-1-yl)ethoxy
2-(4-(2-hydroxyethyl)piperidine-1-yl)ethoxy
2-(4-methylpiperazin-1-yl)ethoxy
2-(4-ethylpiperazin-1-yl)ethoxy
3-(4-methylpiperazin-1-yl)propoxy
2-(4-(2-hydroxyethyl)piperazine-1-yl)ethoxy
2-(4-(3-hydroxypropyl)piperazine-1-yl)ethoxy
(1 methylpiperidin-4-yl)methoxy
2-(1-methylpiperidin-4-yl)ethoxy

Table 1c
R2R3-X4R5R6R7R8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
methoxy
H
H
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
2-methoxyphenyl
2-methoxyphenyl
2-methoxyphenyl
2-methoxyphenyl
2-methoxyphenyl
3-methoxyphenyl
4-methoxyphenyl
2-were
3-were
4-were
2-forfinal
3-torfin the l
4-forfinal
phenyl
phenyl
phenoxy
phenethyl
Cl
methoxy
methyl
H
pyridine-3-yl
pyridine-4-yl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
methoxy
pyridine-2-yl
pyridine-3-yl
pyridine-4-yl
piperidine-1-Il
piperidine-1-Il
piperidine-1-Il
piperidine-1-Il
piperidine-1-Il
piperidine-1-Il
piperidine-1-Il
piperidine-1-Il
piperidine-1-Il
piperidine-1-Il
piperidine-1-Il
piperidine-1-Il
piperidine-1-yl
H
H
H
methoxy
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H

H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
furan-2-yl
furan-2-yl
furan-2-yl
furan-3-yl
thiophene-2-Il
1H-pyrrol-2-yl
2-(methylamino)phenyl
2-(methylamino)phenyl
2-(ethylamino)phenyl
2-forfinal
3-forfinal
4-forfinal
2-were
3-were
4-were
2-methoxyphenyl
3-methoxyphenyl
4-methoxyphenyl
3,4-acid
3,5-acid
furan-2-yl
thiophene-2-Il
thiophene-3-yl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
methoxy
pyridine-3-yl
piperidine-1-Il
pyridine-3-yl
piperidine-1-Il
piperidine-1-Il
methoxy
pyridine-3-yl
pyridine-3-yl
morpholine-4-yl
morpholine-4-yl
morpholine-4-yl
morpholine-4-yl
morpholine-4-yl
morpholine-4-yl
morpholine-4-yl
morpholine-4-yl
morpholine-4-yl
morpholine-4-yl
morpholine-4-yl
morpholine-4-yl
morpholine-4-yl
morpholine-4-yl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H

Table 2a
R3-X4R3-X4
phenyl
the aniline
piperidine-1-Il
morpholine-4-yl
furan-2-yl
furan-3-yl
tetrahydrofuran-2-yl
thiophene-2-Il
thiophene-3-yl
pyridine-2-yl
1H-pyrrol-1-yl
1-methyl-1H-pyrrol-2-yl
1H-pyrazole-1-Il
2-AMINOPHENYL
2-forfinal
2-(trifluoromethyl)phenyl
3-(trifluoromethyl)phenyl
2-nitrophen the
2-hydroxyphenyl
2-methoxyphenyl
3-methoxyphenyl
4-methoxyphenyl
2,3-acid
2-ethoxyphenyl
3-ethoxyphenyl
2-were
2-(deformedarse)phenyl
3-(deformedarse)phenyl
4-(deformedarse)phenyl
2-(triptoreline)phenyl
3-(triptoreline)phenyl
2-(methylamino)phenyl
3-(methylamino)phenyl
4-(methylamino)phenyl
2-(ethylamino)phenyl
3-(ethylamino)phenyl
3-(dimethylamino)phenyl
3-(diethylamino)phenyl

Table 2b
R1R2A
tetrazol-5-yl
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
H
methoxy
H
H
H
H
H
H
H
H
H
H
H
H
5-vinylpyridin-3-yl
5-vinylpyridin-3-yl
2-phenylpyridine-4-yl
6-vinylpyridin-3-yl
6-vinylpyridin-2-yl
5-vinylpyridin-2-yl
4-vinylpyridin-2-yl
5-(2-forfinal)pyridine-3-yl
5-(furan-2-yl)pyridine-3-yl
5-(furan-3-yl)pyridine-3-yl
5-(pyridine-3-yl)pyridine-3-yl
5-(pyridine-4-yl)pyridine-3-yl
6-(pyridine-4-and the)pyridine-3-yl
5-(pyrimidine-2-yl)pyridine-3-yl

Typical examples of the compounds of the present invention further include compounds shown in Table 3a. These compounds are compounds described in Patent document 1. However, it was not known that these compounds have inhibitory effect on collagen production. These compounds applicable to the prevention, treatment and the like, and diseases associated with excessive production of collagen.

Table 3a
Connection # R3X4X2-X3A
1cphenyllinklink2,3-dihydrobenzo[1,4]dioxin-6-yl
2cphenyllinklink5-(1H-pyrrol-1-yl)pyridine-3-yl
3cphenyltie the linkbenzothiazol-2-yl
4cphenyllinklink1-phenyl-1H-pyrazole-5-yl
5cphenyllinklink6-(piperidine-1-yl)pyridine-3-yl
6cphenyllinklink2-(1H-pyrrol-1-yl)pyridine-4-yl
7cphenyllinklink2-hydroxyphenyl
8cphenyllinklink3-biphenyl -
9cphenyllinklink4-biphenyl -
10cphenyllinklink3-(1H-pyrrol-yl)phenyl
11cphenyllinklink4-(1H-pyrrol-1-yl)phenyl
12cphenyllinkCH=CH(E)3,4-acid
13cphenyl(CH2)2link5-(1H-pyrrol-1-yl)pyridine-3-yl
14cbenzofuran-2-yllinklink5-(1H-pyrrol-1-yl)pyridine-3-yl
15c3-chlorophenyllinklink5-(1H-pyrrol-1-yl)pyridine-3-yl
16c2,4-differenllinklink5-(1H-pyrrol-1-yl)pyridine-3-yl
17c3-methoxyphenyl(CH2)2link 5-(1H-pyrrol-1-yl)pyridine-3-yl
18cphenylOlink2-(1H-pyrrol-1-yl)pyridine-4-yl
19cphenylOlink2-hydroxyphenyl
20cphenyl(CH2)2link2-hydroxyphenyl
21c1H-indol-1-yllinklinkphenyl
22c1H-benzimidazole-1-yllinklinkphenyl
23c4-(1H-pyrrol-1-yl)phenyllinklinkphenyl
24cphenyllinkphenyl

If for the unity of the General formula [1] or its salt, there are isomers (for example, optical isomer, geometric isomer, tautomer), the present invention includes these isomers. In addition, the present invention also includes MES, hydrate and various forms of crystalline substance.

Next will be described a method of obtaining compounds of the present invention.

The compound of the present invention receive through a combination of known methods. For example, it can be obtained in the following ways receipt.

The method of obtaining 1

where R21represents a hydrogen atom or a lower alkyl group; R22represents an optionally substituted alkylenes group; L1represents a leaving group; and R1, R2, R3, R4, R5, R6, R7and R8have the same meaning as above.

As compounds of General formula [3a] is known, for example, pyridine-3-baronova acid, 3-(methanesulfonamido)phenylboronic acid, thiophene-2-baronova acid, benzofuran-2-baronova acid and 3-methoxyphenylalanine acid.

As compounds of General formula [3b] are known, for example, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furan.

Compounds of General formula [3a] and [3b] can be obtained, for example, from the corresponding halide compounds, in accordance with the act shall obom, described in JP 2003-206290A or in The Journal of Organic Chemistry, 1995, vol. 60, pp. 7508-7510.

The compound of General formula [1a] can be produced through the interactions of the compounds of General formula [2a] with the compound of General formula [3a] or [3b] in the presence or in the absence of base, in the presence of a palladium catalyst and in the presence or in the absence of ligand.

The solvent used in this reaction is not specifically limited provided that it does not adversely affect the reaction, and examples include water, alcohols, aromatic hydrocarbons, amides, golozhabernyi hydrocarbons, ethers, ketones, acetonitrile, esters and dimethyl sulfoxide. These substances can be used as a mixture.

Examples of the base used if necessary in this reaction include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tribalistic and organic bases such as triethylamine and N,N-diisopropylethylamine. The number of moles used can be 1-50 times, preferably 2-5-fold, relative to the amount in moles of compounds of General formula [2a].

Examples of the palladium catalyst used in this reaction include metal palladium catalysts such as palladium carbon and allavena mobile; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; and organic palladium complexes such as tetrakis(triphenylphosphine)palladium(0), dichloride, bis(triphenylphosphine)palladium(II)dichloride, 1,1'-bis(diphenylphosphino)ferienparadies(II), Tris(dibenzylideneacetone)dipalladium(0) dichloride and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II). These substances can be used in combination. The number of moles used palladium catalyst can be 0,00001-1-fold, preferably of 0.001 to 0.1-fold, relative to the amount in moles of compounds of General formula [2a].

Examples of the ligand used if necessary in this reaction include trialkylphosphine, such as trimethylphosphine and three-tert-butylphosphine; tricyclohexylphosphine, such as tricyclohexylphosphine; triarylphosphine, such as triphenylphosphine and trailerteen; trialkylphosphine, such as trimethylphosphite, triethylphosphite and tributylphosphite; tricyclohexylphosphine, such tricyclohexylphosphine; triarylphosphine, such as triphenylphosphite; salt imidazole, such as chloride, 1,3-bis(2,4,6-trimetilfenil)imidazole; diketones such as acetylacetone and activerelation; amines, such as trimethylamine, triethylamine, Tripropylamine and triisopropanolamine; 1,1'-bis(diphenylphosphino)fer the estimates, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl and 2-(di-tert-butylphosphino)-2',4',6'-triisopropylphenyl; and 2-(di-tert-butylphosphino)biphenyl. These substances can be used in combination. The amount in moles of the used ligand can be 0,00001-1-fold, preferably of 0.001 to 0.1-fold, relative to the amount in moles of compounds of General formula [2a].

The number of moles used compounds of General formula [3a] or [3b] can be 1-50 times, preferably 1-2 times, in relation to the amount in moles of compounds of General formula [2a].

This reaction may preferably be conducted in an atmosphere of inert gas (e.g. nitrogen or argon) at a temperature of from 40 to 170°C for from 1 minute to 96 hours.

The method of obtaining 2

where X4arepresents an oxygen atom or optionally protected aminogroup; and R1, R2, R3, R4, R5, R6, R7, R8and L1have the same meaning as above.

As compounds of the General formula [4a] is known, for example, aniline, benzylamine and phenol. The compound of General formula [4a] can be obtained, for example, from the corresponding halide compound in the usual way.

The total connection f is rmula [1b] can be obtained in accordance with the Method of obtaining 1 by the interactions of the compounds of General formula [2a] with the compound of General formula [4a].

The method of obtaining 3

where R1, R2, R3, R4, R5, R6, R7, R8and X4have the same meaning as above.

As compounds of the General formula [5] is known, for example, methyl-2-amino-4-phenylbenzoate (Patent Document 1); tert-butyl 2-amino-4-phenylbenzoate, tert-butyl 2-amino-4-phenoxybenzoate and tert-butyl 2-amino-4-venetianskt (WO2006/098308).

The compound of General formula [1c] can be obtained by acylation of compounds of General formula [5]. Specific examples of the method include a method using galodamadruga in the presence or in the absence of base.

The solvent used in this reaction is not specifically limited provided that it does not adversely affect the reaction, and examples include amides, golozhabernyi hydrocarbons, aromatic hydrocarbons, ethers, acetonitrile, ketones, esters, sulfolane and dimethylsulfoxide. These substances can be used as a mixture.

Galoyanized used in this reaction may be obtained by interaction of the compounds represented by the General formula [6]:

[Formula 5]

(in which R4, R5, R6, R7and R8have the same values as the pre is raised above), for example, with thionyl chloride or oxalylamino.

The number of moles used galodamadruga may be 1-50 times, preferably 1-5 times, in relation to the amount in moles of compounds of General formula [5].

As compounds of the General formula [6] are known, for example, 2-acetoxy-3-chlorbenzene acid, 2-acetoxy-5-brabantia acid, 2-acetoxy-5-identia acid, 2-acetoxy-5-methylbenzoic acid, 2-acetoxy-5-nitrobenzoic acid, 2-(benzyloxy)-5-brabantia acid, 2-(benzyloxy)-5-nitrobenzoic acid, 2-(benzyloxy)-5-(pyridin-2-yl)benzoic acid and 2-(benzyloxy)-5-(pyridin-3-yl)benzoic acid.

Examples of the base used if necessary in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide; organic bases, such as sodium methoxide, ethoxide sodium tert-piperonyl potassium, triethylamine, N,N-diisopropylethylamine and pyridine; and carbonates, such as sodium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate. The number of moles used can be 1-50 times, preferably 1-5 times, in relation to the amount in moles of compounds of General formula [5].

This reaction can usually be carried out at a temperature of from -78 to 100°C, preferably from 0 to 80°C for from 10 minutes to 24 hours the century

The method of obtaining 4

where R4arepresents a protective group of a phenolic hydroxyl; and R1, R2, R3, R5, R6, R7, R8and X4have the same meaning as above.

The compound of General formula [1e] can be obtained by removing the protective group from compounds of General formula [1d].

Examples of this method include the methods described in W. Greene, et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 370-424, 2007 (John Wiley & Sons, Inc.).

Specific examples of the methods include the reaction of hydrolysis using acid or base, the dealkylation reaction using salt and the reaction of reductive dealkylation, including the reaction of catalytic hydrogenation using a metal catalyst.

(4-1)

Examples of the acid used in the hydrolysis reaction using the acid include formic acid, hydrochloric acid, sulfuric acid, Hydrobromic acid, triperoxonane acid, methanesulfonate acid, aluminium chloride and iodide trimethylsilane. The number of moles of acid used may be 1-100000-fold, preferably 1 to 1,000-fold, relative to the amount in moles of compounds of General formula [1d].

Examples of the base used in the hydrolysis using a base, in luchot inorganic bases, such as sodium hydroxide, potassium hydroxide and lithium hydroxide; organic bases, such as sodium methoxide, ethoxide sodium tert-piperonyl potassium; carbonates such as potassium carbonate and sodium carbonate; and tetrabutylammonium fluoride. The number of moles used can be between 1 and 1,000-fold, preferably 1-50-fold, relative to the amount in moles of compounds of General formula [1d].

Examples of the salt used in the reaction dealkylation using salt include lithium iodide and sodium chloride. The number of moles of the salt used may be 1-100-fold, preferably 1-10-fold, relative to the amount in moles of compounds of General formula [1d].

The solvent used in this reaction is not specifically limited provided that it does not adversely affect the reaction, and examples include water, alcohols, amides, golozhabernyi hydrocarbons, aromatic hydrocarbons, ethers, acetonitrile, ketones and esters. These substances can be used as a mixture.

(4-2)

The solvent used in the reaction of catalytic hydrogenation using a metal catalyst is not specifically limited provided that it does not adversely affect the reaction, and examples include water, alcohols, amides, golozhabernyi angle the hydrogens, aromatic hydrocarbons, ethers, acetonitrile, ketones, esters, acetic acid and pyridine. These substances can be used as a mixture.

Examples of the metal catalyst used in this reaction include palladium metal catalysts such as palladium carbon and palladium black; palladium salt such as palladium oxide and palladium hydroxide; Nickel metal catalysts, such as Raney Nickel, salts of platinum, such as platinum oxide. The amount of the metal catalyst may be 0.001 to 5-fold (by weight), preferably from 0.01 to 1-fold (by weight), relative to the amount of compounds of General formula [1d].

Examples of the hydrogen source include hydrogen, formic acid, formate, such as sodium formate, ammonium formate and formate of triethylamine; cyclohexene; and cyclohexadiene. The number of moles used source of hydrogen can be 2-100-fold, preferably 2-10-fold, relative to the amount in moles of compounds of General formula [1d].

This reaction can be conducted at temperatures from 0 to 200°C, preferably from 0 to 100°C for from 1 minute to 24 hours.

The method of obtaining 5

where R1arepresents a protected carboxyl group or a protected 1H-Tetra the ol-5-ilen group; R1brepresents a carboxyl group or 1H-tetrazol-5-ilen group; and R2, R3, R4, R5, R6, R7, R8and X4have the same meaning as above.

The compound of General formula [1g] can be obtained by removing the protective group from compounds of General formula [1f].

Removing carboxylamide group can be carried out, for example, by the method described in W. Greene, et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 533-643, 2007 (John Wiley & Sons, Inc.).

Removing tetrazolate group can be carried out, for example, by the method described in W. Greene, et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 872-894, 2007 (John Wiley & Sons, Inc.).

Specifically, the compound of General formula [1g] can be obtained in accordance with Method 4.

The method of obtaining 6

where R1crepresents optionally protected 1H-tetrazol-5-ilen group; and R2, R3, R4, R5, R6, R7, R8and X4have the same meaning as above.

The compound of General formula [1h] can be obtained, for example, by the method described in Shinpen Heterokan Kagobutsu, Oyo-hen (New Heterocyclic Compounds, Advanced), pp. 98-100, 2004, Kodansha, or way, in accordance with him. Specifically, the compound of General formula [1h] can be obtained by the reaction ticlopidine the compounds of General formula [7a] with azide in the presence or in the absence of salt.

The solvents used in these reactions are not specifically limited provided that it does not adversely affect the reaction, and examples include ethers, golozhabernyi hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, dimethyl sulfoxide, and amides. These substances can be used as a mixture.

Examples used include azide sodium azide, and the azide of trimethylsilyl. The number of moles used azide can be 1-100-fold, preferably 1-10-fold, relative to the amount in moles of compounds of General formula [7a].

Examples of salts include ammonium chloride. The number of moles of the salt used may be 1-100-fold, preferably 1-10-fold, relative to the amount in moles of compounds of General formula [7a].

This reaction can usually be carried out at a temperature of from -78 to 150°C, preferably from 0 to 120°C for from 10 minutes to 24 hours.

The method of obtaining 7

where R1, R2, R3, R21, R22L1, Z1, Z2, Z3, Z4and Z5have the same meaning as above.

As compounds of General formula [3a] is known, for example, pyridine-3-baronova acid, 3-(methanesulfonamido)phenylboronic acid, thiophene-2-baronova acid, be zofran-2-baronova acid and 3-methoxyphenylalanine acid. As compounds of General formula [3b] are known, for example, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furan. In addition, compounds of General formula [3a] and [3b] can be obtained, for example, from the corresponding halide compounds in accordance with the method described in JP 2003-206290A or in The Journal of Organic Chemistry, 1995, vol. 60, pp. 7508-7510.

The compound of General formula [1i] can be obtained by interaction of the compounds of General formula [2b] with the compound of General formula [3A] or [3b] in the presence or in the absence of base, in the presence of a palladium catalyst and in the presence or in the absence of ligand.

The solvent used in this reaction is not specifically limited provided that it does not adversely affect the reaction, and examples include water, alcohols, aromatic hydrocarbons, amides, golozhabernyi hydrocarbons, ethers, ketones, acetonitrile, esters and dimethyl sulfoxide. These substances can be used as a mixture.

Examples of the base used if necessary in this reaction include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tribalistic; and organic bases such as triethylamine and N,N-diisopropylethylamine. The number of moles used can be 1-50-Crat is a diversified, preferably 2-5-fold, relative to the amount in moles of compounds of General formula [2b].

Examples of the palladium catalyst used in this reaction include palladium metal catalysts such as palladium carbon and palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; and organic palladium complexes such as tetrakis(triphenylphosphine)palladium(0), dichloride, bis(triphenylphosphine)palladium(II)dichloride, 1,1'-bis(diphenylphosphino)ferienparadies(II), Tris(dibenzylideneacetone)dipalladium(0) dichloride and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II). These substances can be used in combination. The number of moles used palladium catalyst can be 0,00001-1-fold, preferably of 0.001 to 0.1-fold, relative to the amount in moles of compounds of General formula [2b].

Examples of the ligand used if necessary in this reaction include trialkylphosphine, such as trimethylphosphine and three-tert-butylphosphine; tricyclohexylphosphine, such as tricyclohexylphosphine; triarylphosphine, such as triphenylphosphine and trailerteen; trialkylphosphine, such as trimethylphosphite, triethylphosphite and tributylphosphite; tricyclohexylphosphine, such as tricyclohexylphosphine; trial LTspice, such as triphenylphosphite; salt imidazole, such as chloride, 1,3-bis(2,4,6-trimetilfenil)imidazole; diketones such as acetylacetone and activerelation; amines, such as trimethylamine, triethylamine, Tripropylamine and triisopropanolamine; 1,1'-bis(diphenylphosphino)ferrocene, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl and 2-(di-tert-butylphosphino)-2',4',6'-triisopropylphenyl; and 2-(di-tert-butylphosphino)biphenyl. These substances can be used in combination. The amount in moles of the used ligand can be 0,00001-1-fold, preferably of 0.001 to 0.1-fold, relative to the amount in moles of compounds of General formula [2b].

The number of moles used compounds of General formula [3a] or [3b] can be 1-50 times, preferably 1-2 times, in relation to the amount in moles of compounds of General formula [2b].

This reaction may preferably be conducted in an atmosphere of inert gas (e.g. nitrogen or argon) at a temperature of from 40 to 170°C for from 1 minute to 96 hours.

The way to obtain 8

where R1, R2, R3, Z1, Z2, Z3, Z4, Z5L1and X4ahave the same meaning as above.

As compounds of General formula [4a] the world is us, for example, aniline, benzylamine and phenol. In addition, the compound of General formula [4a] can be obtained, for example, from the corresponding halide compound in the usual way.

The compound of General formula [1j] can be obtained in accordance with the Method of obtaining 7 by the interactions of the compounds of General formula [2b] with the compound of General formula [4A].

The method of obtaining 9

where R3arepresents a monocyclic heterocyclic ring or bicyclic heterocyclic ring which is bound through the nitrogen atom forming a ring; and R1, R2, Z1, Z2, Z3, Z4, Z5and L1have the same meaning as above.

As compounds of General formula [4b] are known, for example, piperidine, morpholine, thiomorpholine and 1H-pyrazole.

The compound of General formula [1k] can be obtained by interaction of the compounds of General formula [2b] with the compound of General formula [4b]. Specific examples of this reaction include a reaction with a palladium catalyst and a reaction using a copper catalyst.

In the reaction using a palladium catalyst compound of General formula [1k] can be obtained in accordance with the Method of obtaining 7 through the implementation of vzaimodeistviyami General formula [2b] with the compound of General formula [4b].

In the reaction using a copper catalyst compound of General formula [1k] can be obtained by interaction of the compounds of General formula [2b] with the compound of General formula [4b] in the presence or in the absence of base, in the presence or in the absence of ligand and in the presence of a copper catalyst.

The solvent used in this reaction is not specifically limited provided that it does not adversely affect the reaction, and examples include water, alcohols, aromatic hydrocarbons, amides, golozhabernyi hydrocarbons, ethers, ketones, acetonitrile, esters and dimethyl sulfoxide. These substances can be used as a mixture.

Examples of the base used if necessary in this reaction include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate; and organic bases such as triethylamine, N,N-diisopropylethylamine and N-methylmorpholine. The number of moles used can be 1-50 times, preferably 2-5-fold, relative to the amount in moles of compounds of General formula [2b].

Examples of the ligand used if necessary in this reaction include amino acids such as Proline, N,N-dimethylglycine and alanine. The number of moles used the League is Yes can be 1-50 times, preferably 2-5-fold, relative to the amount in moles of compounds of General formula [2b].

Examples of the copper catalyst used in this reaction include copper, copper bromide and copper iodide. These substances can be used in combination. The number of moles used copper catalyst may be 0.01 to 50 times, preferably 0.1 to 5-fold, relative to the amount in moles of compounds of General formula [2b].

The number of moles used compounds of General formula [4b] can be 1-50 times, preferably 1-2 times, in relation to the amount in moles of compounds of General formula [2b].

This reaction may preferably be conducted in an atmosphere of inert gas (e.g. nitrogen or argon) at a temperature of from 10 to 180°C for from 1 minute to 24 hours.

The method of obtaining 10

where one of the Z1a, Z2a, Z3a, Z4aand Z5arepresents a nitrogen atom, one of the remaining four is a group represented by the General formula C-L2(where L2represents a leaving group), and each of the remaining three represents CH; one of the Z1b, Z2b, Z3b, Z4band Z5brepresents a nitrogen atom, one of the remaining four is a group represented by the General formula (C-R11 (in which R11has the same meaning as above), and each of the remaining three represents CH; and R1, R2, R3, R11, R21, R22and X4have the same meaning as above.

The compound of General formula [1l] can be obtained in accordance with the Method of obtaining 7 by the interactions of the compounds of General formula [2c] with the compound of General formula [3c] or [3d].

The method of obtaining 11

where R1, R2, R3, Z1, Z2, Z3, Z4, Z5and X4have the same meaning as above.

As compounds of the General formula [5] is known, for example, methyl-2-amino-4-phenylbenzoate (Patent Document 1) and tert-butyl 2-amino-4-phenylbenzoate (WO2006/098308).

The compound of General formula [1m] can be obtained by acylation of compounds of General formula [5]. Specific examples of the method include a method using galodamadruga in the presence or in the absence of base.

The solvent used in this reaction is not specifically limited provided that it does not adversely affect the reaction, and examples include amides, golozhabernyi hydrocarbons, aromatic hydrocarbons, ethers, acetonitrile, ketones, esters, sulfolan and dime sulfoxide. These substances can be used as a mixture.

Galoyanized used in this reaction may be obtained by interaction of the compounds represented by the General formula [8]:

[Formula 6]

(in which Z1, Z2, Z3, Z4and Z5have the same meaning as above), for example, with thionyl chloride or oxalylamino.

The number of moles used galodamadruga may be 1-50 times, preferably 1-5 times, in relation to the amount in moles of compounds of General formula [5].

Examples of the base used if necessary in this reaction include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate; and organic bases such as triethylamine, pyridine and N,N-diisopropylethylamine.

The number of moles used can be 1-50 times, preferably 1-5 times, in relation to the amount in moles of compounds of General formula [5].

This reaction can usually be carried out at a temperature of from -78 to 100°C, preferably from 0 to 80°C for from 10 minutes to 24 hours.

The method of obtaining 12

where R1a, R1b, R2, R3, Z1, Z2, Z3, Z4, Z5and X4 have the same value, as presented above.

The compound of General formula [1o] can be obtained by removing the protective group from compounds of General formula [1n].

Removing carboxylamide group can be carried out, for example, by the method described in W. Greene, et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 533-643, 2007 (John Wiley & Sons, Inc.).

Removing tetrazolate group can be carried out, for example, by the method described in W. Greene, et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 872-894, 2007 (John Wiley & Sons, Inc.).

Specific examples of the methods include the reaction of hydrolysis using acid or base, the dealkylation reaction using salt and the reaction of reductive dealkylation, including the reaction of catalytic hydrogenation using a metal catalyst.

(12-1)

Examples of the acid used in the hydrolysis reaction using the acid include formic acid, hydrochloric acid, sulfuric acid, Hydrobromic acid, triperoxonane acid, methanesulfonate acid, aluminium chloride and iodide trimethylsilane. The number of moles of acid used may be 1-100000-fold, preferably 1 to 1,000-fold, relative to the amount in moles of compounds of General formula [1n].

Examples of the base used in the hydrolysis using a base include inorganic bases, t is such as sodium hydroxide, the potassium hydroxide and lithium hydroxide; organic bases, such as sodium methoxide, ethoxide sodium tert-piperonyl potassium; carbonates such as potassium carbonate and sodium carbonate; and tetrabutylammonium fluoride.

The number of moles used can be between 1 and 1,000-fold, preferably 1-50-fold, relative to the amount in moles of compounds of General formula [1n].

Examples of the salt used in the reaction dealkylation using salt include lithium iodide and sodium chloride. The number of moles of the salt used may be 1-100-fold, preferably 1-10-fold, relative to the amount in moles of compounds of General formula [1n].

The solvent used in this reaction is not specifically limited provided that it does not adversely affect the reaction, and examples include water, alcohols, amides, golozhabernyi hydrocarbons, aromatic hydrocarbons, ethers, acetonitrile, ketones and esters. These substances can be used as a mixture.

(12-2)

The solvent used in the reaction of catalytic hydrogenation using a metal catalyst is not specifically limited provided that it does not adversely affect the reaction, and examples include water, alcohols, amides, golozhabernyi hydrocarbons, aromatics the e hydrocarbons, ethers, acetonitrile, ketones, esters, acetic acid and pyridine. These substances can be used as a mixture.

Examples of the metal catalyst used in this reaction include palladium metal catalysts such as palladium carbon and palladium black; palladium salt such as palladium oxide and palladium hydroxide; Nickel metal catalysts, such as Raney Nickel; and salts of platinum, such as platinum oxide. The amount of the metal catalyst may be 0.001 to 5-fold (by weight), preferably from 0.01 to 1-fold (by weight), relative to the amount of compounds of General formula [1n].

Examples of the hydrogen source include hydrogen, formic acid, formate, such as sodium formate, ammonium formate and formate of triethylamine; cyclohexene; and cyclohexadiene. The number of moles used source of hydrogen can be 2-100-fold, preferably 2-10-fold, relative to the amount in moles of compounds of General formula [1n].

This reaction can usually be carried out at a temperature of from 0 to 200°C, preferably from 0 to 100°C for from 1 minute to 24 hours.

The method of obtaining 13

where R1c, R2, R3, Z1, Z2, Z3, Z4, Z5and X4have the same value is, as presented above.

The compound of General formula [1p] can be obtained, for example, by the method described in Shinpen Heterokan Kagobutsu, Oyo-hen (New Heterocyclic Compounds, Advanced), pp. 98-100, 2004, Kodansha, or way, in accordance with him. Specifically, the compound of General formula [1p] can be obtained by conducting cycloaddition reaction of compounds of General formula [7b] azide in the presence or in the absence of salt.

The solvents used in these reactions are not specifically limited provided that it does not adversely affect the reaction, and examples include ethers, golozhabernyi hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, dimethyl sulfoxide, and amides. These substances can be used as a mixture.

Examples used include azide sodium azide, and the azide of trimethylsilyl.

The number of moles used azide can be 1-100-fold, preferably 1-10-fold, relative to the amount in moles of compounds of General formula [7b].

Examples of salts include ammonium chloride. The number of moles of the salt used may be 1-100-fold, preferably 1-10-fold, relative to the amount in moles of compounds of General formula [7b].

This reaction can usually be carried out at a temperature of from -78 to 150°C, preferably from 0 to 120°C, for 10 min is t to 24 hours.

Thus obtained compounds of General formula [1] or their salts can be converted to other compounds of the General formula [1] or their salts by known reactions such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenoalkane, dehydration, or hydrolysis, or by a suitable combination of such reactions.

Next will be described the methods of obtaining materials for the production of compounds of the present invention.

The method of obtaining And

where R1, R2, R4, R5, R6, R7, R8and L1have the same meaning as above.

As compounds of the General formula [9a] is known, for example, methyl-2-amino-4-bromobenzoate and tert-butyl 2-amino-4-bromobenzoate (Patent Document 1).

The compound of General formula [2a] can be obtained in accordance with the Method of obtaining 3 by acylation of compounds of General formula [9a].

The method of obtaining B

where R1, R2, R3, R21, R22and L1have the same meaning as above.

As compounds of the General formula [9b] is known, for example, methyl-4-bromo-2-nitrobenzoate, tert-butyl-4-chloro-2-nitrobenzoate and tert-butyl 4-bromo-2-nitrobenzoate (Patent Document 1).

The connection of the soup formula [10a] can be obtained in accordance with the Method of obtaining 1 by the interactions of the compounds of General formula [9b] with the compound of General formula [3a] or [3b].

The method of obtaining C

where R1, R2, R3X4aand L1have the same meaning as above.

The compound of General formula [10b] can be obtained in accordance with the Method of obtaining 2 by interaction of the compounds of General formula [9b] with the compound of General formula [4a].

The method of obtaining D

where R1, R2, R3and X4have the same meaning as above.

The compound of General formula [5] can be obtained by restoring the compounds of General formula [10]. This reaction can be carried out by the method described in Richard C. Larock, et al., Comprehensive Organic Transformations, 2nd Edition, pp. 823-827, 1999 (John Wiley & Sons, Inc.), or way, in accordance with him. Specific examples of the methods include the reaction of catalytic hydrogenation using a metal catalyst and reaction recovery using metal, such as iron or zinc.

The reaction of catalytic hydrogenation of compounds of General formula [10] can be carried out in accordance with the Method of obtaining a (4-2).

When the compound of General formula [10] is subjected to reduction reaction of using metal solvent used is not specifically limited provided that it does not about the negative influence on the reaction, and its examples include water, alcohols, amides, golozhabernyi hydrocarbons, aromatic hydrocarbons, ethers, acetonitrile, ketones and esters. These substances can be used as a mixture.

Examples of the metal used in this reaction include iron, zinc, tin, and tin chloride(II). The number of moles of the metal used may be 1-50 times, preferably 1 to 10-fold, relative to the amount in moles of compounds of General formula [10].

Examples of the acid used, if necessary in this reaction include hydrochloric acid, Hydrobromic acid and acetic acid. The amount of acid used may be 0.001 to 100-fold (about./mass.), preferably 0.01 to 20-fold (about./mass.), in relation to the number of compounds of General formula [10].

This reaction can be conducted at temperatures from 0 to 200°C, preferably from 0 to 100°C for from 1 minute to 24 hours.

The method of obtaining E

where R4a, R5, R6, R7and R8have the same meaning as above.

As compounds of the General formula [6a] is known, for example, 5-amoxicillina acid and 5-isopropoxyaniline acid.

The compound of General formula [6b] can be obtained, for example, by protecting the phenolic hydroxyl group of compounds of the General formula [6a] way, described in W. Greene, et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 370-424, 2007 (John Wiley & Sons, Inc.).

The method of obtaining F

where R13represents a protected carboxyl group; and R5, R6, R7and R8have the same meaning as above.

As compounds of the General formula [11] is known, for example, methyl 2-hydroxy-4-identit and methyl-2-hydroxy-5-isopropoxybenzoic.

The compound of General formula [6a] can be obtained in accordance with the Method of obtaining 4 by removing carboxylamide group with compounds of General formula [11].

The way to obtain G

where R4a, R5, R6, R7and R8have the same meaning as above.

As compounds of the General formula [12] is known, for example, 7-hydroxy-2,3-dihydrobenzo[1,4]dioxin-6-carbaldehyde and 3-formyl-4-hydroxyphenylacetate.

(G-1)

The compound of General formula [13] can be obtained in accordance with the Method of obtaining E by protecting the phenolic hydroxyl group of compounds of General formula [12].

(G-2)

The compound of General formula [6b] can be obtained by interaction of the compounds of General formula [13] with an oxidizing agent in the presence or in the absence of acid and in the presence or in the absence of salt.

actuarial, used in this reaction is not specifically limited provided that it does not adversely affect the reaction, and examples include water, golozhabernyi hydrocarbons, aromatic hydrocarbons, acetonitrile and pyridine. These substances can be used as a mixture.

Examples of the acid used, if necessary in this reaction include inorganic acids such as hydrochloric acid and sulfuric acid; and organic acids such as acetic acid. The number of moles of acid used may be 1 to 1,000-fold relative to the amount in moles of compounds of General formula [13].

Examples of salts used if necessary in this reaction include sodium dihydrophosphate, magnesium sulfate, ammonium sulfate and magnesium chloride. The number of moles of the salt used may be 1-50 times, preferably 1 to 10-fold, relative to the amount in moles of compounds of General formula [13].

Examples of the oxidizing agent used in this reaction include chromates such as sodium dichromate and chromium oxide(VI); permanganates such as potassium permanganate permanganate barium, permanganate calcium and magnesium permanganate; a hydrogen peroxide solution; and sodium chlorite. These substances can be used as a mixture. The amount in moles of the used oxidant may be 1-50-Crat is m, preferably 1-10-fold, relative to the amount in moles of compounds of General formula [13].

This reaction can usually be carried out at temperatures from 0 to 150°C, preferably from 40 to 130°C for from 30 minutes to 48 hours.

The method of obtaining H

where R2, R3, R4, R5, R6, R7, R8X4and L1have the same meaning as above.

As compounds of General formula [14] is known, for example, 2-amino-4-chlorobenzonitrile.

(H-1)

The compound of General formula [15] can be obtained in accordance with the Method of obtaining 3 by acylation of compounds of General formula [14].

(H-2)

If X4is a binder, a compound of General formula [7a] can be obtained in accordance with the Method of obtaining 1 by the interactions of the compounds of General formula [15] with the compound of General formula [3a] or [3b].

(H-3)

If X4represents an oxygen atom or optionally protected aminogroup, the compound of General formula [7a] can be obtained in accordance with the Method of obtaining 2 by interaction of the compounds of General formula [15] with the compound of General formula [4a].

The method of obtaining I

where R1, R2, Z , Z2, Z3, Z4, Z5and L1have the same meaning as above.

As compounds of the General formula [9] is known, for example, methyl-2-amino-4-bromobenzoate and tert-butyl 2-amino-4-bromobenzoate (Patent Document 1).

The compound of General formula [2b] can be obtained in accordance with the Method of obtaining 11 by acylation of compounds of General formula [9a].

The method of obtaining J

where R1, R2, R3aand L1have the same meaning as above.

The compound of General formula [10c] can be obtained in accordance with the Method of obtaining 9 through the implementation of the interaction of the compounds of General formula [9b] with the compound of General formula [4b].

The method of obtaining K

where R1, R2, R22and L1have the same meaning as above.

As compounds of General formula [17] is known, for example, bis(pinacolato)dibor, bis(neopentylglycol)dibor and bis(hexyleneglycol)Tibor.

The compound of General formula [16] can be obtained in accordance with the Method of obtaining 7 by the interactions of the compounds of General formula [9b] with the compound of General formula [17].

The method of obtaining L

where L3is sobo is a leaving group; and R1, R2, R3and R22have the same meaning as above.

As compounds of the General formula [18] is known, for example, 2-bromopyridine and 1-bromo-2-(deformedarse)benzene.

The compound of General formula [10a] can be obtained in accordance with the Method of obtaining 7 by the interactions of the compounds of General formula [16] with the compound of General formula [18].

The method of obtaining M

where R1, R2, R3X4, Z1a, Z2a, Z3a, Z4aand Z5ahave the same meaning as above.

The compound of General formula [2c] can be obtained by acylation of compounds of General formula [5]. Specific examples of the method include a method using galodamadruga in the presence or in the absence of base.

The solvent used in this reaction is not specifically limited provided that it does not adversely affect the reaction, and examples include amides, golozhabernyi hydrocarbons, aromatic hydrocarbons, ethers, acetonitrile, ketones, esters, sulfolane and dimethylsulfoxide. These substances can be used as a mixture.

Galoyanized used in this reaction may be obtained by communicating connection, not only the frame of General formula [8a]:

(in which Z1a, Z2a, Z3a, Z4aand Z5ahave the same meaning as above), for example, with thionyl chloride or oxalylamino.

The number of moles used galodamadruga may be 1-50 times, preferably 1-5 times, in relation to the amount in moles of compounds of General formula [5].

Examples of the base used if necessary in this reaction include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate; and organic bases such as triethylamine, pyridine and N,N-diisopropylethylamine.

The number of moles used can be 1-50 times, preferably 1-5 times, in relation to the amount in moles of compounds of General formula [5].

This reaction can usually be carried out at a temperature of from -78 to 100°C, preferably from 0 to 80°C for from 10 minutes to 24 hours.

The method of obtaining N

where R13, Z1, Z2, Z3, Z4and Z5have the same meaning as above.

As compounds of General formula [8b] known, for example, methyl-5-(furan-3-yl)pyridine-3-carboxylate.

The compound of General formula [8] can be obtained in accordance with the Method of obtaining 12 by removing the carb is xidawang group with compounds of General formula [8b].

The method of obtaining O

where R2, R3, Z1, Z2, Z3, Z4, Z5X4and L1have the same meaning as above.

As compounds of General formula [14] is known, for example, 2-amino-4-chlorobenzonitrile.

(O-1)

The compound of General formula [19] can be obtained in accordance with the Method of obtaining 11 by acylation of compounds of General formula [14].

(O-2)

If X4is a binder, a compound of General formula [7b] can be obtained in accordance with the Method of obtaining 7 by the interactions of the compounds of General formula [19] with a compound of General formula [3a] or [3b].

(O-3)

If X4represents an oxygen atom or optionally protected aminogroup, the compound of General formula [7b] can be obtained in accordance with the Method of obtaining 8 through the implementation of the interaction of the compounds of General formula [19] with a compound of General formula [4a].

The method of obtaining P

where R14represents aminosidine group; and R2, R3, R21, R22and L1have the same meaning as above.

As compounds of General formula [20] is known, for example, N-(5-bromo-4-methoxy-2-were)cetamide.

(P-1)

The compound of General formula [9c] can be obtained by interaction of the compounds of General formula [20] with an oxidizing agent in the presence or in the absence of acid or base and in the presence or in the absence of salt.

The solvent used in this reaction is not specifically limited provided that it does not adversely affect the reaction, and examples include water, golozhabernyi hydrocarbons, aliphatic hydrocarbons and pyridine. These substances can be used as a mixture.

Examples of the acid used, if necessary in this reaction include inorganic acids such as hydrochloric acid and sulfuric acid; and organic acids such as acetic acid.

The number of moles of acid used may be 1 to 1,000-fold relative to the amount in moles of compounds of General formula [20].

Examples of the base used if necessary in this reaction include inorganic bases such as sodium hydroxide and potassium hydroxide; and organic bases such as pyridine.

The number of moles used can be between 1 and 1,000-fold relative to the amount in moles of compounds of General formula [20].

Examples of salts used if necessary in this reaction include magnesium sulfate, sulfate is monia and magnesium chloride.

The number of moles of the salt used may be 1-50 times, preferably 1 to 10-fold, relative to the amount in moles of compounds of General formula [20].

Examples of the oxidizing agent used in this reaction include chromates, such as chromium oxide(VI) and sodium dichromate; and permanganates such as potassium permanganate permanganate barium, permanganate calcium and magnesium permanganate.

The amount in moles of the used oxidant may be 1-50 times, preferably 1 to 10-fold, relative to the amount in moles of compounds of General formula [20].

This reaction can usually be carried out at temperatures from 0 to 150°C, preferably from 40 to 130°C for from 30 minutes to 48 hours.

(P-2)

The compound of General formula [10d] can be obtained in accordance with the Method of obtaining 7 by the interactions of the compounds of General formula [9c] with the compound of General formula [3a] or [3b].

The method of obtaining Q

where R1drepresents a protected carboxyl group; and R2, R3and R14have the same meaning as above.

(Q-1)

The compound of General formula [10e] can be obtained by removing aminosidine group with compounds of General formula [10d].

Removing aminosidine group can be carried out, for example, by the method described in W. Geene, et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 696-868, 2007 (John Wiley & Sons, Inc.).

(Q-2)

The compound of General formula [10f] can be obtained by protecting the carboxyl group of the compounds of General formula [10e].

Protection of the carboxyl group can be carried out, for example, by the method described in W. Greene, et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 533-643, 2007 (John Wiley & Sons, Inc.).

In the compounds used in the above methods of preparation, the compound can form a salt, can also be used as a salt. Examples of such salts include those salts, and salts of compounds of General formula [1].

If the compounds used in the above methods of preparation, there are isomers (for example, optical isomer, geometric isomer and tautomer), these isomers may also be used. In addition, if there are solvate, hydrates and various forms of crystalline substances, these solvate, hydrates and various forms of crystalline materials can also be used. In addition, if the compounds used in the above methods of preparation, contain substituents, which may be protected, for example, in the compound containing the amino group, hydroxyl group or carboxyl group, such a group of pre-protects conventional protecting group, and after the reaction of the protective group which can be removed in a known manner.

Compounds obtained by the above described methods of obtaining, or their salts can be converted to other compounds or their salts by known reactions such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenoalkane, dehydration, or hydrolysis, or by a suitable combination of such reactions.

If the connection of the present invention are used as pharmaceutical medicines, pharmaceutical auxiliary means that are commonly used for the preparation of a pharmaceutical composition, such as a filler, a carrier and a diluent, can be appropriately mixed. The connection may be administered orally or parenterally in the form of tablets, capsules, powder, syrup, granules, pills, suspensions, emulsions, solution, powder preparation, suppository, eye drops, nose drops, ear drops, patch, ointment or injectable solution, in accordance with the General method. The route of administration, dose and frequency of injection can be appropriately selected depending on the age, weight and condition of the patient. Usually, an adult may be from 0.01 to 1000 mg/kg per day orally or parenterally (for example, by injection, intravenous drip or injection in rectal Department) at a time is whether multiple multiple introductions.

Further, the applicability of typical compounds of the present invention will be described in the following Test examples.

Test example 1: Test for inhibition of expression of mRNA encoding the α1 chain of collagen type I

Cell line WI-38 fetal lung fibroblasts human suspended in modified according Dulbecco environment Needle containing 10% fetal bovine serum and 7.5×104cells were sown in 12-well plate and grown for 3 days, or 1.5×105cells were sown and grown for 2 days. After growth of the cells to subconfluent state nutrient medium was replaced modified by Dulbecco medium Needle containing 0.4% fetal bovine serum and 50 μg/ml ascorbic acid, and then grew the cells within 24 hours. Then thereto was added a test compound and, after one hour, added TGF-β1 at a final concentration of 1 ng/ml in twenty-four hours after adding the total RNA was extracted from cells using a kit for RNA extraction (SV Total RNA Isolation System, Promega), and synthesized cDNA using reverse transcriptase (ReverTra Ace, TOYOBO). The level of expression of mRNA encoding the α1 chain of collagen type I, analyzed by means of a device for carrying out PCR in real time (ABI PRISM 7700 Sequence Detection System, Applied Biosystems) according to the method of conducting the Oia real-time PCR using the premix-reagent for PCR in real time (SYBR Premix Ex Taq or SYBR Premix Ex Taq II (Perfect Real Time), TaKaRa). PCR was performed with diluted cDNA as template, using primers specific to gene mRNA, encoding the α1 chain of collagen type I, or gene GAPDH as an internal standard, and measured the reaction product. PCR was performed by incubation at 95°C for 10 seconds, 45 cycles of denaturation at 95°C for 5 seconds and hybridization/elongation at 60°C for 30 seconds. The level of expression of mRNA encoding the α1 chain of collagen type I, corrected for GAPDH, and expressed as relative values, taking the level of expression obtained in the absence of test compounds at 100%.

The results are presented in Tables 4a, 4b, and 4c.

Table 4a
Example No.The degree of inhibition (%) at 10 µmol/lExample No.The degree of inhibition (%) at 10 µmol/l
2A99108A94
4A97A91
6A95A8
7a94117a90
13A93A88
16A80A79
19a83134a90
22A97139a85

94
23a91A92
27A98142a90
29A90143a89
34a82144A96
35A90A93
37AA97
41A99150A93
44a89A84
46a91166a95
50A75A86
65A71A82
68A98180 ° 85
73a96A74
76A72A82
80A95183a81
83A88A95
86a85190A86
89a98A85
92A84A81
95A88A94
97A83A89
100A99207a83
102A8921791
A92A85
A86

Table 4b
Example No.The degree of inhibition (%) at 10 µmol/l
1b72
3b83
4b93
5b72
9b84
11b80
12b87
13b92
16b84
19b90
27b72
29b86
32b81
33b78
35b96
38b94
40b96
44b93
45b90
46b69
51b92
57b84
58b78
61b86
63b65

Table 4c
Example No.The degree of inhibition (%) at 10 µmol/l
2c82

6c89
7c94
8c92
9c76
11c75
16c89
18c82
23c78

Compounds used in the present invention, showed excellent inhibitory effect on collagen production.

Test example 2: Lung fibrosis in mice induced by bleomycin

The test was performed with the use of the eating male mice C57BL/6N (Charles River Laboratories Japan, Inc.) ages 8 to 10.5 weeks. Bleomycin (Nippon Kayaku Co., Ltd.) was dissolved in saline at a concentration of 1.0 or 1.5 mg/ml, and 2 μl/g of the solution were intranasally administered to each mouse for the induction of pulmonary fibrosis. The test compound was dissolved or suspended in 10% aqueous solution polyoxyethylenated castor oil (trade name Cremophor EL) or in water and orally was administered at 10 mg/kg twice a day, from 14-th to 28-th day from the date of induction. In the control group in the same way introduced a 10% aqueous solution polyoxyethylenated castor oil or water. On the 28th day after the day of induction of each mouse was removed easy, and quantitatively measured the collagen content. The extracted light homogenized in 0.5 mol/l aqueous solution of acetic acid containing a mixture of protease inhibitors (Complete, EDTA-free, Roche Diagnostics) in an amount of 1 tablet/50 ml) and was extracted with water-soluble collagen in the presence of 10 mg/ml pepsin (Sigma) overnight. The collagen content was measured using set (Sircol Soluble Collagen assay kit, Biocolor).

The degree of inhibition was determined by the following formula:

The degree of inhibition (%) = [1 - (amount of collagen in the lung in the group with the introduction of the test compound)/(amount of collagen in the lung in the control group)]×100

The collagen content in the lung in groups with the introduction connections Note the ditch 23a, 80a, 83a, 108a, 122a, 143a, 1b, 16b, 19b, 57b or 7c, was lower by 30% or more compared with that in the control group.

It should be noted that the compounds of Examples 23a, 1b and 7c used in the form of their sodium salts.

In addition, the compounds of Examples 122a and 143a used as salts of addition of hydrochloric acid.

Test example 3: Test for toxicity with repeated introduction on rats (oral administration, two weeks)

Test compounds used compounds of Examples 80a, 122a, 139a, 1b, 16b and 19b. It should be noted that the compounds of Examples 80a and 1b used in the form of sodium salts.

Each of the test compounds suspended in 0.5% solution of methylcellulose or distilled water to prepare 100 mg/ml suspension. A suspension of the test compound was administered orally (10 ml/kg, test the connection: 1000 mg/kg) to male SD rats (aged 6 weeks, 5 rats in each group). As a result, on the 14th day after injection, all rats survived.

Test example 4: Inhibitory effect on metabolizing drugs enzyme in the human liver (CYP2C9)

Test compounds used compounds of Examples 80a, 83a, 108a, 117a, 123a, 128a, 139a, 142a and 143a. It should be noted that the compound of Example 80A used in the form of free base.

Used combined liver microsomes of man tolbutamide as a substrate. The reaction was carried out in phosphate buffer (100 mmol/l, pH of 7.4), and the final concentration in the reaction system was adjusted to 0.5 mg/ml protein of human liver microsomes, 200 µmol/l of substrate, 1.55 mmol/l oxidized adenine dinucleotide phosphate (NADP+), 3.3 mmol/l glucose-6-phosphate, 3.3 mmol/l of magnesium chloride and 0.4 units/ml glucose-6-phosphate dehydrogenase (G6PDH). The final concentration of each compound in the reaction solution was adjusted to 0.08-50 µg/ml of the Above reaction solution was subjected to reaction at 37°C for 30 minutes. The reaction was stopped by addition of an equal amount of acetonitrile. After centrifugation the concentration of the metabolite of tolbutamide in the supernatant was quantitatively measured using LC/MS/MS. Inhibitory activity was defined as IC50. As a positive control used sulfaphenazole.

Connection examples 80a, 83a, 108a, 117a, 123a, 128a, 139a, 142a and 143a mattered IC50more than 50 µg/ml.

Compounds of the present invention had a weak inhibitory effect on the metabolizing of medication liver enzyme, and therefore superior in terms of security.

Further, the present invention will be described with reference to Reference examples and Examples, but it is not restricted by them.

Ratio when mixed eluents are volume ratios. Unless otherwise n is specified, the media, when carrying out column chromatography on silica gel represents Purif-Pack SI (60 μm) manufactured by Fuji Silysia Chemical Ltd.

Each of the symbols in each Example has the following value: Ac: acetyl, Bn: benzyl, Boc: tert-butoxycarbonyl,tBu: tert-butyl, Bz: benzoyl, Et: ethyl,iPr: isopropyl, Me: methyl, Pr: propyl, and DMSO-d6: deuterated dimethyl sulfoxide.

Reference example 1a

To a solution of 5-tert-butylsilane acid (0,054 g) in methylene chloride (0.54 ml) was sequentially added pyridine (0,034 ml) and acetic anhydride (0,034 ml)and then stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, and added to the remainder of 1 mol/l hydrochloric acid and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-90% chloroform/methanol] to obtain 0,049 g of 2-acetoxy-5-tert-butylbenzoic acid as a white solid.

1H-NMR(CDCl3) δ: of 1.35 (9H, s)to 2.35 (3H, s), 7,06 (1H, d, J=8,3 Hz), 7,63 (1H, DD, J=8,3, 2,4 Hz)to 8.12 (1H, d, J=2,4 Hz).

Reference examples 2a-4a

The connection structure is given in Table 5a, received as described in Reference example 1a.

Table 5a
Reference example No.Reference example No.Reference example No.
2a3a4a

2-Acetoxy-5-ethoxybenzene acid

1H-NMR(DMSO-d6) δ: of 1.33 (3H, t, J=7.0 Hz), of 2.21 (3H, s)4,06 (2H, q, J=7.0 Hz), to 7.09 (1H, d, J=8,8 Hz), 7,17 (1H, DD, J=8,8, 3.2 Hz), 7,37 (1H, d, J=3.2 Hz), 13,06-13,16 (1H, broadened).

2-Acetoxy-5-isopropoxybenzoic acid

1H-NMR(DMSO-d6) δ: of 1.27 (6H, d, J=6,1 Hz), of 2.21 (3H, s), 4,56-and 4.68 (1H, m), was 7.08 (1H, d, J=8,8 Hz), 7,16 (1H, DD, J=8,8, 2,9 Hz), 7,35 (1H, d, J=2,8 Hz).

2-Acetoxy-5-acetylbenzoic acid

(1H-NMR(CDCl3) δ: of 2.38 (3H, s)to 2.66 (3H, s), 7,26 (1H, d, J=8.6 Hz), 8,23 (1H, DD, J=8,6 and 2.2 Hz), 8,69 (1H, d, J=2.2 Hz).

Reference example 5a

The following compound was obtained as described in Reference example 1a.

5-Acetoxy-2-(benzyloxy)benzoic acid

1H-NMR(CDCl 3) δ: 2,30 (3H, s), from 5.29 (2H, s), 7,13 (1H, d, J=8,9 Hz), 7,30 (1H, DD, J=8,9, 3.0 Hz), 7,38-of 7.48 (5H, m), to $ 7.91 (1H, d, J=3.0 Hz), or 10.60-10,95 (1H, m).

Reference example 6a

The following compound was obtained as described in Reference example 1a.

4-Acetoxy-2-(benzyloxy)benzoic acid

1H-NMR(DMSO-d6) δ: 2,28 (3H, s)to 5.17 (2H, s), 6,77-6,84 (1H, m),? 7.04 baby mortality (1H, d, J=1.7 Hz), 7,29-to 7.35 (1H, m), of 7.36-the 7.43 (2H, m), 7,46-7,53 (2H, m), 7,72 (1H, d, J=8.5 Hz), 12,68 (1H, s).

Reference example 7a

To a solution of methyl 2-hydroxy-4-identity (2.5 g) in N,N-dimethylacetamide (20 ml) was sequentially added potassium carbonate (1.9 g) and benzylbromide (1.2 ml)and then stirred at 80°C for 1 hour. The reaction mixture was cooled to room temperature, and then was added a 1 mol/l hydrochloric acid and ethyl acetate. The organic layer was separated, sequentially washed with 1 mol/l hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-80% hexane/ethyl acetate] to obtain 3.3 g of methyl 2-(benzyloxy)-4-identity in the form of a yellow oily substance.

1H-NMR(CDCl3) δ: 3,88 (3H, s), of 5.15 (2H, s), 7,30-the 7.43 (5H, m), 7,47-7,51 (2H, m), 7,53 (1H, d, J=81 Hz).

Reference example 8a

To a solution of methyl 2-(benzyloxy)-4-identity (1.0 g) in a mixture of dioxane (5.0 ml) and methanol (5.0 ml) was added 2 mol/l aqueous sodium hydroxide solution of 4.1 ml)and then stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, and was added to the residue water. After adjusting the pH to 2.5 by the addition of 6.0 mol/l hydrochloric acid while cooling on ice was added ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added hexane and diisopropyl ether, and collected the obtained solid by filtration with the receipt of 0.93 g of 2-(benzyloxy)-4-identies acid as a white solid.

1H-NMR(CDCl3) δ: 5,27 (2H, s), 7,40-of 7.55 (7H, m), 7,88 (1H, d, J=8,3 Hz), 10,35-10,55 (1H, broadened).

Reference example 9a

To a solution of methyl 2-hydroxy-5-propoxybenzene (0,19 g) in dioxane (3.0 ml) was added 4 mol/l aqueous solution of sodium hydroxide (0,67 ml)and then stirred at room temperature for 1 hour and 30 minutes, and then at 55-60°C for 3 hours. The reaction mixture was cooled to room Tempe is atory, and then added a 10% aqueous citric acid solution (15 ml). The solvent is evaporated under reduced pressure, and was added to the residue ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added hexane, and collecting the solid by filtration with the receipt of 0.13 g of 2-hydroxy-5-propoxybenzene acid as a pale yellow solid.

To a solution of the obtained 2-hydroxy-5-propoxybenzene acid (0.12 g) in a mixture of methylene chloride (3.0 ml) and pyridine (0,12 ml) cooled on ice was added acetic anhydride (0,069 ml)and then stirred at room temperature for 2 hours and 30 minutes. To the reaction mixture was added pyridine (0,050 ml) and acetic anhydride (0,058 ml)and then stirred at room temperature for 50 minutes. The solvent is evaporated under reduced pressure, and was added to the obtained residue, 1 mol/l hydrochloric acid and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica compound is a gel [eluent: 65-55% hexane/ethyl acetate] to obtain 0,091 g of 2-acetoxy-5-propoxybenzene acid as a white solid.

1H-NMR(DMSO-d6) δ: 0,98 (3H, t, J=7.4 Hz), 1,67-to 1.79 (2H, m), of 2.21 (3H, s), of 3.96 (2H, t, J=6.5 Hz), to 7.09 (1H, d, J=8,8 Hz), 7,17 (1H, DD, J=8,8, 3.2 Hz), 7,37 (1H, d, J=3.2 Hz), 13,00-13,24 (1H, broadened).

Reference example 10a

To a solution of 3-formyl-4-hydroxyphenylacetate (0.40 g) in 2-butanone (4,0 ml) was sequentially added potassium carbonate (0.40 g) and benzylbromide (0.25 ml)and then heated under reflux for 2 hours. The reaction mixture was cooled to room temperature, and then was added a saturated aqueous solution of sodium bicarbonate and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-85% hexane/ethyl acetate] to obtain 0.36 g of 4-(benzyloxy)-3-formalparameterlist in the form of a colorless oily substance.

To a solution of acetonitrile (3.6 ml)containing 4-(benzyloxy)-3-formalparameterlist (0.36 g), and water (1.5 ml), two-water containing sodium dihydrophosphate (0.51 g)while cooling on ice consistently added 30% hydrogen peroxide solution (of 0.21 ml) and a solution of sodium chlorite (0.18 g) in water (0.5 ml), then stirred at the same is the temperature for 10 minutes, and then at room temperature for 1 hour. To the reaction mixture were added water and methylene chloride. After adjusting the pH to 3.5 by the addition of 6.0 mol/l hydrochloric acid, the organic layer was separated, sequentially washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure obtaining of 0.38 g of 5-(2-acetoxyethyl)-2-(benzyloxy)benzoic acid as a colorless oily substance.

1H-NMR(CDCl3) δ: 2,03 (3H, s)to 2.94 (2H, t, J=6.8 Hz), 4,27 (2H, t, J=6.8 Hz), from 5.29 (2H, s), was 7.08 (1H, d, J=8.6 Hz), 7,38-7,46 (6H, m), 8,08 (1H, d, J=2.2 Hz), 10,75-10,90 (1H, broadened).

Reference example 11a

To a solution of 7-hydroxy-2,3-dihydrobenzo[1,4]dioxin-6-carbaldehyde (0,23 g) in N,N-dimethylformamide (2 ml) was sequentially added potassium carbonate (0.27 g) and benzylbromide (0.17 ml)and then stirred at 65°C for 2 hours. To the reaction mixture was added benzylbromide (0,077 ml)and then stirred at 65°C for 30 minutes. The reaction mixture was cooled to room temperature and then added to her water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue sight of the Ali method column chromatography on silica gel [eluent: 75-60% hexane/ethyl acetate] to obtain 0.32 g of 7-(benzyloxy)-2,3-dihydrobenzo[1,4]dioxin-6-carbaldehyde as a pale yellow solid.

To the suspension obtained 7-(benzyloxy)-2,3-dihydrobenzo[1,4]dioxin-6-carbaldehyde (0.32 g) in acetonitrile (1.6 ml) was added to the solution of two-water sodium dihydrophosphate (0.50 g) in water (0,60 ml)while cooling on ice consistently added 30% hydrogen peroxide solution (0,20 ml) and a solution of sodium chlorite (0.17 g) in water (0,30 ml), then stirred at the same temperature for 15 minutes and then at room temperature for 1 hour and 30 minutes. The pH of the reaction mixture was adjusted to 1.4 by adding 1 mol/l hydrochloric acid, and added to her water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure to obtain 0.34 g of 7-(benzyloxy)-2,3-dihydrobenzo[1,4]dioxin-6-carboxylic acid as a white solid.

1H-NMR(DMSO-d6) δ: 4,17-4,24 (2H, m), 4,25-4,32 (2H, m), 5,11 (2H, s)6,70 (1H, s), 7.23 percent (1H, s), 7,27-7,34 (1H, m), 7,34-7,42 (2H, m), 7,45-7,53 (2H, m), 12,34 (1H, s).

Reference example 12a

The following compound was obtained as described in Reference example 11a.

6-(Benzyloxy)benzo[1,3]dioxol-5-carboxylic acid

1H-NMR(CDCl3) δ: 5,23 (2H, s), 6,04 (2H, s), to 6.67 (1H, s), 7,38-7,46 (5H, m), to 7.59 (1H, s), at 10.64-10,96 (1H, broadened).

Reference example 13a

To a solution of benzyl 2-(benzyloxy)-4-chlorobenzoate (0.35 g) in toluene (5.3 ml) was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.24 g), tribalistas (0,46 g), palladium(II) acetate (4.5 mg) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (4,1 mg)and then heated under reflux in nitrogen atmosphere for 3 hours and 30 minutes. The reaction mixture was cooled to room temperature, then added to 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.16 g), tribalistas (0.25 g), palladium(II) acetate (4.5 mg) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (4,1 mg)and then heated under reflux in nitrogen atmosphere for 3 hours and 30 minutes. After cooling the reaction mixture to room temperature, thereto was added 10% aqueous citric acid solution and ethyl acetate, and removing insoluble substances by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-50% hexane/ethyl acetate] to obtain 0.35 g of the benzyl-2-(benzyloxy)-4-(pyridin-3-yl)benzoate.

To a solution of the obtained benzyl 2-(benzyloxy)-4-(pyridin-3-yl)benzoate (0.35 g) in a mixture of dioxane (1.8 ml) metanol (1.8 ml) was added 2 mol/l aqueous sodium hydroxide solution (1.3 ml), and then was stirred at room temperature for 1 hour. To the reaction mixture were added water. After adjusting the pH to 4.5 by the addition of 6 mol/l hydrochloric acid to the mixture was added ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0.20 g of 2-(benzyloxy)-4-(pyridin-3-yl)benzoic acid as a pale yellow solid.

1H-NMR(DMSO-d6) δ: to 5.35 (2H, s), 7,29-7,44 (4H, m), 7,50-EUR 7.57 (4H, m), 7,78 (1H, d, J=8.0 Hz), 8,12-8,18 (1H, m), to 8.62 (1H, DD, J=4,6, 1.5 Hz), 8,96 (1H, d, J=2.2 Hz).

Reference examples 14a-16a

Compounds shown in Table 6a, obtained as described in Reference example 13a.

Table 6a
Reference example No.Reference example No.Reference example No.
14a15a 16a

2-(Benzyloxy)-4-phenylbenzene acid

1H-NMR(CDCl3) δ: lower than the 5.37 (2H, s), 7,32 (1H, d, J=1.5 Hz), 7,34-7,52 (9H, m), 7,55-to 7.61 (2H, m), compared to 8.26 (1H, d, J=8.0 Hz), to 10.62-10,96 (1H, broadened).

2-(Benzyloxy)-4-(furan-3-yl)benzoic acid

1H-NMR(DMSO-d6) δ: from 5.29 (2H, s),? 7.04 baby mortality-7,07 (1H, m), 7,27 (1H, DD, J=8,1, 1.0 Hz), 7,28 and 7.36 (1H, m), 7,37-7,46 (3H, m), 7,52-7,58 (2H, m), of 7.70 (1H, d, J=8.1 Hz), 7,76-7,81 (1H, m), 8,31-8,35 (1H, m), 12,56 (1H, s).

2-(Benzyloxy)-4-(pyridin-4-yl)benzoic acid

1H-NMR(DMSO-d6) δ: are 5.36 (2H, s), 7,30 and 7.36 (1H, m), 7,38-7,47 (3H, m), 7,51-EUR 7.57 (2H, m), to 7.59 (1H, d, J=1.5 Hz), 7,75-7,81 (3H, m), 8,66-8,71 (2H, m).

Reference example 17a

To a solution of benzyl 2-(benzyloxy)-5-bromobenzoate (0.40 g) in dimethyl ether of ethylene glycol (4 ml) was added water (1.2 ml), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.25 g), sodium bicarbonate (0.21 g) and bis(triphenylphosphine)palladium(II) dichloride (14 mg)and then heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, then added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.12 g), sodium bicarbonate (0.10 g), and bis(triphenylphosphine)palladium(II) dichloride (14 mg)and then heated under reflux in nitrogen atmosphere for 2 hours. After ohlord is of the reaction mixture to room temperature, thereto was added water and ethyl acetate, and removing insoluble substances by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-45% hexane/ethyl acetate] to obtain 0.29 grams benzyl-2-(benzyloxy)-5-(pyridin-4-yl)benzoate as a white solid.

To a solution of the obtained benzyl 2-(benzyloxy)-5-(pyridin-4-yl)benzoate (0.29 grams) in a mixture of dioxane (2.9 ml) and methanol (2.9 ml) was added 2 mol/l aqueous sodium hydroxide solution (1.1 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue water. After adjusting the pH to 4 by addition of 6 mol/l hydrochloric acid was added ethyl acetate. The reaction mixture was filtered to collect the solids with getting to 0.19 g of 2-(benzyloxy)-5-(pyridin-4-yl)benzoic acid as a white solid.

1H-NMR(DMSO-d6) δ: and 5.30 (2H, s), 7,30-7,44 (4H, m), 7,49-of 7.55 (2H, m), 7,69-7,74 (2H, m), of 7.96 (1H, DD, J=8,7, and 2.6 Hz), of 8.06 (1H, d, J=2.7 Hz), 8,58-8,64 (2H, m), 12,85-13,00 (1H, broadened).

Reference example 18a

To a solution of benzyl 2-(benzyloxy)-4-chlorobenzoate (0.35 g) in di is the Xan (3.5 ml) was added bis(pinacolato)LIBOR (0,41 g), potassium acetate (0.25 g), Tris(dibenzylideneacetone)dipalladium(0) (46 mg) and 15% solution of tricyclohexylphosphine in toluene (0.25 ml)and then stirred under nitrogen atmosphere at room temperature for 30 minutes and then at 80°C for 5 hours and 30 minutes. After cooling the reaction mixture to room temperature, thereto was added Tris(dibenzylideneacetone)dipalladium(0) (46 mg) and 15% solution of tricyclohexylphosphine in toluene (0.25 ml)and then stirred in nitrogen atmosphere at 90°C for 8 hours. After cooling the reaction mixture to room temperature, thereto was added saturated aqueous sodium bicarbonate solution and ethyl acetate, and removing insoluble substances by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 100-75% hexane/ethyl acetate] to obtain benzyl 2-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate.

To a solution of the obtained benzyl 2-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate in the dimethyl ether of ethylene glycol (3.5 ml) was added water (1.1 ml), 2-bromopyridine (0,11 ml), sodium carbonate (0.21 g) and dichloride, bis(triphenyltin is n)palladium(II) (14 mg), and then was heated under reflux in nitrogen atmosphere for 1 hour and 30 minutes. After cooling the reaction mixture to room temperature, thereto was added 2-bromopyridine (0,11 ml), sodium carbonate (0.21 g), and dichloride bis(triphenylphosphine)palladium(II) (14 mg)and then heated under reflux in nitrogen atmosphere for 1 hour and 30 minutes. After cooling the reaction mixture to room temperature, thereto was added water and ethyl acetate, and removing insoluble substances by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 100-80% hexane/ethyl acetate] to obtain 0.18 g benzyl-2-(benzyloxy)-4-(pyridin-2-yl)benzoate.

To a solution of the obtained benzyl 2-(benzyloxy)-4-(pyridin-2-yl)benzoate (0.18 g) in a mixture of dioxane (0.9 ml) and methanol (0.9 ml) was added 2 mol/l aqueous solution of sodium hydroxide (0,69 ml)and then stirred at room temperature for 2 hours. To the reaction mixture were added water. After adjusting the pH to 4 by addition of 6 mol/l hydrochloric acid to the mixture was added ethyl acetate. The organic layer was separated, washed with saturated the aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, hexane, and collecting the solid by filtration to obtain 0.12 g of 2-(benzyloxy)-4-(pyridin-2-yl)benzoic acid as a white solid.

1H-NMR(CDCl3) δ: 5,43 (2H, s), 7,31 and 7.36 (1H, m), 7,40-7,53 (5H, m), of 7.69 (1H, DD, J=8,2, 1.5 Hz), 7,78-7,86 (2H, m), 8,02 (1H, d, J=1.5 Hz), 8,30 (1H, d, J=8,2 Hz), 8,71-8,77 (1H, m), 10,70-10,95 (1H, broadened).

Reference examples 19a and 20a

Compounds shown in Table 7a, obtained as described in Reference example 18a.

Table 7a
Reference example No.Reference example No.
19a20a

2-(Benzyloxy)-4-(pyrimidine-2-yl)benzoic acid

1H-NMR(CDCl3) δ: 5,44 (2H, s), 7,30 (1H, t, J=4.9 Hz), 7,40-7,53 (5H, m), of 8.27 (1H, DD, J=8,3, 1.2 Hz), 8,31-at 8.36 (2H, m), 8,87 (2H, d, J=4.9 Hz), 10,75-10,95 (1H, broadened).

2-(Benzyloxy)-4-(pyrimidine-5-yl)benzoic acid

1H-NMR(CDCl3) δ: 5,41 (2H, s), 7,28 (1H, d, J=1.7 Hz), 7,37 (1H, DD, J=8,1) and 1.7 Hz), 7,42-to 7.50 (5H, m), at 8.36 (1H, d, J=8,1 Hz), to 8.94 (2H, s), 9.28 are (1H, s), 10,55-10,70 (1H, broadened).

Reference example 21a

To benzyl 2-(benzyloxy)-5-bromobenzoate (5.3g) was added dioxane (53 ml), bis(pinacolato)LIBOR (4.0 g), potassium acetate (2.6 g) and complex (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and methylene chloride (0.54 g)and then heated under reflux in nitrogen atmosphere for 2 hours and 30 minutes. After cooling the reaction mixture to room temperature, insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 98-82% hexane/ethyl acetate] to obtain of 5.3 g of benzyl 2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate.

To a solution of the obtained benzyl 2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.8 g) in dimethyl ether of ethylene glycol (18 ml) was added water (5.3 ml), 2-bromopyrimidine (0.95 g), sodium carbonate (1.3 g) and dichloride bis(triphenylphosphine)palladium(II) (0.14 g)and then heated under reflux in nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature, then added to it dichloride bis(triphenylphosphine)palladium(II) (0.14 g)and then heated under reflux in almost the re nitrogen for 5 hours. The reaction mixture was cooled to room temperature and then added to her water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 80-50% hexane/ethyl acetate] to obtain 1.4 g of the benzyl-2-(benzyloxy)-5-(pyrimidine-2-yl)benzoate.

To a solution of the obtained benzyl 2-(benzyloxy)-5-(pyrimidine-2-yl)benzoate (1.4 g) in a mixture of dioxane (10 ml) and methanol (5 ml) was added 2 mol/l aqueous sodium hydroxide solution (8.6 ml)and then stirred at room temperature for 4 hours. To the reaction mixture was added toluene, and the separated water layer. After adjusting the pH to 1 by addition of 6 mol/l hydrochloric acid, the solid was collected by filtration to obtain 0.65 g of 2-(benzyloxy)-5-(pyrimidine-2-yl)benzoic acid as a white solid.

1H-NMR(DMSO-d6) δ: 5,31 (2H, s), 7,30 was 7.45 (5H, m), 7,50-EUR 7.57 (2H, m), and 8.50 (1H, DD, J=8,8, 2.4 Hz), a total of 8.74 (1H, d, J=2.4 Hz), 8,88 (2H, d, J=4.9 Hz), 12,82-12,88 (1H, broadened).

Reference example 22a

The following compound was obtained as described in Reference example 21a.

2-(Benzyloxy)-5-(pyrimidine-5-yl)benzoic acid

1H-NMR(DSO-d 6) δ: and 5.30 (2H, s), 7.29 trend was 7.45 (4H, m), 7,49-of 7.55 (2H, m), 7,94 (1H, DD, J=8,8, 2.4 Hz), of 8.04 (1H, d, J=2.4 Hz), 9,13 (2H, s)to 9.15 (1H, s), 12,93 (1H, s).

Reference example 23a

To a solution of methyl 2-(benzyloxy)-4-identity (0.20 g) in dimethyl sulfoxide (1.5 ml) was added 1H-pyrazole (0,044 g), D-Proline (0,013 g), potassium carbonate (0.15 g) and copper iodide(I) (0,010 g)and then stirred in nitrogen atmosphere at 90°C for 2 hours. The reaction mixture was cooled to room temperature, then added to it D-Proline (0,013 g) and copper iodide(I) (0,010 g)and then stirred in nitrogen atmosphere at 100°C for 2 hours. After cooling the reaction mixture to room temperature, thereto was added water and ethyl acetate, and removing insoluble substances by filtration. The organic layer was separated, sequentially washed with water and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 100-60% hexane/ethyl acetate] to obtain 0.12 g of methyl 2-(benzyloxy)-4-(1H-pyrazole-1-yl)benzoate as a white solid.

To a solution of the obtained methyl 2-(benzyloxy)-4-(1H-pyrazole-1-yl)benzoate (0.11 g) in a mixture of dioxane (1.1 ml) and methanol (1.1 ml) was added 2 mol/l aqueous solution of Hydra is xida sodium high (0.56 ml), and then was stirred at room temperature for 2 hours. To the reaction mixture were added water. After adjusting the pH to 3 by addition of 6 mol/l hydrochloric acid was added ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, hexane, and collecting the solid by filtration to obtain 0.10 g of 2-(benzyloxy)-4-(1H-pyrazole-1-yl)benzoic acid as a white solid.

1H-NMR(CDCl3) δ: of 5.39 (2H, s), 6,50-to 6.57 (1H, m), 7,34 (1H, DD, J=8,6 and 2.2 Hz), 7,40-7,51 (5H, m), 7,74-7,80 (2H, m), 8,01 (1H, d, J=2.2 Hz), of 8.28 (1H, d, J=8.6 Hz), 10,50-10,70 (1H, broadened).

Reference example 24a

The following compound was obtained as described in Reference example 23a.

2-(Benzyloxy)-5-(1H-pyrazole-1-yl)benzoic acid

1H-NMR(CDCl3) δ: to 5.35 (2H, s), of 6.49 (1H, DD, J=2,4, 1.9 Hz), 7.23 percent-7,28 (1H, m), 7,41-of 7.48 (5H, m), 7,72 (1H, d, J=1.4 Hz), 7.95 is-to 7.99 (1H, m), 8,07 (1H, DD, J=9,0, 2,9 Hz), 8,39 (1H, d, J=2,9 Hz), 10,75-10,90 (1H, broadened).

Reference example 25a

To a solution of methyl 2-(benzyloxy)-4-identity (0.20 g) in dimethyl sulfoxide (1 ml) was added 1H-imidazole (0,044 g), D-Proline (0,013 g), potassium carbonate (0.15 g) and copper iodide(I) (0,010 g), then p is remedial in nitrogen atmosphere at 90°C for 1 hour. The reaction mixture was cooled to room temperature, then added to it dimethylsulfoxide (0.5 ml), D-Proline (0,013 g) and copper iodide(I) (0,010 g)and then stirred in nitrogen atmosphere at 90°C for 2 hours. After cooling the reaction mixture to room temperature, thereto was added water and ethyl acetate, and removing insoluble substances by filtration. The organic layer was separated, sequentially washed with water and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-20% hexane/ethyl acetate] to obtain of 0.13 g of methyl 2-(benzyloxy)-4-(1H-imidazol-1-yl)benzoate as a white solid.

To a solution of the obtained methyl 2-(benzyloxy)-4-(1H-imidazol-1-yl)benzoate (0,13 g) in a mixture of dioxane (0,65 ml) and methanol (0,65 ml) was added 2 mol/l aqueous solution of sodium hydroxide (0.63 ml)and then stirred at room temperature for 3 hours. While cooling on ice to the reaction mixture was added 6 mol/l hydrochloric acid (to 0.21 ml)and the solvent evaporated under reduced pressure. To the obtained residue was added water, and collecting the solid by filtration. To the obtained solid substance was added to the dioxane (1 ml) and 4 mol/l solution of florodora in dioxane (0.5 ml), and then was stirred at room temperature for 1 hour. The solid substance was collected from the reaction mixture by filtration to obtain 0,097 g of the hydrochloride of 2-(benzyloxy)-4-(1H-imidazol-1-yl)benzoic acid as a white solid.

1H-NMR(DMSO-d6) δ: 5,33 (2H, s), 7,32-7,38 (1H, m), 7,39 was 7.45 (2H, m), 7,47 (1H, DD, J=8,3, 2.0 Hz), 7,50-of 7.55 (2H, m), 7,71 (1H, d, J=2.0 Hz), 7,86-to $ 7.91 (2H, m), 8,35 (1H, s)9,68 (1H, s).

Reference example 26a

3-chlorosalicylic acid (0,92 g) was sequentially added N,N-dimethylacetamide (9,2 ml), potassium carbonate (2.2 g) and benzylbromide (1,4 ml)and then stirred at 80°C for 1 hour. The reaction mixture was cooled to room temperature, then added to it the potassium carbonate (0,37 g) and benzylbromide (0,19 ml)and then stirred at 80°C for 1 hour. The reaction mixture was cooled to room temperature, and then was added a 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, sequentially washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 100-95% hexane/ethyl acetate to obtain 1.8 g of the benzyl-2-(benzyloxy)-3-chlorobenzoate in the form of a colorless oily substance.

To a solution of the obtained benzyl 2-(benzyloxy)-3-chlorobenzoate (0.35 g) in toluene (5.3 ml) was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.25 g), tribalistas (0,47 g), palladium(II) acetate (4.5 mg) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (4,1 mg)and then heated under reflux in nitrogen atmosphere for 1 hour and 40 minutes. The reaction mixture was cooled to room temperature, then added to 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.12 g), tribalistas (0,23 g), palladium(II) acetate (4.5 mg) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (4,1 mg)and then heated under reflux in nitrogen atmosphere for 3 hours. After cooling the reaction mixture to room temperature, thereto was added 10% aqueous citric acid solution and ethyl acetate, and removing insoluble substances by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-65% hexane/ethyl acetate] to obtain 0.35 g of the benzyl-2-(benzyloxy)-3-(pyridin-3-yl)benzoate.

To a solution of the obtained benzyl 2-(benzyloxy)-3-(pyridin-3-yl)benzoate (0.35 g) in a mixture of dioxane (3.5 ml)and methanol (3.5 ml) was added 2 mol/l aqueous sodium hydroxide solution (1.3 ml), and then was stirred at room temperature for 1 hour. To the reaction mixture was added 2 mol/l aqueous sodium hydroxide solution (1.3 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue water. After adjusting the pH to 4.5 by the addition of 6 mol/l hydrochloric acid was added ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0.18 g of 2-(benzyloxy)-3-(pyridin-3-yl)benzoic acid as a white solid.

1H-NMR(CDCl3) δ: br4.61 (2H, s), 7,02-was 7.08 (2H, m), 7,22-7,39 (3H, m), 7,39-7,47 (2H, m), a 7.62 (1H, DD, J=7,6, 2.0 Hz), 7,95 (1H, DDD, J=7,8, 2,0, 2,0 Hz), 8,21 (1H, DD, J=7,9, 1.8 Hz), 8,72 (1H, DD, J=4,9, 1,4 Hz), cent to 8.85-of 8.90 (1H, m).

Reference example 27a

The following compound was obtained as described in Reference example 26a.

2-(Benzyloxy)-3-(pyridin-4-yl)benzoic acid

1H-NMR(CDCl3) δ: to 4.62 (2H, s), 7.03 is-was 7.08 (2H, m), 7.23 percent-7,38 (3H, m), the 7.43 (1H, DD, J=7,8, and 7.8 Hz), 7,54-7,58 (2H, m), a 7.62 (1H, DD, J=7,7, 1.8 Hz), 8,23 (1H, DD, J=7,9, 1.8 Hz), a total of 8.74-8,78 (2H, m).

Reference example 28a

To a solution of 5-formyl-2-hydroxybenzoic acid (0.50 g) in N,N-dimethylformamide (5 ml) was sequentially added potassium carbonate (1.2 g) and benzylbromide (0,79 ml), then stirred at room temperature for 10 minutes and then at 100°C for 2 hours. The reaction mixture was cooled to room temperature and then added to her water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, the solid collected by filtration to obtain 0,93 g of benzyl 2-(benzyloxy)-5-formylbenzoate in the form of a white solid.

To the suspension obtained benzyl 2-(benzyloxy)-5-formylbenzoate (0,93 g) in methanol (9 ml) was added para-toluensulfonate (0.55 g) and potassium carbonate (0.39 g)and then heated under reflux for 1 hour and 40 minutes. The reaction mixture was cooled to room temperature, then added to it a pair-toluensulfonate (0,079 g) and potassium carbonate (0,058 g)and then heated under reflux for 1 hour 30 minutes. The reaction mixture was cooled to room temperature and then added to her water and ethyl acetate. The organic layer was separated, washed the feast upon the major aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 70-50% hexane/ethyl acetate] to obtain 0.56 g of methyl 2-(benzyloxy)-5-(oxazol-5-yl)benzoate as a pale yellow solid.

To a solution of the obtained methyl 2-(benzyloxy)-5-(oxazol-5-yl)benzoate (0.55 g) in dioxane (5 ml) was added 2 mol/l aqueous solution of sodium hydroxide (4.5 ml)and then stirred at room temperature for 2 hours and 40 minutes. The solvent is evaporated under reduced pressure, and was added to the residue water. After adjusting the pH to 4.0 by the addition of 6 mol/l hydrochloric acid, the solid was collected by filtration to obtain and 0.46 g of 2-(benzyloxy)-5-(oxazol-5-yl)benzoic acid as a pale yellow solid.

1H-NMR(DMSO-d6) δ: 5,27 (2H, s), 7,28 was 7.45 (4H, m), 7,47-of 7.55 (2H, m), the 7.65 (1H, s), to 7.84 (1H, DD, J=8,7, and 2.1 Hz), to 7.99 (1H, d, J=2.1 Hz), to 8.41 (1H, s), to 12.95 (1H, s).

Reference example 29a

To a suspension of 4-(benzyloxy)-3-(benzyloxycarbonyl)benzoic acid (0.50 g) in methylene chloride (5 ml) was added N,N-dimethylformamide (0,011 ml) and oxacillin (of 0.18 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue toluene. Dissolve the al evaporated under reduced pressure, and was added to the residue dioxane (5 ml). The resulting mixture was added to a solution of hydrazine monohydrate (of 0.67 ml) in water (6,7 ml)and then stirred at room temperature for 30 minutes. The solid substance was collected from the reaction mixture by filtration, and washed obtained solid substance ethanol with the receipt of 0.38 g of benzyl 2-(benzyloxy)-5-(hydrazinophenyl)benzoate as a pale yellow solid.

The suspension obtained benzyl 2-(benzyloxy)-5-(hydrazinophenyl)benzoate (0.20 g) in trimethyl-orthoformate (2 ml) was heated under reflux for 1 hour 30 minutes. The reaction mixture was cooled to room temperature, and then the solvent evaporated under reduced pressure. To the obtained residue were added ethyl acetate and diisopropyl ether, and collected 0.16 g solids by filtration. The obtained solid (0.11 g) was stirred at 200°C for 15 minutes. The reaction mixture was cooled to room temperature and then purified according to the method of column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-50% hexane/ethyl acetate] to obtain 0,079 g of benzyl 2-(benzyloxy)-5-(1,3,4-oxadiazol-2-yl)benzoate as a white solid.

1H-NMR(CDCl3) δ: of 5.26 (2H, s)5,38 (2H, s), 7,16 (1H, d, J=8,8 Hz), 7,30-7,47 (10H, m), 8,18 (1H, DD, J=8,8, 2.3 Hz), 8,43 (1H, s), 8,53 (1H, d, J=2.3 Hz).

References : the first example 30a

The following compound was obtained as described in Reference example 8a.

2-(Benzyloxy)-5-(1,3,4-oxadiazol-2-yl)benzoic acid

1H-NMR(DMSO-d6) δ: 5,33 (2H, s), 7,30-7,37 (1H, m), 7,38-7,47 (3H, m), 7,49-of 7.55 (2H, m), 8,13 (1H, DD, J=8,8, 2.3 Hz), of 8.28 (1H, d, J=2.3 Hz), 9,31 (1H, s).

Reference example 31a

To a solution of benzyl 2-(benzyloxy)-5-bromobenzoate (3.0 g) in toluene (30 ml) was added piperidine (1.1 ml), cesium carbonate (4.9 g), Tris(dibenzylideneacetone)dipalladium(0) (0,069 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (0.18 g) and palladium(II) acetate (0,034 g)and then heated under reflux in nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature, then added to it piperidine (0,37 ml), cesium carbonate (1.2 g), Tris(dibenzylideneacetone)dipalladium(0) (0,069 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (0.18 g) and palladium(II) acetate (0,034 g)and then heated under reflux in nitrogen atmosphere for 5 hours and 30 minutes. After cooling the reaction mixture to room temperature, thereto was added water and ethyl acetate, and removing insoluble substances by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated in conditions below the aqueous pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-80% hexane/ethyl acetate] to obtain 2.4 g of the benzyl-2-(benzyloxy)-5-(piperidine-1-yl)benzoate as a pale yellow solid.

To a solution of the obtained benzyl 2-(benzyloxy)-5-(piperidine-1-yl)benzoate (2.2 g) in a mixture of dioxane (11 ml), ethyl acetate (17 ml) and methanol (5.5 ml)was added 10% palletirovanie coal (1.1 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture was added tetrahydrofuran, and removing insoluble substances by filtration. The solvent is evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 1.1 g of 2-hydroxy-5-(piperidine-1-yl)benzoic acid as a pale yellow solid.

To the obtained 2-hydroxy-5-(piperidine-1-yl)benzoic acid (0,90 g), was added methylene chloride (9.0 ml), pyridine (0,82 ml) and acetic anhydride (0,46 ml)and then stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, and added a 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. the content of inorganic fillers layer and the extract were combined, the resulting mixture was sequentially washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid substance was collected by filtration to obtain 0.55 g of 2-acetoxy-5-(piperidine-1-yl)benzoic acid as a pale yellow solid.

1H-NMR(CDCl3) δ: 1,55-to 1.63 (2H, m), 1,67-to 1.77 (4H, m), 2,31 (3H, s), 3,15-up 3.22 (4H, m), of 6.99 (1H, d, J=8,8 Hz), 7,11-7,20 (1H, m), 7,60 (1H, d, J=2,9 Hz).

Reference example 32a

To a solution of methyl 2,4-dihydroxybenzoate (0.25 g) in N,N-dimethylacetamide (5 ml) was added potassium carbonate (0.31 g) and 1-(methylsulphonyl)piperidine-4-yl methanesulfonate (0,46 g)and then stirred at 90°C for 1 hour. The reaction mixture was cooled to room temperature, then added to it sodium iodide (0,045 g)and then stirred at 90°C for 1 hour. The reaction mixture was cooled to room temperature, then added to it the potassium carbonate (0.10 g) and 1-(methylsulphonyl)piperidine-4-yl methanesulfonate (0.12 g)and then stirred at 90°C for 1 hour. The reaction mixture was cooled to room temperature, and then was added a 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, sequentially washed with 10%aqueous citric acid solution and saturated aqueous sodium chloride, was dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-60% hexane/ethyl acetate] to obtain 0,19 g of methyl 2-hydroxy-4-((1-(methylsulphonyl)piperidine-4-yl)oxy)benzoate as a white solid.

To a solution of the obtained methyl 2-hydroxy-4-((1-(methylsulphonyl)piperidine-4-yl)oxy)benzoate (0,19 g) in a mixture of dioxane (0.95 ml) and methanol (0.95 ml) was added 2 mol/l aqueous solution of sodium hydroxide (0,87 ml)and then stirred at room temperature for 3 hours. To the reaction mixture was added 2 mol/l aqueous solution of sodium hydroxide (0,58 ml)and then heated under reflux for 1 hour 30 minutes. The reaction mixture was cooled to room temperature and then added to her water. After adjusting the pH to 3 by addition of 6 mol/l hydrochloric acid was added ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain 0.18 g of 2-hydroxy-4-((1-(methylsulphonyl)piperidine-4-yl)oxy)benzoic acid as a white solid.

When cooled on ice to a suspension of the obtained 2-hydroxy-4-((1(methylsulphonyl)piperidine-4-yl)oxy)benzoic acid (0.18 g) in methylene chloride (1.8 ml) was sequentially added pyridine (0,12 ml) and acetic anhydride (0,065 ml), and then was stirred at room temperature for 1 hour. While cooling on ice to the reaction mixture was sequentially added pyridine (0,023 ml) and acetic anhydride (0,016 ml)and then stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, and added to the remainder of 1 mol/l hydrochloric acid and ethyl acetate. The organic layer was separated, sequentially washed with 1 mol/l hydrochloric acid, water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0.18 g of 2-acetoxy-4-((1-(methylsulphonyl)piperidine-4-yl)oxy)benzoic acid as a white solid.

1H-NMR(CDCl3) δ: 1,97-to 2.13 (4H, m), of 2.34 (3H, s), 2,82 (3H, s), 3.27 to 3,47 (4H, m), 4,59-of 4.67 (1H, m), 6,63 (1H, d, J=2.5 Hz), at 6.84 (1H, DD, J=8,8, 2,5 Hz), 8,07 (1H, d, J=8,8 Hz).

Reference example 33a

To 2-hydroxy-5-(piperidine-4-yl)benzoic acid (1.6 g) was added 2 mol/l aqueous solution of sodium hydroxide (25 ml) and (di-tert-butyl)dicarbonate (2.1 g)and then stirred at room temperature for 19 hours. The pH of the reaction mixture was adjusted to 3.0 by adding 10% aqueous citric is islote, and then collect the solid by filtration. To a solution of the obtained solid in N,N-dimethylacetamide (20 ml) was sequentially added potassium carbonate (2.6 g) and benzylbromide (1.6 ml)and then stirred at 55°C for 1 hour and 45 minutes. The reaction mixture was cooled to room temperature and then added to her water and chloroform. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel (AB., KP-Sil, eluent: 97-80% chloroform/methanol), and then purified according to the method of column chromatography [Biotage AB, KP-Sil, eluent: 95-80% hexane/ethyl acetate], to obtain the 0,42 g of tert-butyl 4-(4-(benzyloxy)-3-(benzyloxycarbonyl)phenylpiperidine-1-carboxylate as a colorless oily substance.

1H-NMR(CDCl3) δ: to 1.48 (9H, s), 1,50-of 1.65 (2H, m), 1,72 of-1.83 (2H, m), 2,54-of 2.66 (1H, m), 2,68-of 2.86 (2H, m), 4,14-4,32 (2H, m), 5,14 (2H, s), to 5.35 (2H, s), of 6.96 (1H, d, J=8.6 Hz), 7,21 was 7.45 (11H, m), to 7.67 (1H, d, J=2,4 Hz).

Reference example 34a

The following compound was obtained as described in Reference example 8a.

2-(Benzyloxy)-5-(1-(tert-butoxycarbonyl)piperidine-4-yl)benzoic acid

1H-NMR(DMSO-d6) δ: 1,34 of 1.50 (2H, m)of 1.41 (9H, s), 1,67-to 1.79 (2H, m), 2,60-2,90 (3H, m), 3,9-4,13 (2H, m)to 5.17 (2H, s), 7,11 (1H, d, J=8.6 Hz), 7,27-7,42 (4H, m), 7,44-7,52 (3H, m), br12.62 (1H, s).

Reference example 35a

To a solution of tert-butyl 4-bromo-2-nitrobenzoate (3.0 g) in dimethyl ether of ethylene glycol (30 ml) was added water (9.0 ml), sodium carbonate (2.6 g), 2-methoxyphenylalanine acid (1.8 g) and dichloride bis(triphenylphosphine)palladium(II) (0.14 g)and then heated under reflux in nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then was added a 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 99-91% hexane/ethyl acetate] to obtain 3.3 g of tert-butyl 4-(2-methoxyphenyl)-2-nitrobenzoate as a pale yellow oily substance.

1H-NMR(CDCl3) δ: was 1.58 (9H, s), 3,83 (3H, s), 6,99? 7.04 baby mortality (1H, m),? 7.04 baby mortality-7,10 (1H, m), 7,32 (1H, DD, J=7,6, 1.7 Hz), 7,40 (1H, DDD, J=8,3, to 7.6 and 1.7 Hz), 7,73-to 7.77 (1H, m), 7,78 (1H, DD, J=7,9, and 1.6 Hz), 8,01 (1H, d, J=1.0 Hz).

Reference example 36a

To a solution of tert-butyl 4-bromo-2-nitrobenzoate (0.15 g) in dimethyl ether of ethylene glycol (2.0 ml) was added water (0.6 ml), sodium carbonate (0.16 g), the pet-butyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (0,19 g) and tetrakis(triphenylphosphine)palladium(0) (29 mg), and then was heated under reflux in nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature and then added to it the ethyl acetate and 10% aqueous citric acid solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 91-80% hexane/ethyl acetate] to obtain 0.21 g of tert-butyl 4-(2-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate as a yellow solid.

1H-NMR(CDCl3) δ: of 1.46 (9H, s)to 1.60 (9H, s), 6,14-to 6.22 (1H, broadened), 7,16-of 7.23 (2H, m), 7,38 was 7.45 (1H, m), to 7.67 (1H, DD, J=8,1) and 1.7 Hz), to 7.84 (1H, d, J=8.1 Hz), the 7.85 (1H, d, J=1.7 Hz), of 7.96 (1H, d, J=8,5 Hz).

Reference example 37a

The following compound was obtained as described in Reference example 36a.

Methyl-4-(furan-2-yl)-2-nitrobenzoate

1H-NMR(CDCl3) δ: to 3.92 (3H, s), 6,55 (1H, DD, J=3,4, 1.7 Hz), 6.87 in (1H, d, J=3,4 Hz), EUR 7.57 (1H, d, J=1.7 Hz), 7,80 (1H, d, J=8.1 Hz), 7,88 (1H, DD, J=8,1) and 1.7 Hz), 8,08 (1H, d, J=1.7 Hz).

Reference example 38a

To a solution of methyl-4-chloro-2-nitrobenzoate (0,90 g) in dimethyl ether of ethylene glycol (10 ml) was added water (3.0 ml), sodium carbonate (1.1 g), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dio is Sabalan-2-yl)phenylcarbamate (1.5 g) dichloride and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) (30 mg), and then was heated under reflux in nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature and then added to it the ethyl acetate and 10% aqueous citric acid solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-85% hexane/ethyl acetate] to obtain 1.5 g of methyl 4-(2-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate as a pale yellow solid.

1H-NMR(CDCl3) δ: of 1.45 (9H, s), of 3.97 (3H, s), 6,13-6,21 (1H, broadened), 7,17-of 7.25 (2H, m), 7,40-7,46 (1H, m), 7,71 (1H, DD, J=8,1) and 1.7 Hz), 7,86 (1H, d, J=8.1 Hz), to $ 7.91-of 7.97 (2H, m).

Reference example 39a

The following compound was obtained as described in Reference example 38a.

Methyl-4-(furan-3-yl)-2-nitrobenzoate

1H-NMR(DMSO-d6) δ: of 3.85 (3H, s), 7,15-7,22 (1H, m), to 7.84 (1H, DD, J=1,7, 1,7 Hz), 7,92 (1H, d, J=8.1 Hz), 8,07 (1H, DD, J=8,1) and 1.7 Hz), 8,30 (1H, d, J=1.7 Hz), 8,49-8,55 (1H, m).

Reference example 40a

When cooled on ice to a solution of methyl-4-(2-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate (1.3 g) in N,N-dimethylformamide (15 ml) was added 60% sodium hydride (0.21 g)and then stirred at the room for the Noah temperature for 10 minutes. Then, while cooling on ice to the mixture was added methyliodide (0,32 ml)and then stirred at room temperature for 1 hour. To the reaction mixture was added water, 10% aqueous citric acid solution and diethyl ether. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-85% hexane/ethyl acetate] to obtain 1.1 g of methyl 4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)-2-nitrobenzoate as a pale yellow solid.

1H-NMR(CDCl3) δ: 1,17 was 1.43 (9H, m), 2,94-is 3.08 (3H, m), of 3.94 (3H, s), 7.24 to 7,31 (1H, m), 7,33-7,41 (2H, m), 7,42-7,49 (1H, m), 7,60-7,72 (1H, m), 7,80 (1H, d, J=7.8 Hz), 7,89 (1H, d, J=1.5 Hz).

Reference example 41a

The following compound was obtained as described in Reference example 40a.

Methyl-4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)-2-nitrobenzoate

1H-NMR(CD3OD) δ: of 1.06 (3H, t, J=7,1 Hz), 1,22-of 1.45 (9H, m), 2,85 was 3.05 (1H, m), 3,50-3,70 (1H, m), 3,91 (3H, s), 7,26-7,39 (1H, m), 7,42-rate of 7.54 (3H, m), 7,72-7,80 (1H, m), 7,88 (1H, d, J=7.8 Hz), of 7.90-7,98 (1H, m).

Reference example 42a

To a solution of tert-butyl 4-(2-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate (0.27 g) in acetone (4.0 ml) was added potassium carbonate (0,16g) and dimethylsulfate (0,094 ml), and then was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and then added to her water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-85% hexane/ethyl acetate], and then purified according to the method of column chromatography [eluent: 91-85% hexane/ethyl acetate] to obtain 0,061 g of tert-butyl 4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)-2-nitrobenzoate as a colorless oily substance.

1H-NMR(DMSO-d6) δ: 0,99 of 1.28 (9H, m)and 1.51 (9H, m), 3.00 and-3,11 (3H, m), 7,39-rate of 7.54 (4H, m), 7,74 (1H, d, J=8,3 Hz), 7,83-7,94 (2H, m).

Reference example 43a

To a solution of tert-butyl 4-(2-methoxyphenyl)-2-nitrobenzoate (3.3 grams) in a mixture of 2-propanol (40 ml), water (10 ml) and acetic acid (2.6 ml), was added sodium formate (2.7 g) and 10% palletirovanie coal (0.65 g)and then heated under reflux for 2 hours. The reaction mixture was cooled to room temperature, and then remove insoluble substances by filtration. The solvent is evaporated under reduced pressure, and was added to the residue saturated water races is the thief of sodium bicarbonate and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 99-91% hexane/ethyl acetate] to obtain 3.0 g of tert-butyl 2-amino-4-(2-methoxyphenyl)benzoate as a white oily substance.

1H-NMR(CDCl3) δ: equal to 1.59 (9H, s), of 3.80 (3H, s), 5,65-5,78 (2H, extended), 6,77-6,83 (2H, m), 6,97 (1H, d, J=8.0 Hz), 7,01 (1H, DD, J=7,4, 7,4 Hz), 7,27 was 7.36 (2H, m), 7,81-7,87 (1H, m).

Reference example 44a

To a solution of tert-butyl 4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)-2-nitrobenzoate (0,057 g) in a mixture of ethyl acetate (2.5 ml) and methanol (2.5 ml) was added 10% palletirovanie coal (to 0.011 g). The mixture was stirred in hydrogen atmosphere at room temperature for 3 hours. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-85% hexane/ethyl acetate] to obtain 0,048 g of tert-butyl 2-amino-4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)benzoate as a white solid.

1H-NMR(DMSO-d6) δ: 1,02-to 1.38 (9H, m), and 1.54 (9H, s), 2,83 was 3.05 (3H, m), 6,44 (1H, DD, J=8,2, 1.3 Hz), 6,56-6,74 (3H, m), 7,26-the 7.43 (4H, m), to 7.61-of 7.70 (1H, m).

Compounds shown in table 8a, obtained as described in Reference example 44a.

Table 8a
Reference example No.R3Reference example No.R3
45a46a

Methyl-2-amino-4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)benzoate

1H-NMR(CD3OD) δ: 0,96-1,11 (3H, m), 1,24 of 1.50 (9H, m), 2.77-to 2,95 (1H, m), 3.45 points of 3.75 (1H, m), 3,86 (3H, s), 6,56 (1H, DD, J=8,3) and 1.7 Hz), was 6.73 (1H, d, J=1.7 Hz), 7,17-7,27 (1H, m), 7,33-7,42 (3H, m), 7,75-7,83 (1H, m).

Methyl-2-amino-4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)benzoate

1H-NMR(CDCl3) δ: 1,21-for 1.49 (9H, m), 2,80 totaling 3.04 (3H, m)to 3.89 (3H, s), 6,60-6,72 (2H, m), 7,17-of 7.23 (1H, m), 7.24 to 7,40 (3H, m), 7,83-to $ 7.91 (1H, m).

Reference example 47a

To a suspension of methyl 4-(furan-2-yl)-2-nitrobenzoate (0.14 g) in ethanol (2.1 ml) was added water (0,56 ml), ammonium chloride (18 mg) and iron powder (94 mg)and then heated under reflux for 2 hours 30 minutes. The reaction mixture was cooled to room temperature, then added the to her ammonium chloride (18 mg), powdered iron (31 mg) and water (0,28 ml)and then heated under reflux for 1 hour. The reaction mixture was cooled to room temperature, and then the solvent evaporated under reduced pressure. To the obtained residue was added saturated aqueous sodium bicarbonate solution and ethyl acetate, and removing insoluble substances by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 99-95% hexane/ethyl acetate] to obtain 78 mg of methyl 2-amino-4-(furan-2-yl)benzoate as a pale yellow solid.

1H-NMR(CDCl3) δ: 3,88 (3H, s), 5,72 and 5.86 (2H, extended), of 6.49 (1H, DD, J=3.3, which is 1.8 Hz), 6,72 (1H, d, J=3.3 Hz), 6,94 (1H, DD, J=8,5) and 1.7 Hz), of 6.99 (1H, d, J=1.7 Hz), 7,47-7,51 (1H, m), 7,86 (1H, d, J=8,5 Hz).

Reference example 48a

The following compound was obtained as described in Reference example 47a.

Methyl-2-amino-4-(furan-3-yl)benzoate

1H-NMR(DMSO-d6) δ: of 3.78 (3H, s), 6,61-6,70 (2H, extended), to 6.80 (1H, DD, J=8,6) and 1.7 Hz), at 6.84 (1H, DD, J=1,8,0,7 Hz), 6,97 (1H, d, J=1.7 Hz), of 7.70 (1H, d, J=8.6 Hz), 7,76 (1H, DD, J=1,8) and 1.7 Hz), 8,15-8,19 (1H, m).

Reference example 49a

To the solution met the l-5-amino-2-(benzyloxy)benzoate (4.6 g) in N,N-dimethylformamide (23 ml), was added potassium carbonate (5.1 g) and 1,5-dibromethane (2.5 ml), and then was stirred at 50-55°C for 1 hour at 55-60°C for 1 hour, at 70°C for 1 hour and 30 minutes, and then at 75-80°C for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature and then added to her water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-65% hexane/ethyl acetate] to obtain 4.3 g of methyl 2-(benzyloxy)-5-(piperidine-1-yl)benzoate as a pale yellow oily substance.

To a solution of the obtained methyl 2-(benzyloxy)-5-(piperidine-1-yl)benzoate (4.3 g) in dioxane (45 ml) was added 4 mol/l aqueous sodium hydroxide solution (9.8 ml)and then stirred at room temperature for 1 hour and then at 50-55°C for 2 hours. After cooling the reaction mixture to room temperature, the pH value of the reaction mixture was adjusted to 6.3 by the addition of acetic acid, and the solvent evaporated under reduced pressure. To the obtained residue was added water, and collecting the solid by filtration to obtain 3.7 g of 2-(benzyloxy)-5-(piperidine-1-yl)benzoic acid as white solid which substances.

1H-NMR(CDCl3) δ: 1,52-of 1.62 (2H, m)of 1.65 to 1.76 (4H, m), is 3.08-and 3.16 (4H, m), 5,23 (2H, s), 7,03 (1H, d, J=9.0 Hz), 7,08-7,16 (1H, m), of 7.36 was 7.45 (5H, m), of 7.75 (1H, d, J=3.2 Hz).

Reference example 50a

When cooled on ice to a solution of 2-(benzyloxy)-5-(piperidine-1-yl)benzoic acid (2.5 g) in a mixture of methylene chloride (25 ml) and N,N-dimethylformamide (0,050 ml) was added oxalicacid (0,96 ml)and then stirred at room temperature for 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (25 ml). Then, while cooling on ice, the mixture was added to a solution of tert-butyl 2-amino-4-bromobenzoate (2.0 g) in a mixture of pyridine (0,89 ml) and methylene chloride (20 ml)and then stirred at room temperature for 1 hour and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 80-70% hexane/ethyl acetate] to obtain 3.8 g of tert-butyl 2-(2-(benzyloxy)-5-(piperidine-1-yl)benzamido)-4-bromobenzoate in the form of a yellow firmly what about the substance.

1H-NMR(DMSO-d6) δ: 1,44-and 1.54 (2H, m)of 1.46 (9H, s), 1,57-of 1.66 (4H, m), 2,99-is 3.08 (4H, m), of 5.39 (2H, s),? 7.04 baby mortality-7,14 (2H, m), 7,21-7,34 (3H, m), 7,38-to 7.50 (4H, m), 7,86-a 7.92 (1H, m), 9,00-9,05 (1H, m), 12,17 (1H, s).

Reference example 51a

To 2-(benzyloxy)-5-(pyridin-3-yl)benzoic acid (0.31 g) was added triperoxonane acid (6.0 ml)and then stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the obtained residue, ethyl acetate. The solid substance was collected by filtration to obtain 2-hydroxy-5-(pyridin-3-yl)benzoic acid as a white solid.

To the obtained 2-hydroxy-5-(pyridin-3-yl)benzoic acid was sequentially added methylene chloride (5.0 ml), pyridine (0.25 ml) and acetic anhydride (0,19 ml)and then heated under reflux for 1 hour. The reaction mixture was cooled to room temperature, then added to it pyridine (0,082 ml) and acetic anhydride (0,095 ml)and then heated under reflux for 30 minutes. The reaction mixture was cooled to room temperature, and then the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 99-93% chloroform/methanol] to obtain 0.035 g of 2-acetoxy-5-(PI is one-3-yl)benzoic acid as a white solid.

1H-NMR(DMSO-d6) δ: 2,28 (3H, s), 7,35 (1H, d, J=8,4 Hz), 7,52 (1H, DD, J=8.0 a, 4,8 Hz), 8,00 (1H, DD, J=8,4, 2.4 Hz), 8,13 (1H, DDD, J=8.0 a, 2,2, 1.8 Hz), 8,19 (1H, d, J=2.4 Hz), to 8.62 (1H, DD, J=4,8, 1.8 Hz), of 8.92 (1H, d, J=the 2.2 Hz), 13,10-13,60 (1H, broadened).

Reference example 52a

To a solution of 5-bromo-4-fluoro-2-methylaniline (1,74 g) in methylene chloride (17 ml) was sequentially added pyridine (1.0 ml) and acetylchloride (of 0.67 ml)and then stirred at room temperature for 1 hour. To the reaction mixture was added water, 1 mol/l hydrochloric acid and chloroform. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. Hexane was added to the obtained residue, and collecting the solid by filtration to obtain to 1.83 g of N-(5-bromo-4-fluoro-2-were)ndimethylacetamide in the form of a white solid.

1H-NMR(DMSO-d6) δ: to 2.06 (3H, s)to 2.18 (3H, s), 7,27 (1H, d, J=9.5 Hz), 7,74 (1H, d, J=6.8 Hz), 9,38 (1H, s).

Reference example 53a

When heated under reflux to a solution of N-(5-bromo-4-methoxy-2-were)ndimethylacetamide (1.0 g) in a mixture of water (10 ml), tert-butyl alcohol (10 ml) and magnesium sulfate (0,79 g) was added potassium permanganate (0,98 g)and then heated under reflux in nitrogen atmosphere for 6 hours is 20 minutes. After cooling the reaction mixture to room temperature, insoluble substances were removed by filtration. The solvent is evaporated under reduced pressure, and was added to the residue water and ethyl acetate. The aqueous layer was separated and was added 1 mol/l hydrochloric acid (4 ml) and chloroform. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resulting mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid substance was collected by filtration to obtain 0.36 g of 2-(acetamido)-4-bromo-5-methoxybenzoic acid as a white solid.

1H-NMR(DMSO-d6) δ: 2,11 (3H, s), 3,86 (3H, s), 7,53 (1H, s), 8,68 (1H, s), 10,78 (1H, s).

Reference example 54a

The following compound was obtained as described in Reference example 53a.

2-(Acetamido)-4-bromo-5-Formentera acid

1H-NMR(DMSO-d6) δ: 2,14 (3H, s), 7,81 (1H, d, J=9.3 Hz), 8,77 (1H, d, J=6.8 Hz), 10,92 (1H, s), 13,70-14,44 (1H, broadened).

Reference example 55a

To a solution of di-tert-butyl-dicarbonate (0.75 g) in tetrahydrofuran (1.5 ml) at room temperature was added 4-(dim is thylamino)pyridine (63 mg) and 2-(acetamido)-4-bromo-5-methoxybenzoic acid (0,49 g), and then stirred at the same temperature for 4 hours and 15 minutes. To the reaction mixture at room temperature was added a tetrahydrofuran (2 ml)and then stirred at the same temperature for 3 days. To the reaction mixture at room temperature was added di-tert-butyl)dicarbonate (0,37 g)and then stirred at the same temperature for 1 day. The solvent is evaporated under reduced pressure, and was added to the residue ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, sequentially washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added hexane and diisopropyl ether, and collecting the solid by filtration to obtain 0.40 g of 7-bromo-6-methoxy-2-methyl-4H-3,1-benzoxazin-4-it is in the form of a brown solid.

To the suspension obtained 7-bromo-6-methoxy-2-methyl-4H-3,1-benzoxazin-4-it (0.40 g) in dimethyl ether of ethylene glycol (4 ml) was added water (1.2 ml), phenylboronic acid (0,22 g), sodium carbonate (0,38 g) dichloride and bis(triphenylphosphine)palladium(II) (21 mg)and then heated under reflux in nitrogen atmosphere for 4 hours 30 minutes. The reaction mixture is cooled is about room temperature, and then added to it water and ethyl acetate. The aqueous layer was separated, and the organic layer was extracted with 2 mol/l aqueous solution of sodium hydroxide. The aqueous layer and extract were combined. The pH of the mixture was adjusted to 1 by addition of 6 mol/l hydrochloric acid was added ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0.27 g of 2-(acetamido)-5-methoxy-4-vinylbenzoic acid as a yellow solid.

1H-NMR(DMSO-d6) δ: 2,11 (3H, s), of 3.78 (3H, s), 7,35-7,52 (5H, m), EUR 7.57 (1H, s), 8,39 (1H, s), 10,79 (1H, s).

Reference example 56a

The following compound was obtained as described in Reference example 55a.

2-(Acetamido)-5-fluoro-4-phenylbenzene acid

1H-NMR(DMSO-d6) δ: 2,15 (3H, s), 7,45-to 7.59 (5H, m), 7,79 (1H, d, J=11.2 Hz), at 8.60 (1H, d, J=7,3 Hz), of 10.93 (1H, s), 13,60-of 14.28 (1H, broadened).

Reference example 57a

A solution of 2-(acetamido)-5-methoxy-4-vinylbenzoic acid (0,41 g) in a mixture of dioxane (1.2 ml) and concentrated hydrochloric acid (1.2 ml) was heated under reflux for 3 hours and 40 minutes. The village is E. cooling the reaction mixture to room temperature, the solvent evaporated under reduced pressure, and was added to the residue water. After adjusting the pH to 7 by adding 1 mol/l aqueous solution of sodium hydroxide to the mixture was added chloroform. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure to obtain 2-amino-5-methoxy-4-vinylbenzoic acid as a brown solid.

When cooled on ice to a suspension of the obtained 2-amino-5-methoxy-4-vinylbenzoic acid in methanol (10 ml) was added concentrated sulfuric acid (1 ml)and then heated under reflux for 6 hours. The reaction mixture was cooled to room temperature and adjust pH to 8.0 by the addition of saturated aqueous sodium bicarbonate solution and then added to it the chloroform. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added hexane, and collecting the solid by filtration to obtain 0.24 g of methyl 2-amino-5-methoxy-4-phenylbenzoate in the form of a brown solid.

1H-NMR(DMSO-d6) δ: the 3.65 (3H, s), 3,82 (3H, s), 6.35mm (2H, s), is 6.78 (1H, s), 7,30 (1H, s), 7,32-7,49 (5H, m).

Reference example 58a

The following compound was obtained as described in Reference example 57a.

ethyl-2-amino-5-fluoro-4-phenylbenzoate

1H-NMR(CDCl3) δ: 3,90 (3H, s), 5,42-of 5.81 (2H, extended), of 6.71 (1H, d, J=6.3 Hz), of 7.36-7,47 (3H, m), 7,51-7,56 (2H, m), 7,63 (1H, d, J=11.5 Hz).

Reference example 59a

The following compound was obtained as described in Reference example 50a.

tert-Butyl 2-(2-acetoxy-5-(piperidine-1-yl)benzamido)-4-bromobenzoate

1H-NMR(DMSO-d6) δ: 1,52-to 1.67 (6H, m), and 1.54 (9H, s), are 2.19 (3H, s), 3,18-3,26 (4H, m), to 7.09 (1H, d, J=9.0 Hz), 7,17 (1H, DD, J=8,5, 2,9 Hz), 7,32 (1H, d, J=2,9 Hz), 7,41-of 7.48 (1H, m), 7,89 (1H, d, J=8.5 Hz), 8,78 (1H, d, J=1.7 Hz), 11,47 (1H, s).

Reference example 60a

To a suspension of 2-(benzyloxy)-5-(piperidine-1-yl)benzoic acid (0.56 g) in methylene chloride (3.0 ml) was sequentially added N,N-dimethylformamide (0,010 ml) and oxacillin (of 0.21 ml)and then stirred at room temperature for 1 hour and 20 minutes. While cooling on ice, the reaction mixture was added to a solution of 2-amino-4-chlorobenzonitrile (0,23 g) in a mixture of methylene chloride (3.0 ml) and pyridine (0,30 ml)and then stirred at room temperature for 2 hours and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue 10% aqueous citric acid solution and chloroform, the Organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced Yes the population. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-85% hexane/ethyl acetate] to obtain 2-(benzyloxy)-N-(5-chloro-2-cyanophenyl)-5-(piperidine-1-yl)benzamide as a yellow solid.

To the suspension obtained 2-(benzyloxy)-N-(5-chloro-2-cyanophenyl)-5-(piperidine-1-yl)benzamide in the dimethyl ether of ethylene glycol (3.0 ml) was added water (0,74 ml), phenylboronic acid (0.12 g), sodium carbonate (0.21 g) dichloride and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) (3.0 mg)and then heated under reflux in nitrogen atmosphere for 1 hour. After cooling the reaction mixture to room temperature, thereto was added phenylboronic acid (0.12 g), sodium carbonate (0.21 g), and dichloride, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) (3.0 mg)and then heated under reflux in nitrogen atmosphere for 40 minutes. The reaction mixture was cooled to room temperature and then added to it the chloroform and 10% aqueous citric acid solution. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 90-50% hexane/ethyl acetate] to obtain 0.32 g of 2-(benzyloxy)-N-(4-cyanobiphenyl-3-yl)-5-(piperidine-1-yl)benzamide in the form of VC the CSO solids.

1H-NMR(CDCl3) δ: 1,50-to 1.59 (2H, m), 1,65-of 1.73 (4H, m), 3,07-of 3.12 (4H, m)5,54 (2H, s), 6,92 (1H, d, J=9.0 Hz), 7,01 (1H, DD, J=9,0, 3.2 Hz), 7,26-to 7.50 (9H, m), of 7.64-7,71 (3H, m), 7,87 (1H, d, J=3.2 Hz), 9,05 (1H, d, J=1.4 Hz), 11,08 (1H, s).

Reference example 61a

To a solution of methyl 5-amino-2-(benzyloxy)benzoate (0.40 g) in N,N-dimethylacetamide (3.2 ml) was sequentially added potassium carbonate (0.54 g), potassium iodide (0.11 g), and bis(2-chloroethyl)ether (0,22 ml)and then stirred at 100°C for 3 hours. The reaction mixture was cooled to room temperature and then added to her water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 85-60% hexane/ethyl acetate] to obtain 0.27 g of methyl 2-(benzyloxy)-5-(morpholine-4-yl)benzoate as a pale yellow oily substance.

To a solution of the obtained methyl 2-(benzyloxy)-5-(morpholine-4-yl)benzoate (0.26 g) in ethanol (2.1 ml) was added 4 mol/l aqueous sodium hydroxide solution (0.3 ml)and then stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature, and then was added a 10% aqueous citric acid solution and ethyl acetate. The organic layer once elali, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0.17 g of 2-(benzyloxy)-5-(morpholine-4-yl)benzoic acid as a white solid.

1H-NMR(CDCl3) δ: 3,10-and 3.16 (4H, m), 3,82-to 3.89 (4H, m), a 5.25 (2H, s),? 7.04 baby mortality-7,13 (2H, m), 7,39 was 7.45 (5H, m), 7,73 (1H, d, J=2,9 Hz), 10,80-11,20 (1H, broadened).

Reference example 62a

To a solution of 2-(benzyloxy)-5-(morpholine-4-yl)benzoic acid (11.4 g) in a mixture of tetrahydrofuran (57 ml) and N,N-dimethylformamide (0,013 ml) was added oxalicacid (3.4 ml), then stirred at room temperature for 40 minutes and then was heated to a temperature of sublimation for 1 hour. The reaction mixture was cooled to room temperature, then was added a tetrahydrofuran (23 ml)and then heated under reflux for 30 minutes. After cooling the reaction mixture to room temperature, the solvent evaporated under reduced pressure, and was added to the residue toluene. The solvent is evaporated under reduced pressure, and was added to the residue tetrahydrofuran (23 ml). The resulting mixture was added while cooled on ice to a solution of tert-butyl-2-AMI is about-4-bromobenzoate (9.0 g) in a mixture of pyridine (6,7 ml) and tetrahydrofuran (45 ml), then was stirred at room temperature for 30 minutes and then at 50°C for 30 minutes. After cooling the reaction mixture to room temperature, the solvent evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and ethyl acetate. Insoluble substances were removed by filtration, the organic layer was separated, sequentially washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-60% hexane/ethyl acetate] to obtain 13.8 g of tert-butyl 2-(2-(benzyloxy)-5-(morpholine-4-yl)benzamido)-4-bromobenzoate in the form of a light yellow solid.

1H-NMR(DMSO-d6) δ: of 1.46 (9H, s), 3.00 and-of 3.07 (4H, m), 3,69-of 3.77 (4H, m), 5,41 (2H, s), 7,09-7,17 (2H, m), 7,22-7,34 (3H, m), 7,40-to 7.50 (4H, m), 7,89 (1H, d, J=8.6 Hz), 9,03 (1H, d, J=2.0 Hz), 12,19 (1H, s).

Reference example 63a

When cooled on ice to a solution of 2-(benzyloxy)-5-(1-(tert-butoxycarbonyl)piperidine-4-yl)benzoic acid (0,93 g) in a mixture of methylene chloride (9.0 ml) and N,N-dimethylformamide (0,017 ml) was added oxalicacid (0,29 ml)and then stirred at room is based temperature for 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue toluene. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (4.5 ml). The resulting mixture was added while cooled on ice to a solution of methyl 2-amino-4-bromobenzoate (0.45 g) in a mixture of pyridine (0,40 ml) and methylene chloride (9.0 ml)and then stirred at room temperature for 1 hour. To the reaction mixture were added chloroform and 10% aqueous citric acid solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-70% hexane/ethyl acetate] to obtain 0.65 g of methyl 2-(2-(benzyloxy)-5-(1-(tert-butoxycarbonyl)piperidine-4-yl)benzamido)-4-bromobenzoate in the form of a white solid.

1H-NMR(DMSO-d6) δ: 1,35-is 1.51 (2H, m)of 1.41 (9H, s), 1,69-to 1.79 (2H, m), 2,65-2,90 (3H, m), of 3.73 (3H, s), 4,00-4,12 (2H, m), 5,43 (2H, s), 7,18 (1H, d, J=8,8 Hz), 7,24 and 7.36 (3H, m), 7,38-of 7.48 (4H, m), 7,78 (1H, d, J=2.2 Hz), of 7.90 (1H, d, J=8.6 Hz), 8,99 (1H, d, J=2.2 Hz), 12,00 (1H, s).

Reference example 64a

When cooled on ice to a solution of methyl 2-(2-(benzyloxy)-5-(1-(tert-butoxycarbonyl)piperidine-4-yl)Ben is amido)-4-bromobenzoate (0.65 g) in methylene chloride (6.5 ml) was added triperoxonane acid (1.3 ml), and then was stirred at room temperature for 30 minutes. The reaction mixture was added while cooling on ice to the saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to obtain 0.54 g of methyl 2-(2-(benzyloxy)-5-(piperidine-4-yl)benzamido)-4-bromobenzoate in the form of a white solid.

To a solution of the obtained methyl 2-(2-(benzyloxy)-5-(piperidine-4-yl)benzamido)-4-bromobenzoate (0.54 g) in tetrahydrofuran (5.4 ml), was added acetic acid (0,12 ml), 37% aqueous formaldehyde solution (0.10 ml) and triacetoxyborohydride sodium (0.54 g)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-90% chloroform/methanol] to obtain of 0.48 g of methyl 2-(2-(benzyloxy)-5-(1-methylpiperidin-4-yl)benzamido)-4-bromobenzoate in VI is e light yellow solid.

1H-NMR(CD3OD) δ: 1.70 to at 1.91 (4H, m), 2,14-of 2.24 (2H, m), of 2.34 (3H, s), 2,52-2,62 (1H, m), 2,97 was 3.05 (2H, m in), 3.75 (3H, s), 5,43 (2H, s), 7,12 (1H, d, J=8,8 Hz), 7,22-7,40 (5H, m), 7,41-7,46 (2H, m), 7,89 (1H, d, J=2,4 Hz), to 7.93 (1H, d, J=8.6 Hz), which is 9.09 (1H, d, J=2.0 Hz).

Reference example 1b

To a solution of tert-butyl 4-bromo-2-nitrobenzoate (5.0 g) in dimethyl ether of ethylene glycol (50 ml) was added water (15 ml), sodium carbonate (4.6 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (5,1 g) dichloride and bis(triphenylphosphine)palladium(II) (0.24 g)and then heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature and then added to it the ethyl acetate and water. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 85-75% hexane/ethyl acetate] to obtain 5.8 g of tert-butyl 4-(isoquinoline-4-yl)-2-nitrobenzoate as a brown oily substance.

1H-NMR(DMSO-d6) δ: of 1.55 (9H, s), 7,76-7,83 (1H, m), 7,83-7,88 (2H, m), 7,99-8,02 (2H, m), 8,21 (1H, s), of 8.28 (1H, d, J=8.0 Hz), 8,55 (1H, s), 9,44 (1H, s).

Reference example 2b

To a solution of tert-butyl 4-bromo-2-nitrobenzoate (0.15 g) in dimethyl ether etrange is Olya (2.0 ml) was added water (0.6 ml), sodium carbonate (0.16 g), 3-(tert-butoxycarbonylamino)phenylboronic acid (0.14 g) and tetrakis(triphenylphosphine)palladium(0) (29 mg)and then heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature and then added to it the ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-91% hexane/ethyl acetate] to obtain 0.17 g of tert-butyl 4-(3-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate as a pale yellow solid.

1H-NMR(CDCl3) δ: and 1.54 (9H, s), was 1.58 (9H, s), 6,55-6,63 (1H, broadened), 7,24-7,28 (1H, m), 7,33 (1H, d, J=8.6 Hz), 7,39 (1H, d, J=7.8 Hz), 7,74 (1H, s), 7,80 (1H, d, J=8.1 Hz), to 7.84 (1H, DD, J=7,9, and 1.6 Hz), to 7.99 (1H, d, J=the 1.7 Hz).

Reference example 3b

The following compound was obtained as described in Reference example 2b.

Methyl-4-(furan-2-yl)-2-nitrobenzoate

1H-NMR(CDCl3) δ: to 3.92 (3H, s), 6,55 (1H, DD, J=3,4, 1.7 Hz), 6.87 in (1H, d, J=3,4 Hz), EUR 7.57 (1H, d, J=1.7 Hz), 7,80 (1H, d, J=8.1 Hz), 7,88 (1H, DD, J=8,1) and 1.7 Hz), 8,08 (1H, d, J=1.7 Hz).

Reference example 4b

To a solution of tert-BU the Il-4-bromo-2-nitrobenzoate (0.15 g) in dimethyl ether of ethylene glycol (2.0 ml) was added water (0.6 ml), sodium carbonate (0.16 g), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (0,19 g) and tetrakis(triphenylphosphine)palladium(0) (29 mg)and then heated under reflux in nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature and then added to it the ethyl acetate and 10% aqueous citric acid solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 91-80% hexane/ethyl acetate] to obtain 0.21 g of tert-butyl 4-(2-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate as a yellow solid.

1H-NMR(CDCl3) δ: of 1.46 (9H, s)to 1.60 (9H, s), 6,14-to 6.22 (1H, broadened), 7,16-of 7.23 (2H, m), 7,38 was 7.45 (1H, m), to 7.67 (1H, DD, J=8,1) and 1.7 Hz), to 7.84 (1H, d, J=8.1 Hz), the 7.85 (1H, d, J=1.7 Hz), of 7.96 (1H, d, J=8,5 Hz).

Reference example 5b

To a solution of methyl-4-chloro-2-nitrobenzoate (0,90 g) in dimethyl ether of ethylene glycol (10 ml) was added water (3.0 ml), sodium carbonate (1.1 g), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (1.5 g) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (30 mg)and then heated under reflux in a nitrogen atmosphere is 1 hour 30 minutes. The reaction mixture was cooled to room temperature and then added to it the ethyl acetate and 10% aqueous citric acid solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-85% hexane/ethyl acetate] to obtain 1.5 g of methyl 4-(2-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate as a pale yellow solid.

1H-NMR(CDCl3): of 1.45 (9H, s), of 3.97 (3H, s), 6,13-to 6.22 (1H, broadened), 7,17-of 7.25 (2H, m), 7,40-7,46 (1H, m), 7,71 (1H, DD, J=8,0, 1.7 Hz), 7,86 (1H, d, J=8.1 Hz), to $ 7.91-of 7.97 (2H, m).

Reference example 6b

To a suspension of N-(5-chloro-2-cyanophenyl)-5-vinylpyridin-3-carboxamide (0.20 g) in toluene (3.0 ml) was added phenylboronic acid (88 mg), tribalistas (0.28 g), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (2.5 mg) and palladium(II) acetate (2.7 mg)and then heated under reflux in nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, then added to it 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (2.5 mg) and palladium(II) acetate (2.7 mg)and then heated under reflux in nitrogen atmosphere for 6 hours. After cooling the reaction, see the C to room temperature, thereto was added ethyl acetate and 10% aqueous citric acid solution, and removing insoluble substances by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain a 0.23 g of N-(2-cyano-5-phenylphenyl)-5-vinylpyridin-3-carboxamide as a pale yellow solid.

1H-NMR(DMSO-d6) δ: 7,45 to 7.62 (6H, m), 7,75-7,83 (3H, m), 7,84-of 7.90 (2H, m), of 7.96 (1H, d, J=1.7 Hz), 8,01 (1H, d, J=8.0 Hz), 8,65 (1H, DD, J=2,2, 2,2 Hz), 9,13-9,18 (2H, m), br11.01 (1H, s).

Reference example 7b

To a solution of tert-butyl 4-bromo-2-nitrobenzoate (2.0 g) in dioxane (20 ml) was added potassium acetate (2.0 g), bis(pinacolato)LIBOR (3.4 g) and complex (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and methylene chloride (0.27 g)and then stirred in nitrogen atmosphere at 95-100°C for 2 hours. After cooling the reaction mixture to room temperature, insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 80% hexane/ethyl acetate], and then purified according to the method of column chromatography [eluent: 95-90% hexane/ethyl acetate] to obtain 2.0 g is pet-butyl-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate as a white solid.

1H-NMR(CDCl3) δ: 1.26 in (12H, s)of 1.36 (9H, s), of 7.69 (1H, d, J=7,6 Hz), 7,99-of 8.06 (1H, m), 8,23-of 8.27 (1H, m).

Reference example 8b

The following compound was obtained as described in Reference example 7b.

N,N-Diethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

1H-NMR(CDCl3) δ: 1,15 (6H, t, J=7,1 Hz)of 1.33 (12H, s), 3,37 (4H, q, J=7,1 Hz), 6.75 in-6,84 (1H, m), 7,07-7,17 (2H, m), 7.18 in-to 7.25 (1H, m).

Reference example 9b

To a solution of tert-butyl-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.0 g) in dimethyl ether of ethylene glycol (10 ml) was added water (3 ml), sodium carbonate (0,76 g), 2-bromopyridine (0,42 ml) and tetrakis(triphenylphosphine)palladium(0) (0.17 g)and then heated under reflux in nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then was added a 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 90-85% hexane/ethyl acetate] to obtain 0.32 g of tert-butyl-2-nitro-4-(pyridin-2-yl)benzoate as a pale yellow oily substance.

1H-NMR(CDCl3 ) δ: equal to 1.59 (9H, s), 7,32-7,38 (1H, m), 7,78-7,87 (3H, m), of 8.28 (1H, DD, J=8,1) and 1.7 Hz)and 8.50 (1H, d, J=1.7 Hz), 8,72-8,77 (1H, m).

Reference example 10b

The following compound was obtained as described in Reference example 9b.

tert-Butyl 4-(2-(deformedarse)phenyl)-2-nitrobenzoate

1H-NMR(CDCl3): to 1.59 (9H, s), 6,44 (1H, t, J=73,5 Hz), 7.24 to 7,37 (2H, m), 7,39-7,49 (2H, m), 7,74-of 7.82 (2H, m), 7,93-of 7.97 (1H, m).

Reference example 11b

To a solution of tert-butyl 4-bromo-2-nitrobenzoate (0.50 g) in dimethyl sulfoxide (5 ml) was added 1H-pyrazole (0.14 g), potassium carbonate (0,46 g), D-Proline (38 mg) and copper iodide(I) (32 mg)and then stirred in nitrogen atmosphere at 100°C for 3 hours. After cooling the reaction mixture to room temperature, thereto was added ethyl acetate and water, and removing insoluble substances by filtration. The organic layer was separated, sequentially washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 100-80% hexane/ethyl acetate] to obtain 0.20 g of tert-butyl-2-nitro-4-(1H-pyrazole-1-yl)benzoate as a white solid.

1H-NMR(CDCl3) δ: 1.57 in (9H, s), 6,56 (1H, DD, J=2,6, 1.8 Hz), 7,79 (1H, d, J=1,8 Hz), 88 (1H, d, J=8.5 Hz), 7,95 (1H, DD, J=8,5, and 2.1 Hz), 8,01 (1H, d, J=2.6 Hz), 8,15 (1H, d, J=2.1 Hz).

Reference example 12b

When cooled on ice to a solution of tert-butyl 4-(3-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate (0,30 g) in tetrahydrofuran (5.0 ml) was added 60% sodium hydride (43 mg)and then stirred at the same temperature for 20 minutes. To the reaction mixture while cooling on ice was added ethyliodide (0,087 ml), then stirred at the same temperature for 30 minutes and then at room temperature for 2 hours and 40 minutes. To the reaction mixture at room temperature was added N,N-dimethylformamide (3.0 ml), followed by cooling on ice to it consistently was added 60% sodium hydride (14 mg) and ethyliodide (0,058 ml)and then stirred at room temperature for 1 hour. To the reaction mixture were added water and diethyl ether, the organic layer was separated, sequentially washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and purify the resulting residue by the method of column chromatography on silica gel [eluent: 85-60% hexane/ethyl acetate] to obtain 0.16 g of tert-butyl 4-(3-((tert-butoxycarbonyl)(ethyl)amino)phenyl)-2-nitrobenzoate as a colourless maslanik the CSOs substances.

1H-NMR(CDCl3) δ: 1,19 (3H, t, J=7,1 Hz)of 1.46 (9H, s), was 1.58 (9H, s), of 3.73 (2H, q, J=7,1 Hz), 7,26-to 7.32 (1H, m), 7,38-to 7.50 (3H, m), 7,80-7,83 (2H, m), 7,98 (1H, s).

Reference example 13b

When cooled on ice to a solution of tert-butyl 4-(3-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate (0.17 g) in N,N-dimethylformamide (3.0 ml) was added 60% sodium hydride (24 mg), then stirred at the same temperature for 15 minutes and then at room temperature for 20 minutes. To the reaction mixture while cooling on ice was added methyliodide (0.037 ml)and then stirred at room temperature for 1 hour. To the reaction mixture were added water and diethyl ether, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layer and the extract were combined, the resulting mixture was sequentially washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and purify the resulting residue by the method of column chromatography on silica gel [eluent: 95-85% hexane/ethyl acetate] to obtain 0.17 g of tert-butyl 4-(3-((tert-butoxycarbonyl)(methyl)amino)phenyl)-2-nitrobenzoate as a brown oily substance.

1H-NMR(CDCl3): to 1.48 (9H, s), was 1.58 (9H, s), of 3.32 (3H, s), 7,30 and 7.36 (1H, m), of 7.36-7,41 (1H, m), 7,42-7,53 (2H, m), 7,80-to 7.84 (2H, m), to 7.99 (1H, s).

Reference example 14b

The following compound was obtained as described in Reference example 13b.

Methyl-4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)-2-nitrobenzoate

1H-NMR(CD3OD): of 1.06 (3H, t, J=7,1 Hz), 1,22-of 1.45 (9H, m), 2,85 was 3.05 (1H, broadened), 3,50-3,70 (1H, broadened), 3,91 (3H, s), 7,26-7,39 (1H, m), 7,42-rate of 7.54 (3H, m), 7,72-7,80 (1H, m), 7,88 (1H, d, J=7.8 Hz), of 7.90-7,98 (1H, broadened).

Reference example 15b

The following compound was obtained as described in Reference example 13b.

Methyl-4-(2-((tert-butoxycarbonyl)(isopropyl)amino)phenyl)-2-nitrobenzoate

1H-NMR(CD3OD): to 0.73 (3H, d, J=6.8 Hz), of 1.05 (3H, d, J=6.6 Hz), 1,26 of 1.50 (9H, extended), 3,91 (3H, s), 3,89-of 4.05 (1H, broadened), 7,21-7,30 (1H, m), 7,46-rate of 7.54 (3H, m), 7,78 (1H, DD, J=7,9, and 1.6 Hz), 7,88 (1H, d, J=7.9 Hz), to 7.99 (1H, C).

Reference example 16b

When cooled on ice to a solution of methyl-4-(2-(ethylamino)phenyl)-2-nitrobenzoate (0.27 g) in N,N-dimethylformamide (3.0 ml) was added 60% sodium hydride (54 mg), then stirred at the same temperature for 5 minutes and then at room temperature for 15 minutes. To the reaction mixture while cooling on ice was added methyliodide (0,083 ml)and then stirred at room temperature for 1 hour and then at 50°C for 1 hour. The reaction mixture was cooled to room t is mperature, then added to it methyliodide (0,11 ml)and then stirred at 40-50°C for 2 hours. The reaction mixture was cooled to room temperature and then added to her water and diethyl ether. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 99-95% hexane/ethyl acetate] to obtain 0.12 g of methyl-4-(2-((ethyl)(methyl)amino)phenyl)-2-nitrobenzoate as a yellow oily substance.

1H-NMR(CDCl3): to 0.92 (3H, t, J=7.2 Hz), 2,58 (3H, s), 2,80 (2H, q, J=7.2 Hz), of 3.94 (3H, s), 7,05-to 7.15 (2H, m), 7.23 percent (1H, DD, J=7,6, 1.7 Hz), 7,31-7,39 (1H, m), 7,78 (1H, d, J=8.0 Hz), 7,88 (1H, DD, J=8,0, 1.7 Hz), 8,18 (1H, d, J=1.7 Hz).

Reference example 17b

To a solution of tert-butyl 4-(2-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate (0.27 g) in acetone (4.0 ml) was added potassium carbonate (0.16 g) and dimethylsulfate (0,094 ml)and then heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and then added to her water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous self the volume of magnesium, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-85% hexane/ethyl acetate], and then purified according to the method of column chromatography [eluent: 91-85% hexane/ethyl acetate] to obtain 0,061 g of tert-butyl 4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)-2-nitrobenzoate as a colorless oily substance.

1H-NMR(DMSO-d6) δ: 0,99 of 1.28 (9H, m)and 1.51 (9H, s), 3.00 and-3,11 (3H, m), 7,39-rate of 7.54 (4H, m), 7,74 (1H, d, J=8,3 Hz), 7,83-7,94 (2H, m).

Reference example 18b

To a solution of methyl-4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)-2--nitrobenzoate (0.39 g) in methylene chloride (2.0 ml) at room temperature was added triperoxonane acid (4.5 ml)and then stirred at the same temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 91-85% hexane/ethyl acetate] to obtain 0.27 g of methyl-4-(2-(ethylamino)phenyl)-2-nitrobenzoate as an orange oily the th substance.

1H-NMR(CDCl3): 1,16-of 1.23 (3H, m)and 3.15 (2H, q, J=7,1 Hz), 3,52-3,68 (1H, broadened), 3,93-of 3.97 (3H, m), 6,74 (1H, d, J=8,3 Hz), 6,76-6,83 (1H, m), 7.03 is-to 7.09 (1H, m), 7,27-7,33 (1H, m), 7,74-7,79 (1H, m), 7,80-7,86 (1H, m), 7.95 is-to 7.99 (1H, m).

Reference example 19b

When heated under reflux to a solution of N-(5-bromo-4-methoxy-2-were)ndimethylacetamide (1.0 g) in a mixture of water (10 ml), tert-butyl alcohol (10 ml) and magnesium sulfate (0,79 g) was added potassium permanganate (0,98 g)and then heated under reflux in nitrogen atmosphere for 6 hours and 20 minutes. After cooling the reaction mixture to room temperature, insoluble substances were removed by filtration. The solvent is evaporated under reduced pressure, and was added to the residue water and ethyl acetate. The aqueous layer was separated and was added 1 mol/l hydrochloric acid (4 ml) and chloroform. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resulting mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid substance was collected by filtration to obtain 0.36 g of 2-(acetamido)-4-bromo-5-methoxybenzoic acid as a white solid.

1 H-NMR(DMSO-d6) δ: 2,11 (3H, s), 3,86 (3H, s), 7,53 (1H, s), 8,68 (1H, s), 10,78 (1H, s).

Reference example 20b

To a solution of di-tert-butyl-dicarbonate (0.75 g) in tetrahydrofuran (1.5 ml) at room temperature was added 4-(dimethylamino)pyridine (63 mg) and 2-ndimethylacetamide-4-bromo-5-methoxybenzoic acid (0,49 g)and then stirred at the same temperature for 4 hours and 15 minutes. To the reaction mixture at room temperature was added a tetrahydrofuran (2 ml)and then stirred at the same temperature for 3 days. To the reaction mixture at room temperature was added di-tert-butyl-dicarbonate (0,37 g)and then stirred at the same temperature for 1 day. The solvent is evaporated under reduced pressure, was added to the residue ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, sequentially washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added hexane and diisopropyl ether, and collecting the solid by filtration to obtain 0.40 g of 7-bromo-6-methoxy-2-methyl-4H-3,1-benzoxazin-4-it is in the form of a brown solid.

To the suspension obtained 7-bromo-6-methoxy-methyl-4H-3,1-benzoxazin-4-it (0.40 g) in dimethyl ether of ethylene glycol (4 ml) was added water (1.2 ml), phenylboronic acid (0,22 g), sodium carbonate (0,38 g) dichloride and bis(triphenylphosphine)palladium(II) (21 mg)and then heated under reflux in nitrogen atmosphere for 4 hours 30 minutes. The reaction mixture was cooled to room temperature and then added to her water and ethyl acetate. The aqueous layer was separated and was extracted organic layer 2 mol/l aqueous solution of sodium hydroxide. The aqueous layer and extract were combined, adjusting the pH of the mixture to 1 by addition of 6 mol/l hydrochloric acid was added ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0.27 g of 2-ndimethylacetamide-5-methoxy-4-vinylbenzoic acid as a yellow solid.

1H-NMR(DMSO-d6) δ: 2,11 (3H, s), of 3.78 (3H, s), 7,35-7,52 (5H, m), EUR 7.57 (1H, s), 8,39 (1H, s), 10,79 (1H, s).

Reference example 21b

A solution of 2-ndimethylacetamide-5-methoxy-4-vinylbenzoic acid (0,41 g) in a mixture of dioxane (1.2 ml) and concentrated hydrochloric acid (1.2 ml) was heated under reflux for 3 hours and 40 minutes. After cooling the reaction mixture to room temperature the market, the solvent is evaporated under reduced pressure, and was added to the residue water. After adjusting the pH to 7 by adding 1 mol/l aqueous solution of sodium hydroxide to the mixture was added chloroform. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure to obtain 2-amino-5-methoxy-4-vinylbenzoic acid as a brown solid.

When cooled on ice to a suspension of the obtained 2-amino-5-methoxy-4-vinylbenzoic acid in methanol (10 ml) was added concentrated sulfuric acid (1 ml)and then heated under reflux for 6 hours. The reaction mixture was cooled to room temperature, adjust pH to 8.0 by the addition of saturated aqueous sodium bicarbonate solution, and added to it the chloroform. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added hexane, and collecting the solid by filtration to obtain 0.24 g of methyl 2-amino-5-methoxy-4-phenylbenzoate in the form of a brown solid.

1H-NMR(DMSO-d6) δ: the 3.65 (3H, s), 3,82 (3H, s), 6.35mm (2H, s), is 6.78 (1H, s), 7,30 (1H, s), 7,32-7,49 (5H, m).

Reference example 22b

To a solution of methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (10 g) in dimethyl ether of ethylene glycol (1 ml) was added 2-bromopyrimidine (73 mg), sodium carbonate (81 mg), water (0.3 ml) and dichloride bis(triphenylphosphine)palladium(II) (5.3 mg)and then heated under reflux in nitrogen atmosphere for 1 hour and 30 minutes. After cooling the reaction mixture to room temperature, thereto was added ethyl acetate and water, and removing insoluble substances by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-50% hexane/ethyl acetate] to obtain 30 mg of methyl-5-(pyrimidine-2-yl)pyridine-3-carboxylate as a yellow solid.

To a solution of the obtained methyl-5-(pyrimidine-2-yl)pyridine-3-carboxylate (30 mg) in a mixture of dioxane (0.3 ml) and methanol (0.3 ml) at room temperature was added 2 mol/l aqueous sodium hydroxide solution (of 0.21 ml)and then stirred at the same temperature for 1 hour and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue water and toluene. The aqueous layer was separated and adjusted the pH to 3.8 by adding 1 mol/l hydrochloric acid. The solid substance was collected by filtration to obtain 7,0 mg 5-(pyrimidine-2-yl)pyridine-3-carboxylic acid is a white solid substance.

1H-NMR(DMSO-d6) δ: 7,58 (1H, t, J=4.9 Hz), 9,00 (2H, d, J=4.9 Hz), 9,13 (1H, DD, J=2,0, 2,0 Hz), 9,20 (1H, d, J=2.0 Hz), 9,68 (1H, d, J=2.0 Hz).

Reference example 23b

To a solution of methyl-5-(furan-3-yl)pyridine-3-carboxylate (0.54 g) in methanol (10 ml) at room temperature was added 4 mol/l aqueous sodium hydroxide solution (2.0 ml)and then stirred at the same temperature for 2 hours and 50 minutes. To the reaction mixture at room temperature was added 10% aqueous citric acid solution (8 ml)and the solvent evaporated under reduced pressure. To the obtained residue was added water, and collecting the solid by filtration to obtain 0.33 g of 5-(furan-3-yl)pyridine-3-carboxylic acid as a pale yellow solid.

1H-NMR(DMSO-d6) δ: 7,13-7,17 (1H, m), 7,80-to 7.84 (1H, m), to 8.41-8,48 (2H, m), 8,92-8,96 (1H, m), 9,05-9,11 (1H, m).

Reference example 24b

To a suspension of 5-bromopyridin-3-carboxylic acid (0,23 g) in methylene chloride (5 ml) at room temperature was added N,N-dimethylformamide (8,6 mm) and oxacillin (0,14 ml)and then stirred at the same temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2.5 ml). The reaction mixture at room temperature was added to a solution of tert-butyl-2-amine is-4-phenylbenzoate (0.25 g) in a mixture of methylene chloride (5 ml) and pyridine (0,19 ml), and then stirred at the same temperature for 1 hour. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 100-80% hexane/ethyl acetate] to obtain 0.39 g of tert-butyl 2-(5-bromopyridin-3-carboxamido)-4-phenylbenzoate in the form of a white solid.

1H-NMR(CDCl3) δ: 1,65 (9H, s), 7,37 was 7.45 (2H, m), 7,45-7,53 (2H, m), 7.68 per-7,74 (2H, m), 8,10 (1H, d, J=8.6 Hz), charged 8.52 (1H, DD, J=2.1 a, 2.1 Hz), 8,86 (1H, d, J=2.2 Hz), 9,17 (1H, d, J=2.0 Hz), which 9.22 (1H, d, J=1.9 Hz), to 12.52 (1H, s).

Reference examples 25b-27b

Compounds shown in Table 5b, obtained as described in Reference example 24b.

Table 5b
Reference example No.AReference example No.AReference example No.A
25b26b 2b

tert-Butyl 2-(5-bromopyridin-2-carboxamido)-4-phenylbenzoate

1H-NMR(CDCl3) δ: rate of 1.67 (9H, s), 7,35-the 7.43 (2H, m), 7,43-to 7.50 (2H, m), 7,69 to 7.75 (2H, m), of 8.04 (1H, DD, J=8,5 and 2.2 Hz), of 8.09 (1H, d, J=8,3 Hz), 8,19 (1H, d, J=8,3 Hz), 8,84 (1H, d, J=2.0 Hz), 9,24 (1H, d, J=2.0 Hz), 12,90 (1H, s).

tert-Butyl 2-(4-chloropyridin-2-carboxamido)-4-phenylbenzoate

1H-NMR(CDCl3) δ: 1,68 (9H, s), of 7.36-7,44 (2H, m), 7,44-7,53 (3H, m), 7,69 to 7.75 (2H, m), of 8.09 (1H, d, J=8,3 Hz), 8,31 (1H, d, J=1.4 Hz), 8,67 (1H, d, J=5,2 Hz), the 9.25 (1H, d, J=1.9 Hz), 12,94 (1H, s).

tert-Butyl 2-(6-chloropyridin-3-carboxamido)-4-phenylbenzoate

1H-NMR(DMSO-d6) δ: of 1.55 (9H, s), 7,43-7,50 (1H, m), 7,51-7,58 (2H, m), 7,60 (1H, DD, J=8,3, 1.8 Hz), 7,71-7,76 (2H, m), 7,81 (1H, d, J=8,3 Hz), 8,02 (1H, d, J=8,3 Hz), of 8.37 (1H, DD, J=8,3, and 2.6 Hz), at 8.60 (1H, d, J=1,8 Hz), 8,99 (1H, d, J=2.6 Hz), to 11.56 (1H, s).

Reference example 28b

The following compound was obtained as described in Reference example 24b.

tert-Butyl 4-bromo-2-(5-vinylpyridin-3-carboxamido)benzoate

1H-NMR(CDCl3) δ: 1,64 (9H, s), 7.24 to 7,31 (1H, m), 7,43-7,49 (1H, m), 7,50-7,58 (2H, m), 7,66-7,73 (2H, m), 7,89 (1H, d, J=8.5 Hz), 8,56 (1H, DD, J=2,2, 2,2 Hz), 9,04 (1H, d, J=2.2 Hz), 9,17 (1H, d, J=1.9 Hz), 9,24 (1H, d, J=2.2 Hz), to 12.52 (1H, s).

Reference example 29b

The following compound was obtained as described in Reference example 24b.

N-(5-Chloro-2-cyanophenyl)-5-vinylpyridin-3-carboxamide

1H-NMR(DMSO-d6) δ: 7,46-to 7.64 (H, m), 7,78-of 7.90 (3H, m), 7,98 (1H, d, J=8,3 Hz), 8,59-8,64 (1H, m), which is 9.09-9,19 (2H, m), 11,03 (1H, s).

Reference example 30b

To a solution of tert-butyl 4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)-2-nitrobenzoate (57 mg) in a mixture of ethyl acetate (2.5 ml) and methanol (2.5 ml) was added 10% palletirovanie coal (11 mg). The resulting mixture was stirred at room temperature for 3 hours in hydrogen atmosphere. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-85% hexane/ethyl acetate] to obtain 48 mg of tert-butyl 2-amino-4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)benzoate as a white solid.

1H-NMR(DMSO-d6) δ: 1,02-to 1.38 (9H, m), and 1.54 (9H, s), 2,83-a 3.01 (3H, m), 6,44 (1H, DD, J=8,2, 1.3 Hz), 6,56-6,74 (3H, m), 7,26-the 7.43 (4H, m), to 7.61-of 7.70 (1H, m).

Reference examples 31b-34b

Compounds shown in Table 6b, obtained as described in Reference example 30b.

Table 6b
Reference example No.R3Reference example No.R3
31b/td> 33b
32b34b

tert-Butyl 2-amino-4-(pyridin-2-yl)benzoate

1H-NMR(CDCl3) δ: of 1.61 (9H, s), 5,74 and 5.86 (2H, extended), 7,18 (1H, DD, J=8,3) and 1.7 Hz), 7.23 percent-7,29 (1H, m), of 7.36 (1H, d, J=1.4 Hz), 7,69-7,79 (2H, m), of 7.90 (1H, d, J=8,3 Hz), 8,67-8,72 (1H, m).

tert-Butyl 2-amino-4-(1H-pyrazole-1-yl)benzoate

1H-NMR(CDCl3) δ: 1,60 (9H, s), of 5.82-5,95 (2H, extended), 6,47 (1H, DD, J=2,3, 2.0 Hz), 6.90 to (1H, DD, J=8,8, 2.2 Hz), was 7.08 (1H, d, J=2.2 Hz), 7,72 (1H, d, J=2.0 Hz), 7,88 (1H, d, J=8,8 Hz), to 7.93 (1H, d, J=2.3 Hz).

tert-Butyl 2-amino-4-(3-((tert-butoxycarbonyl)(ethyl)amino)phenyl)benzoate

1H-NMR(CDCl3) δ: of 1.18 (3H, t, J=7,1 Hz)of 1.45 (9H, s)to 1.60 (9H, s), 3,71 (2H, q, J=7,1 Hz), 5,78 (2H, s), for 6.81-6.87 in (2H, m), 7,15-7,24 (1H, m), 7,34-7,44 (3H, m), 7,84-of 7.90 (1H, m).

tert-Butyl 2-amino-4-(3-((tert-butoxycarbonyl)(methyl)amino)phenyl)benzoate

1H-NMR(CDCl3): of 1.47 (9H, s)to 1.60 (9H, s), 3,30 (3H, s), 5,72-of 5.83 (2H, extended), for 6.81-6,86 (2H, m), 7,21-7,27 (1H, m), 7,34-7,41 (2H, m), 7,42 was 7.45 (1H, m), 7,84-7,89 (1H, m).

Reference example 35b

The following compound was obtained as described in Reference example 30b.

Methyl-2-amino-4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)benzoate

1H-NMR(CD3OD): 0,96-1,11 (3H, m), 1,24 of 1.50 (9H, m), 2.77-to 2,95 (1H, m), 3.45 points of 3.75 (1H, m), 3,86 (3H, s), 6,56 (1H, DD, J=8,3) and 1.7 Hz), was 6.73 (1H, d, J=1.7 Hz), 7,17-7,27 (1H, m), 7,33-7,42 (3H, m), 7,75-7,83 (1H, m).

Reference example 36b

The following compound was obtained as described in Reference example 30b.

Methyl-2-amino-4-(2-((tert-butoxycarbonyl)(isopropyl)amino)phenyl)benzoate

1H-NMR(CD3OD): of 0.82 (3H, d, J=6.8 Hz), 0,93 is 1.13 (3H, m), 1,22-of 1.57 (9H, m), 3,80-4,07 (1H, m), 3,86 (3H, s), 6,60-6,70 (1H, m), 6,77 (1H, d, J=1.4 Hz), 7,08-7,24 (1H, broadened), 7,33-7,44 (3H, m), to 7.77 (1H, d, J=8,3 Hz).

Reference example 37b

The following compound was obtained as described in Reference example 30b.

Methyl-2-amino-4-(2-((ethyl)(methyl)amino)phenyl)benzoate

1H-NMR(CDCl3): of 0.90 (3H, t, J=7.0 Hz), 2,61 (3H, s)2,84 (2H, q, J=7.0 Hz), 3,88 (3H, s), 6,85-6,91 (2H, m), of 6.99 (1H, DD, J=7,4, 7,4 Hz), 7,03 (1H, d, J=8,3 Hz), 7,20 (1H, DD, J=7,6, 1.7 Hz), 7.23 percent-7,30 (1H, m), 7,86 (1H, d, J=8.6 Hz).

Reference example 38b

To a solution of tert-butyl 4-(2-(deformedarse)phenyl)-2-nitrobenzoate (0.18 g) in 2-propanol (2.1 ml) was added water (0,53 ml), sodium formate (0,13 g), acetic acid (0,13 ml) and 10% palletirovanie coal (35 mg)and then heated under reflux for 2 hours. The reaction mixture was cooled to room temperature, and then remove insoluble substances by filtration. The solvent of viparita and in conditions of reduced pressure, and added to a mixture of ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 99-91% hexane/ethyl acetate] to obtain 0.15 g of tert-butyl 2-amino-4-(2-(deformedarse)phenyl)benzoate as a yellow oily substance.

1H-NMR(CDCl3): to 1.60 (9H, s), 6,33 (1H, t, J=74,2 Hz), 6,72-of 6.78 (2H, m), 7,20-to 7.32 (2H, m), 7,33-7,42 (2H, m), 7,83-of 7.90 (1H, m).

Reference example 39b

The following compound was obtained as described in Reference example 38b.

Methyl-2-amino-4-(tetrahydrofuran-2-yl)benzoate

1H-NMR(CDCl3): 1,70-to 1.82 (1H, m), 1.93 and-2,03 (2H, m), 2,25-is 2.37 (1H, m), 3,85 (3H, s), 3,89-of 3.97 (1H, m), as 4.02-4,11 (1H, m), 4,82 (1H, DD, J=7,2, 7,2 Hz), 5,65-of 5.82 (2H, extended), 6,53-6,60 (1H, m), 6,64-6,70 (1H, m), 7,80 (1H, d, J=8,3 Hz).

Reference example 40b

To a suspension of methyl 4-(furan-2-yl)-2-nitrobenzoate (0.14 g) in ethanol (2.1 ml) was added water (0,56 ml), ammonium chloride (18 mg) and iron powder (94 mg)and then heated under reflux for 2 hours 30 minutes. The reaction mixture was cooled to room temperature, then added to it the ammonium chloride (18 mg), a yellow powder is PR (31 mg) and water (0,28 ml), and then was heated under reflux for 1 hour. The reaction mixture was cooled to room temperature, and then the solvent evaporated under reduced pressure. To the obtained residue was added saturated aqueous sodium bicarbonate solution and ethyl acetate, and removing insoluble substances by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 99-95% hexane/ethyl acetate] to obtain 78 mg of methyl 2-amino-4-(furan-2-yl)benzoate as a pale yellow solid.

1H-NMR(CDCl3): 3,88 (3H, s), 5,72 and 5.86 (2H, extended), of 6.49 (1H, DD, J=3.3, which is 1.8 Hz), 6,72 (1H, d, J=3.3 Hz), 6,94 (1H, DD, J=8,5) and 1.7 Hz), of 6.99 (1H, d, J=1.7 Hz), 7,47-7,51 (1H, m), 7,86 (1H, d, J=8,5 Hz).

Reference example 41b

The following compound was obtained as described in Reference example 40b.

tert-Butyl 2-amino-4-(isoquinoline-4-yl)benzoate

1H-NMR(DMSO-d6) δ: was 1.58 (9H, s), 6,64-6,72 (1H, m), 6,72-6,84 (2H, extended), 6,91 (1H, s), 7,72-of 7.96 (4H, m), 8,23 (1H, d, J=7.8 Hz), 8,42 (1H, d, J=1.0 Hz), a 9.35 (1H, s).

Example 1a

To a suspension of 2-acetoxy-4-chlorbenzoyl acid (0,076 g) in methylene chloride (1.6 ml) pic is edutella was added N,N-dimethylformamide (2,7 ml) and oxacillin (0,046 ml), and then was stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue toluene. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (1 ml). The resulting mixture was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (0,080 g) in a mixture of pyridine (to 0.060 ml) and methylene chloride (1.6 ml)and then stirred at room temperature for 2 hours. The reaction mixture was purified according to the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 100-85% hexane/ethyl acetate] to obtain of 0.13 g of tert-butyl 2-(2-acetoxy-4-chlorobenzamido)-4-phenylbenzoate.

To a solution of the obtained tert-butyl 2-(2-acetoxy-4-chlorobenzamido)-4-phenylbenzoate (0,13 g) in a mixture of methanol (2.5 ml) and dioxane (2.5 ml) was added potassium carbonate (0.12 g)and then stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, and was added to the residue 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure to obtain 0.11 g of tert-butyl 2-(4-chloro-2-hydroxybenzamide)-4-phenylbenzoate in the form of a white solid substances is A.

A solution of the obtained tert-butyl 2-(4-chloro-2-hydroxybenzamide)-4-phenylbenzoate (0.11 g) in a mixture triperoxonane acid (5 ml) and methylene chloride (2.5 ml) was stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the residue diisopropyl ether. The solid substance was collected by filtration to obtain 0,077 g of 2-(4-chloro-2-hydroxybenzamide)-4-vinylbenzoic acid as a white solid.

1H-NMR(DMSO-d6) δ: 7.03 is-to 7.09 (2H, m), 7,43-7,58 (4H, m), 7,70-7,76 (2H, m), to 7.93 (1H, d, J=9.0 Hz), 8,10 (1H, d, J=8,3 Hz), of 9.02 (1H, d, J=1.7 Hz), 11,75 a 12.05 (1H, broadened), 12,15-12,40 (1H, broadened), 13,30-13,60 (1H, broadened).

Examples 2a-10a

Compounds shown in Table 9a, obtained as described in Example 1a.

Table 9a
Example No.AExample No.A
2a7a
3a8a
4a9a
5a10a
6a

2-(5-Chloro-2-hydroxybenzamide)-4-phenylbenzene acid

1H-NMR(DMSO-d6) δ: 7,05 (1H, d, J=8,8 Hz), 7,43-7,58 (5H, m), 7,70-7,76 (2H, m), of 7.90 (1H, d, J=2,9 Hz), 8,10 (1H, d, J=8,3 Hz), of 9.00 (1H, d, J=1.7 Hz), 11,60-of 11.75 (1H, broadened), 12,25-12,40 (1H, broadened), 13,35-13,60 (1H, broadened).

2-(3-Chloro-2-hydroxybenzamide)-4-phenylbenzene acid

1H-NMR(DMSO-d6) δ: was 7.08 (1H, DD, J=7,9, 7.9 Hz), 7,44 is 7.50 (1H, m), 7,51-7,58 (2H, m), 7,60 (1H, DD, J=8,2, 1.8 Hz), 7,71 (1H, DD, J=7,9, 1.1 Hz), 7,72 for 7.78 (2H, m), 7,82-7,88 (1H, m)to 8.14 (1H, d, J=8,2 Hz), 8,80 (1H, d, J=1,8 Hz), 12,25-12,50 (2H, extended).

2-(2-Hydroxy-5-methylbenzamide)-4-phenylbenzene acid

1H-NMR(DMSO-d6) δ: 2,28 (3H, s), 6,92 (1H, d, J=8,3 Hz), 7,26 (1H, DD, J=8,3) and 1.7 Hz), 7,43-7,58 (4H, m), 7,69-7,76 (3H, m), 8,10 (1H, d, J=8,3 Hz), 9,01 (1H, d, J=1.7 Hz), 11,24 (1H, s), 12,30 (1H, s), 13,40-13,65 (1H, broadened).

2-(2-Hydroxy-3-methoxybenzamido)-4-phenylbenzene acid

1H-NMR(DMSO-d6) is: 3,81-a 3.87 (3H, m)6,91-to 6.95 (1H, m), 7,17-of 7.23 (1H, m), 7,40-to 7.50 (2H, m), 7,50-7,58 (3H, m), 7,70-to 7.77 (2H, m), 8,11 (1H, DD, J=8,3, 2.4 Hz), 8,92-8,96 (1H, m), 11,25 (1H, s), 12,27 (1H, s).

2-(2-Hydroxy-4-methoxybenzamido)-4-phenylbenzene acid

1H-NMR(DMSO-d6) δ: of 3.80 (3H, s), 6,53 (1H, d, J=2.3 Hz), 6,60 (1H, DD, J=8,9, and 2.3 Hz), 7,42-EUR 7.57 (4H, m), 7,70 to 7.75 (2H, m), a 7.85 (1H, d, J=8,9 Hz), 8,10 (1H, d, J=8,3 Hz), 8,97 (1H, d, J=1.7 Hz), 11,82 (1H, s), 12,21 (1H with).

2-(2-Hydroxy-5-methoxybenzamido)-4-phenylbenzene acid

1H-NMR(DMSO-d6) δ: 3,76 (3H, s), of 6.96 (1H, d, J=8,9 Hz), was 7.08 (1H, DD, J=8,9 and 3.1 Hz), 7,43-7,49 (2H, m), 7,49-7,58 (3H, m), 7,71-7,76 (2H, m), 8,10 (1H, d, J=8,3 Hz), 9,03 (1H, d, J=1.7 Hz), 11,00 (1H, s), of 12.33 (1H, s), 13,35-13,65 (1H, broadened).

2-(2-Hydroxy-6-methoxybenzamido)-4-phenylbenzene acid

1H-NMR(DMSO-d6) δ: 3,98 (3H, s), 6,59 (1H, DD, J=8,3, 1.0 Hz), of 6.66 (1H, d, J=8,4 Hz), 7,40 (1H, DD, J=8,4, 8,3 Hz), 7,43-7,50 (1H, m), 7,51-7,58 (3H, m), 7,70-7,76 (2H, m), 8,11 (1H, d, J=8.1 Hz), to 8.94 (1H, s), 12,35 (1H, C)br12.62 (1H, s), 13,60-13,78 (1H, broadened).

2-(5-Acetyl-2-hydroxybenzamide)-4-phenylbenzene acid

1H-NMR(DMSO-d6) δ: 2.57 m) (3H, s), 7,12 (1H, d, J=8.7 Hz), 7,43-7,50 (1H, m), 7,51-7,58 (3H, m), 7,71 for 7.78 (2H, m), of 8.04 (1H, DD, J=8,7, 2.2 Hz), 8,11 (1H, d, J=8,3 Hz), 8,58 (1H, d, J=2.2 Hz), 9,06 (1H, d, J=1.7 Hz), 12,25-12,48 (2H, m), 13,40-13,65 (1H, broadened).

2-(2-Hydroxy-4-(1-(methylsulphonyl)piperidine-4-yloxy)benzamido)-4-phenylbenzene acid

1H-NMR(DMSO-d6), (40°C) δ: 1.70 to of 1.84 (2H, m), 1,96 is 2.10 (2H, m), 2,90 (3H, s), 3,10-up 3.22 (2H, m), 3,30-of 3.42 (2H, m), 4,59-4,70 (1H, m), to 6.57 (1H, d, J=2.4 Hz), of 6.65 (1H, DD, J=8,9, and 2.4 Hz), 7,42-EUR 7.57 (4H, m), 7,69 to 7.75 (2H, m), to 7.84 (1H, d, J=8,9 Hz), 8,10 (1H, d,J=8,3 Hz), of 8.95 (1H, d, J=1.7 Hz), to 11.79 (1H, s), 12,19 (1H, s).

Example 11a

The following compound was obtained as described in Example 1a.

2-(2-Hydroxy-5-methoxybenzamido)-4-(2-methoxyphenyl)benzoic acid

1H-NMR(DMSO-d6) δ: 3,75 (3H, s), of 3.80 (3H, s), to 6.95 (1H, d, J=9.0 Hz),? 7.04 baby mortality for 7.12 (2H, m), 7,16 (1H, d, J=8.6 Hz), 7,30 was 7.45 (4H, m), 8,03 (1H, d, J=8,3 Hz), 8,78 (1H, d, J=1.7 Hz), 11,00 (1H, s)to 12.28 (1H, s).

Example 12a

When cooled on ice to a suspension of 2-acetoxy-5-(piperidine-1-yl)benzoic acid (0.11 g) in methylene chloride (2.0 ml) was sequentially added N,N-dimethylformamide (0,010 ml) and oxacillin (0,044 ml)and then stirred at room temperature for 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2.0 ml). The resulting mixture was added while cooled on ice to a solution of tert-butyl 2-amino-4-(2-methoxyphenyl)benzoate (0.10 g) and pyridine (0,054 ml) in methylene chloride (1.0 ml)and then stirred at room temperature for 1 hour and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated in terms of p is lower pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 91-80% hexane/ethyl acetate] to obtain 0.11 g of tert-butyl 2-(2-acetoxy-5-(piperidine-1-yl)benzamido)-4-(2-methoxyphenyl)benzoate as a pale yellow solid.

To the obtained tert-butyl 2-(2-acetoxy-5-(piperidine-1-yl)benzamido)-4-(2-methoxyphenyl)benzoate (0.11 g) was added dioxane (4.0 ml) and 4 mol/l aqueous sodium hydroxide solution (0.25 ml)and then stirred at 50-55°C for 2 hours. The reaction mixture was cooled to room temperature, and added a 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-60% hexane/ethyl acetate] to obtain 0.025 g of tert-butyl 2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-4-(2-methoxyphenyl)benzoate as a yellow solid.

To the obtained tert-butyl 2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-4-(2-methoxyphenyl)benzoate (0.025 g) was added 4 mol/l solution of florodora in dioxane (3.0 ml), then stirred at room temperature for 3 hours and then at 50-55°C for 1 hour. Reactio the ing the mixture was cooled to room temperature, and then the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0,020 g of the hydrochloride of 2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-4-(2-methoxyphenyl)benzoic acid as a white solid.

1H-NMR(CD3OD) δ: 1,72-of 1.84 (2H, m), 1,96 e 2.06 (4H, m), 3,52-3,62 (4H, m), 3,85 (3H, s), 7.03 is-7,16 (3H, m), 7,35-the 7.43 (3H, m), of 7.64 (1H, DD, J=8,8, 2.7 Hz), 8,04-of 8.09 (1H, m), 8,15 (1H, d, J=8,3 Hz), 8,88 (1H, d, J=1,5 Hz).

Example 13a

To a suspension of 2-(benzyloxy)-4-(pyridin-3-yl)benzoic acid (0,095 g) in methylene chloride (1.4 ml) was sequentially added N,N-dimethylformamide (2,4 μl) and oxacillin (0,040 ml)and then stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, and was added to the residue toluene. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (1.4 ml). The resulting mixture was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (0,070 g) in a mixture of pyridine (0,053 ml) and methylene chloride (1.4 ml)and then stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/l aqueous solution of sodium hydroxide. The organic layer was separated, washed with 1 mol/l aqueous solution of sodium hydroxide and dried over without the one magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-50% hexane/ethyl acetate] to obtain of 0.13 g of tert-butyl 2-(2-(benzyloxy)-4-(pyridin-3-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-4-(pyridin-3-yl)benzamido)-4-phenylbenzoate (0,13 g) in a mixture of methanol (2 ml), dioxane (4 ml) and ethyl acetate (4 ml) was added 10% palletirovanie coal (63 mg)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-40% hexane/ethyl acetate] to obtain 0,077 g of tert-butyl 2-(2-hydroxy-4-(pyridin-3-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

A solution of the obtained tert-butyl 2-(2-hydroxy-4-(pyridin-3-yl)benzamido)-4-phenylbenzoate (0,077 g) in triperoxonane acid (5 ml) was stirred at room temperature for 2 hours and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the obtained residue, water and ethyl acetate. After adjusting the pH to 65 addition of a saturated aqueous solution of sodium bicarbonate, the solid was collected by filtration. To the obtained solid substance was added methanol (3 ml), dioxane (3 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,073 ml). Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether. The solid substance was collected by filtration to obtain 0,063 g 2-(2-hydroxy-4-(pyridin-3-yl)benzamido)-4-phenylbenzoate sodium in the form of a light yellow solid.

1H-NMR(DMSO-d6) δ: 7,31-the 7.43 (4H, m), 7,47-of 7.55 (3H, m), 7,66-7,72 (2H, m), 8,10-by 8.22 (3H, m), 8,60-8,65 (1H, m), 8,91 (1H, d, J=2.0 Hz), 8,99 (1H, d, J=1.9 Hz).

Examples 14a-17a

Compounds shown in Table 10a, obtained as described in Example 13a.

Table 10a
Example No.AExample No.A
14a16a
15a17a

2-(2-Hydroxy-4-(is iridin-4-yl)benzamido)-4-phenylbenzoate sodium

1H-NMR(DMSO-d6) δ: 7,33-7,44 (4H, m), 7,47-rate of 7.54 (2H, m), 7,66-7,72 (2H, m), 7,76-7,83 (2H, m)to 8.12 (1H, d, J=7.8 Hz), 8,15 (1H, d, J=8,3 Hz), 8,60-8,76 (2H, m), 8,91 (1H, d, J=1.7 Hz).

2-(2-Hydroxy-4-(pyrimidine-5-yl)benzamido)-4-phenylbenzoate sodium

1H-NMR(DMSO-d6) δ: 7,34-rate of 7.54 (6H, m), 7,66-7,72 (2H, m)to 8.12 (1H, d, J=8.1 Hz), 8,16 (1H, d, J=8.1 Hz), 8,91 (1H, d, J=1.7 Hz), which 9.22-9,26 (3H, m).

2-(2-Hydroxy-3-(pyridin-3-yl)benzamido)-4-phenylbenzoate sodium

1H-NMR(DMSO-d6) δ: for 7.12 (1H, DD, J=7,8, and 7.8 Hz), 7,34-the 7.43 (2H, m), 7,45-7,53 (3H, m), to 7.61 (1H, DD, J=7,4, 1.1 Hz), 7,65-7,71 (2H, m), 8,00-of 8.06 (1H, m), 8,10-8,16 (2H, m), charged 8.52-8,59 (1H, m), 8,79 (1H, d, J=1.7 Hz), 8,88 (1H, d, J=1.7 Hz).

2-(2-Hydroxy-3-(pyridin-4-yl)benzamido)-4-phenylbenzoate sodium

1H-NMR(DMSO-d6) δ:? 7.04 baby mortality-7,21 (1H, m), 7,32-the 7.43 (2H, m), 7,46-rate of 7.54 (2H, m), to 7.61-7,72 (5H, m), 8,06 is 8.22 (2H, m), 8,56-to 8.70 (2H, m), 8,86-of 8.92 (1H, m).

Example 18a

To a suspension of 2-(benzyloxy)-4-(pyridin-2-yl)benzoic acid (0,095 g) in methylene chloride (1.4 ml) was sequentially added N,N-dimethylformamide (2,4 μl) and oxacillin (0,040 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue toluene. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (1.4 ml). The resulting mixture was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (0,070 g) in a mixture of pyridine (0,053 ml) and methylene chloride (1.4 ml) and then stirred at room temperature for 2 hours. To the reaction mixture was added 1 mol/l aqueous solution of sodium hydroxide. The organic layer was separated, washed with 1 mol/l aqueous solution of sodium hydroxide and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 95-60% hexane/ethyl acetate] to obtain of 0.13 g of tert-butyl 2-(2-(benzyloxy)-4-(pyridin-2-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-4-(pyridin-2-yl)benzamido)-4-phenylbenzoate (0,13 g) in a mixture of methanol (2 ml), dioxane (2 ml) and ethyl acetate (4 ml) was added 10% palletirovanie coal (67 mg)and then stirred in a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. To the reaction mixture were added chloroform. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: chloroform] to obtain 0.11 g of tert-butyl 2-(2-hydroxy-4-(pyridin-2-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

A solution of the obtained tert-butyl 2-(2-hydroxy-4-(pyridin-2-yl)benzamido)-4-phenylbenzoate (0.11 g) in trivero ssnoi acid (5 ml) was stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the obtained residue, water and ethyl acetate. After adjusting the pH to 6.0 by the addition of saturated aqueous sodium bicarbonate solution, the solid is collected by filtration. To the obtained solid substance was added water (4 ml), methanol (4 ml) and dioxane (4 ml)at room temperature was passed through the mixture of gaseous carbon dioxide. The solvent is evaporated under reduced pressure, and was added to the obtained residue, water. The solid substance was collected by filtration to obtain 0,072 g 2-(2-hydroxy-4-(pyridin-2-yl)benzamido)-4-vinylbenzoic acid as a pale yellow solid.

1H-NMR(DMSO-d6) δ: 7,40-7,58 (5H, m), of 7.69 (1H, DD, J=8,3) and 1.7 Hz), 7,72-to 7.77 (2H, m), 7,80 (1H, d, J=1.4 Hz), to 7.93 (1H, DDD, J=7,8, and 7.8, 1.8 Hz), 7,98-of 8.06 (2H, m), 8,11 (1H, d, J=8,3 Hz), 8,69-a total of 8.74 (1H, m), 9,05 (1H, d, J=1.7 Hz), 11,55-11,78 (1H, broadened), 12,40-br12.62 (1H, broadened).

Example 19a

To a suspension of 2-(benzyloxy)-5-(pyridin-4-yl)benzoic acid (0,095 g) in methylene chloride (2 ml) was sequentially added N,N-dimethylformamide (2,4 μl) and oxacillin (0,040 ml)and then stirred at room temperature for 2 hours and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue toluene. The solvent is evaporated in conditions on yunogo pressure, and was added to the residue methylene chloride (1.5 ml). The resulting mixture was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (0,070 g) in a mixture of pyridine (0,053 ml) and methylene chloride (2 ml)and then stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/l aqueous solution of sodium hydroxide. The organic layer was separated, washed with 1 mol/l aqueous solution of sodium hydroxide and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-40% hexane/ethyl acetate] to obtain 0.11 g of tert-butyl 2-(2-(benzyloxy)-5-(pyridin-4-yl)benzamido)-4-phenylbenzoate.

1H-NMR(DMSO-d6) δ: rate of 1.51 (9H, s)5,59 (2H, s), 7,26-7,42 (4H, m), 7,44 to 7.62 (6H, m), to 7.67-7,80 (4H, m), of 7.97 (1H, DD, J=8,8, 2.4 Hz), 8,07 (1H, d, J=8,3 Hz), 8,39 (1H, d, J=2.4 Hz), 8,58-8,67 (2H, m), 9,14 (1H, s), 12,25 (1H, s).

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(pyridin-4-yl)benzamido)-4-phenylbenzoate (0.11 g) in acetic acid (2 ml) was added 10% palletirovanie coal (0.11 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. To the residue was added ethyl acetate and a saturated aqueous solution of BIC is rbonate sodium. The organic layer was separated, sequentially washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added triperoxonane acid (5 ml)and then stirred at room temperature for 5 hours. The solvent is evaporated under reduced pressure, and was added to the residue water and ethyl acetate. After adjusting the pH to 6.5 by the addition of saturated aqueous sodium bicarbonate solution, the solid is collected by filtration, and was added to the obtained solid substance methanol (10 ml), dioxane (10 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,078 ml). Then, insoluble matter was removed by filtration, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0,067 g of sodium 2-(2-hydroxy-5-(pyridin-4-yl)benzamido)-4-phenylbenzoate in the form of a yellow solid.

1H-NMR(DMSO-d6) δ: was 7.08 (1H, d, J=8,8 Hz), was 7.36 (1H, DD, J=8,1) and 1.7 Hz), 7,35-the 7.43 (1H, m), 7,47-rate of 7.54 (2H, m), 7,66-7,72 (2H, m), 7,73-7,79 (2H, m), 7,92-8,00 (1H, m)to 8.12 (1H, d, J=8.1 Hz), 8,54 (1H, d, J=2.2 Hz), at 8.60-to 8.70 (2H, m), 8,91 (1H, d, J=1.7 Hz).

Example 20a

p> To a suspension of 2-(benzyloxy)-4-(1H-pyrazole-1-yl)benzoic acid (0,092 g) in methylene chloride (1.4 ml) was sequentially added N,N-dimethylformamide (2,4 μl) and oxacillin (0,040 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue toluene. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (1.4 ml). The resulting mixture was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (0,070 g) in a mixture of pyridine (0,053 ml) and methylene chloride (1.4 ml)and then stirred at room temperature for 1 hour. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, and separated the organic layer. The obtained organic layer was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 95-70% hexane/ethyl acetate] to obtain 0,098 g of tert-butyl 2-(2-(benzyloxy)-4-(1H-pyrazole-1-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-4-(1H-pyrazole-1-yl)benzamido)-4-phenylbenzoate (0,098 g) in a mixture of ethyl acetate (2 ml), methanol (1 ml) and dioxane (1 ml) was added 10% palletirovanie coal (49 mg)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture obavljale chloroform, and removing insoluble substances by filtration. The solvent is evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: chloroform] to obtain tert-butyl 2-(2-hydroxy-4-(1H-pyrazole-1-yl)benzamido)-4-phenylbenzoate.

A solution of the obtained tert-butyl 2-(2-hydroxy-4-(1H-pyrazole-1-yl)benzamido)-4-phenylbenzoate in triperoxonane acid (5 ml) was stirred at room temperature for 3 hours and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the obtained residue, methanol. The solid substance was collected by filtration to obtain 0,056 g 2-(2-hydroxy-4-(1H-pyrazole-1-yl)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR(DMSO-d6) δ: 6,60 (1H, DD, J=2,6, 1.8 Hz), 7,43-7,58 (6H, m), 7,71-to 7.77 (2H, m), 7,81 (1H, d, J=1.7 Hz), 8,03 (1H, d, J=8,8 Hz), 8,11 (1H, d, J=8,3 Hz), 8,58 (1H, d, J=2.4 Hz), of 9.02 (1H, d, J=1.7 Hz), 11,90 (1H, ), of 12.33 (1H, s), 13,38-13,64 (1H, broadened).

Examples 21a and 22a

Compounds shown in Table 11a, obtained as described in Example 20a.

Table 11a
Example No.AExample No. A
21a22a

2-(2-Hydroxy-4-(pyrimidine-2-yl)benzamido)-4-phenylbenzene acid

1H-NMR(DMSO-d6) δ: 7,43-7,58 (5H, m), 7,71-to 7.77 (2H, m), to 7.99 (1H, DD, J=8,4, and 1.6 Hz), 8,04-to 8.14 (3H, m), 8,96 (2H, d, J=4.9 Hz), 9,07 (1H, d, J=1.7 Hz), are 11.62 (1H, s)12,42 (1H, s), 13,35-13,60 (1H, broadened).

2-(2-hydroxy-5-(1H-pyrazole-1-yl)benzamido)-4-phenylbenzene acid

1H-NMR(DMSO-d6) δ: 6,53 (1H, DD, J=2.1 a, 2.1 Hz), 7,14 (1H, d, J=9.0 Hz), 7,43-7,50 (1H, m), 7,51-7,58 (3H, m), 7,71-to 7.77 (3H, m), of 7.90 (1H, DD, J=8,8, 2,9 Hz), 8,11 (1H, d, J=8,3 Hz), a 8.34 (1H, d, J=2.7 Hz), 8,42 (1H, d, J=2.4 Hz), 9,06 (1H, d, J=1.7 Hz), to 11.52-11,70 (1H, broadened), 12,35-12,50 (1H, broadened).

Example 23a

To a suspension of 2-(benzyloxy)-5-(pyridin-3-yl)benzoic acid (0,095 g) in methylene chloride (2 ml) was sequentially added N,N-dimethylformamide (2,4 μl) and oxacillin (0,040 ml)and then stirred at room temperature for 2 hours and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue toluene. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (1.5 ml). The resulting mixture was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (0,070 g) in a mixture of pyridine (0,053 ml) and methylene chloride (2 ml), and the ATEM was stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/l aqueous solution of sodium hydroxide. The organic layer was separated, washed with 1 mol/l aqueous solution of sodium hydroxide and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-50% hexane/ethyl acetate] to obtain 0.14 g of tert-butyl 2-(2-(benzyloxy)-5-(pyridin-3-yl)benzamido)-4-phenylbenzoate.

1H-NMR(DMSO-d6) δ: rate of 1.51 (9H, s), to 5.58 (2H, s), 7,26-7,42 (4H, m), 7,44-7,63 (7H, m), 7,70 for 7.78 (2H, m), 7,89 (1H, DD, J=8,8, 2.4 Hz), 8,04-8,13 (2H, m), of 8.28 (1H, d, J=2.4 Hz), 8,56 (1H, DD, J=4,6, and 1.4 Hz), 8,89 (1H, d, J=2,4 Hz), 9,12-9,17 (1H, m), 12,25 (1H, s).

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(pyridin-3-yl)benzamido)-4-phenylbenzoate (0.14 g) in a mixture of ethyl acetate (1 ml) and methanol (1 ml) was added 10% palletirovanie coal (14 mg)and then stirred in a hydrogen atmosphere at room temperature for 1 hour and 30 minutes. To the reaction mixture was added 10% palletirovanie coal (14 mg). The reaction mixture was stirred in hydrogen atmosphere at room temperature for 2 hours and 30 minutes. To the reaction mixture was added acetic acid (2 ml) and 10% palletirovanie coal (0.11 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. Insoluble substances were removed put the m filter, and the solvent evaporated under reduced pressure. To the residue was added ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added triperoxonane acid (5 ml)and then stirred at room temperature for 5 hours. The solvent is evaporated under reduced pressure, and was added to the residue water and ethyl acetate. After adjusting the pH to 5 by addition of a saturated aqueous solution of sodium bicarbonate, the solid was collected by filtration to obtain 0,070 g 2-(2-hydroxy-5-(pyridin-3-yl)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR(DMSO-d6) δ: 7,16 (1H, d, J=8.5 Hz), 7,43-to 7.59 (5H, m), 7,70 for 7.78 (2H, m), 7,86 (1H, DD, J=8,5, and 2.3 Hz), 8,05-8,11 (1H, m)to 8.12 (1H, d, J=8.0 Hz), compared to 8.26 (1H, d, J=2.3 Hz), 8,53-8,59 (1H, m), 8,91 (1H, d, J=2.0 Hz), 9,03 (1H, d, J=1.5 Hz).

Example 24a

To a suspension of 7-(benzyloxy)-2,3-dihydrobenzo[1,4]dioxin-6-carboxylic acid (0.33 g) in methylene chloride (3.0 ml) was sequentially added N,N-dimethylformamide (8,8 mm) and oxacillin (0.15 ml)and then stirred at whom atoi temperature for 40 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (3 ml). The resulting mixture was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (0.26 g) in a mixture of pyridine (0,20 ml) and methylene chloride (3.0 ml)and then stirred at room temperature for 40 minutes. The solvent is evaporated under reduced pressure, and added to the remainder of 1 mol/l hydrochloric acid and chloroform. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 90-65% hexane/ethyl acetate] to obtain of 0.49 g of tert-butyl 2-(7-(benzyloxy)-2,3-dihydrobenzo[1,4]dioxin-6-carboxamido)-4-phenylbenzoate in the form of a white solid.

To a solution of the obtained tert-butyl 2-(7-(benzyloxy)-2,3-dihydrobenzo[1,4]dioxin-6-carboxamido)-4-phenylbenzoate (0,49 g) in a mixture of methanol (4 ml) and ethyl acetate (4 ml) was added 10% palletirovanie coal (0.24 g)and then stirred in a hydrogen atmosphere at room temperature for 3 hours. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collected a t ardoe substance by filtration to obtain and 0.37 g of tert-butyl 2-(7-hydroxy-2,3-dihydrobenzo[1,4]dioxin-6-carboxamido)-4-phenylbenzoate in the form of a white solid.

A solution of the obtained tert-butyl 2-(7-hydroxy-2,3-dihydrobenzo[1,4]dioxin-6-carboxamido)-4-phenylbenzoate (0,37 g) in triperoxonane acid (4 ml) was stirred at room temperature for 15 minutes. To the reaction mixture were added methylene chloride (10 ml)and then stirred at room temperature for 1 hour and 15 minutes. The solvent is evaporated under reduced pressure, and was added to the obtained residue, ethyl acetate. The solid substance was collected by filtration to obtain a 0.30 g of 2-(7-hydroxy-2,3-dihydrobenzo[1,4]dioxin-6-carboxamido)-4-vinylbenzoic acid as a white solid.

1H-NMR(DMSO-d6) δ: 4,18-4.26 deaths (2H, m), 4.26 deaths is 4.35 (2H, m), 6.48 in (1H, s), 7,39 (1H, s), 7,41-EUR 7.57 (4H, m), 7.68 per to 7.75 (2H, m), 8,08 (1H, d, J=8,3 Hz), 8,97 (1H, d, J=2.0 Hz), 11,24 (1H, s), 12,19 (1H, s), 13,35-13,60 (1H, broadened).

Example 25a

The following compound was obtained as described in Example 24a.

2-(6-Hydroxybenzo[1,3]dixital-5-carboxamido)-4-phenylbenzene acid

1H-NMR(DMSO-d6) δ: 6,07 (1H, s), 6,60 (1H, d, J=0.7 Hz), 7,34 (1H, d, J=0.7 Hz), 7,42-to 7.59 (4H, m), 7.68 per for 7.78 (2H, m), of 8.09 (1H, d, J=8.0 Hz), 8,90-8,96 (1H, m), 11,85 (1H, s), 12,17 (1H, s), 13,40-13,70 (1H, broadened).

Example 26a

To a solution of 2-(benzyloxy)-4-vinylbenzoic acid (0.18 g) in methylene chloride (2 ml) was sequentially added N,N-dimethylformamide (4,6 mm) and oxalyl the ID (0,077 ml), and then was stirred at room temperature for 25 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2 ml). The resulting mixture was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (0.14 g) in a mixture of pyridine (0.10 ml) and methylene chloride (2 ml)and then stirred at room temperature for 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue water and chloroform. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The reaction mixture was purified according to the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-75% hexane/ethyl acetate → chloroform] to obtain 0.11 g of tert-butyl 2-(2-(benzyloxy)-4-phenylbenzene)-4-phenylbenzoate in the form of a white solid.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-4-phenylbenzene)-4-phenylbenzoate (0.11 g) in a mixture of methanol (4 ml) and chloroform (4 ml) was added 10% palletirovanie charcoal (40 mg), then stirred in hydrogen atmosphere at room temperature for 5 hours and 30 minutes, and then at 35°C for 1 hour. To the reaction mixture was added 10% palletirovanie charcoal (40 mg)and then stirred in atmospheres, the hydrogen at 35°C for 2 hours. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, hexane, and collecting the solid by filtration to obtain tert-butyl 2-(2-hydroxy-4-phenylbenzene)-4-phenylbenzoate.

A solution of the obtained tert-butyl 2-(2-hydroxy-4-phenylbenzene)-4-phenylbenzoate in a mixture of methylene chloride (6 ml) and triperoxonane acid (1 ml) was stirred at room temperature for 3 hours and 10 minutes. To the reaction mixture were added triperoxonane acid (2 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid substance was collected by filtration to obtain 0,076 g 2-(2-hydroxy-4-phenylbenzene)-4-vinylbenzoic acid as a white solid.

1H-NMR(DMSO-d6) δ: 7,29 (1H, d, J=1.7 Hz), 7,31 (1H, DD, J=8,2, 1.8 Hz), 7,40-of 7.60 (7H, m), 7,66-7,79 (4H, m), of 8.00 (1H, d, J=8,3 Hz), 8,11 (1H, d, J=8.1 Hz), 9,04 (1H, d, J=2.0 Hz), 11,66 (1H, s), 12,36 (1H, s), 13,35-13,70 (1H, broadened).

Example 27a

To a suspension of 2-(benzyloxy)-5-(pyridin-2-yl)benzoic acid (0,050 g) in methylene chloride (2 ml) was sequentially added N,N-dimethylformamide (1,5 ml) and oxacillin (0,023 ml)and then stirred the ri room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue toluene. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2 ml). The resulting mixture was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (0,053 g) in a mixture of pyridine (0,033 ml) and methylene chloride (2 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure and purify the resulting residue by the method of column chromatography on silica gel [eluent: 95-70% hexane/ethyl acetate] to obtain 0,038 g of tert-butyl 2-(2-(benzyloxy)-5-(pyridin-2-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

1H-NMR(CDCl3) δ: 1,53 (9H, s)to 5.56 (2H, s), was 7.08 (1H, d, J=8,8 Hz), 7,18 (1H, DDD, J=7,4, to 4.8, 1.2 Hz), 7.23 percent-7,52 (9H, m), 7.68 per-7,81 (4H, m), 8,07 (1H, d, J=8,3 Hz), 8,15 (1H, DD, J=8,8, 2.4 Hz), 8,61-8,66 (1H, m), a total of 8.74 (1H, d, J=2.4 Hz), 9,31-a 9.35 (1H, m), 12,54 (1H, s).

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(pyridin-2-yl)benzamido)-4-phenylbenzoate (0,038 g) in a mixture of ethyl acetate (2 ml) and methanol (4 ml) was added 10% palletirovanie charcoal (20 mg)and then stirred in a hydrogen atmosphere at room temperature for 2 hours and 45 minutes. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography is and silica gel [eluent: 95-70% hexane/ethyl acetate] to obtain 0,021 g of tert-butyl 2-(2-hydroxy-5-(pyridin-2-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

A solution of the obtained tert-butyl 2-(2-hydroxy-5-(pyridin-2-yl)benzamido)-4-phenylbenzoate (0,021 g) in a mixture of methylene chloride (1 ml) and triperoxonane acid (0.5 ml) was stirred at room temperature for 1 hour and 10 minutes. The solvent is evaporated under reduced pressure, and was added to the obtained residue, water. After adjusting the pH to 7 by adding saturated aqueous solution of sodium bicarbonate, the solid was collected by filtration to obtain 0,013 g 2-(2-hydroxy-5-(pyridin-2-yl)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR(DMSO-d6) δ: 7,15 (1H, d, J=8.6 Hz), 7,31-7,39 (1H, m), 7,43-of 7.60 (4H, m), 7,71-7,79 (2H, m), 7,86-of 8.00 (2H, m)to 8.12 (1H, d, J=8.1 Hz), 8,18 (1H, DD, J=8,5 and 2.2 Hz), 8,66 (1H, d, J=4.9 Hz), 8,69 (1H, d, J=2.0 Hz), 9,04-9,10 (1H, m), 11,81 (1H, s), KZT 12.39 (1H, s).

Example 28a

To a suspension of 2-(benzyloxy)-5-(pyrimidine-5-yl)benzoic acid (0,80 g) in methylene chloride (20 ml) was sequentially added N,N-dimethylformamide (0,024 ml) and oxacillin (0,40 ml)and then stirred at room temperature for 1 hour and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (20 ml). The resulting mixture was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (0.74 g) in a mixture of pyridine (0,59 ml) and methylene chloride (20 ml)and then stirred the at room temperature for 1 hour and 10 minutes. The solvent is evaporated under reduced pressure, and was added to the residue water and chloroform. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 80-50% hexane/ethyl acetate] to obtain 1.1 g of tert-butyl 2-(2-(benzyloxy)-5-(pyrimidine-5-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

To the solution obtained tert-butyl 2-(2-(benzyloxy)-5-(pyrimidine-5-yl)benzamido)-4-phenylbenzoate (1.1 g) in a mixture of ethyl acetate (10 ml), methanol (20 ml) and dioxane (20 ml) was added 10% palletirovanie coal (0,57 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours and 20 minutes. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 70-0% hexane/ethyl acetate] to obtain 0.73 g of tert-butyl 2-(2-hydroxy-5-(pyrimidine-5-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

A solution of the obtained tert-butyl 2-(2-hydroxy-5-(pyrimidine-5-yl)benzamido)-4-phenylbenzoate (0.73 g) in a mixture of methylene chloride (25 ml) and Tr is forexpros acid (10 ml) was stirred at room temperature overnight. The solvent is evaporated under reduced pressure, and was added to the obtained residue, water. After adjusting the pH to 6.5 by the addition of saturated aqueous sodium bicarbonate solution, the solid was collected by filtration to obtain 0,49 g 2-(2-hydroxy-5-(pyrimidine-5-yl)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR(DMSO-d6) δ: 7,19 (1H, d, J=8.5 Hz), 7,43-7,50 (1H, m), 7,51-of 7.60 (3H, m), 7,70 for 7.78 (2H, m), to 7.93 (1H, DD, J=8,5, 2,4 Hz)to 8.12 (1H, d, J=8,3 Hz), 8,31 (1H, d, J=2.2 Hz), 9,04 (1H, d, J=1.7 Hz), 9,14 (2H, s), 9,17 (1H, s), 11,72-11,92 (1H, broadened), to 12.28-12,50 (1H, broadened), 13,44-13,72 (1H, broadened).

Example 29a

To a suspension of 2-(benzyloxy)-5-(pyrimidine-2-yl)benzoic acid (0.64 g) in methylene chloride (20 ml) was sequentially added N,N-dimethylformamide is 0.019 ml) and oxacillin (0,32 ml)and then stirred at room temperature for 1 hour and 10 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (20 ml). The resulting mixture was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (0,59 g) in a mixture of pyridine (0,47 ml) and methylene chloride (20 ml)and then stirred at room temperature for 1 hour and 20 minutes. The solvent is evaporated under reduced pressure, and was added to the residue water and ethyl acetate. The organic layer was separated, amywali saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 70-50% hexane/ethyl acetate] to obtain of 0.94 g of tert-butyl 2-(2-(benzyloxy)-5-(pyrimidine-2-yl)benzamido)-4-phenylbenzoate.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(pyrimidine-2-yl)benzamido)-4-phenylbenzoate (0,072 g) in a mixture of ethyl acetate (4 ml) and methanol (4 ml) was added 10% palletirovanie coal (36 mg)and then stirred in a hydrogen atmosphere at room temperature for 2 hours and 45 minutes. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 75-60% hexane/ethyl acetate] to obtain 5 mg of tert-butyl 2-(2-hydroxy-5-(pyrimidine-2-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

A solution of the obtained tert-butyl 2-(2-hydroxy-5-(pyrimidine-2-yl)benzamido)-4-phenylbenzoate (5 mg) in a mixture of methylene chloride (2 ml) and triperoxonane acid (0,50 ml) was stirred at room temperature for 3 hours and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue water and chloroform. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent evaporated in ponie the frame pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 4 mg of 2-(2-hydroxy-5-(pyrimidine-2-yl)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR(DMSO-d6) δ: 7,20-EUR 7.57 (6H, m), of 7.64-to 7.77 (2H, m), of 7.96-8,54 (2H, m), 8,64-9,14 (4H, m).

Example 30a

To 2-(benzyloxy)-4-(furan-3-yl)benzoic acid (0,099 g) was added methylene chloride (2 ml)while cooling on ice was sequentially added N,N-dimethylformamide (3 ml) and oxacillin (0,043 ml), then stirred at the same temperature for 10 minutes and then at room temperature for 50 minutes. To the reaction mixture at room temperature was added oxalicacid (0,043 ml)and then stirred at the same temperature for 20 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2 ml). The resulting mixture while cooling on ice, was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (0.075 g) in a mixture of pyridine (0,057 ml) and methylene chloride (2 ml)and then stirred at room temperature for 1 hour and 30 minutes. The solvent is evaporated under reduced pressure, and added to the remainder of 1 mol/l hydrochloric acid and ethyl acetate. The organic layer was separated, washed with saturated aqueous chloride is sodium and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-80% hexane/ethyl acetate] and was further purified by the method of column chromatography on silica gel [eluent: toluene] obtaining 0,077 g of tert-butyl 2-(2-(benzyloxy)-4-(furan-3-yl)benzamido)-4-phenylbenzoate in the form of a light yellow solid.

To the obtained tert-butyl 2-(2-(benzyloxy)-4-(furan-3-yl)benzamido)-4-phenylbenzoate (0,076 g) was added thioanisole (0,82 ml) and triperoxonane acid (2.6 ml)and then stirred at room temperature for 3 hours and 20 minutes. The solvent is evaporated under reduced pressure, and was added to the residue 2 mol/l aqueous sodium hydroxide solution and toluene. The aqueous layer was separated and adjusted the pH to 4.5 by the addition of 6 mol/l hydrochloric acid. The solid substance was collected by filtration to obtain 0,016 g of 2-(4-(furan-3-yl)-2-hydroxybenzamide)-4-vinylbenzoic acid as a brown solid.

1H-NMR(DMSO-d6) δ: 6,98 (1H, s), 7.23 percent (1H, s), 7,28 (1H, d, J=8,3 Hz), 7,41-to 7.59 (4H, m), 7.68 per-of 7.82 (3H, m), 7,92 (1H, d, J=8,3 Hz), 8,11 (1H, d, J=8,3 Hz), 8,29 (1H, s), 8,99 (1H, s), 11,73 (1H, s), 12,38 (1H, s), 13,30-13,80 (1H, broadened).

Example 31a

To a suspension of 2-(benzyloxy)-5-(oxazol-5-yl)benzoic acid (0.18 g) in methylene chloride (2 ml) PEFC is therefore added N,N-dimethylformamide (4,6 μl) and oxacillin (0,077 ml), and then stirred at the same temperature for 40 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2 ml). The resulting mixture was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (0.14 g) in a mixture of pyridine (0.10 ml) and methylene chloride (2 ml)and then stirred at room temperature for 1 hour and 40 minutes. The solvent is evaporated under reduced pressure, and added to the remainder of 1 mol/l hydrochloric acid, water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 70-50% hexane/ethyl acetate] to obtain 0,22 g of tert-butyl 2-(2-(benzyloxy)-5-(oxazol-5-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

To the obtained tert-butyl 2-(2-(benzyloxy)-5-(oxazol-5-yl)benzamido)-4-phenylbenzoate (0.21 g) was added thioanisole (2.3 ml) and triperoxonane acid (7.7 ml)and then stirred at room temperature for 9 hours and 40 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methanol. The solid substance was collected by filtration to obtain 0.12 g of 2-(2-hydroxy-5-(oxazol-5-yl)benzo the IDO)-4-vinylbenzoic acid as a white solid.

1H-NMR(DMSO-d6) δ: 7,14 (1H, d, J=8,8 Hz), 7,42-to 7.64 (5H, m), 7,69-7,87 (3H, m), 8,11 (1H, d, J=8.1 Hz), of 8.28 (1H, s), 8,42 (1H, s), 9,07 (1H, s), RS 11.80 (1H, s), 12,38 (1H, s), 13,35-13,70 (1H, broadened).

Example 32a

To a suspension of 2-(benzyloxy)-5-(1,3,4-oxadiazol-2-yl)benzoic acid (0,069 g) in methylene chloride (1.2 ml) was sequentially added N,N-dimethylformamide (1,8 ml) and oxacillin (0,030 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue toluene. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (1.2 ml). The resulting mixture was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (to 0.060 g) in a mixture of pyridine (0,045 ml) and methylene chloride (1.2 ml)and then stirred at room temperature for 1 hour. To the reaction mixture were added 10% aqueous citric acid solution, the organic layer was separated, and purified the resulting organic layer according to the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-60% hexane/ethyl acetate] to obtain 0,099 g of tert-butyl 2-(2-(benzyloxy)-5-(1,3,4-oxadiazol-2-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

To the solution obtained tert-butyl 2-(2-(benzyloxy)-5-(1,3,4-oxadiazol-2-yl)benzamido)-4-phenylbenzo is a (0,049 g) in a mixture of ethyl acetate (1 ml) and methanol (1 ml) was added 10% palletirovanie charcoal (25 mg), and then was stirred in hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture was added ethyl acetate, and removing insoluble substances by filtration. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid substance was collected by filtration to obtain 0,034 g of tert-butyl 2-(2-hydroxy-5-(1,3,4-oxadiazol-2-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

A solution of the obtained tert-butyl 2-(2-hydroxy-5-(1,3,4-oxadiazol-2-yl)benzamido)-4-phenylbenzoate (0,034 g) in triperoxonane acid (5 ml) was stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid substance was collected by filtration to obtain 0,027 g 2-(2-hydroxy-5-(1,3,4-oxadiazol-2-yl)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR(DMSO-d6) δ: 7,24 (1H, d, J=8,8 Hz), 7,43-7,51 (1H, m), 7,51-to 7.59 (3H, m), 7,71 for 7.78 (2H, m), 8,06-to 8.14 (2H, m), 8,61 (1H, d, J=2.2 Hz), 9,06 (1H, d, J=1.7 Hz), 9,31 (1H, s), 12,30 (1H, s), 12,43 (1H, s), 13,40-13,62 (1H, broadened).

Example 33a

To a suspension of the hydrochloride of 2-(benzyloxy)-4-(1H-imidazol-1-yl)benzoic acid (0,086 g) in methylene chloride (1.4 ml) was sequentially added N,N-dimethylformamid the (2,0 ml) and oxacillin (0,033 ml), and then was stirred at room temperature for 1 hour and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue toluene. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (1.4 ml). The resulting mixture was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (0,070 g) in a mixture of pyridine (0,053 ml) and methylene chloride (1.4 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained organic layer was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-20% hexane/ethyl acetate] to obtain 0.12 g of tert-butyl 2-(2-(benzyloxy)-4-(1H-imidazol-1-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-4-(1H-imidazol-1-yl)benzamido)-4-phenylbenzoate (0.12 g) in a mixture of ethyl acetate (3.6 ml), methanol (1.8 ml) and dioxane (1.8 ml) was added 10% palletirovanie coal (61 mg)and then stirred in an atmosphere of hydrogen in to the room temperature for 2 hours. To the reaction mixture was added 10% palletirovanie charcoal (30 mg)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture was added chloroform, and removing insoluble substances by filtration. The solvent is evaporated under reduced pressure and purify the resulting residue by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: chloroform] to obtain 0,084 g of tert-butyl 2-(2-hydroxy-4-(1H-imidazol-1-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

A solution of the obtained tert-butyl 2-(2-hydroxy-4-(1H-imidazol-1-yl)benzamido)-4-phenylbenzoate (0,084 g) in triperoxonane acid (5 ml) was stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the residue dioxane (2 ml) and 4 mol/l solution of florodora in dioxane (0.5 ml)and then stirred at room temperature for 4 hours. The solid substance was collected by filtration to obtain 0,064 g 2-(2-hydroxy-4-(1H-imidazol-1-yl)benzamido)-4-vinylbenzoic acid hydrochloride as a white solid.

1H-NMR (DMSO-d6) δ: 7,38 is 7.50 (3H, m), 7,51-to 7.59 (3H, m), 7,71-to 7.77 (2H, m), 7,84-7,88 (1H, m)to 8.12 (1H, d, J=8,3 Hz), 8,13 (1H, d, J=8.5 Hz), compared to 8.26 (1H, DD, J=1,7, 1,7 Hz), of 9.02 (1H, d, J=1.7 Hz), 9,60 (1H, s), 12,23 (1H, C), 12,36 (1H, s).

Example 34a

The following compound was obtained as described in Example 33a.

2-(2-Hydroxy-5-(1H-imidazol-1-yl)benzamido)-4-vinylbenzoic acid hydrochloride

1H-NMR (DMSO-d6) δ: 7,27 (1H, d, J=8,8 Hz), 7,43-7,50 (1H, m), 7,51-7,58 (3H, m), 7,70-7,76 (2H, m), 7,83 (1H, DD, J=8,8, 2,9 Hz), the 7.85-7,89 (1H, m), 8,11 (1H, d, J=8,3 Hz), 8,23 (1H, DD, J=1,7, 1,7 Hz), 8,29 (1H, d, J=2,9 Hz), which is 9.09 (1H, d, J=1.7 Hz), 9,58 (1H, s), 12,08 (1H, s)12,42 (1H, s).

Example 35a

The following compound was obtained as described in Example 33a.

2-(2-Hydroxy-5-(pyridin-2-yl)benzamido)-4-(2-methoxyphenyl)benzoic acid hydrochloride

1H-NMR (DMSO-d6) δ: 3,81 (3H, s), 7,06 for 7.12 (1H, m), 7,15-7,22 (2H, m), 7,32-7,46 (3H, m), 7,50-EUR 7.57 (1H, m), with 8.05 (1H, d, J=8,3 Hz), 8,06-8,18 (2H, m), 8,16 (1H, DD, J=8,6, and 2.3 Hz), 8,64 (1H, d, J=2.3 Hz), 8,69-8,73 (1H, m,), cent to 8.85 (1H, d, J=1.7 Hz), 11,99 (1H, s), of 12.33 (1H, s).

Example 36a

To a suspension of 2-(benzyloxy)-5-(pyridin-4-yl)benzoic acid (0,086 g) in methylene chloride (1.5 ml) successively under cooling on ice, was added N,N-dimethylformamide (0,010 ml) and oxacillin (0,031 ml)and then stirred at room temperature for 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2.5 ml). The resulting mixture while cooling on ice, was added to a solution of tert-butyl 2-amino-4-(2-methoxyphenyl)benzoate (0,070 g) in a mixture of pyridine (0,028 ml) and methylene chloride (1.0 ml), and the ATEM was stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, sequentially washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 50-0% hexane/ethyl acetate] to obtain 0,094 g of tert-butyl 2-(2-(benzyloxy)-5-(pyridin-4-yl)benzamido)-4-(2-methoxyphenyl)benzoate as a white solid.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(pyridin-4-yl)benzamido)-4-(2-methoxyphenyl)benzoate (0,094 g) in a mixture of ethyl acetate (2.5 ml) and methanol (3.5 ml) was added 10% palletirovanie coal (19 mg)and then stirred in a hydrogen atmosphere at room temperature for 3 hours. To the reaction mixture was added 10% palletirovanie coal (19 mg)and then stirred in a hydrogen atmosphere at room temperature for 3 hours. Insoluble substances were removed by filtration, and washed the residue with ethyl acetate and tetrahydrofuran. The filtrate and hybrid washing agent operation liquid were combined, and the solvent evaporated under reduced pressure. The obtained residue was purified by column method chromium is ographie on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), PSQ100B(spherical), eluent: 65-45% hexane/ethyl acetate] to obtain tert-butyl 2-(2-hydroxy-5-(pyridin-4-yl)benzamido)-4-(2-methoxyphenyl)benzoate.

A solution of the obtained tert-butyl 2-(2-hydroxy-5-(pyridin-4-yl)benzamido)-4-(2-methoxyphenyl)benzoate in triperoxonane acid (4.0 ml) was stirred at room temperature for 1 hour and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue toluene. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid substance was collected by filtration to obtain 0,027 g 2-(2-hydroxy-5-(pyridin-4-yl)benzamido)-4-(2-methoxyphenyl)benzoic acid as a pale yellow solid.

To the obtained 2-(2-hydroxy-5-(pyridin-4-yl)benzamido)-4-(2-methoxyphenyl)benzoic acid (0,027 g) was added dioxane (2.5 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,031 ml)and then stirred at room temperature for 2 hours and 30 minutes. The solid substance was collected by filtration to obtain 0,012 g 2-(2-hydroxy-5-(pyridin-4-yl)benzamido)-4-(2-methoxyphenyl)sodium benzoate as a yellow solid.

1H-NMR (DMSO-d6) δ: with 3.79 (3H, s), 7,02-7,16 (3H, m), 7,16-7,22 (1H, m), 7,30-7,41 (2H, m), 7,73-7,79 (2H, m), of 7.97 (1H, DD, J=8,6 and 2.2 Hz), 8,07 (1H, d, J=8.0 Hz), 8,53 (1H, s), 8,63-8,68 (2H, m), 8,68-8,71 (1H, m).

Note the R 37a

To a suspension of 2-(benzyloxy)-5-(pyridin-3-yl)benzoic acid (0.15 g) in tetrahydrofuran (2.0 ml) under cooling on ice was sequentially added N,N-dimethylformamide (0,010 ml) and oxacillin (0,053 ml)and then stirred at room temperature for 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue tetrahydrofuran (3.0 ml). The resulting mixture while cooling on ice, was added to a solution of tert-butyl 2-amino-4-(2-methoxyphenyl)benzoate (0.12 g) in a mixture of pyridine (0,049 ml) and tetrahydrofuran (2.0 ml)and then stirred at room temperature for 1 hour and 30 minutes. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, sequentially washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 70-35% hexane/ethyl acetate] to obtain 0,19 g of tert-butyl 2-(2-(benzyloxy)-5-(pyridin-3-yl)benzamido)-4-(2-methoxyphenyl)benzoate as a white solid.

To the solution obtained tert-butyl 2-(2-(benzyloxy)-5-(pyridin-3-yl)benzamido)-4-(2-methoxyphenyl)benzoate (0,19 g) in MESI ethyl acetate (5.0 ml) and methanol (5.0 ml) was added 10% palletirovanie coal (39 mg), and then was stirred in hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture was added 10% palletirovanie coal (39 mg)and then stirred in a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. To the reaction mixture was added tetrahydrofuran, and removing insoluble substances by filtration. The solvent is evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), PSQ100B (spherical), eluent: 100-91% chloroform/methanol] to obtain tert-butyl 2-(2-hydroxy-5-(pyridin-3-yl)benzamido)-4-(2-methoxyphenyl)benzoate as a white solid.

A solution of the obtained tert-butyl 2-(2-hydroxy-5-(pyridin-3-yl)benzamido)-4-(2-methoxyphenyl)benzoate in triperoxonane acid (4.0 ml) was stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, and was added to the residue toluene. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid is collected by filtration. To the obtained solid substance was added dioxane (2.0 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,49 ml)and then stirred at room temperature for 45 minutes. The reaction is ionic mixture was added 10% aqueous citric acid solution, and collecting the solid by filtration. To the obtained solid substance was added ethanol and water, and collecting the solid by filtration to obtain 0,053 g 2-(2-hydroxy-5-(pyridin-3-yl)benzamido)-4-(2-methoxyphenyl)benzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 3,81 (3H, s), 7,06 for 7.12 (1H, m), 7,12-7,20 (2H, m), 7,33-7,39 (2H, m), 7,39-7,46 (1H, m), 7,46-7,52 (1H, m), a 7.85 (1H, DD, J=8,6, 2.4 Hz), 8,02-8,10 (2H, m), by 8.22 (1H, d, J=2.4 Hz), 8,55 (1H, DD, J=4,6, 1.5 Hz), 8,80 (1H, d, J=1.7 Hz), of 8.90 (1H, d, J=1.9 Hz), of 11.69-RS 11.80 (1H, broadened), 12,31-12,43 (1H, broadened).

Example 38a

To a suspension of 2-acetoxy-5-ethoxybenzoyl acid (0.14 g) in methylene chloride (2 ml) was sequentially added N,N-dimethylformamide (4,6 μl) and oxacillin (0,077 ml)and then stirred at room temperature for 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2 ml). The resulting mixture was added to a solution of methyl 2-amino-4-phenylbenzoate (0.11 g) in a mixture of pyridine (0.10 ml) and methylene chloride (2 ml)and then stirred at room temperature for 2 hours and 10 minutes. The solvent is evaporated under reduced pressure, and was added to the residue water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, is evaporated the solvent under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 90-70% hexane/ethyl acetate] to obtain 0,082 g of methyl 2-(2-acetoxy-5-ethoxybenzoyl)-4-phenylbenzoate in the form of a white solid.

To the obtained methyl 2-(2-acetoxy-5-ethoxybenzoyl)-4-phenylbenzoate (0,082 g) was added methanol (4 ml) and 2 mol/l aqueous sodium hydroxide solution (0.95 ml), then stirred at room temperature for 3 hours and 30 minutes, and then heated to a temperature of sublimation within 30 minutes. The reaction mixture was cooled to room temperature and adjusting the pH to 1.2 addition of 6 mol/l hydrochloric acid. The solid substance was collected by filtration to obtain to 0.055 g of 2-(5-ethoxy-2-hydroxybenzamide)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: of 1.33 (3H, t, J=6.9 Hz), to 4.01 (2H, q, J=6.9 Hz), to 6.95 (1H, d, J=9.0 Hz), 7,07 (1H, DD, J=9,0, 3.2 Hz), 7,40-7,58 (5H, m), 7,70 for 7.78 (2H, m), 8,10 (1H, d, J=8,3 Hz), 9,01 (1H, d, J=1.7 Hz), br11.01 (1H, ), of 12.33 (1H, s), 13,40-13,65 (1H, broadened).

Example 39a

To a solution of 2-acetoxy-4-methylbenzoic acid (0.12 g) in methylene chloride (2 ml) was sequentially added N,N-dimethylformamide (4,6 μl) and oxacillin (0,077 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and added to stop the ku methylene chloride (2 ml). The resulting mixture was added to a solution of methyl 2-amino-4-phenylbenzoate (0.11 g) in a mixture of pyridine (0.10 ml) and methylene chloride (2 ml)and then stirred at room temperature for 1 hour and 10 minutes. The solvent is evaporated under reduced pressure, and was added to the residue water and chloroform. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-70% hexane/ethyl acetate] to obtain 0.14 g of methyl 2-(2-acetoxy-4-methylbenzamide)-4-phenylbenzoate in the form of a white solid.

To the obtained methyl 2-(2-acetoxy-4-methylbenzamide)-4-phenylbenzoate (0.14 g) was added dioxane (3 ml) and 2 mol/l aqueous solution of sodium hydroxide (1.7 ml)and then stirred at room temperature for 2 hours and 30 minutes. The pH of the reaction mixture was adjusted to 3.0 by addition of 6 mol/l hydrochloric acid. The solid substance was collected by filtration to obtain 0,042 g 2-(2-hydroxy-4-methylbenzamide)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 2,31 (3H, s), 6,79-6,86 (2H, m), 7,42-7,58 (4H, m), 7,69-7,76 (2H, m), 7,80 (1H, d, J=7.8 Hz), 8,10 (1H, d, J=8,3 Hz), of 9.00 (1H, d, J=1.7 Hz), 1147 (1H, C), 12,29 (1H, s), 13,40-13,65 (1H, broadened).

Example 40a

To a solution of 2-acetoxy-5-tert-butylbenzoic acid (0,049 g) in methylene chloride (1.5 ml) was sequentially added N,N-dimethylformamide (2 ml) and oxacillin (0,026 ml)and then stirred at room temperature for 25 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2 ml). The resulting mixture was added to a solution of methyl 2-amino-4-phenylbenzoate (0,038 g) in a mixture of pyridine (0,034 ml) and methylene chloride (1.5 ml)and then stirred at room temperature for 1 hour and 15 minutes. To the reaction mixture was added water, 1 mol/l hydrochloric acid and chloroform. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-75% hexane/ethyl acetate] to obtain 0,023 g of methyl 2-(2-acetoxy-5-tert-butylbenzamide)-4-phenylbenzoate in the form of a white solid.

To the obtained methyl 2-(2-acetoxy-5-tert-butylbenzamide)-4-phenylbenzoate (0,023 g) was added methanol (2 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,26 ml)and then stirred p. and room temperature for 15 hours. To the reaction mixture were added toluene. The aqueous layer was separated and adjusted the pH to 3.0 by the addition of 6 mol/l hydrochloric acid. The solid substance was collected by filtration to obtain 0,010 g of 2-(5-tert-butyl-2-hydroxybenzamide)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 1,31 (9H, s), of 6.96 (1H, d, J=8.5 Hz), 7,42-of 7.60 (5H, m), 7,70-7,79 (2H, m), to 7.93 (1H, d, J=2.4 Hz), 8,11 (1H, d, J=8,3 Hz), 9,05 (1H, d, J=1.7 Hz), 11,35 (1H, s)12,42 (1H, s), 13,45-13,80 (1H, broadened).

Example 41a

To a solution of 2-acetoxy-3-methylbenzoic acid (0.12 g) in methylene chloride (2 ml) was sequentially added N,N-dimethylformamide (4,6 μl) and oxacillin (0,077 ml)and then stirred at room temperature for 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2 ml). The resulting mixture was added to a solution of methyl 2-amino-4-phenylbenzoate (0.11 g) in a mixture of pyridine (0.10 ml) and methylene chloride (2 ml)and then stirred at room temperature for 20 minutes. The solvent is evaporated under reduced pressure and purify the resulting residue by the method of column chromatography on silica gel [eluent: 85-70% hexane/ethyl acetate] to obtain 0,063 g of methyl 2-(2-acetoxy-3-methylbenzamide)-4-phenylbenzoate in the form of a white solid.

To the obtained m the Teal-2-(2-acetoxy-3-methylbenzamide)-4-phenylbenzoate (0,062 g) was added methanol (2 ml), dioxane (4 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,77 ml)and then stirred at room temperature for 7 hours. The pH of the reaction mixture was adjusted to 1.1 with the addition of 6 mol/l hydrochloric acid. The solid substance was collected by filtration to obtain 0,044 g 2-(2-hydroxy-3-methylbenzamide)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 2,22 (3H, s), to 6.95 (1H, DD, J=7,6, 7,6 Hz), 7,38-7,51 (2H, m), 7,51-7,63 (3H, m), 7,66-7,80 (3H, m)to 8.14 (1H, d, J=8,3 Hz), 8,83-8,89 (1H, m), cent to 8.85 (1H, s), 12,24 (1H, s), 12,34-12,46 (1H, broadened).

Example 42a

When cooled on ice to a solution of 2-acetoxy-5-isopropoxybenzoic acid (of 0.081 g) in a mixture of methylene chloride (2.0 ml) and N,N-dimethylformamide (0,010 ml) was added oxalicacid (0,040 ml)and then stirred at room temperature for 20 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2.0 ml). The resulting mixture while cooling on ice, was added to a solution of methyl 2-amino-4-phenylbenzoate (0,070 g) in a mixture of pyridine (0.037 ml) and methylene chloride (1.0 ml)and then stirred at room temperature for 1 hour and 45 minutes. The solvent is evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer RA is delali, sequentially washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-80% hexane/ethyl acetate] to obtain 0,072 g of methyl 2-(2-acetoxy-5-isopropoxybenzoic)-4--phenylbenzoate in the form of a white solid.

To the obtained methyl 2-(2-acetoxy-5-isopropoxybenzoic)-4-phenylbenzoate (0,072 g) was added dioxane (5.0 ml) and 4 mol/l aqueous solution of sodium hydroxide (0,20 ml)and then stirred at 50-60°C for 4 hours. The reaction mixture was cooled to room temperature, was added a 4 mol/l aqueous sodium hydroxide solution (of 0.081 ml)and then stirred at 55-60°C for 2 hours. The reaction mixture was cooled to room temperature, was added a 4 mol/l aqueous solution of sodium hydroxide (0,040 ml)and then stirred at 60°C for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and added a 10% aqueous citric acid solution (9 ml). The solid substance was collected by filtration to obtain 0,039 g 2-(2-hydroxy-5-isopropoxybenzoic)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 1,23-of 1.29 (6H, m), 4,45-4,56 (1H, m)6,94 (1H, d, J=8,8 is C), 7,03-7,10 (1H, m), 7,40-7,49 (2H, m), 7,49-7,58 (3H, m), 7,70-to 7.77 (2H, m), 8,10 (1H, d, J=8,3 Hz), 8,98-9,04 (1H, m), 11,03 (1H, s), 12,32 (1H, s), 13,40-13,64 (1H, broadened).

Example 43a

The following compound was obtained as described in Example 42a.

2-(2-Hydroxy-5-propoxybenzene)-4-phenylbenzene acid

1H-NMR (DMSO-d6) δ: 0,99 (3H, t, J=7.4 Hz), 1,66-to 1.79 (2H, m), 3,91 (2H, t, J=6.5 Hz), to 6.95 (1H, d, J=8,8 Hz),? 7.04 baby mortality-7,11 (1H, m), 7,41-7,49 (2H, m), 7,49-7,58 (3H, m), 7,69-to 7.77 (2H, m), 8,10 (1H, d, J=8,3 Hz), 9,01 (1H, C)11,02 (1H, s), of 12.33 (1H, s).

Example 44a

To a suspension of 2-acetoxy-5-(pyridin-3-yl)benzoic acid (0.15 g) in methylene chloride (2 ml) was added N,N-dimethylformamide (5 ml) and oxacillin (0,077 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2 ml). The resulting mixture was added to a solution of methyl 2-amino-4-(furan-2-yl)benzoate (0.11 g) in a mixture of pyridine (0,14 ml) and methylene chloride (2 ml)and then stirred at room temperature for 4 hours. The solvent is evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and chloroform. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated in the conditions of reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 55-20% hexane/ethyl acetate] to obtain 0.18 g of methyl 2-(2-acetoxy-5-(pyridin-3-yl)benzamido)-4-(furan-2-yl)benzoate as a white solid.

To the obtained methyl 2-(2-acetoxy-5-(pyridin-3-yl)benzamido)-4-(furan-2-yl)benzoate (0.18 g) was added dioxane (3 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,19 ml), then stirred at room temperature for 3 hours and 10 minutes, and then at 70°C for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and adjusting the pH to 6.0 by adding 10% aqueous citric acid solution. The solid is collected by filtration, and was added methanol (1.0 ml) and 1 mol/l aqueous solution of sodium hydroxide (to 0.055 ml). The solid substance was collected by filtration to obtain 0,044 g of 4-(furan-2-yl)-2-(2-hydroxy-5-(pyridin-3-yl)benzamido)sodium benzoate as a white solid.

1H-NMR (DMSO-d6) δ: 6,62 (1H, DD, J=3,4, 2.0 Hz), of 6.96 (1H, d, J=3,4 Hz), 7,10 (1H, d, J=8.7 Hz), 7,42 (1H, DD, J=8,1) and 1.7 Hz), 7,52 (1H, DDD, J=7,9, 4,8, 0.7 Hz), 7,78-7,83 (1H, m), 7,89 (1H, DD, J=8,7, and 2.3 Hz), 8,08 (1H, d, J=8.1 Hz), 8,08-of 8.15 (1H, m), to 8.41 (1H, d, J=2.2 Hz), 8,58 (1H, DD, J=4,8, and 1.6 Hz), 8,92-8,99 (2H, m).

Example 45a

When cooled on ice to a solution of 2-acetoxy-5-methoxybenzoic acid (0,070 g) in a mixture of methylene chloride (1.0 m is) and N,N-dimethylformamide (0,010 ml) was added oxalicacid (0.036 ml), and then was stirred at room temperature for 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2 ml). The resulting mixture while cooling on ice, was added to a solution of methyl 2-amino-4-(furan-2-yl)benzoate (to 0.060 g) in a mixture of pyridine (0,034 ml) and methylene chloride (1.0 ml)and then stirred at room temperature for 1 hour and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, sequentially washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-85% hexane/ethyl acetate] to obtain 0,073 g of methyl 2-(2-acetoxy-5-methoxybenzamido)-4-(furan-2-yl)benzoate as a white solid.

To the obtained methyl 2-(2-acetoxy-5-methoxybenzamido)-4-(furan-2-yl)benzoate (0,073 g) was added dioxane (2.0 ml) and 4 mol/l aqueous solution of sodium hydroxide (0,22 ml)and then stirred at 50-55°C for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and added a 10% aqueous solution of citric key is lots (6 ml). The solid substance was collected by filtration to obtain 0,062 g of 4-(furan-2-yl)-2-(2-hydroxy-5-methoxybenzamido)benzoic acid as a white solid.

To the obtained 4-(furan-2-yl)-2-(2-hydroxy-5-methoxybenzamido)benzoic acid (0,062 g) was added ethanol (2.5 ml) and 1 mol/l aqueous solution of sodium hydroxide (0.17 ml)and then stirred at room temperature for 35 minutes. The solid substance was collected by filtration to obtain 0,046 g of 4-(furan-2-yl)-2-(2-hydroxy-5-methoxybenzamido)sodium benzoate as a white solid.

1H-NMR (DMSO-d6) δ: of 3.78 (3H, s), 6,62 (1H, DD, J=3,4, 1.8 Hz), make 6.90 (1H, d, J=9.0 Hz), to 6.95 (1H, d, J=3,4 Hz), 7,10 (1H, DD, J=9,0, 3.0 Hz), 7,40 (1H, DD, J=8,0, 1.7 Hz), 7,58 (1H, d, J=3.0 Hz), 7,78-of 7.82 (1H, m), of 8.06 (1H, d, J=8.0 Hz), to 8.94 (1H, d, J=1.7 Hz).

Example 46a

To a suspension of 2-acetoxy-5-(pyridin-3-yl)benzoic acid (0.14 g) in tetrahydrofuran (4.0 ml) was added N,N-dimethylformamide (0,010 ml) and oxacillin (to 0.060 ml)and then stirred at room temperature for 50 minutes. To the reaction mixture was added oxalicacid (to 0.060 ml)and then stirred at room temperature for 40 minutes. To the reaction mixture was added oxalicacid (0,020 ml)and then stirred at room temperature for 15 minutes. The solvent is evaporated under reduced pressure, and was added to the residue to face hydrofuran (3.0 ml). The resulting mixture while cooling on ice, was added to a solution of methyl 2-amino-4-(furan-3-yl)benzoate (0.10 g) in a mixture of pyridine (0,093 ml) and tetrahydrofuran (1.0 ml)and then stirred at room temperature for 2 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated and washed with saturated aqueous sodium chloride. Insoluble substances were removed by filtration. The obtained filtrate was dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether and ethyl acetate. The solid substance was collected by filtration to obtain 0.11 g of methyl 2-(2-acetoxy-5-(pyridin-3-yl)benzamido)-4-(furan-3-yl)benzoate as a white solid.

To the obtained methyl 2-(2-acetoxy-5-(pyridin-3-yl)benzamido)-4-(furan-3-yl)benzoate (0.11 g) was added dioxane (5.0 ml) and 4 mol/l aqueous solution of sodium hydroxide (0,31 ml)and then stirred at 50-55°C for 1 hours. The reaction mixture was cooled to room temperature, and added a 10% aqueous citric acid solution (6 ml). The solid substance was collected by filtration to obtain of 0.081 g of 4-(furan-3-yl)-2-(2-hydroxy-5-(pyridin-3-yl)benzamido)benzoic acid as a yellow solid.

To the obtained 4-(furan-3-yl)2-(2-hydroxy-5-(pyridin-3-yl)benzamido)benzoic acid (of 0.081 g) was added ethanol (1.5 ml) and 1 mol/l aqueous solution of sodium hydroxide (0,19 ml), and then was stirred at room temperature for 1 hour. The solid substance was collected by filtration to obtain 0,048 g of 4-(furan-3-yl)-2-(2-hydroxy-5-(pyridin-3-yl)benzamido)sodium benzoate as a white solid.

1H-NMR (DMSO-d6) δ: 6,92-6,98 (1H, m), 7,13 (1H, d, J=8.5 Hz), 7,40 (1H, DD, J=8,1, 1.5 Hz), to 7.50 (1H, DD, J=7,9, 4,7 Hz), 7,80 (1H, s), 7,87 (1H, DD, J=8,5 and 2.2 Hz), 8,03-8,13 (1H, m), of 8.06 (1H, d, J=8,3 Hz), 8,24 (1H, s), to 8.34 (1H, d, J=1.7 Hz), 8,51 at 8.60 (1H, m), 8,83 (1H, d, J=1.4 Hz), 8,91-8,97 (1H, m).

Example 47a

When cooled on ice to a solution of 2-acetoxy-5-(pyridin-3-yl)benzoic acid (0.083 g) in a mixture of tetrahydrofuran (2.0 ml) and N,N-dimethylformamide (0,010 ml) was added oxalicacid (or 0.035 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue tetrahydrofuran (3.0 ml). The resulting mixture while cooling on ice, was added to a solution of methyl 2-amino-4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)benzoate (0.10 g) in a mixture of pyridine (0,054 ml) and tetrahydrofuran (1.5 ml)and then stirred at room temperature for 1 hour and 40 minutes. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the flash steam is piss off the solvent under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 70-45% hexane/ethyl acetate] to obtain methyl 2-(2-acetoxy-5-(pyridin-3-yl)benzamido)-4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)benzoate.

A solution of the obtained methyl 2-(2-acetoxy-5-(pyridin-3-yl)benzamido)-4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)benzoate in triperoxonane acid (4.0 ml) was stirred at room temperature for 2 hours and 30 minutes. The solvent is evaporated under reduced pressure, was added toluene. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid is collected by filtration. To the obtained solid substance was added dioxane (4.0 ml) and 1 mol/l aqueous solution of sodium hydroxide (0,40 ml)and then stirred at 50-55°C for 2 hours. The reaction mixture was cooled to room temperature, and then adjust the pH to 7.4 by adding 1 mol/l hydrochloric acid. The solvent is evaporated under reduced pressure, and was added to the obtained residue, water. The solid substance was collected by filtration to obtain to 0.032 g of 4-(2-(ethylamino)phenyl)-2-(2-hydroxy-5-(pyridin-3-yl)benzamido)benzoic acid as a white solid.

To the obtained 4-(2-(ethylamino)FeNi is)-2-(2-hydroxy-5-(pyridin-3-yl)benzamido)benzoic acid (to 0.032 g) was added ethanol (2.0 ml) and 1 mol/l aqueous solution of sodium hydroxide (0,067 ml), and then was stirred at room temperature for 2 hours and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the obtained residue, water. The solid substance was collected by filtration to obtain 0,024 g of 4-(2-(ethylamino)phenyl)-2-(2-hydroxy-5-(pyridin-3-yl)benzamido)sodium benzoate as a white solid.

1H-NMR (DMSO-d6) δ: of 1.12 (3H, t, J=7,1 Hz), 3,06 is 3.15 (2H, m), of 4.49 (1H, t, J=5.5 Hz), 6,65-6,72 (2H, m), 7,02-7,11 (3H, m), 7,16-7,22 (1H, m), 7,53 (1H, DD, J=7,9, 4,8 Hz), 7,84-a 7.92 (1H, m), 8,08-of 8.15 (2H, m), 8,39-to 8.45 (1H, m), 8,55-8,63 (2H, m), 8,93-8,99 (1H, m).

Example 48a

When cooled on ice to a solution of 2-acetoxy-5-methoxybenzoic acid (0,049 g) in a mixture of methylene chloride (1.0 ml) and N,N-dimethylformamide (0,010 ml) was added oxalicacid (0,026 ml)and then stirred at room temperature for 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2.0 ml). The resulting mixture while cooling on ice, was added to a solution of methyl 2-amino-4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)benzoate (0,070 g) in a mixture of pyridine (0,024 ml) and methylene chloride (1.0 ml)and then stirred at room temperature for 1 hour and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and et is latitat. The organic layer was separated, sequentially washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 91-60% hexane/ethyl acetate] to obtain methyl 2-(2-acetoxy-5-methoxybenzamido)-4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)benzoate.

A solution of the obtained methyl 2-(2-acetoxy-5-methoxybenzamido)-4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)benzoate in triperoxonane acid (3.0 ml) was stirred at room temperature for 1 hour and 40 minutes. The solvent is evaporated under reduced pressure, and was added to the residue toluene. The solvent is evaporated under reduced pressure, and was added to the obtained residue, dioxane (3.0 ml) and 4 mol/l aqueous sodium hydroxide solution (0.25 ml), then stirred at 50-55°C for 1 hour and 30 minutes, and then at 55-60°C for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and added to her water. After adjusting the pH to 7.0 by adding 1 mol/l hydrochloric acid, the solvent is evaporated under reduced pressure. To the obtained residue was added water, and collected TV is Joe substance by filtration to obtain 0.025 g of 2-(2-hydroxy-5-methoxybenzamido)-4-(2-(methylamino)phenyl)benzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 2,69 (3H, in), 3.75 (3H, s), 4.80 to 5,10 (1H, broadened), of 6.65 (1H, d, J=8.1 Hz), 6,70 (1H, DD, J=7,4, 7,4 Hz), to 6.95 (1H, d, J=8,8 Hz), 7,01-7,10 (2H, m), 7,19-7,27 (2H, m), 7,40 (1H, d, J=3.2 Hz), of 8.06 (1H, d, J=8.0 Hz), to 8.70 (1H, d, J=1.2 Hz), 10,99 (1H, s), 12,32-12,43 (1H, broadened), 13,24-13,66 (1H, broadened).

Example 49a

To a solution of 2-(benzyloxy)-5-(1-(tert-butoxycarbonyl)piperidine-4-yl)benzoic acid (0,30 g) in methylene chloride (3.0 ml) was added N,N-dimethylformamide (5 ml) and oxacillin (0,093 ml)and then stirred at room temperature for 65 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (3.0 ml). The resulting mixture while cooling on ice, was added to a solution of methyl 2-amino-4-phenylbenzoate (0.14 g) in a mixture of pyridine (0,12 ml) and methylene chloride (3.0 ml)and then stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the residue water and chloroform. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 85-60% hexane/ethyl acetate] to obtain 0,19 g of methyl 2-(2-(Ben is yloxy)-5-(1-(tert-butoxycarbonyl)piperidine-4-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

To a solution of the obtained methyl 2-(2-(benzyloxy)-5-(1-(tert-butoxycarbonyl)piperidine-4-yl)benzamido)-4-phenylbenzoate (0,19 g) in chloroform (2.0 ml) was added triperoxonane acid (1.0 ml)and then stirred at room temperature for 1 hour and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue water. After adjusting the pH to 7.4 by the addition of saturated aqueous sodium bicarbonate solution was added chloroform. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure to obtain 0.15 g of methyl 2-(2-(benzyloxy)-5-(piperidine-4-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

1H-NMR (CDCl3) δ: 1,50-of 1.92 (4H, m), 2,56 is 2.80 (3H, m), 3,10-3,26 (2H, m in), 3.75 (3H, s), 5,42 (2H, s), to 6.95 (1H, d, J=8.6 Hz), 7,20-7,52 (10H, m), 7,70 for 7.78 (2H, m), 8,02 (1H, d, J=2.4 Hz), 8,07 (1H, d, J=8,3 Hz), 9,29 (1H, d, J=1.7 Hz), 12,27 (1H, s).

Example 50a

To a solution of methyl 2-(2-(benzyloxy)-5-(piperidine-4-yl)benzamido)-4-phenylbenzoate (0.10 g) in tetrahydrofuran (3.0 ml), was added 37% aqueous formaldehyde solution (6,3 μl), acetic acid (0,022 ml) and triacetoxyborohydride sodium (0.10 g)and then stirred at room temperature for 3 hours and 30 minutes. The solvent vepari the Ali under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and chloroform. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 98-90% chloroform/methanol] to obtain 0,086 g of methyl 2-(2-(benzyloxy)-5-(1-methylpiperidin-4-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

To a solution of the obtained methyl 2-(2-(benzyloxy)-5-(1-methylpiperidin-4-yl)benzamido)-4-phenylbenzoate (0,086 g) in methanol (3.0 ml) was added 10% palletirovanie coal (43 mg)and then stirred in a hydrogen atmosphere at room temperature for 2 hours and 10 minutes. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. To the obtained residue was added ethyl acetate, and collecting the solid by filtration to obtain 0,058 g of methyl 2-(2-hydroxy-5-(1-methylpiperidin-4-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

To a suspension of the obtained methyl 2-(2-hydroxy-5-(1-methylpiperidin-4-yl)benzamido)-4-phenylbenzoate (0,058 g) in methanol (2.0 ml) was added a 2.0 mol/l aqueous sodium hydroxide solution (0.33 ml)and then stirred at 60°C for 9 hours and 20 minutes. The reaction mixture was cooled to room temperature, and obavljale to her 6 mol/l hydrochloric acid (0,11 ml). The solvent is evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-85% chloroform/methanol] to obtain 0,019 g 2-(2-hydroxy-5-(1-methylpiperidin-4-yl)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 1,83-2,11 (4H, m), 2,66-to 2.85 (4H, m), 2,87-3,11 (2H, m)6,94 (1H, d, J=8.6 Hz), 7,33-7,44 (3H, m), 7,46-rate of 7.54 (2H, m), of 7.64-7,72 (2H, m), 7,87-of 7.96 (1H, m), 8,13 (1H, d, J=8.0 Hz), 8,91 (1H, d, J=1.7 Hz).

1H-NMR (CF3COD) δ: 2,18 is 2.43 (4H, m), 2.95 and-to 3.38 (6H, m), 3,84-4,06 (2H, m), 7,17-7,29 (1H, m), 7,46-7,89 (8H, m), scored 8.38-and 8.50 (1H, m), 8,79-of 8.90 (1H, m).

Example 51a

To a suspension of 2-acetoxy-5-bromobenzoyl acid (5.0 g) in methylene chloride (49 ml) was added N,N-dimethylformamide (0.15 ml) and oxacillin (2.5 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue toluene. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (10 ml). The resulting mixture while cooling on ice, was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (4.9 g) in a mixture of pyridine (3,7 ml) and methylene chloride (49 ml)and then stirred at room temperature for 30 minutes. To the reaction mixture were added 10% aqueous citric acid solution. The organic layer was separated washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-80% hexane/ethyl acetate] to obtain of 8.9 g of tert-butyl 2-(2-acetoxy-5-bromobenzene)-4-phenylbenzoate in the form of a white solid.

1H-NMR (CDCl3) δ: of 1.62 (9H, s), is 2.30 (3H, s), 7,11 (1H, d, J=8.7 Hz), was 7.36 (1H, DD, J=8,3, 1.8 Hz), of 7.36-7,44 (1H, m), 7,44-7,51 (2H, m), 7,63 (1H, DD, J=8,7, 2.4 Hz), to 7.67-7,73 (2H, m), with 8.05 (1H, d, J=2.4 Hz), 8,07 (1H, d, J=8,3 Hz), 9,12 (1H, d, J=1,8 Hz), 11,89 (1H, s).

Examples 52a-57a

Compounds shown in Table 12a, obtained as described in Example 51a.

Table 12a
Example No.AExample No.A
52a55a
53a56a
54a 57a

tert-Butyl 2-(2-(benzyloxy)-4-jogesuido)-4-phenylbenzoate

1H-NMR (DMSO-d6) δ: for 1.49 (9H, s)5,52 (2H, s), 7,25-7,37 (3H, m), 7,43-7,58 (7H, m), to 7.61 (1H, d, J=1.2 Hz), 7,66 to 7.75 (3H, m), with 8.05 (1H, d, J=8,3 Hz), 9,01-9,06 (1H, m), 12,08 (1H, s).

tert-Butyl 2-(2-(benzyloxy)-5-nitrobenzamide)-4-phenylbenzoate

1H-NMR (CDCl3) δ: of 1.55 (9H, s), 5,61 (2H, s), 7,05 (1H, d, J=9.3 Hz), 7,28-7,44 (5H, m), 7,44-7,53 (4H, m), 7,70-7,76 (2H, m), of 8.09 (1H, d, J=8,3 Hz), 8,23 (1H, DD, J=9,3, 2,9 Hz), which is 9.09 (1H, d, J=2,9 Hz), 9,29 (1H, d, J=1.7 Hz), 12,60 (1H, s).

tert-Butyl 2-(2-(benzyloxy)-5-bromobenzene)-4-phenylbenzoate

1H-NMR (CDCl3) δ: 1,53 (9H, s), of 5.48 (2H, s), 6,83 (1H, d, J=8,8 Hz), 7,22-to 7.50 (10H, m), 7,70 to 7.75 (2H, m), of 8.06 (1H, d, J=8,3 Hz), 8,29 (1H, d, J=2.7 Hz), 9,26 (1H, d, J=1.7 Hz), 12,49 (1H, s).

tert-Butyl 2-(2-(benzyloxy)-5-jogesuido)-4-phenylbenzoate

1H-NMR (DMSO-d6) δ: 1.50 in (9H, s), the 5.51 (2H, s), was 7.08 (1H, d, J=8,8 Hz), 7,24 and 7.36 (3H, m), 7,44-7,58 (6H, m), 7.68 per to 7.75 (2H, m), 7,81 (1H, DD, J=8,8, 2.3 Hz), with 8.05 (1H, d, J=8,3 Hz), 8,21 (1H, d, J=2.3 Hz), 9,00-9,06 (1H, m), 12,15 (1H, s).

tert-Butyl 2-(5-acetoxy-2-(benzyloxy)benzamido)-4-phenylbenzoate

1H-NMR (CDCl3) δ: 1,53 (9H, s), of 2.28 (3H, s), of 5.48 (2H, s)6,94 (1H, d, J=9.0 Hz), to 7.09 (1H, DD, J=9,0, 3.0 Hz), 7.24 to 7,51 (9H, m), 7,69 to 7.75 (2H, m), 7,89 (1H, d, J=3.0 Hz), with 8.05 (1H, d, J=8,3 Hz), the 9.25 (1H, d, J=1.9 Hz), to 12.52 (1H, s).

tert-Butyl 2-(5-(2-acetoxyethyl)-2-(benzyloxy)benzamido)-4-phenylbenzoate

1H-NMR (DMSO-d6) δ: for 1.49 (9H, s)of 1.97 (3H, s), is 2.88 (2H, t, J=6.8 Hz), 4,19 (2H, t, J=6.8 Hz), of 5.48 (2H, s), 7,17 (1H, d, J=8.7 G is), 7.23 percent and 7.36 (3H, m), 7,39 (1H, DD, J=8,7, 2.4 Hz), 7,43-to 7.59 (6H, m), 7,69 to 7.75 (2H, m), to 7.84 (1H, d, J=2.4 Hz), with 8.05 (1H, d, J=8,3 Hz), 9,06-9,11 (1H, m), 12,16 (1H, s).

Example 58a

The following compound was obtained as described in Example 51a.

Methyl-2-(2-(benzyloxy)-5-(piperidine-1-yl)benzamido)-4-(furan-2-yl)benzoate

1H-NMR (CDCl3) δ: 1,40-of 2.50 (6H, m), 3,10-of 3.60 (4H, m), of 3.77 (3H, s), 5,46 (2H, s), 6,53 (1H, DD, J=3,4, and 1.6 Hz), 6.89 in (1H, d, J=3,4 Hz), 6,98 for 7.12 (1H, m), 7,25-7,37 (4H, m), 7,40-7,49 (3H, m), 7,52-7,58 (1H, m), 8,00 is 8.22 (1H, m), with 8.05 (1H, d, J=8,3 Hz), of 9.30 (1H, d, J=1.4 Hz), 12,43 (1H, s).

Example 59a

The following compound was obtained as described in Example 51a.

tert-Butyl 2-(2-acetoxy-5-(pyridin-3-yl)benzamido)-4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)benzoate

1H-NMR (CDCl3) δ: 1,21 (9H, s), and 1.63 (9H, s), 2,32 (3H, s), 3,10 (3H, s), 7,05-7,13 (1H, m), 7.18 in-7,29 (1H, m), 7,31-of 7.48 (5H, m), 7,74 (1H, DD, J=8,4, and 2.3 Hz), 7,95 (1H, DDD, J=7,9, and 2.4, 1.7 Hz), of 8.04 (1H, d, J=8,3 Hz), of 8.15 (1H, d, J=2.2 Hz), 8,63 (1H, DD, J=4,8, and 1.6 Hz), 8,88-8,98 (2H, m), 12,06 (1H, s).

Example 60a

To a suspension of 2-acetoxy-5-bromobenzoyl acid (0.16 g) in methylene chloride (2 ml) was added N,N-dimethylformamide (5 ml) and oxacillin (0,077 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2 ml). The resulting mixture was added to a solution of methyl-2-AMI is about-4-phenylbenzoate (0.11 g) in a mixture of pyridine (0.10 ml) and methylene chloride (2 ml), and then was stirred at room temperature for 1 hour and 20 minutes. The solvent is evaporated under reduced pressure, and was added to the residue water and chloroform. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 70-50% hexane/ethyl acetate] to obtain of 0.23 g of methyl 2-(2-acetoxy-5-bromobenzene)-4-phenylbenzoate in the form of a white solid.

1H-NMR (CDCl3) δ: 2,31 (3H, s), of 3.96 (3H, s), 7,10 (1H, d, J=8,8 Hz), of 7.36-7,53 (4H, m), of 7.64 (1H, DD, J=8,8, 2.4 Hz), to 7.67-7,74 (2H, m), of 8.04 (1H, d, J=2.4 Hz), 8,13 (1H, d, J=8,3 Hz), 9,13 (1H, d, J=1.7 Hz), 11,75 (1H with).

Examples 61a and 62a

Compounds shown in Table 13a, obtained as described in Example 60a.

Table 13a
Example No.AExample No.A
61a62a

4-(2-(Methoxycarbonyl)-5-phenylphenyl rebamol)-1,3-phenylene diacetate

1H-NMR (CDCl3) δ: 2,32 (3H, s), of 2.33 (3H, s), of 3.95 (3H, s), 7,06 (1H, d, J=2.2 Hz), 7,16 (1H, DD, J=8,5 and 2.2 Hz), 7,38 (1H, DD, J=8,4, 1.8 Hz), 7,38-7,44 (1H, m), 7,44-7,51 (2H, m), 7.68 per-7,74 (2H, m), 7,95 (1H, d, J=8,5 Hz)to 8.12 (1H, d, J=8.6 Hz), to 9.15 (1H, d, J=1,8 Hz), 11,75 (1H, s).

Methyl-2-(5-acetoxy-2-(benzyloxy)benzamido)-4-phenylbenzoate

1H-NMR (CDCl3) δ: 2,28 (3H, s), of 3.77 (3H, s), the 5.45 (2H, s), 6,98 (1H, d, J=9.0 Hz), 7,12 (1H, DD, J=8,9 and 3.1 Hz), 7,26-7,51 (9H, m), 7.68 per to 7.75 (2H, m), 7,89 (1H, d, J=3.0 Hz), 8,07 (1H, d, J=8,3 Hz), the 9.25 (1H, d, J=2.0 Hz), of 12.33 (1H, s).

Example 63a

The following compound was obtained as described in Example 60a.

tert-Butyl 2-(2-(benzyloxy)-4-nitrobenzamide)-4-phenylbenzoate

1H-NMR (CDCl3) δ: of 1.55 (9H, s)to 5.56 (2H, s), 7.24 to EUR 7.57 (9H, m), 7,69-to 7.77 (2H, m), a 7.85-7,94 (2H, m), of 8.09 (1H, d, J=8,3 Hz), of 8.28 (1H, d, J=8,3 Hz), 9,26 (1H, s), 12,55 (1H, s).

Example 64a

To a solution of tert-butyl 2-(2-acetoxy-5-bromobenzene)-4-phenylbenzoate (to 0.060 g) in a mixture of methanol (1 ml) and dioxane (1 ml) was added potassium carbonate (0,049 g)and then stirred at room temperature for 1 hour. To the reaction mixture were added 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added triperoxonane acid (5 ml), and ZAT is m was stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, and was added to the obtained residue, methanol. The solid substance was collected by filtration to obtain 0,034 g of 2-(5-bromo-2-hydroxybenzamide)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 7,00 (1H, d, J=8.7 Hz), 7,43-7,49 (1H, m), 7,50-7,58 (3H, m), 7,60 (1H, DD, J=8,7, and 2.6 Hz), 7,70 to 7.75 (2H, m), 8,03 (1H, d, J=2.6 Hz), of 8.09 (1H, d, J=8.0 Hz), of 9.00 (1H, d, J=1.7 Hz), are 11.62-RS 11.80 (1H, broadened), 12,24-12,40 (1H, broadened), 13,38-13,60 (1H, broadened).

Example 65a

To a solution of methyl 2-(2-(benzyloxy)-5-(piperidine-1-yl)benzamido)-4-(furan-2-yl)benzoate (of 0.085 g) in dioxane (1 ml) was added water (0,20 ml), sodium formate (0,045 g), acetic acid (0,043 ml) and 10% palletirovanie coal (8 mg), then stirred at room temperature for 3 hours and 30 minutes and then at 60°C for 50 minutes. To the reaction mixture was added 10% palletirovanie coal (8 mg)and then stirred at 70°C for 50 minutes. After cooling the reaction mixture to room temperature, insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0,048 g methyl-4-(furan-2-yl)-2-(2-hydroxy-5-(piperidine-1-yl)benzamido)benzoate.

To a solution of polucen the th methyl-4-(furan-2-yl)-2-(2-hydroxy-5-(piperidine-1-yl)benzamido)benzoate (0,043 g) in a mixture of methanol (1.0 ml) and dioxane (4.0 ml) was added 2 mol/l aqueous sodium hydroxide solution (0.51 ml), and then was stirred at room temperature for 5 hours. To the reaction mixture were added water and toluene, and separated water layer. After adjusting the pH to 1.8 by adding methanesulfonic acid by filtration was collected 0.036 g solids. To the obtained solid substance (0.036 g) was added ethyl acetate (2.0 ml) and methanesulfonyl acid (5,7 μl), and collecting the solid by filtration to obtain 0,034 g methansulfonate 4-(furan-2-yl)-2-(2-hydroxy-5-(piperidine-1-yl)benzamido)benzoic acid as a white solid.

1H-NMR (DMSO-d6-D2O) δ: of 1.56 to 1.76 (2H, m), 1,83-to 1.98 (4H, m), of 2.38 (3H, s), 3.46 in is 3.57 (4H, m), 6,69 (1H, DD, J=3,4, 1.9 Hz), 7,11 (1H, d, J=3,4 Hz), 7,18 (1H, d, J=8,9 Hz), EUR 7.57 (1H, DD, J=8,4, 1.8 Hz), 7,72 (1H, DD, J=8,9, 2,9 Hz), 7,87 (1H, d, J=1.2 Hz), 8,07 (1H, d, J=8,4 Hz), 8,14 is 8.22 (1H, m), the remaining 9.08 (1H, d, J=1,8 Hz).

Example 66a

To a solution of tert-butyl 2-(2-acetoxy-5-(pyridin-3-yl)benzamido)-4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)benzoate (0.28 g) in a mixture of methanol (2 ml) and dioxane (4 ml) was added 2 mol/l aqueous sodium hydroxide solution (2.3 ml)and then stirred at room temperature for 6 hours. The pH of the reaction mixture was adjusted to 5.5 by adding 10% aqueous citric acid solution, and added to it the chloroform. The organic layer was separated, washed with saturated aqueous chlorite is sodium and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added triperoxonane acid (4 ml)and then stirred at room temperature for 20 minutes. The solvent is evaporated under reduced pressure, and was added to the residue toluene. The solvent is evaporated under reduced pressure, was added to the residue 4 mol/l solution of florodora in dioxane (5 ml)and then stirred at room temperature for 5 minutes. The solvent is evaporated under reduced pressure, and was added to the residue diethyl ether. The solid substance was collected by filtration to obtain 0.18 g of the dihydrochloride of 2-(2-hydroxy-5-(pyridin-3-yl)benzamido)-4-(2-(methylamino)phenyl)benzoic acid as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 2,74 (3H, s), 6,86-7,02 (2H, m), 7,12-7,20 (1H, m), 7,25-7,39 (3H, m), 7,98 (1H, DD, J=8,7, and 2.6 Hz), 8,05-of 8.15 (2H, m), scored 8.38 (1H, d, J=2.4 Hz), the rate of 8.75 (1H, d, J=1.7 Hz), 8,81-of 8.90 (2H, m), a 9.25 (1H, d, J=2.0 Hz), 11,95-12,10 (1H, broadened), 12,34 (1H, s).

Example 67a

To tert-butyl 2-(2-acetoxy-5-bromobenzene)-4-phenylbenzoate (0.15 g) was added dimethyl ether of ethylene glycol (1,4 ml), water (0,42 ml), phenylboronic acid (0,045 g), sodium bicarbonate (0,063 g) dichloride and bis(triphenylphosphine)palladium(II) (4 mg)and then heated under reflux in nitrogen atmosphere for 45 minutes. P is a promotional mixture was cooled to room temperature, was added thereto, potassium carbonate (0.12 g)and then stirred under nitrogen atmosphere at room temperature for 2 hours. To the reaction mixture were added water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue were added methanol (2 ml), dioxane (4 ml) and 2 mol/l aqueous sodium hydroxide solution (1.5 ml)and then stirred at room temperature for 1 hour and 40 minutes. The solvent is evaporated under reduced pressure, and added to the remainder of 1 mol/l hydrochloric acid and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-80% hexane/ethyl acetate] and was further purified by the method of column chromatography on silica gel [eluent: chloroform] to obtain 0,086 g of tert-butyl 2-(2-hydroxy-5-phenylbenzene)-4-phenylbenzoate in the form of a white solid.

To a solution of the obtained tert-butyl 2-(2-hydroxy-5-phenylbenzene)-4-phenylbenzoate (of 0.085 g) in methylene chloride (3 ml) EXT is ulali triperoxonane acid (1 ml), and then was stirred at room temperature for 17 hours. The solvent is evaporated under reduced pressure, and was added to the residue ethyl acetate. The solid substance was collected by filtration to obtain 0,072 g 2-(2-hydroxy-5-phenylbenzene)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 7,13 (1H, d, J=8.6 Hz), 7,31-7,39 (1H, m), 7,43-7,51 (3H, m), 7,51-7,58 (3H, m), of 7.64-of 7.70 (2H, m), 7,72-to 7.77 (2H, m), 7,78 (1H, DD, J=8,6, and 2.3 Hz), to 8.12 (1H, d, J=8,3 Hz), 8,21 (1H, d, J=2.3 Hz), 9,05 (1H, d, J=1.7 Hz), 11,64 (1H, s), 12,40 (1H, s), 13,45-13,70 (1H, broadened).

Example 68a

To a suspension of methyl 2-(2-acetoxy-5-bromobenzene)-4-phenylbenzoate (0.14 g) in dimethyl ether of ethylene glycol (1,4 ml) was added water (0,42 ml), 2-Farnborough acid (0,040 g), sodium bicarbonate (to 0.060 g) and bis(triphenylphosphine)palladium(II) dichloride (4 mg)and then heated under reflux in nitrogen atmosphere for 1 hour 10 minutes. The reaction mixture was cooled to room temperature, and added to her water and ethyl acetate. Insoluble substances were removed by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-70% Huck is an/ethyl acetate] and was further purified by the method of column chromatography on silica gel [eluent: 90-70% hexane/ethyl acetate] to obtain 0,073 g of methyl 2-(2-acetoxy-5-(furan-2-yl)benzamido)-4-phenylbenzoate.

To the obtained methyl 2-(2-acetoxy-5-(furan-2-yl)benzamido)-4-phenylbenzoate (0,072 g) was added dioxane (2 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,79 ml)and then stirred at room temperature for 6 hours. The pH of the reaction mixture was adjusted to 1.5 by addition of 2 mol/l hydrochloric acid, and collecting the solid by filtration to obtain to 0.055 g of 2-(5-(furan-2-yl)-2-hydroxybenzamide)-4-vinylbenzoic acid as a yellow solid.

1H-NMR (DMSO-d6) δ: 6,56-6,62 (1H, m), 6,83 (1H, d, J=3,4 Hz), was 7.08 (1H, d, J=8,3 Hz), 7,42-of 7.60 (4H, m), 7,69-to 7.77 (3H, m), 7,78 (1H, DD, J=8,5 and 2.2 Hz), 8,11 (1H, d, J=8,3 Hz), of 8.25 (1H, d, J=1.9 Hz), 9,05 (1H, d, J=the 1.4 Hz), 11,55-RS 11.80 (1H, broadened), 12,30-12,60 (1H, broadened), 13,45-13,65 (1H, broadened).

Example 69a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzene)-4-phenylbenzoate (0.17 g) in dimethyl ether of ethylene glycol (1.7 ml) was added water (0.5 ml), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furan (0,070 g), sodium carbonate (0,076 g) dichloride and bis(triphenylphosphine)palladium(II) (4.2 mg)and then heated under reflux in nitrogen atmosphere for 1 hour and 40 minutes. The reaction mixture was cooled to room temperature, and added to her water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and vepari the Ali solvent under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-80% hexane/ethyl acetate] to obtain 0.14 g of tert-butyl 2-(2-(benzyloxy)-5-(furan-3-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

1H-NMR (CDCl3) δ: 1,53 (9H, s), of 5.50 (2H, s), 6,67-of 6.73 (1H, m), 6,97 (1H, d, J=8,8 Hz), 7.24 to 7,53 (11H, m), to 7.67-7,79 (3H, m), 8,07 (1H, d, J=8,3 Hz), 8,31 (1H, d, J=2.4 Hz), 9,31 (1H, d, J=1.7 Hz), to 12.52 (1H, s).

Example 70a

To tert-butyl 2-(2-(benzyloxy)-5-(furan-3-yl)benzamido)-4-phenylbenzoate (0.14 g) was added thioanisole (1.6 ml) and triperoxonane acid (5.2 ml)and then stirred at room temperature for 4 hours. The solvent is evaporated under reduced pressure, and was added to the residue dioxane. The solvent is evaporated under reduced pressure, and was added to the residue ethyl acetate. The solid substance was collected by filtration to obtain 0,020 g of 2-(5-(furan-3-yl)-2-hydroxybenzamide)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 6.89 in-6,95 (1H, m), 7,05 (1H, d, J=8.5 Hz), 7,42-7,50 (1H, m), 7,50-to 7.59 (3H, m), of 7.70 (1H, DD, J=8,5, 2.4 Hz), 7,72 for 7.78 (3H, m), 8,08-8,15 (3H, m), 9,05 (1H, d, J=1.7 Hz), of 11.45 is 11.58 (1H, broadened), 12,30-12,50 (1H, extended), 13,45-13,65 (1H, broadened).

Example 71a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-(furan-3-yl)benzamido)-4-phenylbenzoate (0,048 g) in a mixture of methane is a (2 ml) and dioxane (2 ml) was added 10% palletirovanie charcoal (20 mg), and then was stirred in hydrogen atmosphere at room temperature for 2 hours. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 97-85% hexane/ethyl acetate] to obtain 0,027 g of tert-butyl 2-(2-hydroxy-5-(tetrahydrofuran-3-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

To a solution of the obtained tert-butyl 2-(2-hydroxy-5-(tetrahydrofuran-3-yl)benzamido)-4-phenylbenzoate (0,027 g) in methylene chloride (5 ml) was added triperoxonane acid (2 ml)and then stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid substance was collected by filtration to obtain 0,023 g of 2-(2-hydroxy-5-(tetrahydrofuran-3-yl)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 1.85 to a 2.00 (1H, m), 2,25-of 2.38 (1H, m), 3.27 to 3,44 (1H, m), 3,53 (1H, DD, J=7,9, 7.9 Hz), 3,81 (1H, DDD, J=7,8, and 7.8, 7.8 Hz), of 3.96 (1H, DDD, J=8,3, 8,3, 4,4 Hz), Android 4.04 (1H, DD, J=7,7, 7,7 Hz), 6,97 (1H, d, J=8,5 Hz), 7,37 (1H, DD, J=8,4, and 2.3 Hz), 7,42-to 7.59 (4H, m), 7,70-to 7.77 (2H, m), 7,81 (1H, d, J=2.2 Hz), 8,10 (1H, d, J=8,3 Hz), 9,03 (1H, d, J=1.7 Hz), 11,35 (1H, s), 12,34 (1H, s), 13,45-13,65 (1H, broadened).

Example 72a

To a suspension of tert-butyl 2-(2-acetoxy-5-bromobenzene)-4-phenylbenzoate (2.5 g) in dioxane (25 ml), was added potassium acetate (1.4 g), bis(pinacolato)LIBOR (1.5 g), and complex (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and methylene chloride (0.20 g)and then heated under reflux in nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and added a saturated aqueous solution of sodium bicarbonate and ethyl acetate. Insoluble substances were removed by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Biotage AB, KP-Sil, eluent: 95-50% hexane/ethyl acetate] to obtain 1.4 g of tert-butyl 2-(2-acetoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

1H-NMR (DMSO-d6) δ: of 1.32 (12H, s), and 1.56 (9H, s), of 2.25 (3H, s), 7,34 (1H, d, J=8.1 Hz), 7,43-7,50 (1H, m), 7,51-7,58 (3H, m), 7.68 per-7,74 (2H, m), of 7.90 (1H, DD, J=8,1) and 1.7 Hz), 8,03 (1H, d, J=8,3 Hz), 8,18 (1H, d, J=1.7 Hz), 8,78 (1H, d, J=1.7 Hz), 11,47 (1H, s).

Example 73a

To a suspension of tert-butyl 2-(2-acetoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-4-phenylbenzoate (0,080 is) in dimethyl ether of ethylene glycol (1 ml) was added water (0.3 ml), 2-amino-6-bromopyridine (0.037 g), sodium bicarbonate (0.036 g) and dichloride bis(triphenylphosphine)palladium(II) (5.0 mg)and then heated under reflux in nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, then added to it bis(triphenylphosphine)palladium(II) dichloride (5.0 mg)and then heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, was added a methanol (0.3 ml) and sodium carbonate (0,046 g)and then heated under reflux in nitrogen atmosphere for 20 minutes. The reaction mixture was cooled to room temperature, and added to her water and ethyl acetate. Insoluble substances were removed by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-60% hexane/ethyl acetate] to obtain 0,032 g of tert-butyl 2-(5-(6-aminopyridine-2-yl)-2-hydroxybenzamide)-4-phenylbenzoate.

To the obtained tert-butyl 2-(5-(6-aminopyridine-2-yl)-2-hydroxybenzamide)-4-phenylbenzoate (to 0.032 g) was added triperoxonane acid (5 ml)and then stirred at whom atoi temperature for 12 hours. The solvent is evaporated under reduced pressure, and added water and ethyl acetate. After adjusting the pH to 6 by addition of a saturated aqueous solution of sodium bicarbonate, the solid was collected by filtration. In the solution of the obtained solid in a mixture of water (1 ml), methanol (0.5 ml) and dioxane (0.5 ml) was injected carbon dioxide, and collecting the solid by filtration to obtain 0,018 g of 2-(5-(6-aminopyridine-2-yl)-2-hydroxybenzamide)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 5,90-x 6.15 (2H, extended), 6,41 (1H, d, J=8.0 Hz), 7,02 (1H, d, J=7,3 Hz), 7,07 (1H, d, J=8.6 Hz), 7,43-7,58 (5H, m), 7,71-to 7.77 (2H, m), with 8.05 (1H, DD, J=8,6, 2.4 Hz), 8,11 (1H, d, J=8,3 Hz), 8,59 (1H, d, J=the 2.4 Hz), 9,06 (1H, d, J=1.7 Hz).

Example 74a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-nitrobenzamide)-4-phenylbenzoate (0.14 g) in a mixture of methanol (1.4 ml) and acetic acid (1.4 ml) was added iron powder (43 mg)and then heated under reflux for 1 hour. The reaction mixture was cooled to room temperature, was added a powder of iron (14 mg)and then heated under reflux for 30 minutes. The reaction mixture was cooled to room temperature, and added a saturated aqueous solution of sodium bicarbonate and ethyl acetate. Insoluble substances were removed by filtrowanie is. The organic layer was separated, sequentially washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-50% hexane/ethyl acetate] to obtain 0,065 g of tert-butyl 2-(5-amino-2-(benzyloxy)benzamido)-4-phenylbenzoate in the form of a yellow solid.

1H-NMR (CDCl3) δ: of 1.52 (9H, s)5,38 (2H, s)of 6.71 (1H, DD, J=8,7, and 2.6 Hz), 6,79 (1H, d, J=8.7 Hz), 7,20-7,53 (10H, m), 7,70 to 7.75 (2H, m), of 8.04 (1H, d, J=8,3 Hz), the 9.25 (1H, d, J=1.7 Hz), 12,40 (1H, s).

Example 75a

The following compound was obtained as described in Example 74a.

tert-Butyl 2-(4-amino-2-(benzyloxy)benzamido)-4-phenylbenzoate

1H-NMR (CDCl3) δ: rate of 1.51 (9H, s), vs. 5.47 (2H, s), 6,16 (1H, d, J=2.2 Hz), 6,33 (1H, DD, J=8,5 and 2.2 Hz), 7,25-7,41 (5H, m), 7,41-to 7.50 (4H, m), 7,70-7,76 (2H, m), 8,02 (1H, d, J=8.1 Hz), with 8.05 (1H, d, J=8.5 Hz), 9.28 are (1H, d, J=1.7 Hz), 12,36 (1H, s).

Example 76a

To a solution of tert-butyl 2-(5-amino-2-(benzyloxy)benzamido)-4-phenylbenzoate (0,064 g) in chloroform (1.5 ml), was added 37% aqueous formaldehyde solution (0,24 ml) and triacetoxyborohydride sodium (0,082 g)and then stirred at room temperature for 4 h the owls 30 minutes. To the reaction mixture were added water and chloroform. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane/ethyl acetate] to obtain 0,063 g of tert-butyl 2-(2-(benzyloxy)-5-(dimethylamino)benzamido)-4-phenylbenzoate.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(dimethylamino)benzamido)-4-phenylbenzoate (0,063 g) in a mixture of methanol (1.5 ml) and ethyl acetate (2.5 ml) was added 10% palletirovanie coal (32 mg)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture was added 10% palletirovanie coal (13 mg)and then stirred in a hydrogen atmosphere at room temperature for 1 hour and 30 minutes. To the reaction mixture were added ethyl acetate. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-85% hexane/ethyl acetate] to obtain 0.036 g of tert-butyl 2-(5-(dimethylamino)-2-hydroxybenzamide)-4-phenylbenzoate.

To the obtained tert-butyl 2-(5-(dimethylamino)-2-hydroxybenzamide is)-4-phenylbenzoate (0.036 g) was added triperoxonane acid (5 ml), and then was stirred at room temperature for 12 hours. The solvent is evaporated under reduced pressure, was added ethyl acetate (1.5 ml) and 4 mol/l solution of florodora in dioxane (0.5 ml)and then stirred at room temperature for 2 hours and 30 minutes. The solid substance was collected by filtration to obtain 0,029 g of the hydrochloride of 2-(5-(dimethylamino)-2-hydroxybenzamide)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: is 3.08 (6H, s), 7,08-7,16 (1H, m), 7,43-7,51 (2H, m), 7,51-7,58 (4H, m), 7,70-7,76 (2H, m), 8,10 (1H, d, J=8,3 Hz), 9,07 (1H, d, J=1.7 Hz), 12,37 (1H, s).

Example 77a

To a solution of tert-butyl 2-(4-amino-2-(benzyloxy)benzamido)-4-phenylbenzoate (0.15 g) in N,N-dimethylacetamide (1.5 ml) was added potassium carbonate (0,084 g) and methyliodide (0,028 ml), then stirred at room temperature for 1 hour and then at 80°C for 30 minutes. The reaction mixture was cooled to room temperature, then added to it the potassium carbonate (0,042 g) and methyliodide is 0.019 ml)and then stirred at 80°C for 20 minutes. The reaction mixture was cooled to room temperature, and added a 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, sequentially washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride and the land is over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 90-70% hexane/ethyl acetate] to obtain 0,056 g of tert-butyl 2-(2-(benzyloxy)-4-(methylamino)benzamido)-4-phenylbenzoate in the form of a white solid substance and 0,049 g of tert-butyl 2-(2-(benzyloxy)-4-(dimethylamino)benzamido)-4-phenylbenzoate in the form of a white solid.

tert-Butyl 2-(2-(benzyloxy)-4-(methylamino)benzamido)-4-phenylbenzoate

1H-NMR (CDCl3) δ: of 1.52 (9H, s), 2,77 (3H, s), 3,98-4,06 (1H, broadened), 5,49 (2H, s), equal to 6.05 (1H, d, J=2.1 Hz), and 6.25 (1H, DD, J=8,7, and 2.1 Hz), 7,22-7,41 (5H, m), 7,41-7,53 (4H, m), 7,70-7,76 (2H, m), 8,03 (1H, d, J=8,3 Hz), 8,08 (1H, d, J=8.7 Hz), 9,29 (1H, d, J=1.7 Hz), 12,37 (1H, s).

tert-Butyl 2-(2-(benzyloxy)-4-(dimethylamino)benzamido)-4-phenylbenzoate

1H-NMR (CDCl3) δ: 1,53 (9H, s), only 2.91 (6H, s), the 5.51 (2H, s), 6,11 (1H, d, J=2.3 Hz), 6,34 (1H, DD, J=9,0, 2.3 Hz), 7,22-7,40 (5H, m), 7,41-of 7.48 (2H, m), 7,50-of 7.55 (2H, m), 7,71-7,76 (2H, m), 8,03 (1H, d, J=8,3 Hz), 8,11 (1H, d, J=9.0 Hz), 9,31 (1H, d, J=2.0 Hz), 12,38-12,41 (1H, broadened).

Example 78a

To a solution of tert-butyl 2-(2-(benzyloxy)-4-(methylamino)benzamido)-4-phenylbenzoate (0,053 g) in a mixture of methanol (1.5 ml), ethyl acetate (3 ml) and dioxane (4.5 ml) was added 10% palletirovanie coal (27 mg)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. Insoluble substances were removed by filtration, and viparis is whether the solvent under reduced pressure. To the obtained residue was added diisopropyl ether, and then collected the solid by filtration to obtain 0,027 g of tert-butyl 2-(2-hydroxy-4-(methylamino)benzamido)-4-phenylbenzoate in the form of a white solid.

To the obtained tert-butyl 2-(2-hydroxy-4-(methylamino)benzamido)-4-phenylbenzoate (0,027 g) was added triperoxonane acid (5 ml)and then stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the residue water and ethyl acetate, and then adjusted the pH to 6 by the addition of saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added hexane and diisopropyl ether, and collecting the solid by filtration with the receipt of 0.014 g of 2-(2-hydroxy-4-(methylamino)benzamido)-4-vinylbenzoic acid as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 2,72 (3H, s), of 5.99 (1H, d, J=2.1 Hz), to 6.22 (1H, DD, J=8,9, and 2.1 Hz), 6,50-only 6.64 (1H, broadened), 7,42-7,49 (2H, m), 7,49-EUR 7.57 (2H, m), 7,58 (1H, d, J=8,9 Hz), 7,69 to 7.75 (2H, m), of 8.09 (1H, d, J=8,3 Hz), to 8.94 (1H, d, J=1.7 Hz), a 12.03 (1H, s), 12,08 of 12.26 (1H, broadened).

Example 79a

The following connection which was olocale, as described in Example 78a.

2-(4-(Dimethylamino)-2-hydroxybenzamide)-4-phenylbenzene acid

1H-NMR (DMSO-d6) δ: 2,99 (6H, s), 6,14 (1H, d, J=2.7 Hz), 6,40 (1H, DD, J=9,0, 2.7 Hz), 7,42-to 7.50 (2H, m), 7,50-EUR 7.57 (2H, m), 7,68 (1H, d, J=9.0 Hz), 7,69 to 7.75 (2H, m), 8,10 (1H, d, J=8,3 Hz), 8,96 (1H, d, J=1.7 Hz), 11,95 (1H, s), 12,18-12,32 (1H, broadened).

Example 80a

To a suspension of tert-butyl 2-(2-(benzyloxy)-5-bromobenzene)-4-phenylbenzoate (0.15 g) in toluene (2.3 ml) was added piperidine (0,040 ml), cesium carbonate (0.18 g), Tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (6.4 mg) and palladium(II) acetate (1.2 mg)and then heated under reflux in nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature, then added to it piperidine (0,040 ml), cesium carbonate (0.18 g), Tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (6.4 mg) and palladium(II) acetate (1.2 mg)and then heated under reflux in nitrogen atmosphere for 5 hours and 30 minutes. The reaction mixture was cooled to room temperature, and added a 10% aqueous citric acid solution and ethyl acetate. Insoluble substances were removed by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the issue is ivali the solvent under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-70% hexane/ethyl acetate] to obtain of 0.13 g of tert-butyl 2-(2-(benzyloxy)-5-(piperidine-1-yl)benzamido)-4-phenylbenzoate as an orange oily substance.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(piperidine-1-yl)benzamido)-4-phenylbenzoate (0,13 g) in a mixture of ethyl acetate (1 ml) and methanol (1 ml) 10% palletirovanie coal (63 mg) was added, and then stirred in a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. To the reaction mixture was added ethyl acetate, and removing insoluble substances by filtration. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid substance was collected by filtration to obtain of 0.081 g of tert-butyl 2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-4-phenylbenzoate in the form of a yellow solid.

To the obtained tert-butyl 2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-4-phenylbenzoate (of 0.081 g) was added triperoxonane acid (5 ml)and then stirred at room temperature for 4 hours. The solvent is evaporated under reduced pressure, was added to the residue ethyl acetate (2 ml) and 4 mol/l solution of florodora in dioxane (0.5 ml)and then stirred at room te is the temperature for 3 hours. The solid substance was collected from the reaction mixture by filtration with the receipt of 0.066 g of the hydrochloride of 2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (CD3OD) δ: 1,75-of 1.88 (2H, m), 1,98-2,12 (4H, m), the 3.65 (4H, DD, J=5,6, and 5.6 Hz), 7,18 (1H, d, J=9.0 Hz), 7,40-7,46 (1H, m), 7,47-rate of 7.54 (3H, m), 7,70-7,76 (3H, m), 8,19 (1H, d, J=3.2 Hz), by 8.22 (1H, d, J=8,3 Hz), 9,06 (1H, d, J=2.0 Hz).

Examples 81a-86a

Compounds shown in Table 14a, obtained as described in Example 80a.

Table 14a
Example No.R7Example No.R7
81a84a
82a85a
83a86a

2-(2-Hydroxy-5-((octahydrate)-1-ylbenzene)-4-vinylbenzoic acid hydrochloride

1H-NMR (DMSO-d6) δ: 1,42-to 1.61 (6H, m)of 1.65 and 1.80 (4H, m), 3,36-to 3.50 (4H, m), 6,82-7,02 (2H, m), 7,08-7,30 (1H, m), 7,43-7,58 (4H, m), 7,70-to 7.77 (2H, m), 8,10 (1H, d, J=8,3 Hz), 9,04 (1H, d, J=1.9 Hz), 12,31 (1H, s).

2-(2-Hydroxy-5-(4-methylpiperidin-1-yl)benzamido)-4-vinylbenzoic acid hydrochloride

1H-NMR (CD3OD) δ: 1,11 (3H, d, J=6.6 Hz), 1,64-of 1.78 (2H, m), 1,84-of 1.97 (1H, m), 2,02 and 2.13 (2H, m), 3,60-3,74 (4H, m), 7,18 (1H, d, J=9.0 Hz), 7,40-7,46 (1H, m), 7,47-rate of 7.54 (3H, m), 7,70-to 7.77 (3H, m), 8,18-8,24 (2H, m), 9,06 (1H, d, J=1.7 Hz).

2-(2-Hydroxy-5-(morpholine-4-yl)benzamido)-4-vinylbenzoic acid hydrochloride

1H-NMR (DMSO-d6) δ: 3,16-of 3.27 (4H, m), 3,80-3,91 (4H, m), 7,03 (1H, d, J=9.0 Hz), of 7.36-to 7.59 (5H, m), to 7.67 for 7.78 (3H, m), 8,10 (1H, d, J=8,3 Hz), 9,03 (1H, d, J=1.7 Hz), 11,22-11,40 (1H, broadened), 12,31 (1H, s).

2-(5-(Diethylamino)-2-hydroxybenzamide)-4--vinylbenzoic acid hydrochloride

1H-NMR (DMSO-d6) δ: was 1.04 (6H, t, J=7,1 Hz), 3,43-3,68 (4H, m), 7,15-7,28 (1H, m), 7,43-7,50 (1H, m), 7,50-7,58 (3H, m), 7.68 per-7,86 (3H, m), 8,10 (1H, d, J=8,3 Hz), 8,16-to 8.34 (1H, m), the remaining 9.08 (1H, d, J=1.7 Hz), 11,93-12,15 (1H, broadened), KZT 12.39 (1H, s).

2-(2-Hydroxy-5-((2-hydroxyethyl)(methyl)amino)benzamido)-4-vinylbenzoic acid hydrochloride

1H-NMR (DMSO-d6), (50°C) δ: 3.04 from (3H, s), 3,42-to 3.58 (4H, m), 7,02 (1H, d, J=9.0 Hz), 7,26-7,38 (1H, m), 7,41-EUR 7.57 (4H, m), to 7.61-7,76 (3H, m), 8,10 (1H, d, J=8,3 Hz), 9,03 (1H, d, J=2.0 Hz), 12,17-to 12.35 (1H, broadened).

2-(5-(Azetidin-1-yl)-2-hydroxybenzamide)-4-vinylbenzoic acid hydrochloride

1H-NMR (CD3OD) δ: 2,66 (2H, qn, J=8.0 Hz), of 4.57 (4H, t, J=8.0 Hz), 7,14 (1H, d, J=9.0 Hz), 7,39-7,46 (1H, m), 7,46-rate of 7.54 (3H, m), to 7.59 (1H, DD, J=9,0, ,8 Hz), 7,70-7,76 (2H, m), of 7.96-8,02 (1H, m), by 8.22 (1H, d, J=8,3 Hz), 9,06 (1H, d, J=1.7 Hz).

Example 87a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzene)-4-phenylbenzoate (0,30 g) in toluene (4.5 ml) was added 4-(tert-butyldimethylsilyloxy)piperidine (0,23 g), cesium carbonate (0,44 g), Tris(dibenzylideneacetone)dipalladium(0) (9.8 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (26 mg) and palladium(II) acetate (4.8 mg)and then heated with reflux in nitrogen atmosphere for 4 hours 30 minutes. The reaction mixture was cooled to room temperature, and added to her water and ethyl acetate. Insoluble substances were removed by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% hexane/ethyl acetate] to obtain 0.32 g of tert-butyl 2-(2-(benzyloxy)-5-(4-(tert-butyldimethylsilyloxy)piperidine-1-yl)benzamido)-4-phenylbenzoate.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(4-(tert-butyldimethylsilyloxy)piperidine-1-yl)benzamido)-4-phenylbenzoate (0.32 g) in tetrahydrofuran (3.2 ml) was added 1.0 mol/l solution of tetrabutylammonium fluoride in tetrahedr is the furan high (0.56 ml), and then was stirred at room temperature for 1 hour. To the reaction mixture were added 1.0 mol/l solution of tetrabutylammonium fluoride in tetrahydrofuran (0,28 ml)and then stirred at room temperature for 4 hours. To the reaction mixture while cooling on ice was added water, and added to her chloroform at room temperature. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 90-40% hexane/ethyl acetate] to obtain of 0.23 g of tert-butyl 2-(2-(benzyloxy)-5-(4-hydroxypiperidine-1-yl)benzamido)-4-phenylbenzoate.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(4-hydroxypiperidine-1-yl)benzamido)-4-phenylbenzoate (0,22 g) in a mixture of methanol (2.2 ml) and ethyl acetate (1.1 ml) was added 10% palletirovanie coal (0.11 g)and then stirred in a hydrogen atmosphere at room temperature for 1 hour. To the reaction mixture was added ethyl acetate, and removing insoluble substances by filtration. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid substance was collected by filtration to obtain 0.18 g of tert-butyl 2-(2-guide the hydroxy-5-(4-hydroxypiperidine-1-yl)benzamido)-4-phenylbenzoate.

A solution of the obtained tert-butyl 2-(2-hydroxy-5-(4-hydroxypiperidine-1-yl)benzamido)-4-phenylbenzoate (0.18 g) in triperoxonane acid (5 ml) was stirred at room temperature for 30 minutes. The solvent is evaporated under reduced pressure, was added to the residue ethyl acetate (2 ml) and 4 mol/l solution of florodora in dioxane (0.5 ml)and then stirred at room temperature for 30 minutes. The solid substance was collected from the reaction mixture by filtration to obtain 0.15 g of the hydrochloride of 2-(2-hydroxy-5-(4-hydroxypiperidine-1-yl)benzamido)-4-vinylbenzoic acid as a pale yellow solid.

1H-NMR (CD3OD) δ: 1,97-2,10 (2H, m), 2,18 of-2.32 (2H, m), 3,56-and 3.72 (2H, m), 3,78-of 3.94 (2H, m), 4,05-4,16 (1H, m), 7,18 (1H, d, J=9.0 Hz), 7,40-7,46 (1H, m), 7,47-rate of 7.54 (3H, m), 7,70 for 7.78 (3H, m), 8,19-8,24 (2H, m), 9,06 (1H, d, J=2.0 Hz).

Example 88a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzene)-4-phenylbenzoate (0.50 g) in toluene (5.0 ml) was added thiomorpholine (0,14 ml), cesium carbonate (0,58 g), Tris(dibenzylideneacetone)dipalladium(0) (8.2 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (21 mg) and palladium(II) acetate (4.0 mg)and then heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, then added to it thiomorpholine (0,045 ml), cesium carbonate (0.15 g), Tris(dibenzo identicon)dipalladium(0) (8.2 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (21 mg) and palladium(II) acetate (4.0 mg)and then heated under reflux in nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature and then added to her water and ethyl acetate. Insoluble substances were removed by filtration. The organic layer was separated, sequentially washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-80% hexane/ethyl acetate] to obtain 0.36 g of tert-butyl 2-(2-(benzyloxy)-5-(thiomorpholine-4-yl)benzamido)-4-phenylbenzoate in the form of a yellow solid.

1H-NMR (DMSO-d6) δ: for 1.49 (9H, s), 2,65-by 2.73 (4H, m), 3,36-3,44 (4H, m), 5,42 (2H, s), 7,09-to 7.15 (2H, m), 7.23 percent-of 7.35 (3H, m), 7,43-to 7.59 (7H, m), 7,69-7,76 (2H, m), of 8.04 (1H, d, J=8,3 Hz), the remaining 9.08-9,12 (1H, m), 12,16 (1H, s).

Example 89a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-(thiomorpholine-4-yl)benzamido)-4-phenylbenzoate (0.10 g) in triperoxonane acid (2.0 ml) was added thioanisole (1.0 ml)and then stirred at room temperature for 24 hours. The solvent is evaporated under reduced pressure, was added to the residue 4 mol/l solution of florodora in dioxane (0.5 ml) and ethyl acetate (1.0 ml), and then was stirred at room temperature for 3 hours. The solid is collected by filtration, and was added to the obtained solid substance, water and ethyl acetate. After adjusting the pH to 6.5 by the addition of saturated aqueous sodium bicarbonate solution, the organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and purify the resulting residue by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: chloroform] to obtain 0,047 g 2-(2-hydroxy-5-(thiomorpholine-4-yl)benzamido)-4-vinylbenzoic acid as a yellow solid.

1H-NMR (DMSO-d6), (40°C) δ: 2,70 was 2.76 (4H, m), 3.33 and-3,39 (4H, m), 6,92 (1H, d, J=8,8 Hz), to 7.15 (1H, DD, J=8,8, 3.1 Hz), 7,41-EUR 7.57 (5H, m), 7,70-7,76 (2H, m), 8,10 (1H, d, J=8.1 Hz), 8,99 (1H, d, J=1.9 Hz), 10,99 (1H, ), 12,20-12,40 (1H, broadened).

Example 90a

When cooled on ice to a solution of 2-(2-hydroxy-5-(thiomorpholine-4-yl)benzamido)-4-vinylbenzoic acid (0.015 g) in a mixture of methylene chloride (1.0 ml) and tetrahydrofuran (0,50 ml) was added meta-chloroperbenzoic acid (7.9 mg)and then stirred at room temperature for 10 minutes. To the reaction mixture were added 2-propanol (2.0 ml), and collecting the solid by Phil is travunia with getting to 0.011 g of 2-(2-hydroxy-5-(1-oxydianiline-4-yl)benzamido)-4-vinylbenzoic acid as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 2.71 to 2,84 (2H, m), 2,92 totaling 3.04 (2H, m), 3,38-3,50 (2H, m), 3,56-3,70 (2H, m), to 6.95 (1H, d, J=9.0 Hz), 7,24 (1H, DD, J=9,0, 2,8 Hz), 7,42-EUR 7.57 (5H, m), 7,70-7,76 (2H, m), 8,10 (1H, d, J=8,3 Hz), 9,01 (1H, d, J=1.7 Hz), 11,07 (1H, s), 12,32-12,54 (1H, broadened).

Example 91a

When cooled on ice to a solution of tert-butyl 2-(2-(benzyloxy)-5-(thiomorpholine-4-yl)benzamido)-4-phenylbenzoate (0.10 g) in methylene chloride (1.5 ml) was added meta-chloroperbenzoic acid (79 mg)and then stirred at room temperature for 30 minutes. While cooling on ice to the reaction mixture was added meta-chloroperbenzoic acid (20 mg)and then stirred at room temperature for 30 minutes. While cooling on ice to the reaction mixture was added meta-chloroperbenzoic acid (40 mg)and then stirred at room temperature for 30 minutes. While cooling on ice to the reaction mixture was added meta-chloroperbenzoic acid (20 mg)and then stirred at room temperature for 30 minutes. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and methylene chloride. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by column method, chromatography the on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0,089 g of tert-butyl 2-(2-(benzyloxy)-5-(1,1,4-taoxintaofei-4-yl)benzamido)-4-phenylbenzoate in the form of a light yellow solid.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(1,1,4-taoxintaofei-4-yl)benzamido)-4-phenylbenzoate (0,086 g) in a mixture of methanol (2.0 ml) and ethyl acetate (3.0 ml) was added 10% palletirovanie coal (43 mg)and then stirred in a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. To the reaction mixture was added dioxane and ethyl acetate, and removing insoluble substances by filtration. The solvent is evaporated under reduced pressure to obtain 0,061 g of tert-butyl 2-(2-hydroxy-5-(1,1-diocletianopolis-4-yl)benzamido)-4-phenylbenzoate.

A solution of the obtained tert-butyl 2-(2-hydroxy-5-(1,1-diocletianopolis-4-yl)benzamido)-4-phenylbenzoate (0,059 g) in triperoxonane acid (5.0 ml) was stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, was added to the residue water and ethyl acetate, and then adjust the pH to 6.5 by the addition of saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated andforming reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0,048 g 2-(2-hydroxy-5-(1,1-diocletianopolis-4-yl)benzamido)-4-vinylbenzoic acid as a yellow solid.

1H-NMR (DMSO-d6) δ: 3,13-of 3.25 (4H, m), to 3.58-3,70 (4H, m), to 6.95 (1H, d, J=8,9 Hz), 7,25 (1H, DD, J=8,9, 3.0 Hz), 7,42-EUR 7.57 (5H, m), 7,70-7,76 (2H, m), 8,10 (1H, d, J=8.0 Hz), of 9.00 (1H, d, J=1.7 Hz), 11,04-11,20 (1H, broadened).

Example 92a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzene)-4-phenylbenzoate (0,30 g) in toluene (4.5 ml) was added 1-methylpiperazine (0,089 ml), cesium carbonate (0.35 g), Tris(dibenzylideneacetone)dipalladium(0) (4.9 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (13 mg) and palladium(II) acetate (2.4 mg)and then heated under reflux in a nitrogen atmosphere within 3 hours. The reaction mixture was cooled to room temperature, then added to it 1-methylpiperazine (to 0.060 ml), cesium carbonate (0.18 g), Tris(dibenzylideneacetone)dipalladium(0) (4.9 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (13 mg) and palladium(II) acetate (2.4 mg)and then heated under reflux in nitrogen atmosphere for 3 hours. After cooling the reaction mixture to room temperature, the solvent evaporated under reduced pressure, and was added to the residue water and chloroform. Insoluble substance is dalali by filtration. The organic layer was separated, sequentially washed with 1 mol/l aqueous solution of sodium hydroxide and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0.26 g of tert-butyl 2-(2-(benzyloxy)-5-(4-methylpiperazin-1-yl)benzamido)-4-phenylbenzoate.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(4-methylpiperazin-1-yl)benzamido)-4-phenylbenzoate (0.26 g) in a mixture of methanol (2.6 ml) and ethyl acetate (1.3 ml) was added 10% palletirovanie coal (0.26 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture was added chloroform, and removing insoluble substances by filtration. The solvent is evaporated under reduced pressure and purify the resulting residue by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain of 0.13 g of tert-butyl 2-(2-hydroxy-5-(4-methylpiperazin-1-yl)benzamido)-4-phenylbenzoate.

To the obtained tert-butyl 2-(2-hydroxy-5-(4-methylpiperazin-1-yl)benzamido)-4-phenylbenzoate (0,13 g) was added triperoxonane acid (5 ml), and ZAT is m was stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, was added to the residue methansulfonate acid (0,034 ml) and ethyl acetate (3 ml)and then stirred at room temperature for 1 hour and 30 minutes. The solid substance was collected by filtration to obtain 0.12 g dimethanesulfonate 2-(2-hydroxy-5-(4-methylpiperazin-1-yl)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 2,33 (6H, s), 2,84 are 2.98 (5H, m), 3,13-3,26 (2H, m), 3,49 is 3.57 (2H, m), 3,65-3,74 (2H, m), 6,97 (1H, d, J=8,9 Hz), 7,21 (1H, DD, J=8,9, 2,9 Hz), 7,43-7,58 (5H, m), 7,70 to 7.75 (2H, m), of 8.09 (1H, d, J=8,3 Hz), 9,04 (1H, d, J=1.7 Hz), 9,48-9,62 (1H, broadened), 10,94-11,06 (1H, broadened), 12,27 (1H, s).

Example 93a

The following compound was obtained as described in Example 92a.

2-(5-(4-Ethylpiperazin-1-yl)-2-hydroxybenzamide)-4-vinylbenzoic acid dimethanesulfonate

1H-NMR (DMSO-d6) δ: 1.26 in (3H, t, J=7,3 Hz), of 2.33 (6H, s), 2,87 are 2.98 (2H, m), is 3.08 of 3.28 (4H, m), 3,54-the 3.65 (2H, m), 3,65-of 3.80 (2H, m), 6,98 (1H, d, J=9.0 Hz), 7,22 (1H, DD, J=9,0, 3.1 Hz), 7,43-EUR 7.57 (5H, m), 7,70 to 7.75 (2H, m,), of 8.09 (1H, d, J=8,3 Hz), 9,04 (1H, d, J=1.7 Hz), 9,26-9,38 (1H, broadened), 10,94-11,04 (1H, broadened), 12,27 (1H, s).

Example 94a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzene)-4-phenylbenzoate (0.15 g) in toluene (2.3 ml) was added dihydrochloride 4-(dimethylamino)piperidine (0.11 g), cesium carbonate (0,44 g), Tris(dibenzylideneacetone)dipalladium(0) (2.5 mg, 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (6.4 mg) and palladium(II) acetate (1.2 mg)and then heated under reflux in nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, the reaction mixture was added cesium carbonate (0,13 g), Tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (6.4 mg) and palladium(II) acetate (1.2 mg)and then heated under reflux in nitrogen atmosphere for 7 hours. The reaction mixture was cooled to room temperature, the reaction mixture was added tribalistas (0.29 grams), Tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (6.4 mg) and palladium(II) acetate (1.2 mg)and then heated under reflux in nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and added to her water and chloroform. Insoluble substances were removed by filtration. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain of 0.13 g of tert-butyl 2-(2-(benzyloxy)-5-(4-(dimethylamino)piperidine-1-yl)benzamido)-4-dryers is benzoate.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(4-(dimethylamino)piperidine-1-yl)benzamido)-4-phenylbenzoate (0,13 g) in a mixture of methanol (1.5 ml) and ethyl acetate (1.5 ml) was added 10% palletirovanie coal (0,13 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture was added chloroform, and removing insoluble substances by filtration. The solvent is evaporated under reduced pressure and purify the resulting residue by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain of 0.066 g of tert-butyl 2-(5-(4-(dimethylamino)piperidine-1-yl)-2-hydroxybenzamide)-4-phenylbenzoate.

To the obtained tert-butyl 2-(5-(4-(dimethylamino)piperidine-1-yl)-2-hydroxybenzamide)-4-phenylbenzoate (of 0.066 g) was added triperoxonane acid (5.0 ml)and then stirred at room temperature for 5 hours. The solvent is evaporated under reduced pressure and purify the resulting residue by the method of reversed-phase column chromatography on silica gel [YMC Co., Ltd., ODS-AM12S05-2520WT, eluent: 40-85% acetonitrile/0.1% aqueous solution triperoxonane acid] with getting to 0.060 g of solid substance. To the obtained solid substance (to 0.060 g) was added ethyl acetate (3.0 ml) and methanesulfonyl acid (0,011 ml)and then stirred p. and room temperature for 5 hours. The solid substance was collected by filtration to obtain 0,045 g dimethanesulfonate 2-(5-(4-(dimethylamino)piperidine-1-yl)-2-hydroxybenzamide)-4-vinylbenzoic acid as a white solid.

1H-NMR (CD3OD) δ: 2,17 of-2.32 (2H, m), a 2.36-of 2.50 (2H, m), 2,73 (6H, s), 2,98 (6H, s), 3,50-3,70 (3H, m), 3,82-of 3.94 (2H, m), 7,13 (1H, d, J=9.0 Hz), 7,39-7,46 (1H, m), 7,46-rate of 7.54 (3H, m), of 7.64 (1H, DD, J=9,0, 2,9 Hz), 7,70-7,76 (2H, m), of 8.06 (1H, d, J=2,9 Hz), 8,21 (1H, d, J=8,3 Hz), 9,06 (1H, d, J=1.7 Hz).

Example 95a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzene)-4-phenylbenzoate (0.15 g) in toluene (2.3 ml) was added N-methyl-2-(pyrrolidin-1-yl)ethylamine (0,086 g), tribalistas (0.17 g), Tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (6.4 mg) and palladium(II) acetate (1.2 mg)and then was heated under reflux in nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, then the reaction mixture was added N-methyl-2-(pyrrolidin-1-yl)ethylamine (0,017 g), tribalistas (0,029 g), Tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (6.4 mg) and palladium(II) acetate (1.2 mg)and then heated under reflux in nitrogen atmosphere for 7 hours and 30 minutes. The reaction mixture was cooled to room temperature, then the reaction mixture was added N-methyl-2-(pyrrolidin-1 and is)ethylamine (0,017 g), tribalistas (0,029 g), Tris(dibenzylideneacetone)dipalladium(0) 2.5 mg, 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (6.4 mg) and palladium(II) acetate (1.2 mg)and then heated under reflux in nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, and added to her water and chloroform. Insoluble substances were removed by filtration. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-90% chloroform/methanol] to obtain 0,097 g of tert-butyl 2-(2-(benzyloxy)-5-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)benzamido)-4-phenylbenzoate.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)benzamido)-4-phenylbenzoate (0,097 g) in a mixture of methanol (1.5 ml) and ethyl acetate (1.5 ml) was added 10% palletirovanie coal (0,097 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture was added chloroform, and removing insoluble substances by filtration. The solvent is evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-95% chloroform/methanol] to obtain 0,048 g of tert-butyl 2-(2-HYDR the xylose-5-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)benzamido)-4-phenylbenzoate.

To the obtained tert-butyl 2-(2-hydroxy-5-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)benzamido)-4-phenylbenzoate (0,048 g) was added triperoxonane acid (5.0 ml)and then stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, was added to the residue water and ethyl acetate, and then adjusted the pH to 7 by adding saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue were added methanol (1.5 ml), dioxane (1.5 ml) and 1.0 mol/l aqueous solution of sodium hydroxide (0,067 ml)and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0,028 g 2-(2-hydroxy-5-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)benzamido)-4-phenylbenzoate sodium in the form of a yellow solid.

1H-NMR (CD3OD) δ: 1,76-1,90 (4H, m), 2,58-2,78 (6H, m), 2,99 (3H, s), 3.43 points-of 3.54 (2H, m), 6,85 (1H, d, J=9.0 Hz), 7,06 (1H, DD, J=9,0, 2,9 Hz), 7,32-7,40 (3H, m), 7,43-to 7.50 (2H, m), to 7.67-7,74 (2H, m), 8,18 (1H, d, J=8,1 Hz), of 9.00 (1H, d, J=1.7 Hz).

Example 96a

The following compound was obtained as described in Example 95a.

2-(2-Hydroxy-5-(METI is(2-(piperidine-1-yl)ethyl)amino)benzamido)-4-phenylbenzoate sodium

1H-NMR (CD3OD) δ: 1,42-and 1.54 (2H, m), 1.56 to 1,72 (4H, m), 2,46 of 2.68 (6H, m), 2,98 (3H, s), 3.45 points of 3.56 (2H, m), 6,85 (1H, d, J=9.0 Hz), 7,06 (1H, DD, J=9,0, 2,9 Hz), 7,32-7,40 (3H, m), 7,43-to 7.50 (2H, m), 7.68 per-7,73 (2H, m), 8,18 (1H, d, J=8,3 Hz), 9,01 (1H, d, J=1.7 Hz).

Example 97a

To a suspension of tert-butyl 2-(2-(benzyloxy)-4-jogesuido)-4-phenylbenzoate (0,22 g) in toluene (3.0 ml) was added N,N,N'-trimethylethylenediamine (0,12 ml), cesium carbonate (0.35 g), Tris(dibenzylideneacetone)dipalladium(0) (3,3 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (8.6 mg) and palladium(II) acetate (1.6 mg)and then heated with reflux in nitrogen atmosphere for 4 hours and 10 minutes. The reaction mixture was cooled to room temperature, then the reaction mixture was added N,N,N'-trimethylethylenediamine (0,12 ml), cesium carbonate (0.35 g), Tris(dibenzylideneacetone)dipalladium(0) (3,3 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (8.6 mg) and palladium(II) acetate (1.6 mg)and then heated under reflux in nitrogen atmosphere for 8 hours. The reaction mixture was cooled to room temperature and then added to her water and chloroform. Insoluble substances were removed by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue PTS is attended by the method of column chromatography on silica gel [eluent: 100-93% chloroform/methanol] to obtain 0,072 g of tert-butyl 2-(2-(benzyloxy)-4-((2-(dimethylamino)ethyl)(methyl)amino)benzamido)-4-phenylbenzoate.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-4-((2-(dimethylamino)ethyl)(methyl)amino)benzamido)-4-phenylbenzoate (0,071 g) in methanol (3.0 ml) was added 10% palletirovanie coal (0.035 g)and then stirred in a hydrogen atmosphere at room temperature for 1 hour and 45 minutes. To the reaction mixture were added methanol (2.0 ml) and chloroform (1.0 ml)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. Insoluble substances were removed by filtration, and then the solvent evaporated under reduced pressure. To the obtained residue was added ethyl acetate, and collecting the solid by filtration to obtain 0,045 g of tert-butyl 2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-hydroxybenzamide)-4-phenylbenzoate in the form of a white solid.

To the obtained tert-butyl 2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-hydroxybenzamide)-4-phenylbenzoate (0,045 g) was added triperoxonane acid (2.0 ml)and then stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and then was added to the residue methanol. After adjusting the pH to 8.0 by addition of a saturated aqueous solution of sodium bicarbonate, the solid substance was collected from the reaction mixture by filtration to obtain 0,028 g of 2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-hydroxyl is samigo)-4-phenylbenzoate sodium in the form of a yellow solid.

1H-NMR (DMSO-d6) δ: 2,70 (6H, s), 2,96 (3H, s), 3.00 and-3,10 (2H, m), 3,63-of 3.77 (2H, m), x 6.15 (1H, d, J=2.2 Hz), 6,40 (1H, DD, J=9,0, 2.2 Hz), 7,35 (1H, DD, J=8,1) and 1.7 Hz), 7,37-7,44 (1H, m), 7,46-of 7.55 (2H, m), 7,63-7,73 (2H, m,), to 7.77 (1H, d, J=9.0 Hz), 8,11 (1H, d, J=8.1 Hz), 8,89 (1H, d, J=1.7 Hz), 12,65-12,90 (1H, broadened).

Example 98a

The following compound was obtained as described in Example 97a.

2-(2-Hydroxy-5-(methyl(2-(methylamino)ethyl)amino)benzamido)-4-phenylbenzoate sodium

1H-NMR (DMSO-d6) δ: 2,66 (3H, s), 2,95 (3H, s), 3,05-and 3.16 (2H, m), 3,53-3,61 (2H, m), to 6.88 (1H, d, J=8,9 Hz), 7,00 (1H, DD, J=8,9, 2.7 Hz), of 7.36-7,46 (3H, m), 7,47-7,56 (2H, m), the 7.65 to 7.75 (2H, m)to 8.14 (1H, d, J=8.0 Hz), 8,89 (1H, d, J=1.7 Hz), of 9.55-10,00 (1H, broadened), 11,55-RS 11.80 (1H, broadened).

Example 99a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzene)-4-phenylbenzoate (0.15 g) in toluene (2.3 ml) was added N-methyl-2-(morpholine-4-yl)ethylamine (0,097 g), tribalistas (0.17 g), Tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (6.4 mg) and palladium(II) acetate (1.2 mg)and then was heated under reflux in nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, then the reaction mixture was added N-methyl-2-(morpholine-4-yl)ethylamine (0,019 g), tribalistas (0,029 g), Tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (6.4 mg) and acetate PAL is adiya(II) (1.2 mg), and then was heated under reflux in nitrogen atmosphere for 6 hours. The reaction mixture was cooled to room temperature and then added to her water and chloroform. Insoluble substances were removed by filtration. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0.12 g of tert-butyl 2-(2-(benzyloxy)-5-(methyl(2-(morpholine-4-yl)ethyl)amino)benzamido)-4-phenylbenzoate.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(methyl(2-(morpholine-4-yl)ethyl)amino)benzamido)-4-phenylbenzoate (0.12 g) in a mixture of methanol (1.5 ml) and ethyl acetate (1.5 ml) was added 10% palletirovanie charcoal (0.12 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. To the reaction mixture were added ethyl acetate. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-95% chloroform/methanol] to obtain 0,074 g of tert-butyl 2-(2-hydroxy-5-(methyl(2-(morpholine-4-yl)ethyl)amino)benzamido)-4-fenib is soata.

To the obtained tert-butyl 2-(2-hydroxy-5-(methyl(2-(morpholine-4-yl)ethyl)amino)benzamido)-4-phenylbenzoate (0,074 g) was added triperoxonane acid (5.0 ml)and then stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the residue water and chloroform. After adjusting the pH to 7.0 by the addition of saturated aqueous sodium bicarbonate solution the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, and the resulting mixture was dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid substance was collected by filtration to obtain 0,024 g 2-(2-hydroxy-5-(methyl(2-(morpholine-4-yl)ethyl)amino)benzamido)-4-vinylbenzoic acid as a yellow solid.

1H-NMR (DMSO-d6), (60°C) δ: 2,95 (3H, s), 3.00 and-3,14 (6H, m), 3,60-3,70 (2H, m), 3.96 points-4,08 (4H, m), to 6.88 (1H, d, J=9.0 Hz), of 6.99 (1H, DD, J=9,0, 2,9 Hz), was 7.36 (1H, d, J=2,9 Hz), 7,38 was 7.45 (2H, m), 7,47-rate of 7.54 (2H, m), 7,66-7,73 (2H, m), 8,17 (1H, d, J=8,3 Hz), 8,93 (1H, d, J=2.0 Hz).

Example 100a

To a suspension of tert-butyl 2-(2-(benzyloxy)-4-jogesuido)-4-phenylbenzoate (0.20 g) in toluene (2.0 ml) was added piperidine (0,049 ml), cesium carbonate (0,22 g), Tris(dibenzylideneacetone)dipalladium(0) (3.0 mg), 2-Diez is cohexisting-2',4',6'-triisopropylphenyl (7.9 mg) and palladium(II) acetate (1.5 mg), and then was heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature and then added to it piperidine (0,033 ml), cesium carbonate (0.11 g), Tris(dibenzylideneacetone)dipalladium(0) (3.0 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (7.9 mg) and palladium(II) acetate (1.5 mg)and then heated under reflux in nitrogen atmosphere for 4 hours 30 minutes. The reaction mixture was cooled to room temperature, and then was added a 10% aqueous citric acid solution and ethyl acetate. Insoluble substances were removed by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-85% hexane/ethyl acetate] to obtain of 0.13 g of tert-butyl 2-(2-(benzyloxy)-4-(piperidine-1-yl)benzamido)-4-phenylbenzoate.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-4-(piperidine-1-yl)benzamido)-4-phenylbenzoate (0,13 g) in a mixture of methanol (1.5 ml) and ethyl acetate (3.0 ml) was added 10% palletirovanie coal (0,063 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture EXT is ulali ethyl acetate. Insoluble substances were removed by filtration, and then the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0,084 g of tert-butyl 2-(2-hydroxy-4-(piperidine-1-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

To the obtained tert-butyl 2-(2-hydroxy-4-(piperidine-1-yl)benzamido)-4-phenylbenzoate (0,084 g) was added triperoxonane acid (5.0 ml)and then stirred at room temperature for 4 hours. The solvent is evaporated under reduced pressure, was added to the residue water and ethyl acetate, and then adjust the pH to 6.5 by the addition of saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether. The solid substance was collected by filtration to obtain 0,063 g 2-(2-hydroxy-4-(piperidine-1-yl)benzamido)-4-vinylbenzoic acid as a pale yellow solid.

1H-NMR (DMSO-d6), (40°C) δ: 1,52-of 1.66 (6H, m), 3,26 is 3.40 (4H, m), 6,34 (1H, d, J=2.5 Hz), to 6.58 (1H, DD, J=9,1, 2,5 Hz), 7,41-7,49 (2H, m), 7,49-7,56 (2H, m), to 7.67 (1H, d, J=9.1 Hz), 7,69-7,74 (2H, m), 8,10 (1H, d, J=8,3 Hz), to 8.94 (1H, d, J=1.7 G is), 11,80-11,94 (1H, broadened), 12,20-to 12.35 (1H, broadened).

Example 101a

The following compound was obtained as described in Example 100a.

2-(5-((2-(Dimethylamino)ethyl)(methyl)amino)-2-hydroxybenzamide)-4-phenylbenzene acid

1H-NMR (DMSO-d6) δ: for 2.83 (6H, s), 2,95 (3H, s), 3,16-3,26 (2H, m), 3,62-3,74 (2H, m), 6.89 in (1H, d, J=9.0 Hz), 7,00 (1H, DD, J=9,0, 2.7 Hz), of 7.36 was 7.45 (3H, m), of 7.48-of 7.55 (2H, m), to 7.67-7,73 (2H, m), 8,13 (1H, d, J=8.1 Hz), 8,88 (1H, d, J=2.0 Hz), 11,53-11,67 (1H, broadened).

Example 102a

The following compound was obtained as described in Example 100a.

2-(5-((2-(Diethylamino)ethyl)(methyl)amino)-2-hydroxybenzamide)-4-phenylbenzene acid

1H-NMR (DMSO-d6) δ: 1.18 to 1.39 in (6H, m), of 2.97 (3H, s), 3,07-of 3.54 (6H, m), 3,63-of 3.80 (2H, m), 6.89 in (1H, d, J=8,9 Hz), 7,00 (1H, DD, J=8,9, and 2.4 Hz), of 7.36 was 7.45 (3H, m), 7,47-of 7.55 (2H, m), 7,66-7,73 (2H, m), 8,15 (1H, d, J=8.0 Hz,), of 8.90 (1H, d, J=1.7 Hz), to 11.56-11,70 (1H, broadened).

Example 103a

The following compound was obtained as described in Example 100a.

2-(5-((3-(Dimethylamino)propyl)(methyl)amino)-2-hydroxybenzamide)-4-phenylbenzene acid

1H-NMR (CD3OD) δ: 2,07-of 2.21 (2H, m), of 2.92 (6H, s), 2,95 (3H, s), 3,21 (2H, t, J=7.4 Hz), 3,37 (2H, t, J=8,3 Hz), 6.87 in (1H, d, J=9.0 Hz), 7,01 (1H, DD, J=9,0, 3.0 Hz), 7,26 (1H, d, J=3.0 Hz), 7,35-7,42 (2H, m), 7,44-7,51 (2H, m), 7.68 per-7,74 (2H, m), 8,19 (1H, d, J=8.0 Hz), 9,03 (1H, d, J=2.0 Hz).

Example 104a

The following compound was obtained as op is Sano in Example 100a.

2-(5-((2-(Dimethylamino)ethyl)(ethyl)amino)-2-hydroxybenzamide)-4-phenylbenzene acid

1H-NMR (CD3OD) δ: 1,11 (3H, t, J=7,1 Hz), 2,95 (6H, s), 3.27 to to 3.34 (2H, m), 3,40 (2H, q, J=7,1 Hz)to 3.64 (2H, t, J=7,1 Hz), 6,93 (1H, d, J=9.0 Hz), to 7.15 (1H, DD, J=9,0, 2,8 Hz), 7,37-7,53 (5H, m), 7,69 to 7.75 (2H, m), by 8.22 (1H, d, J=8,3 Hz), 9,05 (1H, d, J=1.7 Hz).

Example 105a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzene)-4-phenylbenzoate (0.20 g) in toluene (3.0 ml) was added 1,4-dioxa-8 azaspiro[4,5]decane (0,12 ml), cesium carbonate (0.35 g), Tris(dibenzylideneacetone)dipalladium(0) (3,3 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (8.5 mg) and palladium(II) acetate (1.6 mg), and then, they were heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, then the reaction mixture was added Tris(dibenzylideneacetone)dipalladium(0) (3,3 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (8.5 mg) and palladium(II) acetate (1.6 mg)and then heated under reflux in nitrogen atmosphere for 5 hours. The reaction mixture was cooled to room temperature, and added to her water and ethyl acetate. Insoluble substances were removed by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced davlenia.prochie the residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-65% hexane/ethyl acetate] to obtain 0.18 g of tert-butyl 2-(2-(benzyloxy)-5-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)benzamido)-4-phenylbenzoate.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)benzamido)-4-phenylbenzoate (0.18 g) in a mixture of methanol (1.5 ml) and ethyl acetate (1.5 ml) was added 10% palletirovanie coal (0,091 g)and then stirred in a hydrogen atmosphere at room tempearture for 3 hours. To the reaction mixture were added ethyl acetate. Insoluble substances were removed by filtration, and then the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0.12 g of tert-butyl 2-(5-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)-2-hydroxybenzamide)-4-phenylbenzoate in the form of a yellow solid.

To the obtained tert-butyl 2-(5-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)-2-hydroxybenzamide)-4-phenylbenzoate (0,070 g) was added dioxane (1.0 ml) and 6 mol/l hydrochloric acid (1.0 ml)and then heated under reflux for 25 minutes. The reaction mixture was cooled to room temperature, added to her water and ethyl acetate, and then adjust the pH to 5.2 by the addition of saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with the saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: chloroform] to obtain 0,026 g 2-(2-hydroxy-5-(4-oxopiperidin-1-yl)benzamido)-4-vinylbenzoic acid as a yellow solid.

1H-NMR (DMSO-d6) δ: 2,46 (4H, t, J=6.0 Hz), 3,49 (4H, t, J=6.0 Hz), of 6.96 (1H, d, J=8,8 Hz), 7,27 (1H, DD, J=8,8, 3.1 Hz), 7,43-EUR 7.57 (5H, m), 7,70-7,76 (2H, m), 8,10 (1H, d, J=8,3 Hz), of 9.02 (1H, d, J=1.7 Hz), 10,97 (1H, ), of 12.33 (1H, s).

Example 106a

To a solution of tert-butyl 2-(5-acetoxy-2-(benzyloxy)benzamido)-4-phenylbenzoate (0,58 g) in a mixture of methanol (3.0 ml) and dioxane (2.0 ml) was added a 2.0 mol/l aqueous solution of sodium hydroxide (1.6 ml)and then stirred at room temperature for 30 minutes. The solvent is evaporated under reduced pressure, was added to the residue water and chloroform, and then adjust the pH to 4.0 by adding a 2.0 mol/l hydrochloric acid. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain 0.52 g of tert-butyl 2-(2-(benzyloxy)-5-hydroxybenzamide)-4-phenylbenzoate in the form of a white solid.

1H-NMR (CDCl3) δ: of 1.52 (9H, s)5,41 (2H, s)6,40 (1H, s), 6,806,93 (2H, m), 7,21-to 7.50 (9H, m), 7,72-7,79 (2H, m), 7,88 (1H, d, J=2,9 Hz), 8,01-8,08 (1H, m), 9,13 (1H, d, J=1.7 Hz), 12,51 (1H, s).

Example 107a

To a solution of methyl 2-(5-acetoxy-2-(benzyloxy)benzamido)-4-phenylbenzoate (3.8 g) in a mixture of chloroform (5.0 ml), methanol (10 ml) and acetone (10 ml) was added potassium carbonate (1.6 g)and then stirred at room temperature for 1 hour. Insoluble substances were removed by filtration, then the solvent evaporated under reduced pressure, and was added to the residue 1.0 mol/l hydrochloric acid and chloroform. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain 3.4 g of methyl 2-(2-(benzyloxy)-5-hydroxybenzamide)-4-phenylbenzoate in the form of a white solid.

1H-NMR (CDCl3) δ: 3,76 (3H, s), are 5.36 (2H, s), 6,55 (1H, s), 6,85-to 6.95 (2H, m), 7,22-7,51 (9H, m), 7,70-7,81 (3H, m), 8,07 (1H, d, J=8,3 Hz), 9,16 (1H, d, J=1.7 Hz), 12,30 (1H, s).

Example 108a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-hydroxybenzamide)-4-phenylbenzoate (0.15 g) in tetrahydrofuran (3.0 ml) was added 4-hydroxy-1-methylpiperidin (0.17 g), triphenylphosphine (0.39 g) and diisopropylethylamine (0,30 ml)and then stirred at room temperature for 3 hours and 20 minutes. The solvent is evaporated conditions of reduced pressure, and purify the resulting residue by the method of column chromatography on silica gel [eluent: 60-50% hexane/ethyl acetate → 100-90% chloroform/methanol] to obtain tert-butyl 2-(2-(benzyloxy)-5-((1-methylpiperidin-4-yl)oxy)benzamido)-4-phenylbenzoate.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-((1-methylpiperidin-4-yl)oxy)benzamido)-4-phenylbenzoate in methanol (5.0 ml) was added 10% palletirovanie coal (0.11 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours and 40 minutes. Insoluble substances were removed by filtration, and purified the resulting residue by the method of column chromatography on silica gel [eluent: 100-90% chloroform/methanol] to obtain of 0.13 g of tert-butyl 2-(2-hydroxy-5-((1-methylpiperidin-4-yl)oxy)benzamido)-4-phenylbenzoate in the form of a light yellow solid.

A solution of the obtained tert-butyl 2-(2-hydroxy-5-((1-methylpiperidin-4-yl)oxy)benzamido)-4-phenylbenzoate (0,13 g) in triperoxonane acid (2.0 ml) was stirred at room temperature for 2 hours and 20 minutes. The solvent is evaporated under reduced pressure, was added to the residue to 4.0 mol/l solution of florodora in dioxane (2.0 ml)and then stirred at room temperature for 40 minutes. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. Solid is e substance was collected by filtration to obtain 0.12 g of the hydrochloride of 2-(2-hydroxy-5-((1-methylpiperidin-4-yl)oxy)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 1,77-of 1.93 (1H, m), 2.00 in a 2.12 (2H, m), 2,17-of 2.28 (1H, m), 2,72-of 2.86 (3H, m), 3,01-of 3.54 (4H, m), 4,39-and 4.68 (1H, m), of 6.99 (1H, DD, J=8,9, and 5.5 Hz), 7,10-7,22 (1H, m), 7,42-of 7.60 (5H, m), 7.68 per for 7.78 (2H, m), 8,10 (1H, d, J=8,3 Hz), 9,03 (1H, d, J=2.0 Hz), of 10.25-10,45 (1H, broadened), 11,10 (1H, s), 12,25-12,40 (1H, m), 13,35-13,65 (1H, broadened).

Example 109a

The following compound was obtained as described in Example 108a.

2-(5-(2-(dimethylamino)ethoxy)-2-hydroxybenzamide)-4-vinylbenzoic acid hydrochloride

1H-NMR (DMSO-d6) δ: 2,86 (6H, s), 3.46 in-3,54 (2H, m), 4,34 (2H, t, J=5.0 Hz), 7,02 (1H, d, J=9.0 Hz), to 7.15 (1H, DD, J=9,0, 3.2 Hz), 7,42-to 7.59 (5H, m), to 7.67 for 7.78 (2H, m), of 8.09 (1H, d, J=8,3 Hz), 9,04 (1H, d, J=1.7 Hz), 10,10-10,35 (1H, broadened), 11,10 (1H, s), of 12.33 (1H, s), 13,25-13,60 (1H, broadened).

Example 110a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-jogesuido)-4-phenylbenzoate (0,070 g) in toluene (1 ml) was added 1-(tert-butoxycarbonyl)-4-hydroxypiperidine (0,047 g), cesium carbonate (0.075 g), 1,10-phenanthroline (4.2 mg) and copper iodide(I) (2.2 mg)and then heated under reflux in nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature, then the reaction mixture was added 1-(tert-butoxycarbonyl)-4-hydroxypiperidine (0,047 g), cesium carbonate (0.075 g), 1,10-phenanthroline (4.2 mg) and copper iodide(I) (2.2 mg)and then heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture of ohlord is whether to room temperature, then to the reaction mixture was added 1,10-phenanthroline (4.2 mg) and copper iodide(I) (2.2 mg)and then heated under reflux in nitrogen atmosphere for 5 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then was added a 10% aqueous citric acid solution and ethyl acetate. Insoluble substances were removed by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-60% hexane/ethyl acetate] to obtain 0,074 g of tert-butyl 4-(2-(2-(benzyloxy)-5-((1-(tert-butoxycarbonyl)piperidine-4-yl)oxy)benzamido)-4-phenylbenzoate)piperidine-1-carboxylate.

To a solution of the obtained tert-butyl 4-(2-(2-(benzyloxy)-5-((1-(tert-butoxycarbonyl)piperidine-4-yl)oxy)benzamido)-4-phenylbenzoate)piperidine-1-carboxylate (0,072 g) in a mixture of methanol (1 ml) and dioxane (1 ml) was added 2 mol/l aqueous solution of sodium hydroxide (0,13 ml)and then stirred at room temperature for 1 hour. To the reaction mixture was added 2 mol/l aqueous solution of sodium hydroxide (0,089 ml)and then heated under reflux for 20 minutes. After cooling, R is the promo of the mixture to room temperature, the solvent evaporated under reduced pressure, and was added to the obtained residue, water. After adjusting the pH to 3.5 by adding 10% aqueous citric acid solution was added ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To a solution of the obtained residue was added 10% palletirovanie coal (0,039 g) in methanol (1.5 ml) and ethyl acetate (1.5 ml)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture was added ethyl acetate, and removing insoluble substances by filtration. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid substance was collected by filtration to obtain 0,024 g of 2-(5-((1-(tert-butoxycarbonyl)piperidine-4-yl)oxy)-2-hydroxybenzamide)-4-vinylbenzoic acid as a pale yellow solid.

To the obtained 2-(5-((1-(tert-butoxycarbonyl)piperidine-4-yl)oxy)-2-hydroxybenzamide)-4-vinylbenzoic acid (0,024 g) was added triperoxonane acid (2 ml)and then stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, was added to the residue ethyl acetate (0.7 ml) and 4 mol/l solution of florodora in dioxane (0.3 ml), and the eating was stirred at room temperature for 5 hours. The solid substance was collected from the reaction mixture by filtration to obtain 0,017 g of the hydrochloride of 2-(2-hydroxy-5-(piperidine-4-yloxy)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 1,78-1,89 (2H, m), 2,03 with 2.14 (2H, m), 3,02-3,14 (2H, m), 3,19-of 3.32 (2H, m), 4,51-4,60 (1H, m), 6,98 (1H, d, J=8,9 Hz), 7,14 (1H, DD, J=8,9, and 3.2 Hz), 7,43-7,49 (1H, m), 7,49-7,58 (4H, m), 7,70 to 7.75 (2H, m), of 8.09 (1H, d, J=8,3 Hz), 8,60-8,80 (2H, m), of 9.02 (1H, d, J=1.7 Hz), 11,09 (1H, s), 12,30-12,40 (1H, broadened), 13,35-13,60 (1H, broadened).

Example 111a

When cooled on ice to a suspension of the hydrochloride of 2-(2-hydroxy-5-(piperidine-4-yloxy)benzamido)-4-vinylbenzoic acid (0,030 g) in methylene chloride (1 ml) was sequentially added pyridine (0,30 ml) and acetic anhydride (6,7 μl)and then stirred at room temperature for 1 hour. To the reaction mixture was sequentially added pyridine (0,20 ml) and acetic anhydride (5,4 μl)and then stirred at room temperature for 1 hour and 30 minutes. The solvent is evaporated under reduced pressure, was added to the residue, methanol (0.5 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,19 ml)and then stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/l hydrochloric acid (5 ml) and ethyl acetate. The organic layer was separated, then washed by adding 1 mol/l solenoidality, water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added dioxane (0.5 ml), methanol (0.5 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,32 ml)and then stirred at 70°C for 30 minutes. After cooling the reaction mixture to room temperature, the solvent evaporated under reduced pressure, and was added to the obtained residue, water. After adjusting the pH to 3 by addition of 6 mol/l hydrochloric acid, the solid was collected by filtration to obtain 0,022 g of 2-(5-(1-acetylpiperidine-4-yloxy)-2-hydroxybenzamide)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 1,44-to 1.67 (2H, m), 1,83 e 2.06 (2H, m), 2,02 (3H, s), 3,19 is 3.40 (2H, m), 3,63-to 3.73 (1H, m), 3,79-to 3.89 (1H, m), 4,46-4,55 (1H, m), to 6.95 (1H, d, J=8,8 Hz), 7,13 (1H, DD, J=8,8, 2,9 Hz), 7,43-7,58 (5H, m), 7,70-7,76 (2H, m), 8,10 (1H, d, J=8.1 Hz), 9,01 (1H, d, J=1.2 Hz), 11,07 (1H, s), 12,34 (1H, s), 13,40-13,57 (1H, broadened).

Example 112a

When cooled on ice to a suspension of the hydrochloride of 2-(2-hydroxy-5-(piperidine-4-yloxy)benzamido)-4-vinylbenzoic acid (0,030 g) in methylene chloride (1 ml) was sequentially added pyridine (0.5 ml) and methanesulfonamide (9,9 μl)and then stirred at room temperature for 5 hours and 30 minutes. The solvent in perivale under reduced pressure, was added to the residue, methanol (0.5 ml) and 2 mol/l aqueous sodium hydroxide solution (0.5 ml)and then stirred at 70°C for 45 minutes. The reaction mixture was cooled to room temperature, and then was added a 1 mol/l hydrochloric acid (5 ml). The solid is collected by filtration, and purified the resulting solid substance according to the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: chloroform] to obtain 8.0 mg of 2-(2-hydroxy-5-(1-(methylsulphonyl)piperidine-4-yloxy)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6), (40°C) δ: 1,67-to 1.82 (2H, m), 1,94 e 2.06 (2H, m), 2,90 (3H, s), 3,06-3,20 (2H, m), 3,32-3,44 (2H, m), 4,40-4,50 (1H, m), to 6.95 (1H, d, J=9.0 Hz), 7,13 (1H, DD, J=9,0, 3.1 Hz), 7,42-7,56 (5H, m), 7,69 to 7.75 (2H, m), 8,10 (1H, d, J=8.1 Hz), 8,98 (1H, d, J=1.7 Hz).

Example 113a

When cooled on ice to a suspension diacetate 4-(2-(methoxycarbonyl)-5-phenylenecarbonyl)-1,3-phenylene (0.31 g) in methanol (3.1 ml) was added a 28% solution of sodium methoxide in methanol (0.34 g)and then stirred at room temperature for 1 hour. The reaction mixture while cooling on ice was added to 0.5 mol/l hydrochloric acid (20 ml)and then added ethyl acetate. The organic layer was separated, sequentially washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate,and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether to obtain 0.24 g of methyl 2-(2,4-dihydroxybenzamide)-4-phenylbenzoate in the form of a white solid.

1H-NMR (CDCl3) δ: 4,01 (3H, s), of 5.26 (1H, s), of 6.45 (1H, d, J=2.4 Hz), of 6.49 (1H, DD, J=8,8, 2.4 Hz), 7,35-7,53 (4H, m), to 7.67-7,74 (2H, m), of 7.75 (1H, d, J=8,8 Hz), 8,15 (1H, d, J=8,3 Hz), which is 9.09 (1H, d, J=1.7 Hz), 12,14 (1H with), 12,54 (1H, s).

Example 114a

To a suspension of methyl 2-(2,4-dihydroxybenzamide)-4-phenylbenzoate (0.24 g) in tetrahydrofuran (3.6 ml) was added 1-(tert-butoxycarbonyl)-4-hydroxypiperidine (0.15 g), triphenylphosphine (0.21 g) and diisopropylethylamine (0.16 ml)and then stirred at room temperature for 1 hour. To the reaction mixture were added 1-(tert-butoxycarbonyl)-4-hydroxypiperidine (of 0.066 g), triphenylphosphine (0,086 g) and diisopropylethylamine (0,064 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure and purify the resulting residue by the method of column chromatography on silica gel [eluent: 100-75% hexane/ethyl acetate] to obtain 0,050 g of tert-butyl 4-(3-hydroxy-4-(2-(methoxycarbonyl)-5-phenylenecarbonyl)phenoxy)piperidine-1-carboxylate as a white solid.

To the obtained tert-butyl 4-(3-hydroxy-4-(2-(methoxycarbonyl)-5-phenylenecarbonyl)phenoxy)piperidine-1-carboxylate (0.025 g) was added e is ylacetic (1 ml) and 4 mol/l solution of florodora in dioxane (0,50 ml), and then was stirred at room temperature for 3 hours. The solid substance was collected from the reaction mixture by filtration to obtain 0,018 g of methyl 2-(2-hydroxy-4-(piperidine-4-yloxy)benzamido)-4-phenylbenzoate hydrochloride as a white solid.

When cooled on ice to a suspension of the obtained methyl 2-(2-hydroxy-4-(piperidine-4-yloxy)benzamido)-4-phenylbenzoate hydrochloride (0,017 g) in methylene chloride (1 ml) was sequentially added pyridine (0,010 ml) and acetic anhydride (4,0 ml)and then stirred at room temperature for 1 hour. To the reaction mixture was sequentially added pyridine (0,49 ml) and acetic anhydride (4,0 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, sequentially washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure to obtain 0,016 g of methyl 2-(4-((1-acetylpiperidine-4-yl)oxy)-2-hydroxybenzamide)-4-phenylbenzoate in the form of a white solid.

To a solution of the obtained methyl 2-(4-((1-acetylpiperidine-4-yl)oxy)-2-hydroxybenzamide)-4-phenylbenzoate (,016 g) in a mixture of methanol (0.5 ml) and dioxane (0.5 ml) was added 2 mol/l aqueous solution of sodium hydroxide (0,082 ml), and then was stirred at 60°C for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, then the reaction mixture was added methanol (1 ml), dioxane (1 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,082 ml)and then stirred at 60°C for 3 hours. The reaction mixture was cooled to room temperature, and then the solvent evaporated under reduced pressure. To the obtained residue was added water, and then adjusting the pH to 3 by addition of 6 mol/l hydrochloric acid. The solid substance was collected from the reaction mixture by filtration with the receipt of 0.014 g of 2-(4-((1-acetylpiperidine-4-yl)oxy)-2-hydroxybenzamide)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 1,46 is 1.70 (2H, m), 1,87-2,07 (2H, m), 2,02 (3H, s), 3,18-3,44 (2H, m), 3,63-3,74 (1H, m), 3,81-3,91 (1H, m), with 4.64-4,74 (1H, m), to 6.57 (1H, d, J=2.4 Hz), of 6.66 (1H, DD, J=8,8, 2.4 Hz), 7,43-EUR 7.57 (4H, m), 7,70 to 7.75 (2H, m), to 7.84 (1H, d, J=8,8 Hz), 8,10 (1H, d, J=8,3 Hz), 8,96 (1H, d, J=1.7 Hz), 11,81 (1H, s), 12,24 (1H, s).

Example 115a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-jogesuido)-4-phenylbenzoate (0.10 g) in 1-methyl-2-pyrrolidone (of 0.60 ml) was added phenol (0,029 ml), cesium carbonate (0.11 g), 2,2,6,6-tetramethylheptane-3,5-dione (3,4 μl) and copper chloride(I) (8.2 mg)and then stirred in nitrogen atmosphere at 100°C for 2 hours. The reaction mixture was cooled to room temperature, then to allali it 2,2,6,6-tetramethylheptane-3,5-dione (3,4 μl) and copper chloride(I) (8.2 mg), and then was stirred in nitrogen atmosphere at 100°C for 2 hours. The reaction mixture was cooled to room temperature, and then was added a 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-95% hexane/ethyl acetate] to obtain 0,049 g of tert-butyl 2-(2-(benzyloxy)-5-phenoxybenzamide)-4-phenylbenzoate (0,049 g).

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-phenoxybenzamide)-4-phenylbenzoate (0,049 g) in a mixture of methanol (1.5 ml) and ethyl acetate (1.5 ml) was added 10% palletirovanie coal (0.025 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture was added 10% palletirovanie coal (0,050 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture was added ethyl acetate, and removing insoluble substances by filtration. The solvent is evaporated under reduced pressure, and was added to the obtained residue, hexane. The solid substance was collected by filtration to obtain 0,017 g of tert-butyl 2-(2-hydroxy-5-phenoxybenzamide)-4-phenylbenzoate in the de white solid.

To the obtained tert-butyl 2-(2-hydroxy-5-phenoxybenzamide)-4-phenylbenzoate (0,017 g) was added triperoxonane acid (2.0 ml)and then stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid substance was collected by filtration to obtain 0,012 g 2-(2-hydroxy-5-phenoxybenzamide)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 6,95-7,01 (2H, m), 7,07 (1H, d, J=8,8 Hz), 7,07-7,14 (1H, m), 7,21 (1H, DD, J=8,8, 2,9 Hz), 7,34-7,41 (2H, m), 7,41-of 7.48 (1H, m), of 7.48-EUR 7.57 (4H, m), 7.68 per to 7.75 (2H, m), 8,08 (1H, d, J=8.0 Hz), 8,98 (1H, d, J=1.7 Hz), 11,37 (1H, s), of 12.26-to 12.44 (1H, broadened), 13,30-13,55 (1H, broadened).

Example 116a

To a solution of tert-butyl 2-(5-(2-acetoxyethyl)-2-(benzyloxy)benzamido)-4-phenylbenzoate (0,38 g) in a mixture of methanol (1.9 ml) and dioxane (1.9 ml) was added a 2.0 mol/l aqueous solution of sodium hydroxide (0,37 ml)and then stirred at room temperature for 2 hours. To the reaction mixture was added acetic acid (0,012 ml). The solvent is evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is perivale under reduced pressure to obtain 0.35 g of tert-butyl 2-(2-(benzyloxy)-5-(2-hydroxyethyl)benzamido)-4-phenylbenzoate in the form of a white solid.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(2-hydroxyethyl)benzamido)-4-phenylbenzoate (0.17 g) in methylene chloride (3.4 ml) was added triphenylphosphine (0,13 g) and tetrabromide carbon (0.16 g)and then stirred at room temperature for 50 minutes. The reaction mixture was purified according to the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: chloroform], and then purified according to the method of column chromatography [eluent: 100-85% hexane/ethyl acetate], to obtain 0.16 g of tert-butyl 2-(2-(benzyloxy)-5-(2-bromacil)benzamido)-4-phenylbenzoate in the form of a white solid.

1H-NMR (DMSO-d6) δ: 1.50 in (9H, s), of 3.12 (2H, t, J=7,0 Hz), and 3.72 (2H, t, J=7.0 Hz), 5,49 (2H, s), 7,18 (1H, d, J=8.6 Hz), 7.24 to 7,37 (3H, m), 7,42 (1H, DD, J=8,6, 2.4 Hz), 7,43-of 7.60 (6H, m), 7.68 per-to 7.77 (2H, m), 7,87 (1H, d, J=2.4 Hz), with 8.05 (1H, d, J=8.5 Hz), 9,06-9,14 (1H, m), 12,17 (1H, s).

Example 117a

When cooled on ice to a solution of tert-butyl 2-(2-(benzyloxy)-5-(2-bromacil)benzamido)-4-phenylbenzoate (0.10 g) in acetone (1.5 ml) was added 1-methylpiperazine (0,095 ml)and then stirred at room temperature for 30 minutes. Was added potassium carbonate (0.035 g)and then stirred at room temperature for 1 hour. To the reaction mixture were added 1-methylpiperazine (0,095 ml) and potassium carbonate (0.035 g)and then stirred at room temperature for 1 hour. Reactio the ing the mixture was left to settle overnight. The solvent is evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-90% chloroform/methanol] to obtain 0.10 g of tert-butyl 2-(2-(benzyloxy)-5-(2-(4-methylpiperazin-1-yl)ethyl)benzamido)-4-phenylbenzoate.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(2-(4-methylpiperazin-1-yl)ethyl)benzamido)-4-phenylbenzoate (0.10 g) in a mixture of methanol (1.5 ml) and ethyl acetate (1.5 ml) was added 10% palletirovanie charcoal (0.10 g)and then stirred in a hydrogen atmosphere at room temperature for 1 hour. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0,056 g of tert-butyl 2-(2-hydroxy-5-(2-(4-methylpiperazin-1-yl)ethyl)benzamido)-4-phenylbenzoate in the form of a light yellow solid.

To the obtained tert-butyl 2-(2-hydroxy-5-(2-(4-methylpiperazin-1-yl)ethyl)benzamido)-4-fenib is soatu (0,056 g) was added triperoxonane acid (5.0 ml), and then was stirred at room temperature for 19 hours. The solvent is evaporated under reduced pressure, to the residue was sequentially added ethyl acetate (3.0 ml) and methanesulfonyl acid (0,018 ml)and then stirred at room temperature for 1 hour. The solid substance was collected from the reaction mixture by filtration to obtain 0,059 g dimethanesulfonate 2-(2-hydroxy-5-(2-(4-methylpiperazin-1-yl)ethyl)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (CD3OD) δ: 2,74 (6H, s), 3.04 from (3H, s), 3,09-3,17 (2H, m), 3,40-3,95 (10H, m), 7,00 (1H, d, J=8.5 Hz), 7,39-7,53 (5H, m), 7,69-7,76 (2H, m), 7,83 (1H, d, J=2.0 Hz), by 8.22 (1H, d, J=8,3 Hz), 9,06 (1H, d, J=1.9 Hz).

Example 118a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-(2-bromacil)benzamido)-4-phenylbenzoate (to 0.060 g) in acetone (1.2 ml) was added 1-ethylpiperazin (0,065 ml) and potassium carbonate (0,042 g)and then stirred at room temperature for 6 hours. To the reaction mixture were added 1-ethylpiperazin (0,065 ml)and then stirred at room temperature for 9 hours. The solvent is evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and chloroform. The organic layer was separated and dried over anhydrous sodium sulfate, and then evaporated the solvent under reduced pressure the Oia. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-90% chloroform/methanol] to obtain 0,062 g of tert-butyl 2-(2-(benzyloxy)-5-(2-(4-ethylpiperazin-1-yl)ethyl)benzamido)-4-phenylbenzoate.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(2-(4-ethylpiperazin-1-yl)ethyl)benzamido)-4-phenylbenzoate (0,062 g) in a mixture of methanol (1.5 ml) and ethyl acetate (1.5 ml) was added 10% palletirovanie coal (0,062 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure to obtain 0,047 g of tert-butyl 2-(5-(2-(4-ethylpiperazin-1-yl)ethyl)-2-hydroxybenzamide)-4-phenylbenzoate.

To the obtained tert-butyl 2-(5-(2-(4-ethylpiperazin-1-yl)ethyl)-2-hydroxybenzamide)-4-phenylbenzoate (0,047 g) was added triperoxonane acid (5.0 ml)and then stirred at room temperature for 4 hours. The solvent is evaporated under reduced pressure, and consistently added to the residue ethyl acetate (3.0 ml) and methanesulfonyl acid (0,013 ml)and then stirred at room temperature for 5 hours and 30 minutes. The solid substance was collected from the reaction mixture by filtration to obtain 0,048 g dimethanesulfonate 2-(5-(2-(4-ethylpiperazin-1-yl)ethyl)-2-hydroxybenzamide)-4-phenylbenzo Inoi acid as a white solid.

1H-NMR (DMSO-d6) δ: of 1.23 (3H, t, J=7.2 Hz), was 2.34 (6H, s), 2.40 a-3,90 (14H, m), 7,00 (1H, d, J=8,3 Hz), 7,32-7,38 (1H, m), 7,43-7,58 (4H, m), 7,69 to 7.75 (2H, m), 7,83-to $ 7.91 (1H, m), 8,10 (1H, d, J=8,3 Hz), 9,05 (1H, d, J=1,2 Hz), to 11.31 (1H, s), 12,30 (1H, s).

Example 119a

The following compound was obtained as described in Example 118a.

2-(2-Hydroxy-5-(2-(piperazine-1-yl)ethyl)benzamido)-4-vinylbenzoic acid dimethanesulfonate

1H-NMR (DMSO-d6) δ: 2,35 (6H, s), 2,80-3,70 (12H, m), 7,00 (1H, d, J=8,3 Hz), was 7.36 (1H, DD, J=8,4, and 2.3 Hz), 7,43-7,58 (4H, m), 7,69 to 7.75 (2H, m), 7,84-of 7.90 (1H, m), 8,10 (1H, d, J=8,3 Hz), 8,75-9,10 (1H, broadened), 9,05 (1H, d, J=1.7 Hz), to 11.31 (1H, s), 12,30 (1H, s).

Example 120a

To a suspension of 2-acetoxy-5-methylbenzoic acid (0,48 g) in methylene chloride (6.0 ml) was sequentially added N,N-dimethylformamide is 0.019 ml) and oxacillin (0,32 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue toluene. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (6.0 ml). The resulting mixture was added while cooled on ice to a solution of tert-butyl 2-amino-4-phenylbenzoate (0,60 g) in a mixture of pyridine (0.45 ml) and methylene chloride (6.0 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, EXT is ulali to the residue methanol (5.0 ml) and potassium carbonate (1.54 g), and then was stirred at room temperature for 2 hours and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue water and chloroform. The organic layer was separated, sequentially washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0,80 g of tert-butyl 2-(2-hydroxy-5-methylbenzamide)-4-phenylbenzoate in the form of a white solid.

1H-NMR (DMSO-d6) δ: of 1.56 (9H, s), of 2.28 (3H, s), 6,93 (1H, d, J=8,3 Hz), 7,26 (1H, DD, J=8,3, 2.2 Hz), 7,42-7,49 (1H, m), 7,50-EUR 7.57 (3H, m), 7,69 for 7.78 (3H, m), to 7.99 (1H, d, J=8,3 Hz), 8,81 (1H, d, J=1.7 Hz), 11,25 (1H, s), 11,81 (1H, s).

Example 121a

To a suspension of tert-butyl 2-(2-hydroxy-5-methylbenzamide)-4-phenylbenzoate (0,60 g) in acetone (9.0 ml) was sequentially added potassium carbonate (0.51 g) and methoxymethane (0,23 ml)and then stirred at room temperature for 1 hour and 30 minutes. To the reaction mixture was sequentially added potassium carbonate (0.21 g) and methoxymethane (0,11 ml)and then stirred at room temperature for 2 hours. To the reaction mixture was sequentially added potassium carbonate (0.51 g) and ethoxymethylene (0,23 ml), and then was stirred at room temperature for 2 hours and then heated to a temperature of sublimation for 20 minutes. The reaction mixture was cooled to room temperature and then added to her water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-80% hexane/ethyl acetate] to obtain 0.64 g of tert-butyl 2-(2-(methoxyethoxy)-5-methylbenzamide)-4-phenylbenzoate.

To a solution of the obtained tert-butyl 2-(2-(methoxyethoxy)-5-methylbenzamide)-4-phenylbenzoate (0,63 g) in benzene (6.3 ml) was sequentially added N-bromosuccinimide (0.25 g) and azobisisobutyronitrile (0,023 g)and then heated under reflux for 30 minutes. The reaction mixture was cooled to room temperature, and then was added a saturated aqueous solution of sodium bicarbonate and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-9% hexane/ethyl acetate] to obtain 0.51 g of tert-butyl 2-(5-(methyl bromide)-2-(methoxyethoxy)benzamido)-4-phenylbenzoate in the form of a white solid.

1H-NMR (DMSO-d6) δ: 1,60 (9H, s), 3,49 (3H, s), 4,78 (2H, s)5,52 (2H, s), 7,35 (1H, d, J=8.7 Hz), 7,42-7,58 (4H, m), the 7.65 (1H, DD, J=8,7, 2.4 Hz), 7,70-7,76 (2H, m), 8,07 (1H, d, J=8,3 Hz), 8,13 (1H, d, J=2.4 Hz), 9,13 (1H, d, J=1.5 Hz), 12,17 (1H, s).

Example 122a

When cooled on ice to a suspension of tert-butyl 2-(5-(methyl bromide)-2-(methoxyethoxy)benzamido)-4-phenylbenzoate (0.15 g) in acetone (2.3 ml) was added 1-methylpiperazine (0.16 ml)and then stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, and was added to the residue 1.0 mol/l aqueous sodium hydroxide solution and chloroform. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-95% chloroform/methanol] to obtain 0.14 g of tert-butyl 2-(2-(methoxyethoxy)-5-((4-methylpiperazin-1-yl)methyl)benzamido)-4-phenylbenzoate in the form of a yellow oily substance.

When cooled on ice to a solution of the obtained tert-butyl 2-(2-(methoxyethoxy)-5-((4-methylpiperazin-1-yl)methyl)benzamido)-4-phenylbenzoate (0.14 g) in methylene chloride (3.0 ml) was added triperoxonane acid (1.5 ml)and then stirred at room the Oh temperature for 4 hours and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid is collected by filtration, was added to the obtained solid substance in ethyl acetate (5.0 ml) and methanesulfonyl acid (0.036 ml)and then stirred at room temperature for 4 hours. The solid substance was collected from the reaction mixture by filtration to obtain 0.11 g dimethanesulfonate 2-(2-hydroxy-5-((4-methylpiperazin-1-yl)methyl)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (CD3OD) δ: 2,73 (6H, s), a 3.01 (3H, s), 3,20-3,90 (8H, extended), to 4.38 (2H, s), 7,10 (1H, d, J=8.6 Hz), 7,40-7,46 (1H, m), 7,46-rate of 7.54 (3H, m), a 7.62 (1H, DD, J=8,6, and 2.1 Hz), 7,69 to 7.75 (2H, m), of 8.06 (1H, d, J=2.1 Hz), by 8.22 (1H, d, J=8,3 Hz), 9,05 (1H, d, J=1.7 Hz).

Examples 123a and 124a

Compounds shown in Table 15a, obtained as described in Example 122a.

Table 15a
Example No.R7Example No.R7
123a124a

2-(5-((4-Atile the Razin-1-yl)methyl)-2-hydroxybenzamide)-4-vinylbenzoic acid dimethanesulfonate

1H-NMR (D2O) δ: is 1.31 (3H, t, J=7,2 Hz), and 2.79 (6H, s), 3,20-3,70 (10H, m), 4,10 (2H, s), PC 6.82 (1H, d, J=7.8 Hz), 6,98-to 7.15 (1H, m), 7.18 in-of 7.48 (7H, m), 7,58-7,72 (1H, m), scored 8.38 (1H, s).

2-(2-Hydroxy-5-((4-isopropylpiperazine-1-yl)methyl)benzamido)-4-vinylbenzoic acid dimethanesulfonate

1H-NMR (DMSO-d6) δ: 1,24 (6H, d, J=6,1 Hz), of 2.33 (6H, s), 3.00 and-3,70 (11H, m), was 7.08 (1H, d, J=8,8 Hz), 7,43-7,58 (5H, m), 7.68 per-7,76 (2H, m), 8,00-to 8.14 (1H, m), 8,10 (1H, d, J=8.6 Hz), 9,06 (1H, d, J=1.7 Hz), to 11.52-of 11.75 (1H, broadened), of 12.33 (1H, s).

Example 125a

The following compound was obtained as described in Example 122a.

2-(5-((4-Aminopiperidin-1-yl)methyl)-2-hydroxybenzamide)-4-vinylbenzoic acid dimethanesulfonate

1H-NMR (CD3OD) δ: 1,88-2,04 (2H, m), 2,23-of 2.34 (2H, m), 2,71 (6H, s), 3,12-of 3.27 (2H, m), 3,40-of 3.54 (1H, m), to 3.58-3,70 (2H, m), 4,37 (2H, s), 7,11 (1H, d, J=8.6 Hz), 7,40-7,46 (1H, m), 7,47-rate of 7.54 (3H, m), to 7.61 (1H, DD, J=to 8.6 and 2.1 Hz), 7,70 to 7.75 (2H, m), with 8.05 (1H, d, J=2.1 Hz), by 8.22 (1H, d, J=8,3 Hz), 9,06 (1H, d, J=1.7 Hz).

Example 126a

The following compound was obtained as described in Example 122a.

2-(2-Hydroxy-5-((4-(methylamino)piperidine-1-yl)methyl)benzamido)-4-vinylbenzoic acid dimethanesulfonate

1H-NMR (DMSO-d6) δ: 1,64-of 1.80 (2H, m), 2,16-of 2.28 (2H, m), of 2.38 (6H, s), 2,55-2,60 (3H, m), 2,90-of 3.07 (2H, m), 3,13-of 3.31 (1H, m), 3,42 of 3.56 (2H, m), 4,24-4,34 (2H, m), 7,11 (1H, d, J=8.5 Hz), 7,42-of 7.60 (5H, m), 7.68 per-7,76 (2H, m), 8,06-to 8.14 (2H, m), 8,62-8,76 (1H, m), 9,06 (1H, d, J=1.7 Hz), 9,46-9,63 (1H, broadened), 11,76 (1H, s), of 12.33 (1H, s).

Example 127a

When cooled on ice to a suspension of 1-propylpiperazine dihydrochloride (0,13 g) in acetone (1.8 ml) was sequentially added potassium carbonate (0,19 g) and tert-butyl 2-(5-(methyl bromide)-2-(methoxyethoxy)benzamido)-4-phenylbenzoate (0.12 g)and then stirred at room temperature for 5 hours and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and chloroform. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0,088 g of tert-butyl 2-(2-(methoxyethoxy)-5-((4-propylpiperazine-1-yl)methyl)benzamido)-4-phenylbenzoate.

To the obtained tert-butyl 2-(2-(methoxyethoxy)-5-((4-propylpiperazine-1-yl)methyl)benzamido)-4-phenylbenzoate (0,088 g) was added triperoxonane acid (5.0 ml)and then stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, was added to the residue ethyl acetate (3.0 ml) and methanesulfonyl acid (0,022 ml)and then stirred at room temperature for 2 hours and 30 minutes. The solid substance was collected from the reaction mixture by filtrowanie is obtaining 0,067 g dimethanesulfonate 2-(2-hydroxy-5-((4-propylpiperazine-1-yl)methyl)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: from 0.90 (3H, t, J=7,3 Hz), 1,55 was 1.69 (2H, m), of 2.34 (6H, s), 2,90-3,70 (12H, m), was 7.08 (1H, d, J=8.0 Hz), 7,43-to 7.59 (5H, m), to 7.67-7,76 (2H, m), 7,99-of 8.15 (1H, m), 8,10 (1H, d, J=8,3 Hz), 9,06 (1H, d, J=2,0 Hz), 11,55-of 11.75 (1H, broadened), of 12.33 (1H, s).

Example 128a

The following compound was obtained as described in Example 127a.

2-(5-((4-(dimethylamino)piperidine-1-yl)methyl)-2-hydroxybenzamide)-4-vinylbenzoic acid dimethanesulfonate

1H-NMR (CD3OD) δ: 1,96-to 2.13 (2H, m), 2,33 at 2.45 (2H, m), of 2.72 (6H, s), of 2.92 (6H, s), 3,10-of 3.23 (2H, m), 3.46 in-to 3.64 (1H, m), 3,66-of 3.78 (2H, m), 4,39 (2H, s), 7,12 (1H, d, J=8.5 Hz), 7,40-7,46 (1H, m), 7,47-rate of 7.54 (3H, m), 7,63 (1H, DD, J=8,5, 1.9 Hz), 7,70-7,76 (2H, m), of 8.06 (1H, d, J=1.9 Hz), by 8.22 (1H, d, J=8.6 Hz), 9,06 (1H, d, J=1.7 Hz).

Example 129a

When cooled on ice to a suspension of tert-butyl 2-(5-(methyl bromide)-2-(methoxyethoxy)benzamido)-4-phenylbenzoate (0.10 g) in acetone (1.5 ml) was added piperidine (0,094 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical C., Inc., silica gel 60 (spherical), eluent: 100-95% chloroform/methanol] to obtain 0,080 g of tert-butyl 2-(2-(methoxyethoxy)-5-(piperidine-1-yl)methyl)benzamido)-4-phenylbenzoate.

When cooled on ice to a solution of the obtained tert-butyl 2-(2-(methoxyethoxy)-5-(piperidine-1-yl)methyl)benzamido)-4-phenylbenzoate (0,080 g) in methylene chloride (2.0 ml) was added triperoxonane acid (1.0 ml)and then stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the obtained residue, ethyl acetate. The solid is collected by filtration. To the obtained solid substance was added ethyl acetate (1.0 ml) and 4.0 mol/l solution of florodora in dioxane (0,20 ml)and then stirred at room temperature for 3 hours. The solid substance was collected from the reaction mixture by filtration to obtain 0,020 g of the hydrochloride of 2-(2-hydroxy-5-(piperidine-1-yl)methyl)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (CD3OD) δ: 1,43-to 1.60 (1H, m), 1,65-1,90 (3H, m), 1,90-of 2.05 (2H, m), 2,92-of 3.06 (2H, m), 3.45 points is 3.57 (2H, m), or 4.31 (2H, s), 7,10 (1H, d, J=8.5 Hz), 7,40-7,46 (1H, m), 7,47-rate of 7.54 (3H, m), 7,58 (1H, DD, J=8,5 and 2.2 Hz), 7,70-7,76 (2H, m), 8,02 (1H, d, J=2.2 Hz), 8,23 (1H, d, J=8,3 Hz), 9,06 (1H, d, J=1.7 Hz).

Example 130a

To tert-butyl 2-(5-(methyl bromide)-2-(methoxyethoxy)benzamido)-4-phenylbenzoate (0,030 g) was added N-dimethylformamide (1 ml), potassium carbonate (0,039 g) and 1-(tert-butoxycarbonyl)piperidine (0,053 g)and then stirred at 90-100°C for 15 minutes. The reaction mixture was cooled to room temperature and then added to her water and chloroform. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added triperoxonane acid (2 ml)and then stirred at room temperature for 20 minutes. The solvent is evaporated under reduced pressure, and was added to the residue water. After adjusting the pH to 6.7 by addition of a saturated aqueous solution of sodium bicarbonate, the solid substance was collected by filtration. To the obtained solid substance was added methanol and methansulfonate acid (0,010 g). The solid substance was collected by filtration to obtain 0.015 g dimethanesulfonate 2-(2-hydroxy-5-(piperazine-1-yl)methyl)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: of 2.34 (6H, s), 2,80-of 3.80 (10H, m), to 7.09 (1H, d, J=7.8 Hz), 7,43-7,58 (5H, m), 7,69 to 7.75 (2H, m), 8,04-to 8.14 (1H, m), 8,10 (1H, d, J=8,3 Hz), 8,65-of 8.95 (1H, broadened), 9,06 (1H, d, J=1.5 Hz), 11,60-RS 11.80 (1H, broadened), of 12.33 (1H, s).

Examples 131a-133a

Compounds shown in Table 16a, obtained as described in Example 130a.

Table 16a
Example No.R7Example No.R7Example No.R7
131a132a133a

2-(5-((Dimethylamino)methyl)-2-hydroxybenzamide)-4-vinylbenzoic acid methanesulfonate

1H-NMR (DMSO-d6) δ: 2,30 (3H, s), 2,73 (6H, s), 4.26 deaths (2H, s), 7,10 (1H, d, J=8.6 Hz), 7,44-7,58 (5H, m), 7,69 to 7.75 (2H, m), 8,08-8,13 (2H, m), 9,06 (1H, d, J=1.7 Hz), 9,42-9,58 (1H, broadened), 11,68-11,78 (1H, broadened), to 12.28-12,38 (1H, broadened).

2-(2-Hydroxy-5-(morpholine-4-yl)methyl)benzamido)-4-vinylbenzoic acid methanesulfonate

1H-NMR (DMSO-d6) δ: 2,32 (3H, s), 3.00 and-3,19 (2H, m), 3,20-of 3.46 (2H, m), 3,53-3,71 (2H, m), 3,88-of 4.05 (2H, m), 4,34 (2H, s), 7,11 (1H, d, J=8.5 Hz), 7,43-7,58 (5H, m), 7,69 to 7.75 (2H, m), 8,10 (1H, d, J=8,3 Hz)to 8.12 (1H, d, J=2.2 Hz), 9,06 (1H, d, J=1.7 Hz), 9,62-9,85 (1H, broadened), 11,74 (1H, s), of 12.33 (1H, s).

2-(2-Hydroxy-5-((4-methyl-1,4-diazepan-1-yl)methyl)benzamido)-4-vinylbenzoic acid dimethanesulfonate

1H-NMR (CD3OD) δ: 2,27-to 2.41 (2H, m), 2,73 (6H, s)of 3.00 (3H, s), 3,24-3,88 (8H, m), 4,48 (2H, s), 7,13 (1H, d, J=8.5 Hz), 7,39-7,56 (4H, m), and 7.6 (1H, DD, J=8,5, and 2.1 Hz), 7,69-to 7.77 (2H, m), 8,08 (1H, d, J=2.1 Hz), by 8.22 (1H, d, J=8,3 Hz), 9,05 (1H, d, J=1.7 Hz).

Examples 134a

When cooled on ice to a solution of N,N,N'-trimethylethylenediamine (0,089 ml) in acetone (1.8 ml) was added tert-butyl 2-(5-(methyl bromide)-2-(methoxyethoxy)benzamido)-4-phenylbenzoate (0.12 g)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and chloroform. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-90% chloroform/methanol] to obtain 0,070 g of tert-butyl 2-(5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-2-(methoxyethoxy)benzamido)-4-phenylbenzoate.

To the obtained tert-butyl 2-(5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-2-(methoxyethoxy)benzamido)-4-phenylbenzoate (0,070 g) was added triperoxonane acid (5.0 ml)and then stirred at room temperature for 8 hours. The solvent is evaporated under reduced pressure, and was added to the residue water and ethyl acetate. After adjusting the pH to 6.3 by the addition of saturated aqueous sodium bicarbonate solution the organic layer based on separate treatment and, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0,045 g of 2-(5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-2-hydroxybenzamide)-4-vinylbenzoic acid as a white solid.

1H-NMR (CD3OD) δ: 2,30 (3H, s), only 2.91 (2H, t, J=5,9 Hz), 2,98 (6H, s), 3,37 (2H, t, J=5,9 Hz), 3,66 (2H, s), make 6.90 (1H, d, J=8,3 Hz), 7,30 (1H, DD, J=8,3, 2.0 Hz), 7,35-the 7.43 (2H, m), 7,44-7,52 (2H, m), 7.68 per-7,74 (2H, m,), to 8.20 (1H, d, J=8.0 Hz), 8,32 (1H, d, J=2.0 Hz), of 9.00 (1H, d, J=1.9 Hz).

Example 135a

When cooled on ice to a solution of 4-acetoxy-2-(benzyloxy)benzoic acid (0.35 g) in a mixture of methylene chloride (5.0 ml) and N,N-dimethylformamide (0,020 ml) was added oxalicacid (0.15 ml)and then stirred at room temperature for 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (3.0 ml). The resulting mixture while cooling on ice, was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (0,30 g) in a mixture of pyridine (0,14 ml) and methylene chloride (2.5 ml)and then stirred at room temperature for 3 hours and 20 minutes. The solvent is evaporated under reduced pressure, and added to the remainder of nasy the n aqueous solution of sodium bicarbonate and ethyl acetate. The organic layer was separated, sequentially washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 91-80% hexane/ethyl acetate] to obtain 0.34 g of tert-butyl 2-(4-acetoxy-2-(benzyloxy)benzamido)-4-phenylbenzoate in the form of a white solid.

To a solution of the obtained tert-butyl 2-(4-acetoxy-2-(benzyloxy)benzamido)-4-phenylbenzoate (0.34 g) in dioxane (5.0 ml) was added 4 mol/l aqueous solution of sodium hydroxide (0,47 ml)and then stirred at 50-55°C for 2 hours. The reaction mixture was cooled to room temperature, and added a 10% aqueous citric acid solution (15 ml) and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0.29 grams of tert-butyl 2-(2-(benzyloxy)-4-hydroxybenzamide)-4-phenylbenzoate in the form of a white solid.

1H-NMR (DMSO-d6) δ: 1.50 in (9H, s)5,49 (2H, s), 6,46-6,55 (2H, m), 7,25-7,38 (3H, m), 7,42-7,58 (6H, m), 7.68 per to 7.75 (2H, m), 7,89 (1H, d, J8,6 Hz), 8,03 (1H, d, J=8,3 Hz), 9,11 (1H, d, J=1.4 Hz), of 10.25 (1H, s), 12,17 (1H, s).

Example 136a

To a solution of tert-butyl 2-(2-(benzyloxy)-4-hydroxybenzamide)-4-phenylbenzoate (0.29 grams) in N,N-dimethylformamide (5.0 ml) was added potassium carbonate (1.6 g) and 1,2-dibromethane (2,6 ml)and then stirred at 120°C for 1 hour and 45 minutes. The reaction mixture was cooled to room temperature, and added a 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-91% hexane/ethyl acetate] to obtain 0,19 g of tert-butyl 2-(2-(benzyloxy)-4-(2-bromoethoxy)benzamido)-4-phenylbenzoate in the form of a white solid.

1H-NMR (DMSO-d6) δ: 1.50 in (9H, s), with 3.79 (2H, t, J=5.4 Hz), 4,37 (2H, t, J=5.4 Hz), to 5.56 (2H, s)of 6.71 (1H, DD, J=8,8, 2.2 Hz), 6,74 (1H, d, J=2.2 Hz), 7.24 to 7,37 (3H, m), 7,43-7,58 (6H, m), 7.68 per to 7.75 (2H, m), 7,98 (1H, d, J=8,8 Hz), of 8.04 (1H, d, J=8,3 Hz), 9,10 (1H, d, J=1.4 Hz), 12,17 (1H, s).

Example 137a

The following compound was obtained as described in Example 136a.

tert-Butyl 2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate

1H-NMR (CDCl3) δ: of 1.52 (9H, s), 3,61 (2H, t, J=6.2 Hz), 4,30 (2H, t, J=6.2 Hz), 5,44 (2H, s), make 6.90 (1H, is, J=9.0 Hz), of 6.96 (1H, DD, J=9,0, 3.2 Hz), 7,26-to 7.50 (9H, m), 7,69-7,76 (3H, m), of 8.06 (1H, d, J=8,3 Hz), 9,26 (1H, d, J=1.7 Hz), 12,50 (1H, s).

Example 138a

The following compound was obtained as described in Example 136a.

Methyl-2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate

1H-NMR (CDCl3) δ: 3,62 (2H, t, J=6.2 Hz), of 3.77 (3H, s), or 4.31 (2H, t, J=6.2 Hz), of 5.40 (2H, s), to 6.95 (1H, d, J=9.0 Hz), 7,00 (1H, DD, J=9,0, 3.2 Hz), 7.23 percent-7,52 (9H, m), 7,69-to 7.77 (3H, m), 8,08 (1H, d, J=8,3 Hz), the 9.25 (1H, d, J=1.7 Hz), of 12.33 (1H, s).

Example 139a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-hydroxybenzamide)-4-phenylbenzoate (0,090 g) in N,N-dimethylacetamide (1.8 ml) was added potassium carbonate (0.075 g), potassium iodide (0,090 g) and N-(2-chloroethyl)the research hydrochloride (0,041 g)and then stirred at 100°C for 1 hour. The reaction mixture was cooled to room temperature and then added to her water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 80-25% hexane/ethyl acetate] to obtain 0,058 g of tert-butyl 2-(2-(benzyloxy)-5-(2-(morpholine-4-yl)ethoxy)benzamido)-4-phenylbenzoate in the form of a light yellow solid.

To a solution of the obtained tert-butyl 2-(2-(who ensilage)-5-(2-(morpholine-4-yl)ethoxy)benzamido)-4-phenylbenzoate (0,058 g) in a mixture of methanol (1.5 ml) and ethyl acetate (1.5 ml) was added 10% palletirovanie coal (0,058 g), and then was stirred in hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture was added 10% palletirovanie coal (0,029 g)and then stirred in a hydrogen atmosphere at room temperature for 1 hour. To the reaction mixture were added ethyl acetate. Then, insoluble matter was removed by filtration, and the solvent evaporated under reduced pressure. To the obtained residue was added triperoxonane acid (5.0 ml)and then stirred at room temperature for 4 hours. The solvent is evaporated under reduced pressure, was added to the residue ethyl acetate (2.5 ml) and 4.0 mol/l solution of florodora in dioxane (0,30 ml)and then stirred at room temperature for 2 hours. The solid substance was collected from the reaction mixture by filtration to obtain 0,033 g of the hydrochloride of 2-(2-hydroxy-5-(2-(morpholine-4-yl)ethoxy)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (CD3OD) δ: 3,15-of 3.75 (4H, extended), to 3.67 (2H, t, J=4.9 Hz), 3.75 to-4,20 (4H, extended), 4,43 (2H, t, J=4.9 Hz), 6,97 (1H, d, J=9.0 Hz), 7,21 (1H, DD, J=9,0, 3.1 Hz), 7,39-7,46 (1H, m), 7,46-of 7.55 (4H, m), 7,70-7,76 (2H, m), 8,21 (1H, d, J=8,3 Hz), 9,06 (1H, d, J=2.0 Hz).

Example 140a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-hydroxybenzamide)-4-phenylbenzoate (to 0.060 g) in tetrahydrofuran (1.2 ml) was added 1-(2-what hydroxyethyl)pyrrolidine (0,016 ml), triphenylphosphine (0,038 g) and diisopropylethylamine (0,029 ml)and then stirred at room temperature for 25 minutes. To the reaction mixture were added 1-(2-hydroxyethyl)pyrrolidine (0,016 ml), triphenylphosphine (0,038 g) and diisopropylethylamine (0,029 ml)and then stirred at room temperature for 20 minutes. To the reaction mixture were added 1-(2-hydroxyethyl)pyrrolidine (0,016 ml), triphenylphosphine (0,038 g) and diisopropylethylamine (0,029 ml)and then stirred at room temperature for 30 minutes. To the reaction mixture were added 1-(2-hydroxyethyl)pyrrolidine (0,016 ml), triphenylphosphine (0,038 g) and diisopropylethylamine (0,029 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure and purify the resulting residue by the method of column chromatography on silica gel [eluent: 80-0% hexane/ethyl acetate] to obtain 0,071 g of tert-butyl 2-(2-(benzyloxy)-5-(2-(pyrrolidin-1-yl)ethoxy)benzamido)-4-phenylbenzoate.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(2-(pyrrolidin-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0,071 g) in a mixture of methanol (1.5 ml) and ethyl acetate (1.5 ml) was added 10% palletirovanie coal (0,071 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. Insoluble substances were removed by filtration, and privale the solvent under reduced pressure. To the obtained residue was added triperoxonane acid (5.0 ml)and then stirred at room temperature for 4 hours. The solvent is evaporated under reduced pressure, was added to the residue ethyl acetate (2.5 ml) and 4.0 mol/l solution of florodora in dioxane (0,30 ml)and then stirred at room temperature for 1 hour and 30 minutes. The solid substance was collected from the reaction mixture by filtration to obtain 0.036 g of the hydrochloride of 2-(2-hydroxy-5-(2-(pyrrolidin-1-yl)ethoxy)benzamido)-4-vinylbenzoic acid as a light brown solid.

1H-NMR (DMSO-d6) δ: 1,82-2,10 (4H, m), 3,05-3,20 (2H, m), 3,52-3,66 (4H, m), or 4.31 (2H, t, J=5.0 Hz), 7,01 (1H, d, J=8,9 Hz), 7,16 (1H, DD, J=8,9, and 3.2 Hz), 7,43-7,58 (5H, m), 7,69 to 7.75 (2H, m), of 8.09 (1H, d, J=8,3 Hz), 9,04 (1H, d, J=1.7 Hz), 10,10-10,30 (1H, broadened), 11,08 (1H, s), 12,32 (1H, s), 13,30-13,55 (1H, broadened).

Example 141a

To tert-butyl 2-(2-(benzyloxy)-5-hydroxybenzamide)-4-phenylbenzoate (0.15 g) was sequentially added N,N-dimethylformamide (3.0 ml), potassium carbonate (0.12 g) and 1-(3-bromopropyl)-4-methylpiperazine (0,30 g)and then stirred at 100°C for 1 hour and 20 minutes. To the reaction mixture were added potassium carbonate (0.12 g)and then stirred at 100°C for 50 minutes. To the reaction mixture were added water and chloroform. The organic layer was separated, washed with a saturated aqueous solution of chloride of soda which I was dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-92% chloroform/methanol] to obtain to 0.060 g of tert-butyl 2-(2-(benzyloxy)-5-(3-(4-methylpiperazin-1-yl)propoxy)benzamido)-4-phenylbenzoate.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(3-(4-methylpiperazin-1-yl)propoxy)benzamido)-4-phenylbenzoate (0,059 g) in a mixture of methanol (1.0 ml) and chloroform (1.0 ml) was added 10% palletirovanie coal (0,023 g)and then stirred in a hydrogen atmosphere at room temperature for 1 hour and 20 minutes. To the reaction mixture was added 10% palletirovanie coal (0,058 g)and then stirred in a hydrogen atmosphere at room temperature for 3 hours. To the reaction mixture were added methanol (2.0 ml), chloroform (2.0 ml) and 10% palletirovanie coal (by 0.055 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours and 50 minutes. To the reaction mixture was added 10% palletirovanie coal (0.025 g)and then stirred in a hydrogen atmosphere at room temperature for 4 hours and 30 minutes. Insoluble substances were removed by filtration, and then the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-90% chloroform/methanol] to obtain 0,026 g t is et-butyl-2-(2-hydroxy-5-(3-(4-methylpiperazin-1-yl)propoxy)benzamido)-4-phenylbenzoate.

To the obtained tert-butyl 2-(2-hydroxy-5-(3-(4-methylpiperazin-1-yl)propoxy)benzamido)-4-phenylbenzoate (0,024 g) was added triperoxonane acid (1.0 ml)and then stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, and was added to the residue water and methanol. After adjusting pH to 7.5 dobavleniem saturated aqueous solution of sodium bicarbonate, the solid substance was collected by filtration. To the obtained solid substance was added ethyl acetate (2.0 ml) and methanesulfonyl acid (5,0 ál), and the solvent evaporated under reduced pressure. To the obtained residue was added ethyl acetate, and collecting the solid by filtration to obtain 0,020 g dimethanesulfonate 2-(2-hydroxy-5-(3-(4-methylpiperazin-1-yl)propoxy)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (CD3OD) δ: 2,22-of 2.34 (2H, m), of 2.72 (6H, s), to 3.02 (3H, s), 3,36-3,90 (10H, m), 4,18 (2H, t, J=5.7 Hz), 6,94 (1H, d, J=9.0 Hz), 7,14 (1H, DD, J=9,0, 3.2 Hz), 7,39-rate of 7.54 (5H, m), 7,69-to 7.77 (2H, m), by 8.22 (1H, d, J=8,3 Hz), 9,07 (1H, d, J=1.7 Hz).

Example 142a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate (1.5 g) in acetone (7.5 ml) was added potassium carbonate (1.0 g) and 1-methylpiperazine (0,83 ml)and then heated under reflux for 2 hours. The reaction is mesh was cooled to room temperature, was added thereto, potassium carbonate (0.34 g) and 1-methylpiperazine (0,28 ml)and then heated under reflux for 2 hours. After cooling the reaction mixture to room temperature, the solvent evaporated under reduced pressure, and was added to the residue water and chloroform. The organic layer was separated and solvent was removed under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-95% chloroform/methanol] to obtain tert-butyl 2-(2-(benzyloxy)-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate in methanol (8.0 ml) was added 10% palletirovanie coal (0.75 g)and then stirred in a hydrogen atmosphere at room temperature for 5 hours. Insoluble substances were removed by filtration, and then the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 1.2 g of tert-butyl 2-(2-hydroxy-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate.

To the obtained tert-butyl 2-(2-hydroxy-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate (1.2 g) add the Yali triperoxonane acid (10 ml), and then was stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, and was added to the residue 30% aqueous solution of methanol. After adjusting the pH to 6.7 by addition of a saturated aqueous solution of sodium bicarbonate, the solid substance was collected from the reaction mixture by filtration to obtain 0,86 g 2-(2-hydroxy-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzamido)-4-vinylbenzoic acid.

To a solution of the obtained 2-(2-hydroxy-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzamido)-4-vinylbenzoic acid (0.10 g) in a mixture of tetrahydrofuran (2.0 ml) and ethanol (1.0 ml) was added water (1.0 ml), methanesulfonyl acid (0,029 ml) and activated charcoal (0,020 g)and then stirred at room temperature for 30 minutes. Insoluble substances were removed by filtration, and then the solvent evaporated under reduced pressure. To the obtained residue was added acetone, and collecting the solid by filtration to obtain 0,095 g dimethanesulfonate 2-(2-hydroxy-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: at 2.36 (6H, s), 2,87 (3H, s), 2,99-4,05 (10H, m), 4,22-4,34 (2H, m), 7,00 (1H, d, J=9.0 Hz), 7,14 (1H, DD, J=8,7, 3.1 Hz), 7,43-to 7.59 (5H, m), 7.68 per-7,76 (2H, m), 8,10 (1H, d, J=8,3 Hz), 9,04 (1H, d, J=1,5 Hz), 10,99-11,10 (1H, broadened), 12,32 (1H, s).

Example 143a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate (1.6 g) in acetone (8.0 ml) was added potassium carbonate (1.5 g) and 1-ethylpiperazine (1.0 ml)and then heated under reflux for 5 hours. After cooling the reaction mixture to room temperature, insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-90% chloroform/methanol] to obtain tert-butyl 2-(2-(benzyloxy)-5-(2-(4-ethylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate in the form of a yellow oily substance.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(2-(4-ethylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate in methanol (20 ml) was added 10% palletirovanie coal (1.7 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. To the reaction mixture was added 10% palletirovanie coal (0,70 g)and then stirred in a hydrogen atmosphere at room temperature for 3 hours. Insoluble substances were removed by filtration, and then the solvent evaporated under reduced pressure to obtain tert-butyl 2-(5-(2-(4-ethylpiperazin-1-yl)ethoxy)-2-hydroxybenzamide)-4-phenylbenzoate in the form of a white solid.

To the resulting t is et-butyl-2-(5-(2-(4-ethylpiperazin-1-yl)ethoxy)-2-hydroxybenzamide)-4-phenylbenzoate added triperoxonane acid (10 ml), and then was stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the residue 30% aqueous solution of methanol (16 ml). After adjusting the pH to 6.5 by the addition of saturated aqueous sodium bicarbonate solution, the solid is collected from the reaction mixture by filtration to obtain 1.1 g of 2-(5-(2-(4-ethylpiperazin-1-yl)ethoxy)-2-hydroxybenzamide)-4-vinylbenzoic acid as a white solid.

To the suspension obtained 2-(5-(2-(4-ethylpiperazin-1-yl)ethoxy)-2-hydroxybenzamide)-4-vinylbenzoic acid (0.10 g) in ethanol (2.0 ml) was added methanesulfonyl acid (0,027 ml), tetrahydrofuran (3.0 ml) and activated charcoal (0,020 g)and then stirred at room temperature for 30 minutes. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. To the obtained residue was added acetone, and collecting the solid by filtration to obtain 0,090 g dimethanesulfonate 2-(5-(2-(4-ethylpiperazin-1-yl)ethoxy)-2-hydroxybenzamide)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: of 1.23 (3H, t, J=7,3 Hz), a 2.36 (6H, s), 3,02-3,78 (12H, m), 4,21-4,34 (2H, m), 7,00 (1H, d, J=9.0 Hz), 7,14 (1H, DD, J=9,0, 3.2 Hz), 7,42-to 7.59 (5H, m), 7.68 per-7,76 (2H, m), 8,10 (1H, d, J=8,3 Hz), 9,01-9,07 (1H, m), 10,99-11,09 (1H, broadened), 12,32 (1H, s).

Note the R 144a

To N,N-dimethylformamide (1 ml) was added tert-butyl 2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate (0,030 g), potassium carbonate (0.10 g) and 1-(tert-butoxycarbonyl)piperidine (0,093 g)and then stirred at 90-100°C for 3 hours. The reaction mixture was cooled to room temperature and then added to her water and chloroform. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue were added tetrahydrofuran (1.5 ml), water (0.1 ml), 10% palletirovanie coal (to 0.060 g), sodium formate (7.5 mg) and acetic acid (7.5 mg)and then stirred at 60°C for 2 hours. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate solution and chloroform. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 80-50% hexane/ethyl acetate] to obtain 0.025 g of tert-butyl 4-(2-(3-(2-(tert-butoxycarbonyl)-5-phenylenecarbonyl)-4-hydroxyphenoxy)ethyl)piperidine-1-carboxylate.

To the obtained tert-butyl 4-(2-(3-(2-(tert-butoxycarbonyl)-5-phenylmercury mail)-4-hydroxyphenoxy)ethyl)piperidine-1-carboxylate (0.025 g) was added triperoxonane acid (2 ml), and then was stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, and was added to the residue water. After adjusting the pH to 6.3 by the addition of saturated aqueous sodium bicarbonate solution, the solid is collected by filtration. To the obtained solid substance was added methanol and methansulfonate acid, and then added ethyl acetate. The solid substance was collected by filtration to obtain 0,010 g dimethanesulfonate 2-(2-hydroxy-5-(2-(piperazine-1-yl)ethoxy)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 2,31 (6H, s), 2,80-of 3.80 (10H, m), 4,16-4,32 (2H, m), of 6.99 (1H, d, J=8,8 Hz), 7,08-7,17 (1H, m), 7,43-to 7.59 (5H, m), 7.68 per-7,76 (2H, m), of 8.09 (1H, d, J=8.5 Hz), 9,01-9,07 (1H, m), 11,03 (1H, s), 12,32 (1H, ).

Example 145a

To a solution of methyl 2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate (0.20 g) in acetone (2.0 ml) was added potassium carbonate (0.15 g) and diethylamine (0,11 ml)and then heated under reflux for 4 hours and 30 minutes. The reaction mixture was cooled to room temperature, then added to it the potassium carbonate (0,049 g) and diethylamine (0.037 ml)and then heated under reflux for 1 hour. The reaction mixture was cooled to room temperature, then added to it the potassium carbonate (0,049 g) and diethylamine (,037 ml), and then was heated under reflux for 1 hour and 15 minutes. The reaction mixture was cooled to room temperature, then added to it the potassium carbonate (0,049 g) and diethylamine (0.037 ml)and then heated under reflux for 5 hours and 30 minutes. The reaction mixture was cooled to room temperature, and added to it water, saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-97% chloroform/methanol] to obtain 0.15 g of methyl 2-(2-(benzyloxy)-5-(2-(diethylamino)ethoxy)benzamido)-4-phenylbenzoate.

To a solution of the obtained methyl 2-(2-(benzyloxy)-5-(2-(diethylamino)ethoxy)benzamido)-4-phenylbenzoate (0.15 g) in a mixture of methanol (3.0 ml) and ethyl acetate (3.0 ml) was added 10% palletirovanie coal (0,030 g)and then stirred in a hydrogen atmosphere at room temperature for 3 hours. Insoluble substances were removed by filtration, and then the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-96% chloroform/methanol] to obtain 0,087 g of methyl 2-(5-(2-(who ethylamino)ethoxy)-2-hydroxybenzamide)-4-phenylbenzoate in the form of a white solid.

To the obtained methyl 2-(5-(2-(diethylamino)ethoxy)-2-hydroxybenzamide)-4-phenylbenzoate (0,087 g) was added dioxane (3.0 ml) and 4 mol/l aqueous solution of sodium hydroxide (0,19 ml), then stirred at room temperature for 2 hours and 30 minutes, and then at 50-55°C for 2 hours. The reaction mixture was cooled to room temperature and adjust pH to 6.9 by adding methanesulfonic acid, and the solvent evaporated under reduced pressure. To the obtained residue was added water, and collecting the solid by filtration to obtain 0,079 g of 2-(5-(2-(diethylamino)ethoxy)-2-hydroxybenzamide)-4-vinylbenzoic acid.

To the obtained 2-(5-(2-(diethylamino)ethoxy)-2-hydroxybenzamide)-4-vinylbenzoic acid (0,079 g) was added ethanol (3.0 ml) and methanesulfonyl acid (0,011 ml)and then stirred at room temperature for 1 hour and 30 minutes. The solid substance was collected from the reaction mixture by filtration to obtain 0,049 g methanesulfonate 2-(5-(2-(diethylamino)ethoxy)-2-hydroxybenzamide)-4-vinylbenzoic acid as a white solid.

1H-NMR (CD3OD) δ: 1,39 (6H, t, J=7,3 Hz), 2,69 (3H, s), 3,32-to 3.41 (4H, m), 3,62 (2H, t, J=4.9 Hz), 4,37 (2H, t, J=4.9 Hz), of 6.96 (1H, d, J=9.0 Hz), 7,19 (1H, DD, J=9,0, 2,9 Hz), 7,39 was 7.45 (1H, m), 7,45-7,53 (4H, m), 7,69 to 7.75 (2H, m), to 8.20 (1H, d, J=8,3 Hz), 9,05 (1H, d, J=1.7 Hz).

Example 146a

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-4-(2-(morpholine-4-yl)ethoxy)benzamido)-4-phenylbenzoate (0,059 g) in a mixture of methanol (2.0 ml) and ethyl acetate (2.0 ml) was added 10% palletirovanie coal (0,012 g)and then stirred in a hydrogen atmosphere at room temperature for 3 hours. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration. To the obtained solid substance doba is Lyali triperoxonane acid (4.0 ml), and then was stirred at room temperature for 3 hours. To the reaction mixture was added toluene, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration. To the obtained solid substance was added ethanol (4.0 ml). After adjusting the pH to 7.7 by adding 1 mol/l aqueous solution of sodium hydroxide, the solid was collected by filtration to obtain to 0.011 g of 2-(2-hydroxy-4-(2-(morpholine-4-yl)ethoxy)benzamido)-4-vinylbenzoic acid as a white solid.

To the obtained 2-(2-hydroxy-4-(2-(morpholine-4-yl)ethoxy)benzamido)-4-vinylbenzoic acid (0,011 g) was added ethanol (2.0 ml) and methanesulfonyl acid (0,010 ml)and then stirred at room temperature for 3 hours and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the obtained residue, ethanol. The solid substance was collected by filtration to obtain 6,1 mg methanesulfonate 2-(2-hydroxy-4-(2-(morpholine-4-yl)ethoxy)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 2,31 (3H, s), 3,10-4,10 (10H, m)to 4.41 (2H, t, J=4.6 Hz), is 6.61 (1H, d, J=2.4 Hz), of 6.68 (1H, DD, J=9,0, 2.4 Hz), 7,42-7,58 (4H, m), 7.68 per-7,76 (2H, m), of 7.90 (1H, d, J=9.0 Hz), 8,10 (1H, d, J=8,3 Hz), 8,98 (1H, d, J=1.7 Hz), 11.87 per (1H, s), 12,25 (1H, s).

Example 147a

The following compound was obtained as described in Example 146a.

2-(2-Hydroxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzamido)-4-vinylbenzoic acid dimethanesulfonate

1H-NMR (DMSO-d6) δ: 2,35 (6H, s), of 2.86 (3H, s), 3,12-3,70 (10H, m), 4,24-to 4.38 (2H, m), 6,59 (1H, d, J=2.0 Hz), 6,62-6,70 (1H, m), 7,42-7,58 (4H, m), 7.68 per-7,76 (2H, m), 7,88 (1H, d, J=8,8 Hz), 8,10 (1H, d, J=8,3 Hz), 8,98 (1H, d, J=1.7 Hz), up 11,86 (1H, s), 12,24 (1H, s).

Example 148a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-(piperidine-1-yl)benzamido)-4-bromobenzoate (0.10 g) in dimethyl ether of ethylene glycol (2.0 ml) was added water (0,60 ml), 2-methylphenylimino acid (0,029 g), sodium carbonate (0,047 g) dichloride and bis(triphenylphosphine)palladium(II) (2.5 mg)and then heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and added to her water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 99-91% hexane/ethyl acetate] to obtain 0.10 g of tert-butyl 2-(2-(benzyloxy)-5-(piperidine-1-yl)benzamido)-4-(2-were)benzoate.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(piperidine-1-yl)benzamido)-4-(2-were)b is soata (0.10 g) in a mixture of methanol (2.0 ml) and ethyl acetate (2.0 ml) was added 10% palletirovanie coal (0,020 g), and then was stirred in hydrogen atmosphere at room temperature for 2 hours and 45 minutes. Insoluble substances were removed by filtration, and then the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 99-91% hexane/ethyl acetate] to obtain 0,063 g of tert-butyl 2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-4-(2-were)benzoate as a yellow solid.

A solution of the obtained tert-butyl 2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-4-(2-were)benzoate (0,063 g) in triperoxonane acid (3.0 ml) was stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and added water and ethanol. After adjusting the pH to 5.5 by the addition of saturated aqueous sodium bicarbonate solution, the solid was collected by filtration to obtain 0,048 g 2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-4-(2-were)benzoic acid as a yellow solid.

1H-NMR (DMSO-d6) δ: 1,46-of 1.56 (2H, m), 1,60-1,70 (4H, m)to 2.29 (3H, s), 3.00 and-is 3.08 (4H, m)6,91 (1H, d, J=9.0 Hz), 7,14-7,22 (2H, m), 7.24 to 7,38 (4H, m), 7,39-7,44 (1H, m), 8,08 (1H, d, J=8.1 Hz), 8,66 (1H, d, J=1.5 Hz), 10,91-11,08 (1H, broadened), 12,24-12,40 (1H, broadened).

Examples 149a-155a

Compounds shown in Table 17a, obtained as described in Example 148a.

Table 17a
Example No.R3Example No.R3
149a153a
150a154a

151a155a
152a

2-(2-Hydroxy-5-(piperidine-1-yl)benzamido)-4-(3-were)benzoic acid

1H-NMR (CDCl3) δ: 1,57 is 1.70 (2H, m), 1.91 a-2,05 (4H, m), 2,42 (3H, s), 3,30-of 3.43 (4H, m), 7,05 (1H, d, J=9.0 Hz), 7,19 (1H, d, J=7,6 Hz), 7,29-7,39 (3H, m), 7,41-7,47 (2H, m), 8,07 (1H, d, J=2.4 Hz), 8,11 (1H, d, J=8,3 Hz), 8,97 (1H, d, J=1.7 Hz).

2-(2-Hydroxy-5-(piperidine-1-yl)benzamido)-4-(4-were)benzoic acid

1H-NMR (DMSO-d6 ) δ: 1,47-of 1.56 (2H, m), 1,61-1,71 (4H, m), of 2.38 (3H, s), 2,99-is 3.08 (4H, m)6,91 (1H, d, J=8,9 Hz), 7,17 (1H, DD, J=8,9 and 2.5 Hz), 7,34 (2H, d, J=7.9 Hz), the 7.43 (1H, d, J=2.5 Hz), 7,46-7,52 (1H, m), 7,63 (2H, d, J=7.9 Hz), 8,08 (1H, d, J=8,3 Hz), of 9.00 (1H, s), 10,95-11,09 (1H, broadened), 12,29-12,43 (1H, broadened).

4-(2-Forfinal)-2-(2-hydroxy-5-(piperidine-1-yl)benzamido)benzoic acid

1H-NMR (DMSO-d6) δ: 1,46-of 1.55 (2H, m), 1,60 was 1.69 (4H, m), 2,99-of 3.06 (4H, m), 6.90 to (1H, d, J=9.0 Hz), 7,17 (1H, DD, J=9,0, 2,8 Hz), 7,33-7,44 (4H, m), 7,46-of 7.55 (1H, m), 7,56-to 7.64 (1H, m), 8,11 (1H, d, J=8,3 Hz), of 8.90 (1H, ), of 10.93-11,10 (1H, broadened), 12,36-12,54 (1H, broadened).

4-(3-Forfinal)-2-(2-hydroxy-5-(piperidine-1-yl)benzamido)benzoic acid

1H-NMR (DMSO-d6) δ: 1,47-of 1.56 (2H, m), 1,61 is 1.70 (4H, m), 3.00 and-of 3.07 (4H, m)6,91 (1H, d, J=8,9 Hz), 7,17 (1H, DD, J=8,9, 2,9 Hz), 7,26-7,34 (1H, m), 7,44 (1H, d, J=2,9 Hz), 7,52-7,63 (4H, m), 8,10 (1H, d, J=8,3 Hz), 9,01 (1H, d, J=1.7 Hz), 10,92-11,12 (1H, broadened), to 12.28-12,48 (1H, broadened).

4-(4-Forfinal)-2-(2-hydroxy-5-(piperidine-1-yl)benzamido)benzoic acid

1H-NMR (DMSO-d6) δ: 1,46-of 1.56 (2H, m), 1.60-to 1,71 (4H, m), 2,99-is 3.08 (4H, m)6,91 (1H, d, J=8,9 Hz), 7,17 (1H, DD, J=8,9, 2,8 Hz), 7,33-7,41 (2H, m), the 7.43 (1H, d, J=2,8 Hz), 7,46-7,53 (1H, m), 7,73-of 7.82 (2H, m), of 8.09 (1H, d, J=8,3 Hz), 8,96-of 9.02 (1H, m), 10,96-11,08 (1H, broadened), 12,31-12,46 (1H, broadened).

2-(2-Hydroxy-5-(piperidine-1-yl)benzamido)-4-(3-methoxyphenyl)benzoic acid

1H-NMR (DMSO-d6) δ: 1,47-of 1.56 (2H, m), 1,61 is 1.70 (4H, m), 3.00 and-a 3.06 (4H, m), 3,85 (3H, s)6,91 (1H, d, J=9.0 Hz), 7,01-7,07 (1H, m), 7,17 (1H, DD, J=9,0, 2,9 Hz), 7,22-of 7.25 (1H, m), 7,26-to 7.32 (1H, m), 7,41-7,49 (2H, m), 7,51 (1H, DD, J=8,3) and 1.7 Hz), of 8.09 (1H, d, J=8,3 Hz), 8,98 (1H, d, J=1.7 Hz), 1,92-11,12 (1H, broadened), 12,30-12,50 (1H, broadened).

2-(2-Hydroxy-5-(piperidine-1-yl)benzamido)-4-(4-methoxyphenyl)benzoic acid

1H-NMR (DMSO-d6) δ: 1,47-of 1.55 (2H, m), 1,61 was 1.69 (4H, m), 3.00 and-a 3.06 (4H, m), 3,83 (3H, s)6,91 (1H, d, J=9.0 Hz), 7,07 for 7.12 (2H, m), 7,17 (1H, DD, J=9,0, 3.0 Hz), 7,42 (1H, d, J=3.0 Hz), 7,47 (1H, DD, J=8,3, 2.0 Hz), 7,66-7,71 (2H, m), 8,07 (1H, d, J=8,3 Hz), 8,97 (1H, d, J=2.0 Hz), 10,95-11,12 (1H, broadened), 12,30-12,50 (1H, broadened).

Example 156a

To a solution of tert-butyl 2-(2-acetoxy-5-(piperidine-1-yl)benzamido)-4-bromobenzoate (0,080 g) in dimethyl ether of ethylene glycol (2.0 ml) was added water (0,60 ml), thiophene-2-Bronevoy acid (0,024 g), sodium carbonate (0,041 g) dichloride and bis(triphenylphosphine)palladium(II) (2.2 mg)and then heated under reflux in nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and added a 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-85% hexane/ethyl acetate] to obtain 0,027 g of tert-butyl 2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-4-(thiophene-2-yl)benzoate as a yellow solid substances is A.

To a solution of the obtained tert-butyl 2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-4-(thiophene-2-yl)benzoate (0,027 g) in a mixture of dioxane (2.0 ml) and methanol (2.0 ml) was added 1 mol/l aqueous solution of sodium hydroxide (0.17 ml)and then stirred at 50-55°C for 1 hour. The reaction mixture was cooled to room temperature, was added a 1 mol/l aqueous solution of sodium hydroxide (0,11 ml)and then stirred at 50-55°C for 2 hours. The reaction mixture was cooled to room temperature, was added a 1 mol/l aqueous solution of sodium hydroxide (0,056 ml)and then stirred at 55°C for 1 hour. The reaction mixture was cooled to room temperature, was added a 1 mol/l aqueous solution of sodium hydroxide (0,056 ml)and then stirred at 60°C for 2 hours. The reaction mixture was cooled to room temperature, and then adjust the pH to 7.7 by adding 10% aqueous citric acid solution, and was added water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, and the resulting mixture was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-80% chloroform/methanol] to obtain 0,011 g 2-(2-hydroxy-5-(piperidine-1-yl)be the Sumida)-4-(thiophene-2-yl)benzoic acid as an orange solid.

1H-NMR (DMSO-d6) δ: 1,47-of 1.56 (2H, m), 1,61 is 1.70 (4H, m), 2,99-of 3.07 (4H, m), 6.90 to (1H, d, J=8,8 Hz), 7,16 (1H, DD, J=8,8, 2,9 Hz), 7,21 (1H, DD, J=5,1, and 3.7 Hz), 7,42 (1H, d, J=2,9 Hz), 7,52 (1H, DD, J=8,4, 2.0 Hz), to 7.64 (1H, DD, J=3,7, 1.2 Hz), 7,69 (1H, DD, J=5,1, 1.2 Hz), with 8.05 (1H, d, J=8,4 Hz), 9,04 (1H, d, J=2.0 Hz), 10,94-11,13 (1H, broadened).

Example 157a

To a solution of tert-butyl 2-(2-acetoxy-5-(piperidine-1-yl)benzamido)-4-bromobenzoate (0,080 g) in dimethyl ether of ethylene glycol (2.0 ml) was added water (0,60 ml), 1-(tert-butoxycarbonyl)-1H-pyrrol-2-Bronevoy acid (0,024 g), sodium carbonate (0,041 g) dichloride and bis(triphenylphosphine)palladium(II) (2.2 mg)and then heated under reflux in nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature, was added a sodium carbonate (0,016 g)and then heated under reflux in nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature, and added a 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-80% hexane/ethyl acetate] to obtain tert-butyl 2-(2-acetoxy-5-piperidine-1-yl)benzamido)-4-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)benzoate.

To a solution of the obtained tert-butyl 2-(2-acetoxy-5-(piperidine-1-yl)benzamido)-4-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)benzoate in dioxane (2.0 ml) was added methanol (2.0 ml) and 4 mol/l aqueous solution of sodium hydroxide (0,19 ml)and then stirred at 55°C for 1 hour. The reaction mixture was cooled to room temperature, then was added a 4 mol/l aqueous solution of sodium hydroxide (0,077 ml)and then stirred at 60°C for 2 hours. The reaction mixture was cooled to room temperature, then adjust the pH to 7.8 by adding 10% aqueous citric acid solution, and was added water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-91% chloroform/methanol] to obtain 8 mg of 2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-4-(1H-pyrrol-2-yl)benzoic acid as a yellow solid.

1H-NMR (DMSO-d6) δ: 1,47-of 1.56 (2H, m), 1,61 is 1.70 (4H, m), 3.00 and-a 3.06 (4H, m), 6,16-to 6.22 (1H, m), 6,60-of 6.65 (1H, m), 6.89 in (1H, d, J=9.0 Hz), 6,92-6,97 (1H, m), 7,17 (1H, DD, J=9,0, 2,8 Hz), 7,39-7,47 (1H, m), 7,41 (1H, d, J=2,8 Hz), to 7.99 (1H, d, J=8.5 Hz), cent to 8.85 (1H, d, J=1.5 Hz), 11.11 is-11,27 (1H, broadened), 11,49-for 11.55 (1H, broadened).

Example 158a

When about is ladanyi on ice to a solution of 2-(benzyloxy)-5-bromobenzoyl acid (0,074 g) in a mixture of methylene chloride (2.0 ml) and N,N-dimethylformamide (0,010 ml) was added oxalicacid (0,026 ml), and then was stirred at room temperature for 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2.0 ml). The resulting mixture was added to a solution of methyl 2-amino-5-methoxy-4-phenylbenzoate (0,052 g) in a mixture of pyridine (0,025 ml) and methylene chloride (1.0 ml)and then stirred at room temperature for 3 hours. The reaction mixture was purified according to the method of column chromatography on silica gel [eluent: 95-85% hexane/ethyl acetate] to obtain of 0.045 g of methyl 2-(2-(benzyloxy)-5-bromobenzene)-5-methoxy-4-phenylbenzoate in the form of a white solid.

1H-NMR (CDCl3) δ: of 3.80 (3H, s), 3,85 (3H, s), the 5.45 (2H, s), 6.87 in (1H, d, J=8,8 Hz), 7,27-7,40 (4H, m), 7,40-7,47 (5H, m), EUR 7.57 (1H, s), 7,62-7,66 (2H, m), of 8.28 (1H, d, J=2.7 Hz), of 8.92 (1H, s), 12,08 (1H, s).

Example 159a

The following compound was obtained as described in Example 158a.

Methyl-2-(2-(benzyloxy)-5-bromobenzene)-5-fluoro-4-phenylbenzoate

1H-NMR (CDCl3) δ: with 3.79 (3H, s), 5,46 (2H, s), to 6.88 (1H, d, J=8,8 Hz), 7,22-7,37 (4H, m), 7,38-7,51 (5H, m), of 7.64-7,72 (2H, m), 7,80 (1H, d, J=11.2 Hz), 8,25-8,31 (1H, m), 9,11 (1H, d, J=7,1 Hz), 12,15-12,24 (1H, broadened).

Example 160a

To a solution of methyl 2-(2-(benzyloxy)-5-bromobenzene)-5-methoxy-4-phenylbenzoate (0,045 g) in toluene (2.0 ml) was added piperidine (0,012 ml), cesium carbonate (0,054 g), Tris(dibenzylideneacetone)dipalladium(0) (2,3mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (5.9 mg) and palladium(II) acetate (1.1 mg)and then heated under reflux in nitrogen atmosphere for 2 hours and 20 minutes. The reaction mixture was cooled to room temperature, and added to it the ethyl acetate and water. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-85% hexane/ethyl acetate] to obtain 0,034 g of methyl 2-(2-(benzyloxy)-5-(piperidine-1-yl)benzamido)-5-methoxy-4-phenylbenzoate in the form of a yellow solid.

1H-NMR (CDCl3) δ: 1,49-to 1.60 (2H, m), 1,64-of 1.74 (4H, m), 3.04 from-3,14 (4H, m), 3,76 (3H, s), of 3.84 (3H, s), are 5.36 (2H, s)6,91 (1H, d, J=9.0 Hz), of 6.99 (1H, DD, J=9,0, 2,9 Hz), 7,22-7,39 (4H, m), 7,39-7,46 (4H, m), 7,56 (1H, ), to 7.61-to 7.68 (2H, m), 7,76 (1H, d, J=3.2 Hz), of 8.92 (1H, s), 12,04 (1H, s).

Example 161a

The following compound was obtained as described in Example 160a.

Methyl-2-(2-(benzyloxy)-5-(piperidine-1-yl)benzamido)-5-fluoro-4-phenylbenzoate

1H-NMR (CDCl3) δ: 1,49-to 1.59 (2H, m), 1,65-of 1.74 (4H, m), 3,05-3,13 (4H, m in), 3.75 (3H, s), lower than the 5.37 (2H, m), 6,92 (1H, d, J=8,9 Hz), 7,00 (1H, DD, J=8,9, and 3.2 Hz), 7.23 percent-7,34 (3H, m), 7,37 is 7.50 (5H, m), of 7.64-7,72 (2H, m), 7,73-7,81 (2H, m), 9,12 (1H, d, J=7,3 Hz), 12,15 (1H, s).

Example 162a

To the solution met the l-2-(2-(benzyloxy)-5-(piperidine-1-yl)benzamido)-5-methoxy-4-phenylbenzoate (0,034 g) in a mixture of methanol (2.5 ml) and ethyl acetate (2.5 ml) was added 10% palletirovanie coal (6,8 mg), and then was stirred in hydrogen atmosphere at room temperature for 2 hours. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. To the obtained residue was added hexane and diisopropyl ether, and collecting the solid by filtration to obtain 0,020 g of methyl 2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-5-methoxy-4-phenylbenzoate in the form of a yellow solid.

To the obtained methyl 2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-5-methoxy-4-phenylbenzoate (0,020 g) was added dioxane (3.0 ml) and 1 mol/l aqueous solution of sodium hydroxide (0,13 ml)and then stirred at 50-55°C for 1 hour. The reaction mixture was cooled to room temperature, and added a 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue were added ethanol (2.0 ml) and methanesulfonyl acid (0,010 ml)and then stirred at room temperature for 10 minutes. Then, the solid substance was collected by filtration to obtain 0,012 g methanesulfonate 2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-5-methoxy-4-vinylbenzoic acid as a light brown solid.

1H-NMR (CD3OD) δ: 1.70 to of 2.20 (6H, m), 2,70 (3H, s), 3,60-3,74 (4H, m), 3,86 (3H, s), 7,17 (1H, d, J=9.0 Hz), 7,34-to 7.50 (3H, m), 7,54-to 7.64 (2H, m), 7.68 per to 7.75 (1H, m), to 7.77 (1H, s), 8,18 (1H, d, J=2,9 Hz), 8,68 (1H, s).

Example 163a

The following compound was obtained as described in Example 162a.

5-fluoro-2-(2-(hydroxy-5-(piperidine-1-yl)benzamido)-4-vinylbenzoic acid methanesulfonate

1H-NMR (CD3OD) δ: 1,74-of 1.85 (2H, m), 1,97-2,07 (4H, m), 2,69 (3H, s), 3,57-the 3.65 (4H, m), to 7.15 (1H, d, J=9.0 Hz), 7,42-7,47 (1H, m), 7,47-rate of 7.54 (2H, m), to 7.61-7,66 (2H, m), 7,68 (1H, DD, J=9,0, 3.2 Hz), to $ 7.91 (1H, d, J=11,2 Hz), 8,15 (1H, d, J=3.2 Hz), of 8.92 (1H, d, J=7,6 Hz).

Example 164a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzene)-4-phenylbenzoate (to 0.060 g) in toluene (0,90 ml) was added morpholine (0,014 ml), cesium carbonate (0,070 g), Tris(dibenzylideneacetone)dipalladium(0) (1.0 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (2.6 mg) and palladium(II) acetate (0.5 mg)and then heated under reflux in nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, then added to it morpholine (4,7 ml), cesium carbonate (0.035 g), Tris(dibenzylideneacetone)dipalladium(0) (1.0 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (2.6 mg) and palladium(II) acetate (0.5 mg)and then heated under reflux in nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to on the th temperature, and added to it 10% aqueous citric acid solution and ethyl acetate. Insoluble substances were removed by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-60% hexane/ethyl acetate] to obtain to 0.060 g of tert-butyl 2-(2-(benzyloxy)-5-(morpholine-4-yl)benzamido)-4-phenylbenzoate in the form of a light yellow solid.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(morpholine-4-yl)benzamido)-4-phenylbenzoate (to 0.060 g) in a mixture of ethyl acetate (1.5 ml) and methanol (1.5 ml) was added 10% palletirovanie coal (0,030 g)and then stirred in a hydrogen atmosphere at room temperature for 3 hours and 30 minutes. To the reaction mixture were added ethyl acetate. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether. The solid substance was collected by filtration to obtain 0.036 g of tert-butyl 2-(2-hydroxy-5-(morpholine-4-yl)benzamido)-4-phenylbenzoate in the form of a yellow solid.

To the obtained tert-butyl 2-(2-hydroxy-5-(morpholine-4-yl)benzamido)-4-penile is Tatu (0.036 g) was added triperoxonane acid (3 ml), and then was stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the obtained residue, water and 2-propanol. After adjusting the pH to 6.0 by the addition of saturated aqueous sodium bicarbonate solution, the solid was collected by filtration to obtain 0,027 g 2-(2-hydroxy-5-(morpholine-4-yl)benzamido)-4-vinylbenzoic acid as a yellow solid.

1H-NMR (DMSO-d6) δ: 2,99-is 3.08 (4H, m), 3,71-of 3.80 (4H, m)6,94 (1H, d, J=9.0 Hz), 7,18 (1H, DD, J=9,0, 3.0 Hz), 7,40-7,58 (5H, m), 7,70-to 7.77 (2H, m), 8,10 (1H, d, J=8,3 Hz), of 9.02 (1H, d, J=1.7 Hz), 10,99 (1H, s), 12,30-12,41 (1H, broadened).

Examples 165a and 166a

Compounds are presented in Table 18a, obtained as described in Example 80a.

Table 18a
Example No.R7Example No.R7
149a153a

2-(2-Hydroxy-5-(2-methylpiperidin-1-yl)benzamido)-4-vinylbenzoic acid hydrochloride

1H-NMR (DMSO-d6) δ: 1,00 (3H, d, J=6.4 Hz), 1,62-215 (6H, m), 3,39-3,70 (2H, m), 3.72 points-a 3.87 (1H, m), 7,21 (1H, d, J=8.6 Hz), 7,42-7,50 (1H, m), 7,50-7,58 (3H, m), 7,70-7,76 (2H, m), 7,86-7,98 (1H, m), 8,10 (1H, d, J=8.1 Hz), 8.34 per-to 8.45 (1H, m), 9,07 (1H, d, J=1.7 Hz), 11,66-up 11,86 (1H, broadened), 11,94-12,11 (1H, broadened), 12,37 (1H, s), 13,30-13.56MHz (1H, broadened).

2-(2-Hydroxy-5-(3-methylpiperidin-1-yl)benzamido)-4-vinylbenzoic acid hydrochloride

1H-NMR (DMSO-d6) δ: of 0.94 (3H, d, J=6.6 Hz), of 1.16 to 1.34 (1H, m), 1,74-of 2.27 (4H, m), 3,03-of 3.60 (4H, m), 7,17 (1H, d, J=8,8 Hz), 7,43-7,50 (1H, m), 7,51-to 7.59 (3H, m), 7.68 per to 7.75 (2H, m), to 7.77-7,88 (1H, broadened), 8,11 (1H, d, J=8.0 Hz,), 8,17-to 8.40 (1H, broadened), 9,07 (1H, d, J=1.7 Hz), 11,76-12,09 (1H, broadened), 12,36 (1H, s).

1H-NMR (DMSO-d6-D2O) δ: 0,97 (3H, d, J=6.6 Hz), 1,19 is 1.34 (1H, m), 1,76-of 2.16 (4H, m), 3,13-of 3.25 (1H, m), 3,35-of 3.60 (3H, m), 7,20 (1H, d, J=8,8 Hz), 7,45-7,63 (4H, m), 7,70-7,80 (3H, m), 8,13 (1H, d, J=8.1 Hz), to 8.20 (1H, d, J=2,9 Hz), 9,01 (1H, d, J=1.5 Hz).

Examples 167a-169a

The compounds presented in Table 19a, obtained as described in Example 87a.

Table 19a
Example No.R7Example No.R7Example No.R7
167a168a 169a

2-(2-Hydroxy-5-(3-hydroxypiperidine-1-yl)benzamido)-4-vinylbenzoic acid hydrochloride

1H-NMR (CD3OD) δ: 1,80 for 2.01 (3H, m), 2,31-2,47 (1H, m), 3,45-3,62 (2H, m), 3,67 is 3.76 (2H, m), 4,19-4.26 deaths (1H, m), 7,18 (1H, d, J=9.0 Hz), 7,39 was 7.45 (1H, m), 7,47-7,53 (3H, m), 7,70 for 7.78 (3H, m), 8,19-8,23 (2H, m), 9,05 (1H, d, J=1.7 Hz).

2-(2-Hydroxy-5-(4-(hydroxymethyl)piperidine-1-yl)benzamido)-4-vinylbenzoic acid hydrochloride

1H-NMR (CD3OD) δ: 1,73-to 1.87 (2H, m), 1,90 for 2.01 (1H, m), 2,10-2,19 (2H, m), of 3.56 (2H, d, J=5.8 Hz), 3,63-with 3.79 (4H, m), 7,18 (1H, d, J=9.0 Hz), 7,40 was 7.45 (1H, m), 7,47-7,53 (3H, m), 7,70 to 7.75 (2H, m), 7,76 (1H, DD, J=9,0 and 3.1 Hz), 8,21 (1H, d, J=3.1 Hz), 8,21 (1H, d, J=8,3 Hz), 9,05 (1H, d, J=1.7 Hz).

2-(2-Hydroxy-5-(4-(2-hydroxyethyl)piperidine-1-yl)benzamido)-4-vinylbenzoic acid hydrochloride

1H-NMR (CD3OD) δ: 1,59-of 1.66 (2H, m), 1,68 of-1.83 (2H, m), 1,90-2,03 (1H, m), 2,10-of 2.20 (2H, m), 3,60 is 3.76 (6H, m), 7,17 (1H, d, J=9.0 Hz), 7,39 was 7.45 (1H, m), 7,47-7,53 (3H, m), 7,70 to 7.75 (2H, m), 7,76 (1H, DD, J=9,0, 2,9 Hz), 8,18-8,23 (2H, m), 9,05 (1H, d, J=1.7 Hz).

Example 170a

To a solution of 2-(benzyloxy)-5-(piperidine-1-yl)benzoic acid (0,084 g) in methylene chloride (1.4 ml) was sequentially added N,N-dimethylformamide (2,1 μl) and oxacillin (to 0.032 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the obtained residue, toluene. Races shall foretell evaporated under reduced pressure, and was added to the obtained residue, methylene chloride (1.0 ml). The resulting mixture while cooling on ice, was added to a solution of tert-butyl 2-amino-4-phenoxybenzoate (0,070 g) in a mixture of pyridine (0,070 ml) and methylene chloride (1.4 ml)and then stirred at room temperature for 1 hour. To the reaction mixture were added 10% aqueous citric acid solution, the organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-80% hexane/ethyl acetate] to obtain 0,093 g of tert-butyl 2-(2-(benzyloxy)-5-(piperidine-1-yl)benzamido)-4-phenoxybenzoate in the form of a yellow oily substance.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(piperidine-1-yl)benzamido)-4-phenoxybenzoate (0,093 g) in a mixture of ethyl acetate (1.5 ml) and methanol (1.5 ml) was added 10% palletirovanie coal (0,047 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture were added chloroform. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), elwen is: 80-70% hexane/ethyl acetate] to obtain 0,067 g of tert-butyl 2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-4-phenoxybenzoate in the form of a yellow solid.

To the obtained tert-butyl 2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-4-phenoxybenzoate (0,067 g) was added triperoxonane acid (5 ml)and then stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the residue water and 2-propanol. After adjusting the pH to 6.0 by the addition of saturated aqueous sodium bicarbonate solution, the solid was collected by filtration to obtain 0,053 g 2-(2-hydroxy-5-(piperidine-1-yl)benzamido)-4-phenoxybenzoic acid as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 1,46-and 1.54 (2H, m), 1,59 by 1.68 (4H, m), 2,97 totaling 3.04 (4H, m), 6,76 (1H, DD, J=9,0, 2.6 Hz), to 6.88 (1H, d, J=8,8 Hz), 7,11-7,20 (3H, m), 7.23 percent-7,30 (1H, m), 7,32 (1H, d, J=2.7 Hz), 7,44-7,52 (2H, m), of 8.04 (1H, d, J=9.0 Hz), 8,39 (1H, d, J=2.6 Hz), 10,79-10,94 (1H, broadened), 12,40-to 12.58 (1H, broadened).

Example 171a

The following compound was obtained as described in Example 170a.

2-(2-Hydroxy-5-(piperidine-1-yl)benzamido)-4-phenoxybenzoic acid

1H-NMR (DMSO-d6) δ: 1,46-of 1.56 (2H, m), 1,59 is 1.70 (4H, m), 2,88-3,06 (8H, m), 6.89 in (1H, d, J=9.0 Hz), 7,07 (1H, DD, J=8,2, 1.5 Hz), 7,13-7,22 (2H, m), 7.23 percent-to 7.32 (4H, m), of 7.36-7,40 (1H, m), 7,92 (1H, d, J=8,4 Hz), to 8.57 (1H, d, J=1.5 Hz), 10,96-11,12 (1H, broadened), 12,22-12,40 (1H, broadened).

Example 172a

To a suspension of 2-(benzyloxy)-N-(4-cyanobiphenyl-3-yl)-5-(piperidine-1-yl)benzamide (0.25 g) in N,N-dimethy the formamide (2.5 ml) was added sodium azide (0,065 g) and ammonium chloride (0,053 g), and then was stirred at 110°C for 2 hours. The reaction mixture was cooled to room temperature, then added to it sodium azide (0,065 g) and ammonium chloride (0,053 g)and then stirred at 110°C for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, was added thereto, then sodium azide (0,032 g) and ammonium chloride (0,026 g)and then stirred at 110°C for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, then added to it sodium azide (0,032 g) and ammonium chloride (0,026 g)and then stirred at 110°C for 1 hour. The reaction mixture was cooled to room temperature and then added to it the chloroform and water. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-90% chloroform/methanol]and then purified according to the method of column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-93% chloroform/methanol], to obtain 0.18 g of 2-(benzyloxy)-N-(5-phenyl-2-(1H-tetrazol-5-yl)phenyl)-5-(piperidine-1-yl)benzamide as a brown solid.

To a solution of the obtained 2-(benzyloxy)-N-(5-phenyl-2-(1H-tetrazol-5-yl)phenyl)-5-(piperidine-1-yl)benzamide (0,095 g) in a mixture of ethyl acetate (6.0 ml) and methanol (3.0 ml) was added 10% of ballad rowany coal (0,050 g), and then was stirred in hydrogen atmosphere at room temperature for 1 hour. To the reaction mixture was added 10% palletirovanie coal (0,050 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. Insoluble substances were removed by filtration, and then the solvent evaporated under reduced pressure. To the obtained residue was added ethyl acetate (2.0 ml) and 4.0 mol/l solution of florodora in ethyl acetate (2.0 ml)and then stirred at room temperature for 10 minutes. The solid substance was collected from the reaction mixture by filtration to obtain 0,016 g of the hydrochloride of 2-hydroxy-N-(5-phenyl-2-(1H-tetrazol-5-yl)phenyl)-5-(piperidine-1-yl)benzamide in the form of a brownish-red solid.

1H-NMR (DMSO-d6) δ: 1.56 to around 1.74 (2H, m), 1,87 is 2.01 (4H, m), 3,24-3,70 (4H, m), 7,18 (1H, d, J=9.0 Hz), 7,43-7,50 (1H, m), 7,50-of 7.60 (2H, m), 7,72 (1H, DD, J=8,2, 1.8 Hz), 7,75-7,89 (3H, m), with 8.05 (1H, d, J=8.0 Hz), compared to 8.26-of 8.37 (1H, m), 8,86 (1H, d, J=2.0 Hz), 11,67 (1H, s), 11,82-12,09 (1H, broadened).

1H-NMR (DMSO-d6-D2O) δ: 1.60-to of 1.73 (2H, m), 1,86-to 1.98 (4H, m), of 3.54 (4H, t, J=5.4 Hz), 7,22 (1H, d, J=9.0 Hz), 7,45-7,52 (1H, m), 7,53 to 7.62 (2H, m), 7,73 (1H, DD, J=8,1, 1.8 Hz), 7,73-of 7.82 (3H, m), 8,02 (1H, d, J=8.1 Hz), 8,23 (1H, d, J=3.0 Hz), 8,81 (1H, d, J=1,8 Hz).

Example 173a

To a solution of methyl 2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate (0.40 g) in 1-methyl-2-pyrrolidone (2.0 ml) was added carbonate ka the Oia (0.12 g) and 1-(tert-butoxycarbonyl)piperidine (0.15 g), and then was stirred at 90°C for 45 minutes. The reaction mixture was cooled to room temperature and then added to her water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-0% hexane/ethyl acetate] to obtain 0.36 g of tert-butyl 4-(2-(4-(benzyloxy)-3-(2-(methoxycarbonyl)-5-phenylenecarbonyl)phenoxy)ethyl)piperidine-1-carboxylate as a white solid.

When cooled on ice to a solution of the obtained tert-butyl 4-(2-(4-(benzyloxy)-3-(2-(methoxycarbonyl)-5-phenylenecarbonyl)phenoxy)ethyl)piperidine-1-carboxylate (0.36 g) in methylene chloride (5.0 ml) was added triperoxonane acid (1.0 ml)and then stirred at room temperature for 4 hours. To the reaction mixture were added water. After adjusting the pH to 8.0 by the addition of saturated aqueous sodium bicarbonate solution the organic layer was separated, washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure obtaining of 0.30 g of methyl 2-(2-(benzyloxy)-5-(2-(piperaz the n-1-yl)ethoxy)benzamido)-4-phenylbenzoate in the form of a yellow oily substance.

1H-NMR (CDCl3) δ: 2,48-2,63 (4H, m), 2,78 (2H, t, J=5.7 Hz), only 2.91 (4H, t, J=4.9 Hz), 3,76 (3H, s), of 4.12 (2H, t, J=5.7 Hz), 5,38 (2H, s), 6,91-7,01 (2H, m), 7.23 percent-7,52 (9H, m), 7.68 per-to 7.77 (3H, m), 8,08 (1H, d, J=8,3 Hz), 9,26 (1H, d, J=1.7 Hz), 12,31 (1H, s).

Example 174a

To a solution of methyl 2-(2-(benzyloxy)-5-(2-(piperazine-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0,084 g) in 2-butanone (1.3 ml) was added potassium carbonate (0,031 g) and 3-bromo-1-propanol (0,013 ml)and then heated under reflux for 1 hour. The reaction mixture was cooled to room temperature, and then was added a saturated aqueous solution of sodium bicarbonate and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-91% chloroform/methanol] to obtain 0.036 g of methyl 2-(2-(benzyloxy)-5-(2-(4-(3-hydroxypropyl)piperazine-1-yl)ethoxy)benzamido)-4-phenylbenzoate in the form of a light yellow oily substance.

To a solution of the obtained methyl 2-(2-(benzyloxy)-5-(2-(4-(3-hydroxypropyl)piperazine-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0.036 g) in a mixture of ethyl acetate (1.5 ml) and methanol (1.5 ml) was added 10% palletirovanie coal (0,018 g), and then paramashiva and in an atmosphere of hydrogen at room temperature for 2 hours and 30 hours. To the reaction mixture was added 10% palletirovanie coal (0,018 g)and then stirred in a hydrogen atmosphere at room temperature for 3 hours. Insoluble substances were removed by filtration, and then the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain to 0.011 g of methyl 2-(2-hydroxy-5-(2-(4-(3-hydroxypropyl)piperazine-1-yl)ethoxy)benzamido)-4-phenylbenzoate in the form of a light yellow solid.

To a solution of the obtained methyl 2-(2-hydroxy-5-(2-(4-(3-hydroxypropyl)piperazine-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0,011 g) in a mixture of methanol (1.0 ml) and dioxane (1.0 ml) was added a 2.0 mol/l aqueous solution of sodium hydroxide (0,031 ml)and then stirred at 50°C for 1 hour. To the reaction mixture was added 2 mol/l aqueous solution of sodium hydroxide (0,031 ml)and then stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature and then added to her water. After adjusting the pH to 6.5 by adding 1.0 mol/l hydrochloric acid was added ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined. The resulting mixture was washed with a saturated aqueous solution of CHL is reed sodium and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain a 6.5 mg of 2-(2-hydroxy-5-(2-(4-(3-hydroxypropyl)piperazine-1-yl)ethoxy)benzamido)-4-vinylbenzoic acid as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 1.70 to of 1.84 (2H, m), 2,84-3,90 (14H, m), is 4.15 (2H, t, J=4,8 Hz)6,91 (1H, d, J=9.0 Hz), to 7.15 (1H, DD, J=8,9, 2,8 Hz), 7,38 was 7.45 (2H, m), of 7.48-of 7.55 (2H, m), of 7.64 (1H, d, J=2,9 Hz), to 7.67-7,73 (2H, m), 8,13 (1H, d, J=8.1 Hz), of 8.92 (1H, d, J=1.7 Hz).

1H-NMR (DMSO-d6) δ: 1,72-to 1.87 (2H, m), 2,75-3,35 (12H, m), 3,49 (2H, t, J=6,1 Hz), 4,13-4,22 (2H, m)6,94 (1H, d, J=9.0 Hz), 7,17 (1H, DD, J=9,0, 2.7 Hz), 7,38-of 7.48 (2H, m), 7,49-7,58 (2H, m), EUR 7.57 (1H, d, J=2.7 Hz), 7,66-of 7.75 (2H, m)to 8.14 (1H, d, J=8.0 Hz), of 8.90 (1H, d, J=1.7 Hz).

Example 175a

When cooled on ice to a solution of methyl 2-(2-(benzyloxy)-5-(2-(piperazine-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0.12 g) in a mixture of methylene chloride (2.4 ml) and pyridine (0,027 ml) was added acetic anhydride (0,025 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent evaporated in terms Pont is a negative pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-95% chloroform/methanol] to obtain methyl 2-(5-(2-(4-acetylpiperidine-1-yl)ethoxy)-2-(benzyloxy)benzamido)-4-phenylbenzoate in the form of a colorless oily substance.

To a solution of the obtained methyl 2-(5-(2-(4-acetylpiperidine-1-yl)ethoxy)-2-(benzyloxy)benzamido)-4-phenylbenzoate in a mixture of ethyl acetate (1.5 ml) and methanol (1.5 ml) was added 10% palletirovanie charcoal (0.15 g)and then stirred in a hydrogen atmosphere at room temperature for 1 hour and 30 minutes. To the reaction mixture were added chloroform and methanol. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0.083 g of methyl 2-(5-(2-(4-acetylpiperidine-1-yl)ethoxy)-2-hydroxybenzamide)-4-phenylbenzoate in the form of a light yellow solid.

To a suspension of the obtained methyl 2-(5-(2-(4-acetylpiperidine-1-yl)ethoxy)-2-hydroxybenzamide)-4-phenylbenzoate (0.083 g) in 2-propanol (1.5 ml) was added a 2.0 mol/l aqueous solution of sodium hydroxide (0,24 ml)and then stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature, and added to her water. After adjusting the values of pH to 6.5 by adding 1.0 mol/l hydrochloric acid, the solvent is evaporated under reduced pressure. To the obtained residue was added water, and collecting the solid by filtration. To the obtained solid substance was added ethyl acetate (2.0 ml) and 4.0 mol/l solution of florodora in dioxane (0.10 ml)and then stirred at room temperature for 3 hours and 30 minutes. The solid substance was collected from the reaction mixture by filtration to obtain 0,038 g of the hydrochloride of 2-(5-(2-(4-acetylpiperidine-1-yl)ethoxy)-2-hydroxybenzamide)-4-vinylbenzoic acid as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 2,05 (3H, s), 2,96-3,30 (3H, m), 3,44-a-3.84 (5H, m), 3,90-of 4.12 (1H, m), 4,34-4,49 (3H, m), 7,02 (1H, d, J=8,8 Hz), to 7.15 (1H, DD, J=8,8, 2,9 Hz), 7,42-to 7.59 (5H, m), 7,70-7,76 (2H, m), of 8.09 (1H, d, J=8,3 Hz), 9,02-9,06 (1H, m), 11,00-11,20 (2H, m), 12,31 (1H, s).

Example 176a

When cooled on ice to a solution of methyl 2-(2-(benzyloxy)-5-(2-(piperazine-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0.11 g) in a mixture of methylene chloride (2.2 ml) and pyridine (0,024 ml) was added methanesulfonamide (0,018 ml)and then stirred at room temperature for 1 hour. To the reaction mixture was sequentially added pyridine (0,016 ml) and methanesulfonamide (9,0 ml)and then stirred at room temperature for 1 hour and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and ethyl acetate. About the organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 50-0% hexane/ethyl acetate] to obtain of 0.085 g of methyl 2-(2-(benzyloxy)-5-(2-(4-(methylsulphonyl)piperazine-1-yl)ethoxy)benzamido)-4-phenylbenzoate in the form of a white solid.

To a solution of the obtained methyl 2-(2-(benzyloxy)-5-(2-(4-(methylsulphonyl)piperazine-1-yl)ethoxy)benzamido)-4-phenylbenzoate (of 0.085 g) in a mixture of ethyl acetate (3.0 ml), methanol (1.5 ml) and dioxane (6.0 ml) was added 10% palletirovanie coal (of 0.085 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0,063 g of methyl 2-(2-hydroxy-5-(2-(4-(methylsulphonyl)piperazine-1-yl)ethoxy)benzamido)-4-phenylbenzoate in the form of a light yellow solid.

To a suspension of the obtained methyl 2-(2-hydroxy-5-(2-(4-(methylsulphonyl)piperazine-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0,063 g) in 2-propanol (1.2 ml) was added a 2.0 mol/l aqueous solution of hydroxide intothree the (0.17 ml), and then was stirred at 50°C for 2 hours. The reaction mixture was cooled to room temperature and then added to her water. After adjusting the pH to 6.5 by adding 1.0 mol/l hydrochloric acid, the solid was collected by filtration. To the obtained solid substance was added ethyl acetate (2.0 ml) and 4.0 mol/l solution of florodora in dioxane (0.10 ml)and then stirred at room temperature for 1 hour. The solid substance was collected from the reaction mixture by filtration to obtain 0.025 g of the hydrochloride of 2-(2-hydroxy-5-(2-(4-(methylsulphonyl)piperazine-1-yl)ethoxy)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (CD3OD) δ: 2,98 (3H, s), 3.46 in-3,74 (8H, m), 3,71 (2H, t, J=4.9 Hz), of 4.44 (2H, t, J=4.9 Hz), 6,98 (1H, d, J=9.0 Hz), 7,22 (1H, DD, J=9,0, 3.2 Hz), 7,39-7,46 (1H, m), 7,47-7,53 (3H, m), 7,54 (1H, d, J=3.2 Hz), 7,70 to 7.75 (2H, m), by 8.22 (1H, d, J=8.1 Hz), 9,06 (1H, d, J=1.7 Hz).

Example 177a

To a solution of methyl 2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate (0.25 g) in 1-methyl-2-pyrrolidone (1.3 ml) was added potassium carbonate (0.15 g) and azetidine hydrochloride (0,046 g)and then stirred at 90°C for 45 minutes. The reaction mixture was cooled to room temperature and then added to her water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over besod the first sodium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-90% chloroform/methanol] to obtain 0,088 g of methyl 2-(5-(2-(azetidin-1-yl)ethoxy)-2-(benzyloxy)benzamido)-4-phenylbenzoate in the form of a light yellow oily substance.

To a solution of the obtained methyl 2-(5-(2-(azetidin-1-yl)ethoxy)-2-(benzyloxy)benzamido)-4-phenylbenzoate (0,088 g) in a mixture of ethyl acetate (1.5 ml), methanol (1.5 ml) and dioxane (1.5 ml) was added 10% palletirovanie coal (0,088 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture was added 10% palletirovanie coal (0,088 g)and then stirred in a hydrogen atmosphere at room temperature for 3 hours. Insoluble substances were removed by filtration, and then the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0,033 g of methyl 2-(5-(2-(azetidin-1-yl)ethoxy)-2-hydroxybenzamide)-4-phenylbenzoate in the form of a light yellow solid.

To a suspension of the obtained methyl 2-(5-(2-(azetidin-1-yl)ethoxy)-2-hydroxybenzamide)-4-phenylbenzoate (0,032 g) in 2-propanol (1.0 ml) was added a 2.0 mol/l aqueous solution of sodium hydroxide (0,11 ml)and then stirred at 50°C more than the s 1 hour. The reaction mixture was cooled to room temperature, and added to her water. After adjusting the pH to 6.0 by adding 1.0 mol/l hydrochloric acid, the solid was collected by filtration. To the obtained solid substance was added ethyl acetate (1.5 ml) and 4.0 mol/l solution of florodora in dioxane (0.10 ml)and then stirred at room temperature for 1 hour and 30 minutes. The solid substance was collected from the reaction mixture by filtration to obtain 0,021 g of the hydrochloride of 2-(5-(2-(azetidin-1-yl)ethoxy)-2-hydroxybenzamide)-4-vinylbenzoic acid as a pale yellow solid.

1H-NMR (CD3OD) δ: 2,40-to 2.55 (1H, m), 2,58-by 2.73 (1H, m), 3,66 (2H, t, J=4.9 Hz), 4,22-4,36 (6H, m), of 6.96 (1H, d, J=9.0 Hz), 7,18 (1H, DD, J=9,0, 3.1 Hz), 7,39-7,47 (1H, m), 7,47-of 7.55 (4H, m), 7,70-7,76 (2H, m), by 8.22 (1H, d, J=8,3 Hz), 9,07 (1H, d, J=1.7 Hz).

Examples 178a-182a

Compounds shown in Table 20a, obtained as described in Example 177a.

Table 20a
Example No.R7Example No.R7Example No.R7
178a 180a182a

179a181a

2-(2-Hydroxy-5-(2-(4-hydroxypiperidine-1-yl)ethoxy)benzamido)-4-vinylbenzoic acid hydrochloride

1H-NMR (DMSO-d6) δ: 1.60-to is 1.82 (2H, m), 1,89-2,02 (2H, m), 2,98-3,72 (7H, m), 4,30-and 4.40 (2H, m), 4,94-5,14 (1H, m), 7,01 (1H, d, J=8,8 Hz), to 7.15 (1H, DD, J=8,8, 3.2 Hz), 7,43-EUR 7.57 (5H, m), 7,70 to 7.75 (2H, m), of 8.09 (1H, d, J=8.0 Hz), 9,03 (1H, d, J=1.7 Hz), 9,80-10,02 (1H, broadened), 11,08 (1H, s), 12,36 (1H, s).

2-(2-Hydroxy-5-(2-(4-(2-hydroxymethyl)piperidine-1-yl)ethoxy)benzamido)-4-vinylbenzoic acid hydrochloride

1H-NMR (DMSO-d6) δ: 1,40-1,72 (3H, m), of 1.78-1.90 (2H, m), 2.95 and-3,10 (2H, m), 3,18-of 3.64 (6H, m), 4,30-and 4.40 (2H, m), 4,58-4,74 (1H, broadened), 7,01 (1H, d, J=9.0 Hz), to 7.15 (1H, DD, J=9,0, 3.1 Hz), 7,43-7,58 (5H, m), 7,70 to 7.75 (2H, m), 8,10 (1H, d, J=8.0 Hz), 9,04 (1H, s), 9,60-9,88 (1H, broadened), 11,09 (1H, s), 12,30-12,46 (1H, broadened).

2-(2-Hydroxy-5-(2-(4-(hydroxyethyl)piperidine-1-yl)ethoxy)benzamido)-4-vinylbenzoic acid hydrochloride

1H-NMR (DMSO-d6) δ: 1.30 and of 1.74 (5H, m), 1,76-of 1.94 (2H, m), 2,93-to 3.09 (2H, m), 3,40-of 3.64 (6H, m), 4,28-4,56 (3H, m), 7,01 (1H, d, J=8 Hz), 7,14 (1H, DD, J=8,9, 3.0 Hz), 7,43-7,58 (5H, m), 7,70 to 7.75 (2H, m), of 8.09 (1H, d, J=8,3 Hz), 9,04 (1H, d, J=1.7 Hz), 9,66-9,94 (1H, broadened), 11,08 (1H, s), 12,35 (1H, s).

2-(5-(2-(Homopiperazin-1-yl)ethoxy)-2-hydroxybenzamide)-4-vinylbenzoic acid hydrochloride

1H-NMR (DMSO-d6) δ: 1,53-of 1.73 (4H, m), 1,76-of 1.92 (4H, m), 3,18-of 3.60 (6H, m), 4,35 (2H, t, J=4.9 Hz), 7,01 (1H, d, J=9.0 Hz), to 7.15 (1H, DD, J=9,0, 3.2 Hz), 7,42-7,58 (5H, m), 7,69-7,76 (2H, m), of 8.09 (1H, d, J=8,3 Hz), 9,04 (1H, d, J=1.7 Hz), 9,98-10,14 (1H, broadened), 11,08 (1H, s), of 12.33 (1H, s), 13,30-13,52 (1H, broadened).

2-(5-(2-(Ethyl(2-hydroxyethyl)amino)ethoxy)-2-hydroxybenzamide)-4-vinylbenzoic acid hydrochloride

1H-NMR (DMSO-d6) δ: of 1.28 (3H, t, J=7.2 Hz), 3,18-of 3.42 (4H, m), 3,52-the 3.65 (2H, m), with 3.79 (2H, t, J=5.0 Hz), 4,36 (2H, t, J=5,0), 5,26-5,49 (1H, broadened), 7,02 (1H, d, J=8,9 Hz), 7,14 (1H, DD, J=8,9, and 3.2 Hz), 7,43-7,58 (5H, m), 7,69-7,76 (2H, m), of 8.09 (1H, d, J=8.0 Hz), 9,04 (1H, d, J=1.7 Hz), 9,72-10,00 (1H, broadened), 11,10 (1H, s), 12,36 (1H, s).

Example 183a

To a solution of methyl 2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate (0,080 g) in acetone (1.6 ml) was added potassium carbonate (0.14 g) and 1-propylpiperazine the dihydrochloride (0.12 g)and then heated under reflux for 4 hours. After cooling the reaction mixture to room temperature, the solvent evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and chloroform. The organic layer was separated and dried over anhydrous sulfate n is sodium, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain of 0.081 g of methyl 2-(2-(benzyloxy)-5-(2-(4-propylpiperazine-1-yl)ethoxy)benzamido)-4-phenylbenzoate in the form of a light yellow oily substance.

To a solution of methyl 2-(2-(benzyloxy)-5-(2-(4-propylpiperazine-1-yl)ethoxy)benzamido)-4-phenylbenzoate (of 0.081 g) in a mixture of methanol (1.5 ml) and ethyl acetate (1.5 ml) was added 10% palletirovanie coal (of 0.081 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. To the reaction mixture were added chloroform. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0,043 g of methyl 2-(2-hydroxy-5-(2-(4-propylpiperazine-1-yl)ethoxy)benzamido)-4-phenylbenzoate as an orange solid.

To the obtained methyl 2-(2-hydroxy-5-(2-(4-propylpiperazine-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0,043 g) was added methanol (2.0 ml) and 2.0 mol/l aqueous solution of sodium hydroxide (0,12 ml)and then stirred at 50°C for 1 hour. To the reaction mixture was added 2 mol/l aqueous solution of the hydroxide is sodium (0.25 ml), and then was stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature and then added to her water. After adjusting the pH to 6.0 by adding a 2.0 mol/l hydrochloric acid, the solid was collected by filtration. To the obtained solid substance was added ethyl acetate (3.0 ml) and methanesulfonyl acid (9,2 μl)and then stirred at room temperature for 4 hours. The solid substance was collected from the reaction mixture by filtration to obtain 0.035 g dimethanesulfonate 2-(2-hydroxy-5-(2-(4-propylpiperazine-1-yl)ethoxy)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (CD3OD) δ: of 1.05 (3H, t, J=7.4 Hz), 1,74-of 1.88 (2H, m), of 2.72 (6H, s), 3,17-3,26 (2H, m), 3,45-3,90 (10H, m), 4,43 (2H, t, J=4.9 Hz), 6,97 (1H, d, J=9.0 Hz), 7,22 (1H, DD, J=9,0, 3.2 Hz), 7,39-7,56 (5H, m), 7,69-7,76 (2H, m), by 8.22 (1H, d, J=8,3 Hz), 9,06 (1H, d, J=1.7 Hz).

Examples 184a and 185a

Compounds shown in Table 21a, obtained as described in Example 183a.

Table 21a
Example No.R7Example No.R7
184a

2-(2-Hydroxy-5-(2-(4-isopropylpiperazine-1-yl)ethoxy)benzamido)-4-vinylbenzoic acid dimethanesulfonate

1H-NMR (CD3OD) δ: USD 1.43 (6H, d, J=6.6 Hz), of 2.72 (6H, s), 3,40-4,00 (11H, m), 4,43 (2H, t, J=4.9 Hz), 6,97 (1H, d, J=9.0 Hz), 7,22 (1H, DD, J=9,0, 2,9 Hz), 7,39-7,46 (1H, m), 7,47-7,56 (4H, m), 7,70-7,76 (2H, m), by 8.22 (1H, d, J=8,3 Hz), 9,06 (1H, d, J=1.7 Hz).

2-(2-Hydroxy-5-(2-(4-(2-hydroxyethyl)piperazine-1-yl)ethoxy)benzamido)-4-vinylbenzoic acid dimethanesulfonate

1H-NMR (CD3OD) δ: 2,73 (6H, s), 3,39-3,47 (2H, m), 3,60-3,90 (10H, m), 3,90-3,98 (2H, m), 4,40-4,48 (2H, m), 6,97 (1H, d, J=9.0 Hz), 7.23 percent (1H, DD, J=9,0, 3.1 Hz), 7,39-of 7.55 (5H, m), 7.68 per to 7.75 (2H, m), to 8.20 (1H, d, J=8,3 Hz), 9,05 (1H, d, J=1.7 Hz).

Example 186a

To a solution of methyl 2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate (2.0 g) in acetone (20 ml) was added potassium carbonate (2.0 g) and thiomorpholine (1.1 ml)and then heated under reflux for 4 hours. The reaction mixture was cooled to room temperature, was added thereto thiomorpholine (0,55 ml)and then heated under reflux for 2 hours 30 minutes. After cooling the reaction mixture to room temperature, the solvent evaporated under reduced pressure, and was added to the residue water and chloroform. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent evaporated in condition is the conditions of reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 70 pass within 40% hexane/ethyl acetate] to obtain 1.9 g of methyl 2-(2-(benzyloxy)-5-(2-(thiomorpholine-4-yl)ethoxy)benzamido)-4-phenylbenzoate in the form of a white solid.

To the obtained methyl 2-(2-(benzyloxy)-5-(2-(thiomorpholine-4-yl)ethoxy)benzamido)-4-phenylbenzoate (0,80 g) was added thioanisole (3.2 ml) and triperoxonane acid (10 ml)and then stirred at room temperature for 18 hours. The solvent is evaporated under reduced pressure, and was added to the residue saturated aqueous sodium bicarbonate solution and chloroform. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 70-0% hexane/ethyl acetate 100-95% chloroform/methanol] to obtain 0.54 g of methyl 2-(2-hydroxy-5-(2-(thiomorpholine-4-yl)ethoxy)benzamido)-4-phenylbenzoate in the form of a brown solid.

To the obtained methyl 2-(2-hydroxy-5-(2-(thiomorpholine-4-yl)ethoxy)benzamido)-4-phenylbenzoate (0.15 g) was added methanol (5.0 ml) and 2.0 mol/l aqueous sodium hydroxide solution (1.5 ml), and then paramesh the Wali at 40-50°C for 1 hour and 30 minutes. After cooling the reaction mixture to room temperature and adjust pH to 6.8 by adding 10% aqueous citric acid solution, the solid is collected by filtration. To the obtained solid substance was added ethyl acetate (5.0 ml) and methanesulfonyl acid (0,015 ml)and then stirred at room temperature for 1 hour. The solid substance was collected from the reaction mixture by filtration to obtain 0.12 g methanesulfonate 2-(2-hydroxy-5-(2-(thiomorpholine-4-yl)ethoxy)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (CD3OD) δ: 2,69 (3H, s), 2.95 and-3,11 (4H, m), 3,50-a 3.83 (4H, m), the 3.65 (2H, t, J=5.0 Hz), to 4.41 (2H, t, J=5.0 Hz), to 6.95 (1H, d, J=9.0 Hz), 7,19 (1H, DD, J=9,0, 3.2 Hz), 7,38-7,53 (5H, m), 7.68 per-7,74 (2H, m), 8,19 (1H, d, J=8,3 Hz), 9,05 (1H, d, J=1.7 Hz).

Example 187a

To a solution of methyl 2-(2-(benzyloxy)-5-hydroxybenzamide)-4-phenylbenzoate (0.50 g) in tetrahydrofuran (5.0 ml) was added tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (0.26 g), triphenylphosphine (0.35 g) and diisopropylethylamine (0,26 ml)and then stirred at room temperature for 30 minutes. To the reaction mixture was added triphenylphosphine (0.35 g) and diisopropylethylamine (0,26 ml)and then stirred at room temperature for 30 minutes. To the reaction mixture was added triphenylphosphine (0.35 g) and diisopropyl who, in primary forms (of 0.26 ml), and then was stirred at room temperature for 30 minutes. The solvent is evaporated under reduced pressure and purify the resulting residue by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane/ethyl acetate] to obtain methyl 2-(2-(benzyloxy)-5-((1-(tert-butoxycarbonyl)piperidine-4-yl)methoxy)benzamido)-4-phenylbenzoate in the form of a yellow oily substance.

When cooled on ice to a solution of the obtained methyl 2-(2-(benzyloxy)-5-((1-(tert-butoxycarbonyl)piperidine-4-yl)methoxy)benzamido)-4-phenylbenzoate in methylene chloride (9.4 ml) was added triperoxonane acid (1.9 ml)and then stirred at room temperature for 30 minutes. The reaction mixture while cooling on ice was added to saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain of 0.30 g of methyl 2-(2-(benzyloxy)-5-(piperidine-4-ylethoxy)benzamido)-4-phenylbenzoate in the form of a light yellow solid.

1H-NMR (DMSO-d6-D-sub> 2O) δ: 1,10-of 1.23 (2H, m), 1,64-of 1.74 (2H, m), 1,74 is 1.86 (1H, m), 2,41-2,52 (2H, m), 2,89 are 2.98 (2H, m), 3,76 (3H, s), with 3.79 (2H, d, J=6.3 Hz), of 5.39 (2H, s), 7,11 (1H, DD, J=9,0, 3.2 Hz), 7,21 (1H, d, J=9.0 Hz), 7,25-to 7.35 (3H, m), 7,43-7,51 (4H, m), 7,52-to 7.59 (3H, m), 7,70-7,76 (2H, m), 8,07 (1H, d, J=8,3 Hz), 9,04 (1H, d, J=1.5 Hz).

Example 188a

The following compound was obtained as described in Example 187a.

Methyl-2-(2-(benzyloxy)-5-(2-(piperidine-4-yl)ethoxy)benzamido)-4-phenylbenzoate

1H-NMR (DMSO-d6) δ: 1.10 is of 1.28 (2H, m), of 1.57-1.77 in (5H, m), 2,56-to 2.67 (2H, m), 3.00 and-3,10 (2H, m), 3,76 (3H, s), 3.96 points-4,06 (2H, m), 5,41 (2H, s), 7,10 (1H, DD, J=9,2, a 3.2 Hz), 7,20 (1H, d, J=9,2 Hz), 7,24 and 7.36 (3H, m), 7,43-to 7.59 (7H, m), 7,70-to 7.77 (2H, m), 8,07 (1H, d, J=8,3 Hz), 9,04-of 9.09 (1H, m), a 12.03 (1H, s).

Example 189a

To a solution of methyl 2-(2-(benzyloxy)-5-(piperidine-4-ylethoxy)benzamido)-4-phenylbenzoate (0,13 g) in chloroform (1.9 ml), was added 37% aqueous formaldehyde solution (0.17 ml) and triacetoxyborohydride sodium (0,073 g)and then stirred at room temperature for 1 hour and 30 minutes. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and chloroform. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to receive the receiving 0.11 g of methyl 2-(2-(benzyloxy)-5-((1-methylpiperidin-4-yl)methoxy)benzamido)-4-phenylbenzoate in the form of a colorless oily substance.

To a solution of the obtained methyl 2-(2-(benzyloxy)-5-((1-methylpiperidin-4-yl)methoxy)benzamido)-4-phenylbenzoate (0.11 g) in a mixture of ethyl acetate (1.5 ml) and methanol (1.5 ml) was added 10% palletirovanie coal (0.11 g)and then stirred in a hydrogen atmosphere at room temperature for 1 hour and 30 minutes. To the reaction mixture were added chloroform. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0,070 g of methyl 2-(2-hydroxy-5-((1-methylpiperidin-4-yl)methoxy)benzamido)-4-phenylbenzoate in the form of a light yellow solid.

To a suspension of the obtained methyl 2-(2-hydroxy-5-((1-methylpiperidin-4-yl)methoxy)benzamido)-4-phenylbenzoate (0,070 g) in 2-propanol (1.0 ml) was added a 2.0 mol/l aqueous solution of sodium hydroxide (0,37 ml)and then stirred at 50°C for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature and then added to her water. After adjusting the pH to 6.0 by adding 1 mol/l hydrochloric acid, the solid was collected by filtration. To the obtained solid substance was added ethyl acetate (2.0 ml) and 4 mol/l solution of florodora in dioxane (0,20 ml)and then stirred at room temperature for 2 hours. Solid is emesto collected from the reaction mixture by filtration to obtain 0,058 g of the hydrochloride of 2-(2-hydroxy-5-(1-methylpiperidin-4-ylethoxy)benzamido)-4-vinylbenzoic acid as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 1,47-to 1.63 (2H, m), 1,82-2,04 (3H, m), 2,70-and 2.79 (3H, m), 2,88-3,03 (2H, m), 3,40-to 3.49 (2H, m), 3,82-to 3.89 (2H, m), 6,97 (1H, d, J=9.0 Hz), was 7.08 (1H, DD, J=9,0, 3.1 Hz), 7,43-7,58 (5H, m), 7,69-7,76 (2H, m), of 8.09 (1H, d, J=8,3 Hz), of 9.02 (1H, d, J=1.7 Hz), 9,66-9,80 (1H, broadened), 11,03 (1H, s)to 12.28-12,38 (1H, broadened), 13,38-13,52 (1H, broadened).

Example 190a

The following compound was obtained as described in Example 189a.

2-(2-Hydroxy-5-(2-(1-methylpiperidin-4-yl)ethoxy)benzamido)-4-vinylbenzoic acid hydrochloride

1H-NMR (DMSO-d6-D2O) δ: of 1.33 to 1.48 (2H, m), 1,64-of 1.88 (3H, m), 1,88-to 1.98 (2H, m), is 2.74 (3H, s), 2,87 are 2.98 (2H, m), 3,36 is-3.45 (2H, m), 3,97-4,06 (2H, m), 6,97 (1H, d, J=8,8 Hz), was 7.08 (1H, DD, J=8,8, 3.2 Hz), 7,42-to 7.50 (2H, m), 7,51-to 7.59 (3H, m), 7,70-7,76 (2H, m), 8,11 (1H, d, J=8,3 Hz), 9,01 (1H, d, J=1.7 Hz).

Examples 191a-194a

Compounds shown in Table 22a, obtained as described in Example 164a.

Table 22a
Example No.R7Example No.R7
191a193a
192a 194a

2-(5-((2S,6R)-2,6-Dimethylmorpholine-4-yl)-2-hydroxybenzamide)-4-phenylbenzene acid

1H-NMR (DMSO-d6) δ: of 1.16 (6H, d, J=6,1 Hz), 2,22 (2H, DD, J=11,0, a 10.6 Hz), 3,44 (2H, d, J=a 10.6 Hz), 3,67-of 3.78 (2H, m), 6,92 (1H, d, J=8,8 Hz), 7,16 (1H, DD, J=8,8, 3.0 Hz), 7,42-7,58 (5H, m), 7,70-7,76 (2H, m), of 8.09 (1H, d, J=8,3 Hz), 9,03 (1H, d, J=1.7 Hz), 10,89 (1H, s), 12,24-12,36 (1H, broadened).

2-(2-Hydroxy-5-(1,4-oxazepan-4-yl)benzamido)-4-phenylbenzene acid

1H-NMR (DMSO-d6) δ: 1,88-to 1.98 (2H, m), 3,51-3,62 (6H, m), 3,71-of 3.77 (2H, m), to 6.88 (1H, d, J=9.0 Hz), 6,98 (1H, DD, J=9,0, 2,9 Hz), 7,21 (1H, d, J=2,9 Hz), 7,42-7,58 (4H, m), 7,70-to 7.77 (2H, m), 8,10 (1H, d, J=8,3 Hz), 9,03 (1H, d, J=1.7 Hz), is 10.68 (1H, s), 12,30-12,42 (1H, broadened).

2-(2-Hydroxy-5-(4-methyl-3-oxopiperidin-1-yl)benzamido)-4-phenylbenzene acid

1H-NMR (DMSO-d6+D2O) δ: 2.91 in (3H, s), 3,36-of 3.48 (4H, m), of 3.69 (2H, s), 6,98 (1H, d, J=9.0 Hz), 7,21 (1H, DD, J=9,0, 2,9 Hz), the 7.43 (1H, d, J=2,9 Hz), 7,44-of 7.60 (4H, m), 7,70 for 7.78 (2H, m)to 8.12 (1H, d, J=8,3 Hz), 8,97 (1H, d, J=1.7 Hz).

2-(5-(4-Ethyl-3-oxopiperidin-1-yl)-2-hydroxybenzamide)-4-phenylbenzene acid

1H-NMR (DMSO-d6) δ with 1.07 (3H, t, J=7,1 Hz), 3,15-of 3.48 (6H, m), 3,68 (2H, s)6,94 (1H, d, J=8,9 Hz), 7,21 (1H, DD, J=8,9, 2,9 Hz), 7,40-EUR 7.57 (5H, m), 7.68 per-7,76 (2H, m), 8,10 (1H, d, J=8,3 Hz), 8,99 (1H, d, J=1.9 Hz), 11,02-11,22 (1H, broadened).

1H-NMR (DMSO-d6-D2O) δ: 1,08 (3H, t, J=7.2 Hz), 3,34-3,50 (6H, m), of 3.69 (2H, s), 6,97 (1H, d, J=9.0 Hz), 7,21 (1H, DD, J=9,0, 3.0 Hz), 7,42-to 7.59 (4H, m), the 7.43 (1H, d, J=3.0 Hz), 7,70-to 7.77 (2H, m)to 8.12 (1H, d, J=8,3 Hz), 8,97 (1H, d, J=1.7 Hz).

Example 195a

The following compound was obtained as described in Example 164a.

2-(2-Hydroxy-4-(morpholine-4-yl)benzamido)-4-phenylbenzene acid

1H-NMR (DMSO-d6) δ: 3,22 be 3.29 (4H, m), 3,69-of 3.77 (4H, m), 6,40 (1H, d, J=2.4 Hz), only 6.64 (1H, DD, J=9,3, 2.4 Hz), 7,42-EUR 7.57 (4H, m), 7,69-7,76 (3H, m), 8,10 (1H, d, J=8,3 Hz), of 8.95 (1H, d, J=2.0 Hz), 11,85 (1H, s), 12,19-to 12.28 (1H, broadened).

Example 196a

To tert-butyl 2-(2-(benzyloxy)-5-(morpholine-4-yl)benzamido)-4-bromobenzoate (0.20 g) was added dimethyl ether of ethylene glycol (2.0 ml), water (0,60 ml), furan-2-Bronevoy acid (0,047 g), sodium carbonate (0,093 g) dichloride and bis(triphenylphosphine)palladium(II) (4,9 mg)and then stirred at 75°C for 2 hours. The reaction mixture was cooled to room temperature, was added thereto dichloride bis(triphenylphosphine)palladium(II) (4,9 mg)and then stirred at 75°C for 2 hours. The reaction mixture was cooled to room temperature, and added to her water and ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 85-70% hexane/ethyl acetate] to obtain 0.14 g of tert-butyl 2-(2-(benzyloxy)-5-(morpholine-4-yl)benzamido)-4-(furan-2-yl)benzoate as a pale yellow solid which substances.

To a solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(morpholine-4-yl)benzamido)-4-(furan-2-yl)benzoate (0.14 g) in a mixture of methanol (2.0 ml) and ethyl acetate (2.0 ml) was added 10% palletirovanie coal (0,029 g)and then stirred in a hydrogen atmosphere at room temperature for 1 hour. To the reaction mixture were added chloroform. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 85-75% hexane/ethyl acetate] to obtain of 0.085 g of tert-butyl 4-(furan-2-yl)-2-(2-hydroxy-5-(morpholine-4-yl)benzamido)benzoate as a yellow solid.

To the obtained tert-butyl-4-(furan-2-yl)-2-(2-hydroxy-5-(morpholine-4-yl)benzamido)benzoate (of 0.085 g) was added triperoxonane acid (2.0 ml)and then stirred at room temperature for 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue water and 2-propanol. After adjusting the pH to 6.0 by the addition of saturated aqueous sodium bicarbonate solution, the solid was collected by filtration to obtain 0,064 g of 4-(furan-2-yl)-2-(2-hydroxy-5-(morpholine-4-yl)benzamido)benzoic acid as a yellow solid.

1H-NMR (DMSO-d6) δ: 2,99-is 3.08 (4H, m), 3,71-379 (4H, m)of 6.68 (1H, DD, J=3,4, 1.5 Hz), 6,94 (1H, d, J=9.0 Hz), 7,12 (1H, d, J=3,4 Hz), 7,18 (1H, DD, J=9,0, 3.0 Hz), 7,42 (1H, d, J=3.0 Hz), 7,54 (1H, DD, J=8,3) and 1.7 Hz), 7,88 (1H, d, J=1.5 Hz), with 8.05 (1H, d, J=8,3 Hz), 9,06 (1H, d, J=1.7 Hz), 10,99 (1H, s), 12,38 (1H, s).

Examples 197a-210a

Compounds shown in Table 23a, obtained as described in Example 196a.

Table 23a
Example No.R3Example No.R3Example No.R3
197a202a207a
198a203a208a
199a204a 209a
200a205a210a
201a206a

4-(2-Forfinal)-2-(2-hydroxy-5-(morpholine-4-yl)benzamido)benzoic acid

1H-NMR (DMSO-d6) δ: 2,98-to 3.09 (4H, m), 3,70-3,81 (4H, m)6,94 (1H, d, J=9.0 Hz), 7,18 (1H, DD, J=9,0, 2,9 Hz), 7,32 was 7.45 (4H, m), 7,46-of 7.55 (1H, m), 7,56-to 7.64 (1H, m), 8,11 (1H, d, J=8,3 Hz), 8,91 (1H, s), 10,97 (1H, s), 12,29 (1H, s), 13,20-14,00 (1H, broadened).

4-(3-Forfinal)-2-(2-hydroxy-5-(morpholine-4-yl)benzamido)benzoic acid

1H-NMR (DMSO-d6) δ: 2,99-is 3.08 (4H, m), 3.72 points-of 3.80 (4H, m)6,94 (1H, d, J=8,9 Hz), 7,18 (1H, DD, J=8,9, 3.0 Hz), 7,26-to 7.35 (1H, m), the 7.43 (1H, d, J=3.0 Hz), 7,52-7,63 (4H, m), 8,10 (1H, d, J=8,3 Hz), of 9.02 (1H, d, J=2.0 Hz), 10,99 (1H, s), 12,32 (1H, s).

4-(4-Forfinal)-2-(2-hydroxy-5-(morpholine-4-yl)benzamido)benzoic acid

1H-NMR (DMSO-d6) δ: 2,98-is 3.08 (4H, m), 3.72 points-of 3.80 (4H, m)6,94 (1H, d, J=9.0 Hz), 7,18 (1H, DD, J=9,0, 2,9 Hz), 7,33-7,41 (2H, m), 7,42 (1H, d, J=2,9 Hz), 7,47-7,53 (1H, m), 7,73-of 7.82 (2H, m), of 8.09 (1H, d, J=8,3 Hz), 8,99 (1H, d, J1,7 Hz), 10,99 (1H, s), of 12.33 (1H, s).

2-(2-Hydroxy-5-(morpholine-4-yl)benzamido)-4-(2-were)benzoic acid

1H-NMR (DMSO-d6) δ: to 2.29 (3H, s), 2,97-of 3.06 (4H, m), 3,70-with 3.79 (4H, m), 6,93 (1H, d, J=9.0 Hz), 7,13-7,22 (2H, m), 7.23 percent-7,41 (5H, m), 8,07 (1H, d, J=8.1 Hz), 8,66 (1H, d, J=1.5 Hz), 10,95 (1H, s), 12,30 (1H, s), 13,25-13,85 (1H, broadened).

2-(2-Hydroxy-5-(morpholine-4-yl)benzamido)-4-(3-were)benzoic acid

1H-NMR (DMSO-d6) δ: 2,41 (3H, s), 2,98-is 3.08 (4H, m), 3,70-of 3.80 (4H, m)6,94 (1H, d, J=8,9 Hz), 7,18 (1H, DD, J=8,9, 2,9 Hz), 7,27 (1H, d, J=7,3 Hz), 7,37-7,58 (5H, m), of 8.09 (1H, d, J=8,3 Hz), 8,99 (1H, d, J=1.7 Hz), 10,99 (1H, s), of 12.33 (1H, s), 13,10-13,95 (1H, broadened).

2-(2-Hydroxy-5-(morpholine-4-yl)benzamido)-4-(4-were)benzoic acid

1H-NMR (DMSO-d6) δ: of 2.38 (3H, s), 2,97-is 3.08 (4H, m), 3,68-of 3.80 (4H, m)6,94 (1H, d, J=8,9 Hz), 7,18 (1H, DD, J=8,9, 2,9 Hz), 7,34 (2H, d, J=8.0 Hz), 7,42 (1H, d, J=2,9 Hz), 7,49 (1H, DD, J=8,3, 1.8 Hz), 7,63 (2H, d, J=8.0 Hz), 8,08 (1H, d, J=8,3 Hz), of 9.00 (1H, d, J=1,8 Hz), 11,00 (1H, s), 12,35 (1H, s).

2-(2-Hydroxy-5-(morpholine-4-yl)benzamido)-4-(2-methoxyphenyl)benzoic acid

1H-NMR (DMSO-d6) δ: 2,99-of 3.07 (4H, m), 3,71-of 3.78 (4H, m), of 3.80 (3H, s), 6,93 (1H, d, J=8,8 Hz),? 7.04 baby mortality for 7.12 (1H, m), 7,13-7,20 (2H, m), 7,32 (1H, DD, J=8,2, 1.8 Hz), 7,35 (1H, DD, J=7,6, 1.7 Hz), 7,38-7,46 (2H, m), 8,03 (1H, d, J=8,2 Hz), 8,78 (1H, d, J=1.7 Hz), 11,05 (1H, s), 12,30-12,54 (1H, broadened), 13,10-13,90 (1H, broadened).

2-(2-Hydroxy-5-(morpholine-4-yl)benzamido)-4-(3-methoxyphenyl)benzoic acid

1H-NMR (DMSO-d6) δ: 3,00-of 3.07 (4H, m), 3,70-with 3.79 (4H, m), 3,85 (3H, s)6,94 (1H, d, J=8,9 Hz), 7,01-7,07 (1H, m), 7,18 (1H, DD, J=8,9 and 3.1 Hz), 7,21-7,26 (1H, m), 7,26-to 7.32 (1H, m), and 7.4 (1H, d, J=3.1 Hz), was 7.45 (1H, DD, J=7,9, 7.9 Hz), 7,52 (1H, DD, J=8,3, 1.8 Hz), of 8.09 (1H, d, J=8,3 Hz), 8,99 (1H, d, J=1,8 Hz), 10,99 (1H, s), 12,31 (1H, s), 13,20-13,90 (1H, broadened).

2-(2-Hydroxy-5-(morpholine-4-yl)benzamido)-4-(4-methoxyphenyl)benzoic acid

1H-NMR (DMSO-d6) δ: 2,99-is 3.08 (4H, m), 3,71-of 3.80 (4H, m), 3,83 (3H, s)6,94 (1H, d, J=8,8 Hz), 7,06-7,13 (2H, m), 7,18 (1H, DD, J=8,8, 3.0 Hz), 7,42 (1H, d, J=3.0 Hz), 7,47 (1H, DD, J=8,3, 1.8 Hz), 7,65-7,72 (2H, m), 8,06 (1H, d, J=8,3 Hz), 8,98 (1H, d, J=1,8 Hz), 11,00 (1H, s), of 12.33 (1H, s).

4-(Furan-3-yl)-2-(2-hydroxy-5-(morpholine-4-yl)benzamido)benzoic acid

1H-NMR (DMSO-d6) δ: 2,98-to 3.09 (4H, m), 3,70-3,81 (4H, m), 6,93 (1H, d, J=8,9 Hz), 6,94-7,00 (1H, m), 7,18 (1H, DD, J=8,9, 2,9 Hz), 7,42 (1H, d, J=2,9 Hz), 7,46 (1H, DD, J=8,3, 1.5 Hz), 7,80-a 7.85 (1H, m), 8,02 (1H, d, J=8,3 Hz), 8,30 (1H, s), 8,86 (1H, d, J=1.5 Hz), 11,02 (1H, s)to 12.28 (1H, s).

4-(Benzo[1,3]dixital-5-yl)-2-(2-hydroxy-5-(morpholine-4-yl)benzamido)benzoic acid

1H-NMR (DMSO-d6) δ: 2,99-is 3.08 (4H, m), 3,71-of 3.80 (4H, m), 6,11 (2H, s), 6,93 (1H, d, J=9.0 Hz), 7,07 (1H, d, J=8.1 Hz), 7,18 (1H, DD, J=9,0, 3.0 Hz), 7.23 percent (1H, DD, J=8,1, 1.8 Hz), 7,29 (1H, d, J=1,8 Hz), 7,42 (1H, d, J=3,0 Hz), was 7.45 (1H, DD, J=8,3) and 1.7 Hz), with 8.05 (1H, d, J=8,3 Hz), to 8.94 (1H, d, J=1.7 Hz), 10,99 (1H, s), 12,27-12,40 (1H, broadened).

4-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-2-(2-hydroxy-5-(morpholine-4-yl)benzamido)benzoic acid

1H-NMR (DMSO-d6) δ: 3,00-of 3.07 (4H, m), 3.72 points-with 3.79 (4H, m), or 4.31 (4H, s), 6,93 (1H, d, J=9.0 Hz), 6,98? 7.04 baby mortality (1H, m), 7,18 (1H, DD, J=8,9, 3.0 Hz), 7.18 in-7,24 (2H, m), 7,42 (1H, d, J=3.0 Hz), was 7.45 (1H, DD, J=8,4, 1.8 Hz), 8,04 (1H, d, J=8,4 Hz), to 8.94 (1H, d, J=1,8 Hz), 10,97 (1H, s), 12,30 (1H, s).

4-(3,4-Acid)-2-(2-hydroxy-5-(morpho is in-4-yl)benzamido)benzoic acid

1H-NMR (DMSO-d6) δ: 2,99-of 3.06 (4H, m), 3,70-of 3.77 (4H, m), of 3.80 (3H, s), of 3.84 (3H, s), 6.89 in (1H, d, J=9.0 Hz),? 7.04 baby mortality for 7.12 (1H, m), 7,16 (1H, DD, J=9,0, 2.7 Hz), 7,20-7,26 (2H, m), 7,41 (1H, DD, J=8,3) and 1.7 Hz), 7,47 (1H, d, J=2.7 Hz), of 8.06 (1H, d, J=8,3 Hz), 8,89 (1H, d, J=1.7 Hz), 11,30-11,90 (1H, broadened), 13,90 accounted for 14.45 (1H, broadened).

4-(3,5-Acid)-2-(2-hydroxy-5-(morpholine-4-yl)benzamido)benzoic acid

1H-NMR (DMSO-d6) δ: 2,99-of 3.07 (4H, m), 3,71-with 3.79 (4H, m), 3,83 (6H, s), 6,60 (1H, DD, J=2,2, 2,2 Hz), PC 6.82 (2H, d, J=2.2 Hz), 6,94 (1H, d, J=9.0 Hz), 7,17 (1H, DD, J=9,0, 3.1 Hz), 7,42 (1H, d, J=3.1 Hz), 7,51 (1H, DD, J=of 8.3, 1.9 Hz), 8,07 (1H, d, J=8,3 Hz), of 8.95 (1H, d, J=1.9 Hz), 10,98 (1H, s)to 12.28 (1H, s), 13,30-13,80 (1H, broadened).

Example 211a

To tert-butyl 2-(2-(benzyloxy)-5-(morpholine-4-yl)benzamido)-4-bromobenzoate (0.20 g) was added dimethyl ether of ethylene glycol (2.0 ml), water (0,60 ml), thiophene-2-Bronevoy acid (0,054 g), sodium carbonate (0,093 g) dichloride and bis(triphenylphosphine)palladium(II) (4,9 mg)and then heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and added to her water and ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 85-70% hexane/ethyl acetate] to obtain 0,19 g of tert-butyl 2-(2-(benzyloxy)-5-(morpholine-4-yl)benzamido-4-(thiophene-2-yl)benzoate as a pale yellow solid.

To the obtained tert-butyl 2-(2-(benzyloxy)-5-(morpholine-4-yl)benzamido)-4-(thiophene-2-yl)benzoate (to 0.19 g) was added thioanisole (2.0 ml) and triperoxonane acid (6.8 ml)and then stirred at room temperature for 24 hours. The solvent is evaporated under reduced pressure, and was added to the residue ethyl acetate. The solid is collected by filtration, and was added to the obtained solid substance, water and 2-propanol. After adjusting the pH to 6.0 by the addition of saturated aqueous sodium bicarbonate solution, the solid was collected by filtration to obtain 0.11 g of 2-(2-hydroxy-5-(morpholine-4-yl)benzamido)-4-(thiophene-2-yl)benzoic acid as a yellow solid.

1H-NMR (DMSO-d6) δ: 2,98-to 3.09 (4H, m), 3,70-of 3.80 (4H, m)6,94 (1H, d, J=9.0 Hz), 7,18 (1H, DD, J=9,0, 2,9 Hz), 7,21 (1H, DD, J=5,1, and 3.7 Hz), 7,42 (1H, d, J=2,9 Hz), 7,53 (1H, DD, J=8,3) and 1.7 Hz), to 7.61-to 7.67 (1H, m), to 7.67-7,73 (1H, m), of 8.04 (1H, d, J=8,3 Hz), 9,06 (1H, d, J=1.7 Hz), 10,96 (1H, s), 12,36 (1H, s), 13,26-13,80 (1H, broadened).

Example 212a

The following compound was obtained as described in Example 211a.

2-(2-Hydroxy-5-(morpholine-4-yl)benzamido)-4-(thiophene-3-yl)benzoic acid

1H-NMR (DMSO-d6) δ: 2,98-is 3.08 (4H, m), 3,70-3,81 (4H, m)6,94 (1H, d, J=8,9 Hz), 7,18 (1H, DD, J=8,9, 3.0 Hz), 7,42 (1H, d, J=3.0 Hz), 7,53 to 7.62 (2H, m), 7,72 (1H, DD, J=5,1, 2,9 Hz), 7,98-8,03 (1H, m), with 8.05 (1H, d, J=8,3 Hz), 9,01 (1H, d, J=1.7 Hz), br11.01 (1H, s), 12,27 (1H, s), 13,20-13,80 (1H, sireny is).

Example 213a

To methyl 2-(2-(benzyloxy)-5-(1-methylpiperidin-4-yl)benzamido)-4-bromobenzoate (0,090 g) was added dimethyl ether of ethylene glycol (0,90 ml), water (0,27 ml), 3-methoxyphenylalanine acid (0,030 g), sodium carbonate (0,044 g) dichloride and bis(triphenylphosphine)palladium(II) (2,3 mg)and then heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and added to her water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-92% chloroform/methanol] to obtain 0,093 g of methyl 2-(2-(benzyloxy)-5-(1-methylpiperidin-4-yl)benzamido)-4-(3-methoxyphenyl)benzoate as a pale brown solid.

To a solution of the obtained methyl 2-(2-(benzyloxy)-5-(1-methylpiperidin-4-yl)benzamido)-4-(3-methoxyphenyl)benzoate (0,093 g) in a mixture of methanol (2.0 ml) and ethyl acetate (2.0 ml) was added 10% palletirovanie coal (0,050 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture were added chloroform. Insoluble substances were removed by filtration, and evaporated rest ritel under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-92% chloroform/methanol] to obtain 0,026 g of methyl 2-(2-hydroxy-5-(1-methylpiperidin-4-yl)benzamido)-4-(3-methoxyphenyl)benzoate as a white solid.

To a suspension of the obtained methyl 2-(2-hydroxy-5-(1-methylpiperidin-4-yl)benzamido)-4-(3-methoxyphenyl)benzoate (0,026 g) in methanol (1.0 ml) was added a 2.0 mol/l aqueous solution of sodium hydroxide (0,27 ml)and then stirred at 50°C for 3 hours. After cooling the reaction mixture to room temperature and adjust pH to 6.0 by adding a 2.0 mol/l hydrochloric acid, the solid was collected by filtration to obtain 0.025 g of 2-(2-hydroxy-5-(1-methylpiperidin-4-yl)benzamido)-4-(3-methoxyphenyl)benzoic acid as a pale yellow solid.

1H-NMR (DMSO-d6+D2O) δ: 1,85-2,12 (4H, m), 2,80-to 2.94 (1H, m), and 2.83 (3H, s), 3.04 from-and 3.16 (2H, m), 3,47-3,59 (2H, m), of 3.84 (3H, s), of 6.96 (1H, d, J=8,3 Hz), 7,01 (1H, DD, J=8,3, 2.0 Hz), 7,16-7,22 (1H, m), 7,27 (1H, d, J=8.0 Hz), 7,38-to 7.50 (3H, m), 7,92 (1H, d, J=2.2 Hz), 8,15 (1H, d, J=8.1 Hz), of 8.90 (1H, d, J=1.7 Hz).

Examples 214a and 215a

Compounds shown in Table 24a, obtained as described in Example 213a.

Table 24a
Example No.R 3Example No.R3
214a215a

4-(3-Forfinal)-2-(2-hydroxy-5-(1-methylpiperidin-4-yl)benzamido)benzoic acid

1H-NMR (DMSO-d6+D2O) δ: 1,84-2,12 (4H, m), 2,80-to 2.94 (1H, m), and 2.83 (3H, s), 3.04 from-3,18 (2H, m), 3,48-of 3.60 (2H, m), of 6.96 (1H, d, J=8.6 Hz), 7,21-7,30 (1H, m), 7,37 to 7.62 (5H, m), 7,92 (1H, d, J=1.9 Hz), 8,17 (1H, d, J=8,3 Hz), of 8.92 (1H, d, J=1.7 Hz).

4-(4-Forfinal)-2-(2-hydroxy-5-(1-methylpiperidin-4-yl)benzamido)benzoic acid

1H-NMR (DMSO-d6+D2O) δ: 1,83-2,12 (4H, m), 2,80-2,95 (1H, m), and 2.83 (3H, s), 3,02-3,20 (2H, m), 3.46 in-of 3.60 (2H, m), of 6.96 (1H, d, J=8.6 Hz), 7,31-7,44 (4H, m), 7,70 for 7.78 (2H, m), to 7.93 (1H, d, J=1.9 Hz), 8,15 (1H, d, J=8,3 Hz), 8,89 (1H, d, J=1.9 Hz).

Example 216a

To tert-butyl 2-(2-(benzyloxy)-4-jogesuido)-4-phenylbenzoate (1.2 g) was added dimethyl ether of ethylene glycol (12 ml), water (3.6 ml), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0,49 g), sodium carbonate (0.50 g) and dichloride bis(triphenylphosphine)palladium(II) (14 mg)and then heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, was added thereto dichloride bis(triphenylphosphine)palladium(II) (28 mg)and then heated with reverse Kholodilin the lump in nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature, was added thereto dichloride bis(triphenylphosphine)palladium(II) (28 mg)and then heated under reflux in nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature, and added to her water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 80-60% hexane/ethyl acetate] to obtain 0.55 g of tert-butyl 2-(2-(benzyloxy)-4-(pyridin-4-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

1H-NMR (DMSO-d6) δ: rate of 1.51 (9H, s), to 5.66 (2H, s), 7,25-7,37 (3H, m), 7,44-7,49 (1H, m), 7,51-to 7.59 (6H, m), 7,62-7,66 (1H, m), 7,71 for 7.78 (4H, m), 8,04-8,11 (2H, m), 8,66-8,73 (2H, m), 9,07-9,12 (1H, m), 12,21 (1H, s).

Example 217a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-(pyridin-2-yl)benzamido)-4-phenylbenzoate (0.12 g) in acetic acid (5 ml) was added 10% palletirovanie coal (to 0.060 g)and then stirred in hydrogen atmosphere (5 kg/cm2) at 80°C for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and added to it the methanol and acetic acid. Insoluble substances were removed by filtration, and delete will dissolve the l under reduced pressure. To the residue was added chloroform and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0,062 g of tert-butyl 2-(2-hydroxy-5-(piperidine-2-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

1H-NMR (CDCl3) δ: 1,46 is 1.75 (4H, m)to 1.67 (9H, s), 1,81-to 1.98 (2H, m), 2.77-to 2,89 (1H, m), 3,14-of 3.25 (1H, m)to 3.64 (1H, DD, J=10,8, and 2.1 Hz), 6,97 (1H, d, J=8,4 Hz), was 7.36 (1H, DD, J=8,4, 1.7 Hz), 7,38-7,44 (1H, m), 7,44-7,52 (3H, m), 7,66-7,73 (2H, m), to $ 7.91 (1H, d, J=1.7 Hz), 8,08 (1H, d, J=8,3 Hz), 9,05 (1H, d, J=1.7 Hz), 12,55 (1H, s).

To a solution of the obtained tert-butyl 2-(2-hydroxy-5-(piperidine-2-yl)benzamido)-4-phenylbenzoate (0,040 g) in methylene chloride (1.5 ml), was added 37% aqueous formaldehyde solution (8,2 μl), acetic acid (9,7 μl) and triacetoxyborohydride sodium (0,045 g)and then stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and added chloroform. Insoluble substances were removed by filtration, and then was added a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with saturated aqueous sodium chloride and who left the house taking over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-92% chloroform/methanol] to obtain 0,040 g of tert-butyl 2-(2-hydroxy-5-(1-methylpiperidin-2-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

To the obtained tert-butyl 2-(2-hydroxy-5-(1-methylpiperidin-2-yl)benzamido)-4-phenylbenzoate (0,040 g) was added triperoxonane acid (2.0 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue methanol and water. After adjusting the pH to 6.0 by the addition of saturated aqueous sodium bicarbonate solution, the solid is collected from the reaction mixture by filtration to obtain 0,034 g 2-(2-hydroxy-5-(1-methylpiperidin-2-yl)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6+D2O) δ: 1.56 to at 1.73 (1H, m), 1,80-2,12 (5H, m), 2,48 (3H, s), 3,01-3,19 (1H, m), 3,45-3,59 (1H, m), 4,12-the 4.29 (1H, m), to 7.09 (1H, d, J=8.6 Hz), 7,39-7,47 (2H, m), of 7.48 to 7.62 (3H, m), 7,65-7,74 (2H, m), of 8.00 (1H, d, J=1.7 Hz), 8,14 (1H, d, J=8.0 Hz), 8,89 (1H, d, J=1.5 Hz).

Example 218a

The following compound was obtained as described in Example 217a.

2-(2-Hydroxy-4-(1-methylpiperidin-4-yl)benzamido)-4-phenylbenzene acid

1H-NMR (DMSO-d6) δ: 1,76-of 2.08 (4H, m), 2,72-2,84 1H, m), was 2.76 (3H, s), 2,87-to 3.02 (2H, m), 3,40-of 3.53 (2H, m), 6,74-6,84 (2H, m), 7,35-the 7.43 (2H, m), 7,46-rate of 7.54 (2H, m), of 7.64-7,71 (2H, m), 7,88 (1H, d, J=8.1 Hz), to 8.12 (1H, d, J=8.0 Hz), 8,87 (1H, d, J=1.7 Hz).

Example 219a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-(pyridin-3-yl)benzamido)-4-phenylbenzoate (0.88 g) in acetic acid (15 ml) was added 10% palletirovanie coal (0,44 g)and then stirred in hydrogen atmosphere (5 kg/cm2) at 80°C for 3 hours. The reaction mixture was cooled to room temperature, and added to it the methanol and acetic acid. Insoluble substances were removed by filtration. The solvent was removed under reduced pressure, and was added to the residue chloroform and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0.51 g of tert-butyl 2-(2-hydroxy-5-(piperidine-3-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

To the obtained tert-butyl 2-(2-hydroxy-5-(piperidine-3-yl)benzamido)-4-phenylbenzoate (0.10 g) was added triperoxonane acid (2.0 ml)and then stirred at room temperature for 3 hours. Rastvoritelyami under reduced pressure, and was added to the residue methanol and water. After adjusting the pH to 6.0 by addition of a saturated aqueous solution of sodium bicarbonate, the solid substance was collected from the reaction mixture by filtration to obtain 0,088 g 2-(2-hydroxy-5-(piperidine-3-yl)benzamido)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6+D2O) δ: 1,68-2,04 (4H, m), 2,92-to 3.09 (3H, m), 3,26-to 3.41 (2H, m), 7,01 (1H, d, J=8.6 Hz), 7,40-to 7.50 (3H, m), 7,50-to 7.59 (2H, m), to 7.67-7,74 (2H, m), 7,82 (1H, d, J=2.0 Hz), 8,15 (1H, d, J=8.1 Hz), of 8.90 (1H, d, J=1.7 Hz).

Example 220a

To tert-butyl 2-(2-hydroxy-5-(piperidine-2-yl)benzamido)-4-phenylbenzoate (0.015 g) was added triperoxonane acid (1.0 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue methanol and water. After adjusting the pH to 6.0 by the addition of saturated aqueous sodium bicarbonate solution, the solid is collected from the reaction mixture by filtration. The solid substance was added ethyl acetate (1.0 ml) and 2.5 mol/l solution of florodora in ethyl acetate (1.0 ml)and then stirred at room temperature for 30 minutes. The solid substance was collected from the reaction mixture by filtration to obtain 0,010 g of the hydrochloride of 2-(2-hydroxy-5-(piperidine-2-yl)benzamido)-4-phenylbenzene sour the s in the form of a white solid.

1H-NMR (DMSO-d6+D2O) δ: 1,56-of 1.78 (2H, m), 1,79 is 2.01 (4H, m), 2,98-of 3.12 (1H, m), 3.27 to 3,37 (1H, m), 4,20 (1H, DD, J=11,2, a 3.2 Hz), 7,10 (1H, d, J=8.5 Hz), 7,44-of 7.60 (5H, m), 7,70-7,76 (2H, m), of 8.09 (1H, d, J=2.4 Hz), to 8.12 (1H, d, J=8,3 Hz), 9,03 (1H, d, J=2.0 Hz).

Example 221a

To a solution of tert-butyl 2-(2-(benzyloxy)-5-(pyridin-4-yl)benzamido)-4-phenylbenzoate (0,77 g) in acetic acid (20 ml) was added 10% palletirovanie charcoal (0.35 g)and then stirred in hydrogen atmosphere (5 kg/cm2) at 70-80°C for 7 hours. The reaction mixture was cooled to room temperature, and added to her acetic acid, methanol and chloroform. Insoluble substances were removed by filtration. The solvent was removed under reduced pressure, and then was added to the residue chloroform and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0.36 g of tert-butyl 2-(2-hydroxy-5-(piperidine-4-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

1H-NMR (CDCl3) δ: 1,59-of 1.78 (2H, m)to 1.67 (9H, s), 1.91 a-2,03 (2H, m), 2,60-to 2.74 (1H, m), was 2.76-is 2.88 (2H, m), 3,19-of 3.32 (2H, m), 6,98 (1H, d, J=8.5 Hz), 7,33 (1H, DD, J=8,5 and 2.2 Hz), 7,37 (H, DD, J=8,4, 1.9 Hz), 7,38-7,53 (3H, m), 7,66-to 7.77 (3H, m), of 8.09 (1H, d, J=8,4 Hz), the remaining 9.08 (1H, d, J=1.9 Hz), 12,57 (1H, s).

Example 222a

To a suspension of tert-butyl 2-(2-hydroxy-5-(piperidine-4-yl)benzamido)-4-phenylbenzoate (0.10 g) in methylene chloride (1.0 ml), was added acetaldehyde (0,016 ml), acetic acid (0,024 ml) and triacetoxyborohydride sodium (0.11 g)and then stirred at room temperature for 1 hour. To the reaction mixture was sequentially added acetaldehyde (0,016 ml) and triacetoxyborohydride sodium (0.11 g)and then stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, and was added to the residue ethyl acetate. After removing insoluble substances by filtration was added saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-90% chloroform/methanol] to obtain of 0.045 g of tert-butyl 2-(5-(1-ethylpiperazin-4-yl)-2-hydroxybenzamide)-4-phenylbenzoate in the form of a light yellow solid.

To the obtained tert-butyl 2-(5-(1-ethylpiperazin-4-yl)-2-hydroxybenzamide)-4-phenylbenzoate (0,g) was added triperoxonane acid (2.0 ml), and then was stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the residue methanol and water. After adjusting the pH to 6.0 by the addition of saturated aqueous sodium bicarbonate solution, the solid is collected from the reaction mixture by filtration to obtain 5.0 mg of 2-(5-(1-ethylpiperazin-4-yl)-2-hydroxybenzamide)-4-vinylbenzoic acid as a white solid.

1H-NMR (DMSO-d6+D2O) δ: of 1.29 (3H, t, J=7,3 Hz), 1.85 to to 2.15 (4H, m), 2,83-3,10 (3H, m), 3,10-of 3.23 (2H, m), 3,54-3,66 (2H, m), of 6.96 (1H, d, J=8,3 Hz), 7,38-of 7.48 (3H, m), 7,50-EUR 7.57 (2H, m), 7,66-7,74 (2H, m), 7,94 (1H, d, J=1,2 Hz), 8,16 (1H, d, J=8,3 Hz), of 8.92 (1H, d, J=1.7 Hz).

Example 223a

The following compound was obtained as described in Example 222a.

2-(2-Hydroxy-5-(1-propylpiperidine-4-yl)benzamido)-4-phenylbenzene acid

1H-NMR (DMSO-d6+D2O) δ: of 0.95 (3H, t, J=7.5 Hz), 1,64-to 1.79 (2H, m), 1,88-2,12 (4H, m), 2,81 is 3.15 (5H, m), 3,49-to 3.67 (2H, m), of 6.96 (1H, d, J=8,3 Hz), 7,37-7,47 (3H, m), 7,49-EUR 7.57 (2H, m), 7,66-7,74 (2H, m), 7,95 (1H, d, J=1,7 Hz), 8,16 (1H, d, J=8.1 Hz), of 8.92 (1H, d, J=1.7 Hz).

Example 224a

To a suspension of methyl 2-(2-(benzyloxy)-5-(piperidine-4-yl)benzamido)-4-phenylbenzoate (0,13 g) in acetonitrile (1.9 ml) was sequentially added potassium carbonate (0,033 mg) and isopropylated (0,024 ml)and then heated under reflux for 1 hour is. The reaction mixture was cooled to room temperature was sequentially added thereto potassium carbonate (6,7 mg) and isopropylated (4,8 mm)and then heated under reflux for 2 hours. After cooling the reaction mixture to room temperature, the solvent evaporated under reduced pressure, and was added to the residue ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-95% chloroform/methanol] to obtain 0.12 g of methyl 2-(2-(benzyloxy)-5-(1-isopropylpiperazine-4-yl)benzamido)-4-phenylbenzoate as an orange oily substance.

To a solution of the obtained methyl 2-(2-(benzyloxy)-5-(1-isopropylpiperazine-4-yl)benzamido)-4-phenylbenzoate (0.12 g) in a mixture of ethyl acetate (1.5 ml) and methanol (1.5 ml) was added 10% palletirovanie charcoal (0.12 g)and then stirred in a hydrogen atmosphere at room temperature for 1 hour. To the reaction mixture was added chloroform, and removing insoluble substances by filtration. The solvent is evaporated under reduced pressure to obtain 0,086 g of methyl 2-(2-hydroxy-5-(1-isopropylate the one-4-yl)benzamido)-4-phenylbenzoate as an orange solid.

To a suspension of the obtained methyl 2-(2-hydroxy-5-(1-isopropylpiperazine-4-yl)benzamido)-4-phenylbenzoate (0,086 g) in 2-propanol (1.5 ml) was added a 2.0 mol/l aqueous solution of sodium hydroxide (0,27 ml)and then stirred at 50°C for 1 hour. To the reaction mixture was added 2 mol/l aqueous solution of sodium hydroxide (0,091 ml)and then stirred at 50°C for 30 minutes. The reaction mixture was cooled to room temperature, and added to her water. After adjusting the pH to 6.0 by adding 1.0 mol/l hydrochloric acid, the solid was collected by filtration to obtain 0,062 g 2-(2-hydroxy-5-(1-isopropylpiperazine-4-yl)benzamido)-4-vinylbenzoic acid as a pale yellow solid.

1H-NMR (DMSO-d6-D2O) δ: is 1.31 (6H, d, J=6.6 Hz), 1,91 and 2.13 (4H, m), 2,83 are 2.98 (1H, m), 3,03-3,19 (2H, m), 3.43 points-of 3.54 (3H, m), to 6.95 (1H, d, J=8.6 Hz), 7,37-7,46 (3H, m), 7,49-EUR 7.57 (2H, m), 7,66-7,74 (2H, m), 7,98 (1H, d, J=2,0 Hz), 8,17 (1H, d, J=8.0 Hz), of 8.92 (1H, d, J=1.7 Hz).

Example 225a

To a solution of methyl 2-(2-(benzyloxy)-5-(piperidine-4-yl)benzamido)-4-phenylbenzoate (0.11 g) in tetrahydrofuran (1.0 ml), was added acetic acid (0,023 ml), 2-(tert-butyldimethylsilyloxy)acetaldehyde (0,046 ml) and triacetoxyborohydride sodium (0.11 g)and then stirred at room temperature for 13 hours. The solvent is evaporated under reduced pressure, and EXT is ulali to the residue ethyl acetate. After removing insoluble substances by filtration was added saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-92% chloroform/methanol] to obtain of 0.13 g of methyl 2-(2-(benzyloxy)-5-(1-(2-(tert-butyldimethylsilyloxy)ethyl)piperidine-4-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

To a solution of the obtained methyl 2-(2-(benzyloxy)-5-(1-(2-(tert-butyldimethylsilyloxy)ethyl)piperidine-4-yl)benzamido)-4-phenylbenzoate (0,13 g) in tetrahydrofuran (1.3 ml) was added 1.0 mol/l solution of tetrabutylammonium fluoride in tetrahydrofuran (0,38 ml)and then stirred at room temperature for 4 hours. While cooling on ice to the reaction mixture were added water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-92% chloroform/methanol] to obtain of 0.085 g of methyl 2-(2-(benzyloxy)-5-(1-(2-hydroxyethyl)piperidine-4-yl)Bentham is up)-4-phenylbenzoate in the form of a white solid.

To a solution of the obtained methyl 2-(2-(benzyloxy)-5-(1-(2-hydroxyethyl)piperidine-4-yl)benzamido)-4-phenylbenzoate (of 0.085 g) in a mixture of ethyl acetate (1.0 ml) and methanol (1.0 ml) was added 10% palletirovanie coal (0,040 g)and then stirred in a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture was added 10% palletirovanie coal (0,040 g)and then stirred in a hydrogen atmosphere at room temperature for 4 hours. Insoluble substances were removed from the reaction mixture by filtration, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-92% chloroform/methanol] to obtain 0.035 g of methyl 2-(2-hydroxy-5-(1-(2-hydroxyethyl)piperidine-4-yl)benzamido)-4-phenylbenzoate in the form of a white solid.

To the obtained methyl 2-(2-hydroxy-5-(1-(2-hydroxyethyl)piperidine-4-yl)benzamido)-4-phenylbenzoate (0.035 g) was added methanol (1.0 ml) and 2.0 mol/l aqueous solution of sodium hydroxide (0,37 ml)and then stirred at 50°C for 2 hours. After cooling the reaction mixture to room temperature and adjust pH to 6.0 by adding a 2.0 mol/l hydrochloric acid, the solid was collected by filtration to obtain 0,030 g 2-(2-hydroxy-5-(1-(2-hydroxyethyl)piperidine-4-yl)benzamido)-4-vinylbenzoic acid in the form of b the logo solids.

1H-NMR (DMSO-d6+D2O) δ: 1,92-to 2.13 (4H, m), 2,86-of 3.00 (1H, m), 3,05-of 3.27 (4H, m), to 3.58-to 3.73 (2H, m), of 3.77-a 3.87 (2H, m), 6,98 (1H, d, J=8.6 Hz), 7,40-7,49 (3H, m), 7,50-7,58 (2H, m), to 7.67 to 7.75 (2H, m), of 7.90 (1H, d, J=1.7 Hz), is 8.16 (1H, d, J=8.0 Hz), of 8.92 (1H, d, J=1.5 Hz).

Example 1b

To a suspension of 5-phenylpyridine-3-carboxylic acid (44 mg) in methylene chloride (0.5 ml) at room temperature was added N,N-dimethylformamide (0,9 mm) and oxacillin (0,023 ml)and then stirred at the same temperature for 1 hour. The reaction mixture at room temperature was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (40 mg) in a mixture of methylene chloride (1 ml) and triethylamine (0.17 ml)and then stirred at the same temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue ethyl acetate and 10% aqueous citric acid solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Trikonex AB, FlashTube 2008, eluent: hexane/ethyl acetate = 2/1] to obtain tert-butyl-4-phenyl-2-(5-vinylpyridin-3-carboxamido)benzoate.

To the obtained tert-butyl-4-phenyl-2-(5-vinylpyridin-3-carboxamido)benzoate was added triperoxonane acid is the (5 ml), and then was stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the obtained residue, ethyl acetate. The solid substance was collected by filtration to obtain 40 mg of 4-phenyl-2-(5-vinylpyridin-3-carboxamido)benzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 7,45-to 7.61 (7H, m), 7,72 for 7.78 (2H, m), 7,81-7,87 (2H, m), 8,15 (1H, d, J=8,3 Hz), 8,56 (1H, DD, J=2,2, 2,2 Hz), of 9.02 (1H, d, J=1.7 Hz), 9,14 (1H, d, J=2.0 Hz), to 9.15 (1H, d, J=2.0 Hz), of 12.33 (1H, s).

Example 2b

The following compound was obtained as described in Example 1b.

4 Phenoxy-2-(5-vinylpyridin-3-carboxamido)benzoic acid

1H-NMR (DMSO-d6) δ: 6,83 (1H, DD, J=8,8, 2,5 Hz), 7,17-7,22 (2H, m), 7,27-7,33 (1H, m), 7,46-to 7.59 (5H, m), 7,79-a 7.85 (2H, m), of 8.09 (1H, d, J=8,8 Hz), at 8.36 (1H, d, J=2.5 Hz), 8,49 (1H, DD, J=2,2, 2,1 Hz), 9,07 (1H, d, J=2.1 and Hz), 9,13 (1H, d, J=2.2 Hz), 12,54 (1H, s).

Example 3b

To a suspension of 6-vinylpyridin-3-carboxylic acid (44 mg) in methylene chloride (0.5 ml) at room temperature was added N,N-dimethylformamide (0,9 mm) and oxacillin (0,023 ml)and then stirred at the same temperature for 1 hour. The reaction mixture at room temperature was added to a solution of tert-butyl 2-amino-4-phenylbenzoate (40 mg) in a mixture of methylene chloride (1 ml) and triethylamine (0.17 ml)and then stirred at the same temp is the temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue ethyl acetate and 10% aqueous citric acid solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Trikonex AB, FlashTube 2008, eluent: hexane/ethyl acetate = 2/1] to obtain tert-butyl-4-phenyl-2-(6-vinylpyridin-3-carboxamido)benzoate.

To the obtained tert-butyl-4-phenyl-2-(6-vinylpyridin-3-carboxamido)benzoate was added triperoxonane acid (5 ml)and then stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the obtained residue, methanol. The solid substance was collected by filtration to obtain 53 mg of 4-phenyl-2-(6-vinylpyridin-3-carboxamido)benzoic acid as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 7,44-of 7.60 (7H, m), 7,72-7,79 (2H, m), 8,16 (1H, d, J=8,3 Hz), 8,18 compared to 8.26 (3H, m), 8,39 (1H, DD, J=8,3, 2.4 Hz), 9,02-9,06 (1H, m), 9,24 (1H, d, J=1.7 Hz), 12,30 (1H, s).

Examples 4b and 5b

Compounds shown in Table 7b, obtained as described in Example 3b.

Table 7b
Example No.AExample No.A
4b5b

4-Phenyl-2-(2-phenylpyridine-4-carboxamido)benzoic acid

1H-NMR (DMSO-d6) δ: 7,45 to 7.62 (7H, m), 7,72 for 7.78 (2H, m), to 7.84 (1H, DD, J=4,9, 1,6 Hz), 8,13-to 8.20 (3H, m), to 8.41 (1H, s), to 8.94 (1H, d, J=4.9 Hz), of 9.02 (1H, d, J=1.7 Hz), KZT 12.39 (1H, s).

4-Phenyl-2-(6-vinylpyridin-2-carboxamido)benzoic acid

1H-NMR (DMSO-d6) δ: 7,45-to 7.61 (7H, m), 7,73-7,80 (2H, m), 8,16 is 8.22 (3H, m), 8,29-at 8.36 (1H, m), 8,43-of 8.50 (2H, m), 9.28 are (1H, d, J=1.7 Hz), 13,33 (1H, s), 13,60-13,80 (1H, broadened).

Example 6b

To a suspension of 5-phenylpyridine-3-carboxylic acid (60 mg) in methylene chloride (2 ml) at room temperature was added N,N-dimethylformamide (2,3 μl) and oxacillin (0,039 ml)and then stirred at the same temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (1.5 ml). The reaction mixture at room temperature was added to a solution of tert-butyl 2-amino-4-(isoquinoline-4-yl)benzoate (80 mg) in a mixture of methylene chloride (2 ml) and pyridine (0,050 ml)and then stirred at the same temperature for 1 hour. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-50% hexane/ethyl acetate] to obtain 0.10 g of tert-butyl 4-(isoquinoline-4-yl)-2-(5-vinylpyridin-3-carboxamido)benzoate as a white solid.

To the obtained tert-butyl 4-(isoquinoline-4-yl)-2-(5-vinylpyridin-3-carboxamido)benzoate (0.10 g) was added triperoxonane acid (5 ml)and then stirred at room temperature for 4 hours. The solvent is evaporated under reduced pressure, and was added to the residue ethyl acetate and water. After adjusting the pH to 6.5 by adding 2 mol/l aqueous solution of sodium hydroxide, the solid was collected by filtration to obtain 81 mg of 4-(isoquinoline-4-yl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid as a pale yellow solid.

To the obtained 4-(isoquinoline-4-yl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid (81 mg) was added methanol (5 ml), dioxane (5 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,091 ml)and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and the collected solid vases is in by filtration to obtain 83 mg of 4-(isoquinoline-4-yl)-2-(5-vinylpyridin-3-carboxamido)sodium benzoate as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 7,21 (1H, DD, J=7,9, 1.8 Hz), 7,46-7,53 (1H, m), 7,54-to 7.61 (2H, m), 7,73-7,79 (1H, m), 7,80-7,87 (3H, m), of 7.96 shed 8.01 (1H, m), 8,20-of 8.28 (2H, m), 8,49 (1H, s), at 8.60 (1H, DD, J=2,2, 2,2 Hz), 8,88 (1H, d, J=1,8 Hz), which is 9.09 (1H, d, J=2.2 Hz), 9,17 (1H, d, J=2.0 Hz), 9,37 (1H, s).

Example 7b

The following compound was obtained as described in Example 6b.

4-Phenyl-2-(5-(pyrimidine-2-yl)pyridine-3-carboxamido)sodium benzoate

1H-NMR (DMSO-d6) δ: 7,33 (1H, DD, J=8,1, 1.9 Hz), 7,37-the 7.43 (1H, m), 7,47-rate of 7.54 (2H, m), 7,60 (1H, t, J=4.9 Hz), 7,66-7,72 (2H, m)to 8.12 (1H, d, J=8.1 Hz), 9,01-9,06 (3H, m), 9.28 are (1H, DD, J=2,1, 2.0 Hz), 9,35 (1H, d, J=2.1 and Hz), 9,67 (1H, d, J=2.0 Hz).

Example 8b

To a suspension of 5-phenylpyridine-3-carboxylic acid (57 mg) in methylene chloride (1.2 ml) at room temperature was added N,N-dimethylformamide (2,2 μl) and oxacillin (0.037 ml)and then stirred at the same temperature for 1 hour and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (1.2 ml). The reaction mixture at room temperature was added to a solution of tert-butyl 2-amino-4-(1H-pyrazole-1-yl)benzoate (62 mg) in a mixture of methylene chloride (1.2 ml) and pyridine (0,048 ml)and then stirred at the same temperature for 2 hours. To the reaction mixture were added methylene chloride and 1 mol/l aqueous solution of sodium hydroxide. The organic layer was separated, sequentially PR is mawali 1 mol/l aqueous solution of sodium hydroxide and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-70% hexane/ethyl acetate] to obtain 68 mg of tert-butyl 2-(5-vinylpyridin-3-carboxamido)-4-(1H-pyrazole-1-yl)benzoate as a white solid.

To the obtained tert-butyl 2-(5-vinylpyridin-3-carboxamido)-4-(1H-pyrazole-1-yl)benzoate (68 mg) was added triperoxonane acid (5 ml)and then stirred at room temperature for 4 hours. The solvent is evaporated under reduced pressure, and was added to the obtained residue, methanol. The solid substance was collected by filtration to obtain 53 mg of 2-(5-vinylpyridin-3-carboxamido)-4-(1H-pyrazole-1-yl)benzoic acid.

To the obtained 2-(5-vinylpyridin-3-carboxamido)-4-(1H-pyrazole-1-yl)benzoic acid (53 mg) was added methanol (2 ml), dioxane (2 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,083 ml)and the solvent evaporated under reduced pressure. To the obtained residue was added water and acetone, and collecting the solid by filtration to obtain 23 mg of 2-(5-vinylpyridin-3-carboxamido)-4-(1H-pyrazole-1-yl)sodium benzoate as a white solid.

1H-NMR (DMSO-d6) δ: 6,56 (1H, DD, J=1,9, 1.9 Hz), 7,44-rate of 7.54 (2H, m), 7,55 to 7.62 (2H, m), to 7.77 (1H, d, J=1.5 Hz), 7,81-7,87 (2H, m)to 8.12 (1H, d, J=8,3 Hz), 8,45 (H, d, J=2.4 Hz), 8,59-8,64 (1H, m), 9,10 (1H, d, J=2.2 Hz), 9,17-which 9.22 (2H, m).

Example 9b

The following compound was obtained as described in Example 8b.

4-(2-Deformedarse)phenyl)-2-(5-vinylpyridin-3-carboxamido)sodium benzoate

1H-NMR (DMSO-d6) δ: of 6.96-7,42 (4H, m), 7,45-7,53 (3H, m), 7,53-to 7.61 (2H, m), 7,80-7,87 (2H, m), 8,11 (1H, d, J=7.8 Hz), 8,59 (1H, s), 8,82 (1H, s), 9,10 (1H, s), 9,17 (1H, s).

Example 10b

When cooled on ice to a suspension of 5-phenylpyridine-3-carboxylic acid (0.11 g) in tetrahydrofuran (3.0 ml) was added N,N-dimethylformamide (0,010 ml) and oxacillin (0,059 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue tetrahydrofuran (5.5 ml). While cooling on ice, the reaction mixture was added to a solution of tert-butyl 2-amino-4-(pyridin-2-yl)benzoate (0.12 g) in a mixture of tetrahydrofuran (2.0 ml) and pyridine (0,073 ml)and then stirred at room temperature for 4 hours and 30 minutes. To the reaction mixture were added 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica compound is hardly [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 80-55% hexane/ethyl acetate] to obtain a solid substance. To the obtained solid substance was added ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration with the receipt of 0.13 g of tert-butyl 2-(5-vinylpyridin-3-carboxamido)-4-(pyridin-2-yl)benzoate as a pale yellow solid.

To the obtained tert-butyl 2-(5-vinylpyridin-3-carboxamido)-4-(pyridin-2-yl)benzoate (0,13 g) was added triperoxonane acid (4.0 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid is collected by filtration. To the obtained solid substance was added dioxane (3.0 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,19 ml)and then stirred at room temperature for 1 hour. To the reaction mixture were added 10% aqueous citric acid solution and ethyl acetate and collecting the solid by filtration to obtain 74 mg of 2-(5-vinylpyridin-3-carboxamido)-4-(pyrid the h-2-yl)benzoic acid as a white solid.

To the obtained 2-(5-vinylpyridin-3-carboxamido)-4-(pyridin-2-yl)benzoic acid (74 mg), was added ethanol (2.0 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,094 ml)and then stirred at room temperature for 1 hour and 30 minutes. The solid substance was collected by filtration to obtain 59 mg of 2-(5-vinylpyridin-3-carboxamido)-4-(pyridin-2-yl)sodium benzoate as a white solid.

1H-NMR (DMSO-d6) δ: of 7.36-7,42 (1H, m), 7,47-rate of 7.54 (1H, m), 7,55 to 7.62 (2H, m), 7,74 (1H, DD, J=8,2) and 1.7 Hz), 7,82-7,88 (2H, m), 7,89-of 7.97 (2H, m), 8,16 (1H, d, J=8,2 Hz), 8,63 (1H, DD, J=2,1, 2.0 Hz), 8,72 (1H, d, J=4.6 Hz), 9,11 (1H, d, J=2.1 Hz), of 9.21 (1H, d, J=2.0 Hz), to 9.45 (1H, d, J=1.7 Hz).

Example 11b

To a suspension of 5-phenylpyridine-3-carboxylic acid (73 mg) in methylene chloride (2 ml) at room temperature was added N,N-dimethylformamide (3 ml) and oxacillin (0,047 ml)and then stirred at the same temperature for 40 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2 ml). The reaction mixture at room temperature was added to a solution of tert-butyl 2-amino-4-(3-((tert-butoxycarbonyl)(ethyl)amino)phenyl)benzoate (0,13 g) in a mixture of methylene chloride (2 ml) and pyridine (0,062 ml)and then stirred at the same temperature for 20 minutes. The solvent is evaporated under reduced pressure, and PTS who attended the obtained residue by the method of column chromatography on silica gel [eluent: 90-60% hexane/ethyl acetate] to obtain 0.15 g of tert-butyl 4-(3-((tert-butoxycarbonyl)(ethyl)amino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate in the form of a white solid.

To a solution of the obtained tert-butyl 4-(3-((tert-butoxycarbonyl)(ethyl)amino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate (0.15 g) in methylene chloride (2.0 ml) at room temperature was added triperoxonane acid (2.0 ml)and then stirred at the same temperature for 7 hours and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the obtained residue, methanol (3 ml) and dioxane (1 ml). The pH was adjusted to 13.0 by adding 2 mol/l aqueous sodium hydroxide solution and then to pH 4.6 by adding 10% aqueous citric acid solution. The solid substance was collected by filtration to obtain 0.10 g of 4-(3-(ethylamino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid as a pale yellow solid.

1H-NMR (DMSO-d6) δ: to 1.21 (3H, t, J=7,1 Hz), 3,11 (2H, q, J=7,1 Hz), 6,61-6,69 (1H, m), 6,84-6,93 (2H, m), 7.23 percent (1H, DD, J=7,8, and 7.8 Hz), 7,45 to 7.62 (4H, m), 7,80-7,88 (2H, m)to 8.12 (1H, d, J=8,3 Hz), 8,55 (1H, DD, J=2.1 a, 2.1 a Hz), 8,98 (1H, d, J=1.7 Hz), 9,11-9,18 (2H, m), 12,37 (1H, s).

Examples 12b and 13b

Compounds shown in Table 8b, obtained as described in Example 11b.

Table 8b
Example No.R3Example No. R3
12b13b

4-(2-(Methylamino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid

1H-NMR (DMSO-d6) δ: 2,70 (3H, s), 6,64 to 6.75 (2H, m), 7,02-to 7.09 (1H, m), 7,22-to 7.32 (2H, m), 7,46-7,53 (1H, m), 7,54-to 7.61 (2H, m), 7,80-7,87 (2H, m)to 8.12 (1H, d, J=8.0 Hz), 8,50-8,55 (1H, m), a total of 8.74 (1H, d, J=1.4 Hz), 9,11 (1H, d, J=2.2 Hz), 9,14 (1H, d, J=2.2 Hz), 12,38 (1H, s).

4-(3-(Methylamino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid

1H-NMR (DMSO-d6) δ: 2,75 (3H, s), 6,63 (1H, DD, J=8,2, 1.8 Hz), 6,85-6,92 (2H, m), 7,25 (1H, DD, J=7,8, and 7.8 Hz), 7,46-rate of 7.54 (2H, m), 7,54-to 7.61 (2H, m), 7,81-7,87 (2H, m)to 8.12 (1H, d, J=8,2 Hz), 8,56 (1H, DD, J=2.1 a, 2.1 Hz), 8,98 (1H, d, J=1,8 Hz), 9,14 (1H, d, J=2.1 Hz), to 9.15 (1H, d, J=2.1 Hz), 12,36 (1H, s).

Example 14b

The following compound was obtained as described in Example 11b.

2-(5-(2-Forfinal)pyridine-3-carboxamido)-4-phenylbenzene acid

1H-NMR (DMSO-d6) δ: 7,38-7,51 (3H, m), 7,52-of 7.60 (4H, m), 7,70 for 7.78 (3H, m), 8,15 (1H, d, J=8,3 Hz), of 8.47-charged 8.52 (1H, m), 9,00-9,05 (2H, m), 9,18 (1H, d, J=2.2 Hz), 12,37 (1H, s).

Example 15b

When cooled on ice to a solution of 5-phenylpyridine-3-carboxylic acid (0,48 g) in a mixture of tetrahydrofuran (4.8 ml) and N,N-dimethylformamide (0,010 ml) was added oxalicacid (0,23 ml)and then stirred PR the room temperature for 40 minutes. The reaction mixture while cooling on ice, was added to a solution of methyl 2-amino-4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)benzoate (to 0.80 g) in a mixture of tetrahydrofuran (8.0 ml) and pyridine (of 0.44 ml)and then stirred at room temperature for 1 hour and 10 minutes. To the reaction mixture were added ethyl acetate and water. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 85-70% hexane/ethyl acetate] to obtain 0,86 g methyl-4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate as a white solid.

1H-NMR (CD3OD) δ: 1,02-of 1.16 (3H, m), 1.18 to a 1.46 (9H, m), 2,83-to 3.02 (1H, m), 3,52-a-3.84 (1H, m)4,00 (3H, s), 7.18 in-to 7.35 (2H, m), 7,39-to 7.59 (6H, m), 7,72 for 7.78 (2H, m), 8,09-to 8.20 (1H, m), 8,56-8,61 (1H, m), 8,77-of 8.90 (1H, m), of 9.02 (1H, d, J=2.2 Hz), 9,12 (1H, d, J=2.2 Hz).

Example 16b

To a solution of methyl-4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate (0.84 g) in a mixture of methanol (4,2 ml) and dioxane (4,2 ml) at room temperature was added 2 mol/l aqueous sodium hydroxide solution (3.8 ml)and then stirred at the same temperature for 3 hours and 10 minutes. After adjusting the pH to 4.9 is by adding 10% aqueous citric acid solution was added chloroform. The organic layer was separated, sequentially washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 0,80 g of 4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid as a white solid.

To the obtained 4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid (0,79 g) was added triperoxonane acid (7.9 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the obtained residue, 30% aqueous solution of ethanol. After adjusting the pH to 5.0 by the addition of 4.0 mol/l aqueous solution of sodium hydroxide, the solid was collected by filtration to obtain and 0.61 g of 4-(2-(ethylamino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid as a yellow solid.

To the obtained 4-(2-(ethylamino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid (0,60 g), was added ethanol (18 ml) and 1.0 mol/l aqueous sodium hydroxide solution (1.3 ml)and then stirred at room temperature for 1 hour. Dissolve the al evaporated under reduced pressure, and was added to the obtained residue, 10% aqueous solution of ethanol. The solid substance was collected by filtration to obtain 0,57 g of 4-(2-(ethylamino)phenyl)-2-(5-vinylpyridin-3-carboxamido)sodium benzoate as a pale yellow solid.

1H-NMR (DMSO-d6) δ: of 1.12 (3H, t, J=7,1 Hz), 3,03-3,17 (2H, m), to 4.41-to 4.52 (1H, m), 6,65-of 6.73 (2H, m), 7,00-was 7.08 (2H, m), 7,14-of 7.23 (1H, m), 7,45 to 7.62 (3H, m), 7,78-7,87 (2H, m), 8,11 (1H, d, J=7.8 Hz), 8,56-to 8.62 (1H, m), 8,68-8,73 (1H, m), 9,06-9,11 (1H, m), 9,14-9,19 (1H, m).

Example 17b

To a solution of 5-phenylpyridine-3-carboxylic acid (26 mg) in a mixture of methylene chloride (1.5 ml) and N,N-dimethylformamide (0,010 ml) at room temperature was added oxalicacid (0,014 ml)and then stirred at the same temperature for 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2.0 ml). The reaction mixture at room temperature was added to a solution of methyl 2-amino-4-(2-((tert-butoxycarbonyl)(isopropyl)amino)phenyl)benzoate (42 mg) in a mixture of methylene chloride (1.0 ml) and pyridine (0,013 ml)and then stirred at the same temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the residue ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, sequentially washed with 10% aqueous citric acid solution and nasy the n aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 80-70% hexane/ethyl acetate] to obtain methyl-4-(2-((tert-butoxycarbonyl)(isopropyl)amino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate.

To the obtained methyl-4-(2-((tert-butoxycarbonyl)(isopropyl)amino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate was added triperoxonane acid (3.0 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure and the obtained residue was sequentially added dioxane (3.0 ml) and 1 mol/l aqueous sodium hydroxide solution (0.33 ml), then stirred at room temperature for 30 minutes and then at 50°C for 1 hour. The reaction mixture was cooled to room temperature, then was added a 1 mol/l aqueous sodium hydroxide solution (0.33 ml)and then stirred at 50°C for 40 minutes. After cooling the reaction mixture to room temperature, the solvent evaporated under reduced pressure. To the obtained residue was added water, and collecting the solid by filtration to obtain 24 mg of 4-(2-(isopropylamino)phenyl)-2-(5-vinylpyridin-3-carboxamido)sodium benzoate as a yellow solid.

1H-NMR (DMSO-d6) δ: of 1.12 (6H, d,J=6.3 Hz), 3,59-3,70 (1H, m), 4,13 (1H, d, J=8.5 Hz), of 6.68 (1H, DD, J=7,3, 7,3 Hz), 6,74 (1H, d, J=8.0 Hz), 7,00-was 7.08 (2H, m), 7,19 (1H, DD, J=7,6, 7,6 Hz)to 7.50 (1H, DD, J=7,3, 7,3 Hz), 7,54 to 7.62 (2H, m), 7,80-7,87 (2H, m,), 8,11 (1H, d, J=8.0 Hz), 8,59 (1H, s), 8,68-a total of 8.74 (1H, m), which is 9.09 (1H, d, J=1.9 Hz), 9,17 (1H, d, J=1.7 Hz).

Example 18b

To a solution of 5-phenylpyridine-3-carboxylic acid (84 mg) in a mixture of methylene chloride (2 ml) and N,N-dimethylformamide (3,2 ml) at room temperature was added oxalicacid (0,054 ml)and then stirred at the same temperature for 1 hour and 20 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2 ml). The reaction mixture at room temperature was added to a solution of methyl 2-amino-5-methoxy-4-phenyl)benzoate (90 mg) in a mixture of methylene chloride (2 ml) and pyridine (0,071 ml)and then stirred at the same temperature for 50 minutes. The solvent is evaporated under reduced pressure and purify the resulting residue by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 75-30% hexane/ethyl acetate] to obtain 0.12 g of methyl-5-methoxy-4-phenyl-2-(5-vinylpyridin-3-carboxamido)benzoate as a brown solid.

To the suspension obtained methyl-5-methoxy-4-phenyl-2-(5-vinylpyridin-3-carboxamido)benzoate (0.11 g) in methanol (2.2 ml) at room temperature was added 2 mol/l aqueous races is the thief of sodium hydroxide (1.3 ml), and then stirred at the same temperature for 30 minutes. To the reaction mixture were added chloroform (3 ml) and methanol (2 ml)and then stirred at room temperature for 4 hours. The solvent is evaporated under reduced pressure, and was added to the obtained residue, ethanol and water. After adjusting the pH to 1 by addition of 6 mol/l hydrochloric acid, the solid was collected by filtration to obtain 88 mg of 5-methoxy-4-phenyl-2-(5-vinylpyridin-3-carboxamido)benzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: a 3.83 (3H, s), 7,38 to 7.62 (8H, m), to 7.67 (1H, s), 7,80-7,89 (2H, m), 8,49-8,55 (1H, m), 8,58 (1H, s), 9,10 (1H, d, J=2.0 Hz), 9,13 (1H, d, J=2.2 Hz), 11,96 (1H, s).

Example 19b

To a solution of 5-phenylpyridine-3-carboxylic acid (86 mg) in a mixture of methylene chloride (1.5 ml) and N,N-dimethylformamide (0,010 ml) at room temperature was added oxalicacid (0,047 ml)and then stirred at the same temperature for 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2.0 ml). The reaction mixture at room temperature was added to a solution of methyl 2-amino-4-(furan-2-yl)benzoate (78 mg) in a mixture of methylene chloride (1.5 ml) and pyridine (0,044 ml)and then stirred at the same temperature for 1 hour and 20 minutes. The solvent is evaporated in the conditions of reduced pressure, and was added to the residue ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, sequentially washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-20% hexane/ethyl acetate] to obtain 76 mg of methyl 4-(furan-2-yl)-2-(5-vinylpyridin-3-carboxamido)benzoate as a pale yellow solid.

To the suspension obtained methyl-4-(furan-2-yl)-2-(5-vinylpyridin-3-carboxamido)benzoate (76 mg) in dioxane (3.0 ml) at room temperature was added 2 mol/l aqueous solution of sodium hydroxide (0,19 ml)and then stirred at the same temperature for 3 hours and 20 minutes. To the reaction mixture at room temperature was added 2 mol/l aqueous solution of sodium hydroxide (0,19 ml)and then stirred at 50-55°C for 4 hours. After cooling the reaction mixture to room temperature, the solvent evaporated under reduced pressure. To the obtained residue was added 1 mol/l hydrochloric acid (1.5 ml). The solid substance was collected by filtration to obtain 69 mg of 4-(furan-2-yl)-2-(5-vinylpyridin-3-carboxamido)benzoic to the slots in the form of a white solid.

To the obtained 4-(furan-2-yl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid (69 mg) was added ethanol (4.5 ml) and 2 mol/l aqueous sodium hydroxide solution (of 0.085 ml)and then stirred at room temperature for 1 hour and 20 minutes. The solid substance was collected by filtration to obtain 31 mg of 4-(furan-2-yl)-2-(5-vinylpyridin-3-carboxamido)sodium benzoate as a white solid.

1H-NMR (DMSO-d6) δ: 6,63 (1H, DD, J=3.3, which is 1.7 Hz), 6,94 (1H, d, J=3.3 Hz), 7,39 (1H, DD, J=8,1) and 1.7 Hz), to 7.50 (1H, DD, J=7,3, 7,3 Hz), 7,54 to 7.62 (2H, m), 7,78-7,87 (3H, m), 8,08 (1H, d, J=8.1 Hz), 8,61 (1H, DD, J=2.1 a, 2.1 Hz), 9,06 (1H, d, J=1.5 Hz), 9,10 (1H, d, J=2.0 Hz), 9,18 (1H, d, J=1.7 Hz).

Example 20b

The following compound was obtained as described in Example 19b.

2-(5-Vinylpyridin-3-carboxamido)-4-(tetrahydrofuran-2-yl)benzoate sodium

1H-NMR (DMSO-d6) δ: 1,64-of 1.75 (1H, m), 1,91 is 2.01 (2H, m), 2,27-of 2.38 (1H, m), 3,83 (1H, DDD, J=7,4, to 7.4, 7.4 Hz), to 4.01 (1H, DDD, J=7,1, of 7.1 and 7.1 Hz), 4,82 (1H, DD, J=7,2, 7,2 Hz), 6,97 (1H, d, J=8.1 Hz), to 7.50 (1H, DD, J=7,2, 7,2 Hz), 7,54-to 7.61 (2H, m), 7,80-7,86 (2H, m), of 8.00 (1H, d, J=7.8 Hz), 8,57-to 8.62 (1H, m), 8,67 (1H, s), 9,07-9,11 (1H, m), 9,15-9,19 (1H, m).

Example 21b

The following compound was obtained as described in Example 19b.

2-(5-(Furan-2-yl)pyridine-3-carboxamido)-4-phenylbenzoate sodium

1H-NMR (DMSO-d6) δ: of 6.71 (1H, DD, J=3,4, 1.7 Hz), 7,25 (1H, d, J=3,4 Hz), 7,34 (1H, DD, J=8,1, 2.0 Hz), 7,40 (1H, DD, J=7,3, 7,3 Hz), 7,47-rate of 7.54 (2H, m), 7,66-7,72 (2H, m), 792 (1H, d, J=1.7 Hz), to 8.12 (1H, d, J=8.1 Hz), 8,61 (1H, DD, J=2,0, 2,0 Hz), of 9.02 (1H, d, J=2.0 Hz), 9,11 (1H, d, J=2.0 Hz), 9,14 (1H, d, J=2.0 Hz).

Example 22b

The following compound was obtained as described in Example 19b.

2-(5-(Furan-3-yl)pyridine-3-carboxamido)-4-phenylbenzoate sodium

1H-NMR (DMSO-d6) δ: 7,14 (1H, s), 7,31-7,37 (1H, m), 7,40 (1H, DD, J=7,1, 7,1 Hz), 7,47-of 7.55 (2H, m), 7,65-7,73 (2H, m), 7,87 (1H, d, J=1.5 Hz), 8,13 (1H, d, J=8.0 Hz), 8,42 (1H, s), 8,55 (1H, d, J=2.0 Hz), 9,01-9,05 (1H, m), 9,06-9,12 (2H, m).

Example 23b

To a solution of 5-phenylpyridine-3-carboxylic acid (83 mg) in a mixture of methylene chloride (3.0 ml) and N,N-dimethylformamide (0,010 ml) at room temperature was added oxalicacid (0,046 ml)and then stirred at the same temperature for 30 minutes. The solvent is evaporated under reduced pressure, and was added to the residue methylene chloride (2.5 ml). The reaction mixture while cooling on ice, was added to a solution of methyl 2-amino-4-(2-((ethyl)(methyl)amino)phenyl)benzoate (99 mg) in a mixture of methylene chloride (1.5 ml) and pyridine (0,042 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the residue ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, sequentially washed with 10% aqueous citric acid solution and saturated in the s ' solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-85% hexane/ethyl acetate] to obtain 0.10 g methyl-4-(2-((ethyl)(methyl)amino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate as a yellow solid.

To a solution of the obtained methyl-4-(2-((ethyl)(methyl)amino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate (0.10 g) in dioxane (3.0 ml) at room temperature was added 1 mol/l aqueous solution of sodium hydroxide (0,67 ml), then stirred at the same temperature for 1 hour and then at 55°C for 1 hour and 30 minutes. After cooling the reaction mixture to room temperature and adjust pH to 7.3 by adding 1 mol/l hydrochloric acid, the solvent is evaporated under reduced pressure. To the obtained residue was added water, and collecting the solid by filtration. To the obtained solid substance was sequentially added ethanol (1.5 ml) and 1 mol/l aqueous solution of sodium hydroxide (0,091 ml)and then stirred at room temperature for 1 hour. Then, the solvent was evaporated under reduced pressure, and was added to the obtained residue, water. The solid substance was collected by filtration to obtain 2.5 mg of 4-(2-((ethyl)(methyl)amino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate three is in the form of a yellow solid.

1H-NMR (DMSO-d6) δ: 0,86 (3H, t, J=7.0 Hz), to 2.57 (3H, s), of 2.81 (2H, q, J=7.0 Hz),? 7.04 baby mortality-7,11 (1H, m), to 7.15 (1H, d, J=8.1 Hz), 7,24 (1H, DD, J=7,4, and 1.6 Hz), 7,31-7,38 (1H, m), 7,44 (1H, DD, J=8,3) and 1.7 Hz), 7,47-7,53 (1H, m), 7,54-to 7.61 (2H, m), 7,81-7,87 (2H, m), of 8.09 (1H, d, J=8,3 Hz), 8,54 (1H, DD, J=2.1 a, 2.1 Hz), 8,87 (1H, d, J=1.7 Hz), 9,12 (1H, d, J=2.1 Hz), 9,14 (1H, d, J=2.1 Hz).

Example 24b

To a solution of tert-butyl 4-bromo-2-(5-vinylpyridin-3-carboxamido)benzoate (0.10 g) in dimethyl ether of ethylene glycol (2.0 ml) was added water (0.6 ml), sodium carbonate (70 mg), 2-nitrophenylarsonic acid (44 mg) and tetrakis(triphenylphosphine)palladium(0) (13 mg)and then heated under reflux in nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, then added to it sodium carbonate (23 mg), 2-nitrophenylarsonic acid (37 mg), and tetrakis(triphenylphosphine)palladium(0) (13 mg)and then heated under reflux in nitrogen atmosphere for 2 hours and 50 minutes. The reaction mixture was cooled to room temperature, and added a 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (Speri the definition), eluent: 91-80% hexane/ethyl acetate] to obtain 68 mg of tert-butyl 4-(2-nitrophenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate as a pale green solid.

1H-NMR (CDCl3) δ: of 1.66 (9H, s), 7,06 (1H, DD, J=8,2, 1.8 Hz), 7,43-7,49 (1H, m), 7,50-to 7.59 (4H, m), of 7.64-7,73 (3H, m), 7,93-to 7.99 (1H, m), of 8.09 (1H, d, J=8,2 Hz), 8,56 (1H, DD, J=2,2, 2,1 Hz), 8,99 (1H, d, J=1.7 Hz), 9,04 (1H, d, J=2.2 Hz), 9,26 (1H, d, J=2.1 Hz), 12,60 (1H, s).

Example 25b

To a solution of tert-butyl 4-(2-nitrophenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate (0.28 g) in a mixture of chloroform (3.0 ml) and methanol (2.0 ml) was added 10% palletirovanie coal (0,13 g)and then stirred in a hydrogen atmosphere at room temperature for 5 hours and 40 minutes. Insoluble substances were removed by filtration, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 100-90% chloroform/methanol] to obtain 0,22 g of tert-butyl 4-(2-AMINOPHENYL)-2-(5-vinylpyridin-3-carboxamido)benzoate as a pale yellow solid.

1H-NMR (DMSO-d6) δ: of 1.55 (9H, s), 7,00-7,19 (2H, m), 7,21 and 7.36 (2H, m), 7,44 (1H, DD, J=8,2, 1,6 Hz), 7,47 to 7.62 (3H, m), 7,82-of 7.90 (2H, m), of 8.00 (1H, d, J=8,2 Hz), 8,35 (1H, d, J=1.6 Hz), to 8.62 (1H, DD, J=2,0, 2,0 Hz), 9,10-which 9.22 (2H, m), are 11.62 (1H, s).

Example 26b

To tert-butyl 4-(2-nitrophenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate (68 mg) time to relax is whether triperoxonane acid (3.0 ml), and then was stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid is collected by filtration, the obtained solid substance was sequentially added dioxane (3.0 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,053 ml)and then stirred at room temperature for 1 hour 50 minutes. To the reaction mixture were added water. After adjusting the pH to 6.3 by adding 1 mol/l hydrochloric acid, the solid was collected by filtration to obtain 47 mg of 4-(2-nitrophenyl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 7,20-7,27 (1H, m)to 7.50 (1H, DD, J=7,4, 7,4 Hz), 7,53-to 7.61 (2H, m), of 7.64 (1H, d, J=7.8 Hz), 7,72 (1H, DD, J=7,8, and 7.8 Hz), 7,80-7,89 (3H, m), 8,08 (1H, d, J=8.0 Hz), 8,14 (1H, d, J=8.1 Hz), 8,50-to 8.57 (1H, m), 8,66-8,72 (1H, m), 9,11 (1H, d, J=1.7 Hz), 9,14 (1H, d, J=1.7 Hz), 12,49-12,64 (1H, broadened).

Example 27b

The following compound was obtained as described in Example 26b.

4-(2-AMINOPHENYL)-2-(5-vinylpyridin-3-carboxamido)benzoic acid

1H-NMR (DMSO-d6) δ: 6,69 (1H, DD, J=7,3, 7,3 Hz), for 6.81 (1H, d, J=7.8 Hz), 7,05-7,16 (2H, m), 7,33 (1H, d, J=8.1 Hz), 7,46 to 7.62 (3H, m), 7,80-7,87 (2H, m)to 8.12 (1H, d, J=8,3 Hz), 8,53 (1H, s), 8,78 (1H, s), which is 9.09-9,17 (2H, m), of 12.33 (1H, s).

Example 28b

To the obtained tert-butyl 4-(2-(benzylamino)Fe who yl)-2-(5-vinylpyridin-3-carboxamido)benzoate (75 mg) was added triperoxonane acid (1.0 ml), and then was stirred at room temperature for 6 hours and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the obtained residue, methanol (2 ml). After adjusting the pH to 12.0 by the addition of 2 mol/l aqueous solution of sodium hydroxide, the solvent is evaporated under reduced pressure. To the obtained residue was added water, and collecting the solid by filtration to obtain 68 mg of 4-(2-(benzylamino)phenyl)-2-(5-vinylpyridin-3-carboxamido)sodium benzoate as a pale green solid.

1H-NMR (DMSO-d6) δ: 4,28 is 4.36 (2H, m), are 5.36 (1H, t, J=5.5 Hz), is 6.54 (1H, d, J=8.0 Hz), 6,61-6,69 (1H, m), 7,01-to 7.15 (3H, m), 7,17-7,24 (1H, m), 7,27-7,42 (4H, m), 7,45 to 7.62 (3H, m), 7,80-7,87 (2H, m)to 8.14 (1H, d, J=8.0 Hz,), at 8.60 (1H, DD, J=2.1 a, 2.1 Hz), 8,81 (1H, d, J=1.7 Hz), which is 9.09 (1H, d, J=2.1 Hz), 9,18 (1H, d, J=2.1 Hz).

Example 29b

To a solution of N-(2-cyano-5-phenylphenyl)-5-vinylpyridin-3-carboxamide (0.11 g) in N,N-dimethylformamide (1.1 ml) at room temperature was added sodium azide (38 mg) and ammonium chloride (31 mg)and then stirred at 110°C for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature and then added to it in ethyl acetate and 1.0 mol/l hydrochloric acid (6.0 ml). The solid substance was collected by filtration to obtain 84 mg of 5-phenyl-N-(5-phenyl-2-(1H-tetrazol-5-yl)phenyl)pyridine-3-carboxamide as a yellow TV is Gogo substances.

1H-NMR (DMSO-d6) δ: 7,44-7,63 (6H, m), 7,75-7,83 (3H, m), 7,87-to 7.93 (2H, m), 8,13 (1H, d, J=8.0 Hz), 8,70 is 8.75 (1H, m), 8,78 (1H, d, J=1.5 Hz), 9,18 (1H, d, J=2.2 Hz), 9,20 (1H, d, J=2.0 Hz), 11,60 (1H, s).

Example 30b

To a suspension of tert-butyl 4-bromo-2-(5-vinylpyridin-3-carboxamido)benzoate (0.10 g) in dimethyl ether of ethylene glycol (2.0 ml) was added water (0.6 ml), sodium carbonate (70 mg), 2-methoxyphenylalanine acid (40 mg) and tetrakis(triphenylphosphine)palladium(0) (13 mg)and then heated under reflux in nitrogen atmosphere for 1 hour. After cooling the reaction mixture to room temperature, insoluble substances were removed by filtration, and was added to the residue 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 91-80% hexane/ethyl acetate] to obtain 61 mg of tert-butyl 4-(2-methoxyphenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate as a white solid.

To the obtained tert-butyl 4-(2-methoxyphenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate (61 mg) was added triperoxonane acid (4.0 ml)and then stirred at room temperature for 1 cha is and. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid is collected by filtration, and was added to the obtained residue, dioxane (3.0 ml), water and 2 mol/l aqueous solution of sodium hydroxide (0,080 ml). After adjusting the pH to 7.6 by adding 1 mol/l hydrochloric acid, the solid was collected by filtration to obtain 32 mg of 4-(2-methoxyphenyl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 3,81 (3H, s), to 7.09 (1H, DD, J=7,4, 7,4 Hz), 7,18 (1H, d, J=8,3 Hz), 7,33-7,40 (2H, m), 7,40-7,47 (1H, m)to 7.50 (1H, DD, J=7,3, 7,3 Hz), 7,53-to 7.61 (2H, m), 7,80-7,87 (2H, m), of 8.09 (1H, d, J=8,3 Hz), charged 8.52-8,56 (1H, m), 8,80 cent to 8.85 (1H, m), 9,12 (1H, d, J=2.0 Hz), 9,14 (1H, d, J=2.2 Hz), 12,35-12,49 (1H, broadened).

Example 31b

To a suspension of tert-butyl 4-bromo-2-(5-vinylpyridin-3-carboxamido)benzoate (0.10 g) in dimethyl ether of ethylene glycol (2.0 ml) was added water (0,60 ml), 2-tiefenbronn acid (34 mg), sodium carbonate (70 mg) and tetrakis(triphenylphosphine)palladium(0) (13 mg)and then heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature and then added to it the ethyl acetate and 10% aqueous citric acid solution. The organic layer was separated, washed with saturated aqueous sodium chloride and is sewed over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-85% hexane/ethyl acetate] to obtain tert-butyl 2-(5-vinylpyridin-3-carboxamido)-4-(thiophene-2-yl)benzoate.

To the obtained tert-butyl 2-(5-vinylpyridin-3-carboxamido)-4-(thiophene-2-yl)benzoate was added triperoxonane acid (4.0 ml)and then stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid substance was collected by filtration to obtain 54 mg of 2-(5-vinylpyridin-3-carboxamido)-4-(thiophene-2-yl)benzoic acid as a white solid.

To the suspension obtained 2-(5-vinylpyridin-3-carboxamido)-4-(thiophene-2-yl)benzoic acid (54 mg) in ethanol (4.0 ml) at room temperature was added 1 mol/l aqueous solution of sodium hydroxide (0,13 ml)and then stirred at the same temperature for 2 hours and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the obtained residue, water. The solid substance was collected by filtration to obtain 35 mg of 2-(5-vinylpyridin-3-carboxamido)-4-(thiophene-2-yl)sodium benzoate as a white solid.

1H-NMR (DMSO-d6) δ: 7,157,21 (1H, m), 7,40 (1H, DD, J=8,1) and 1.7 Hz), 7,46-7,63 (5H, m), 7,81-7,88 (2H, m), 8,08 (1H, d, J=8.1 Hz), 8,58-8,64 (1H, m), 9,06 (1H, d, J=1.7 Hz), 9,11 (1H, d, J=1.9 Hz), 9,19 (1H, d, J=1.7 Hz).

Examples 32b-43b

Compounds shown in Table 9b, obtained as described in Example 31b.

Table 9b
Example No.R3Example No.R3Example No.R3
32b36b40b
33b37b41b
34b38b42b
35b39b43b

4-(2-Were)-2-(5-vinylpyridin-3-carboxamido)sodium benzoate

1H-NMR (DMSO-d6) δ: to 2.29 (3H, s), 7,00 (1H, DD, J=8,1) and 1.7 Hz), 7,22-to 7.35 (4H, m), 7,46-7,53 (1H, m), 7,54-to 7.61 (2H, m), 7,80-7,86 (2H, m), 8,10 (1H, d, J=8.1 Hz), 8,59 (1H, DD, J=2.1 a, 2.1 Hz), 8,67 (1H, d, J=1.7 Hz), which is 9.09 (1H, d, J=2.1 Hz), 9,17 (1H, d, J=2.1 Hz).

2-(5-Vinylpyridin-3-carboxamido)-4-(2-(trifluoromethyl)phenyl)benzoate sodium

1H-NMR (DMSO-d6) δ: 6,98 (1H, d, J=7.8 Hz), 7,44-7,53 (2H, m), 7,54-to 7.61 (2H, m), of 7.64 (1H, DD, J=7,7, 7,7 Hz), of 7.75 (1H, DD, J=7,4, 7,4 Hz), 7,80-of 7.90 (3H, m), of 8.09 (1H, d, J=7.8 Hz), 8,56-to 8.62 (1H, m), to 8.70 (1H, s), which is 9.09 (1H, d, J=1.5 Hz), 9,16 (1H, d, J=1.5 Hz).

2-(5-vinylpyridin-3-carboxamido)-4-(3-(trifluoromethyl)phenyl)benzoate sodium

1H-NMR (DMSO-d6) δ: 7,44 (1H, d, J=8,3 Hz), 7,47-rate of 7.54 (1H, m), 7,55-7,63 (2H, m), 7,73-7,81 (2H, m), 7,82-7,89 (2H, m), of 7.96 (1H, s), 7,99-of 8.06 (1H, m), 8,18 (1H, d, J=8.0 Hz), 8,61-8,67 (1H, m), 9,07 is 9.15 (2H, m), of 9.21 (1H with).

4-(3-Methoxyphenyl)-2-(5-vinylpyridin-3-carboxamido)sodium benzoate

1H-NMR (DMSO-d6) δ: of 3.85 (3H, s), 6,94-7,03 (1H, m), 7,20 (1H, s), 7,26 (1H, d, J=7,6 Hz), 7,31-7,37 (1H, m), 7,42 (1H, DD, J=7,9, 7.9 Hz), to 7.50 (1H, DD, J=7,3, 7,3 Hz), 7,54-7,63 (2H, m), 7,81-7,89 (2H, m)to 8.12 (1H, d, J=8.0 Hz), to 8.62 (1H, s), of 9.02 (1H, s), 9,10 (1H, d, J=1.7 Hz), 9,17-9,24 (1H, m).

4-(4-Methoxyphenyl)-2-(5-vinylpyridin-3-carbox the Mido)sodium benzoate

1H-NMR (DMSO-d6) δ: 3,82 (3H, s),? 7.04 baby mortality-7,11 (2H, m), 7,35 (1H, DD, J=8,2, 1.8 Hz), 7,46-7,53 (1H, m), 7,54-to 7.61 (2H, m), 7,62-of 7.69 (2H, m), 7,80-7,87 (2H, m), 8,10 (1H, d, J=8,2 Hz), at 8.60 (1H, DD, J=2,1, 2.0 Hz), of 9.00 (1H, d, J=1,8 Hz), 9,11 (1H, d, J=2.1 Hz), 9,18 (1H, d, J=2.0 Hz).

4-(2,3-Acid)-2-(5-vinylpyridin-3-carboxamido)sodium benzoate

1H-NMR (DMSO-d6) δ: 3,61 (3H, s), 3,86 (3H, s), 6,91-6,97 (1H, m), 7,06-7,19 (3H, m), 7,46-7,53 (1H, m), 7,54 to 7.62 (2H, m), 7,80-7,87 (2H, m), 8,07 (1H, d, J=8.0 Hz), at 8.60 (1H, s), 8,82 (1H, s), 9,06-9,12 (1H, m), 9,15-9,20 (1H, m).

4-(2-Ethoxyphenyl)-2-(5-vinylpyridin-3-carboxamido)sodium benzoate

1H-NMR (DMSO-d6) δ: is 1.31 (3H, t, J=7.0 Hz), 4,07 (2H, q, J=7.0 Hz), 7,05 (1H, DD, J=7,3, 7,3 Hz), 7,12 (1H, d, J=8.6 Hz), 7,20 (1H, d, J=8.0 Hz), 7,30-7,40 (2H, m)to 7.50 (1H, DD, J=7,2, 7,2 Hz), 7,54-7,63 (2H, m), 7,80-7,89 (2H, m), 8,07 (1H, d, J=8.0 Hz), at 8.60 (1H, s)8,89 (1H, s), which is 9.09 (1H, d, J=1.7 Hz), 9,16-9,23 (1H, m).

4-(3-Ethoxyphenyl)-2-(5-vinylpyridin-3-carboxamido)sodium benzoate

1H-NMR (DMSO-d6) δ: to 1.38 (3H, t, J=7.0 Hz), of 4.12 (2H, q, J=7.0 Hz), of 6.96 (1H, DD, J=8,1, 2.4 Hz), 7,16-7,20 (1H, m), 7,24 (1H, d, J=7,6 Hz), 7,33 (1H, DD, J=7,9, and 1.4 Hz), 7,40 (1H, DD, J=7,9, 7.9 Hz), 7,46-7,53 (1H, m), 7,54 to 7.62 (2H, m), 7,81-7,87 (2H, m), 8,11 (1H, d, J=8.0 Hz), to 8.62 (1H, DD, J=1,9, 1.8 Hz), of 9.02 (1H, d, J=1.5 Hz), 9,10 (1H, d, J=1.9 Hz), 9,19 (1H, d, J=1,8 Hz).

2-(5-vinylpyridin-3-carboxamido)-4-(2-(triptoreline)phenyl)benzoate sodium

1H-NMR (DMSO-d6) δ: 7,09-7,16 (1H, m), 7,46 to 7.62 (7H, m), 7,80-7,87 (2H, m), 8,11 (1H, d, J=8.0 Hz), 8,57-8,63 (1H, m), 8,81-8,86 (1H, m), which is 9.09 (1H, d, J=2.0 Hz), 9,17 (1H, d, J=2.0 Hz).

2-(5-Vinylpyridin-3-carboxamido)-4-(3-(triptoreline)phenyl)benzoate sodium

1H-NMR (DMSO-d6) δ: of 7.36 was 7.45 (2H, m), 7,47-rate of 7.54 (1H, m), 7,55-of 7.69 (4H, m), 7,72 for 7.78 (1H, m), 7,82-7,88 (2H, m), 8,15 (1H, d, J=8.0 Hz), 8,60-8,65 (1H, m), 9,06 (1H, d, J=1.7 Hz), 9,11 (1H, d, J=2.2 Hz), 9,20 (1H, d, J=1,9 Hz).

4-(3-(Deformedarse)phenyl)-2-(5-vinylpyridin-3-carboxamido)sodium benzoate

1H-NMR (DMSO-d6) δ: 7,16-7,63 (9H, m), 7,81-7,88 (2H, m)to 8.14 (1H, d, J=8.0 Hz), 8,60-8,65 (1H, m), 9,04 (1H, d, J=1.7 Hz), 9,10 (1H, d, J=2.2 Hz), 9,20 (1H, d, J=1.7 Hz).

4-(2-Isopropoxyphenyl)-2-(5-vinylpyridin-3-carboxamido)sodium benzoate

1H-NMR (DMSO-d6) δ: 1,24 (6H, d, J=6,1 Hz), 4,58 (1H, septet, J=6,1 Hz), 7,03 (1H, DD, J=7,4, 7,4 Hz), 7,12 (1H, d, J=8,3 Hz), 7,18 (1H, DD, J=8.0 a, 1,6 Hz), 7,29-7,37 (2H, m), 7,46-7,53 (1H, m), 7,54-to 7.61 (2H, m), 7,80-7,87 (2H, m), with 8.05 (1H, d, J=8.0 Hz), 8,59 (1H, DD, J=2,2, 2,2 Hz), 8,88 (1H, d, J=1.6 Hz), which is 9.09 (1H, d, J=2.2 Hz), 9,17 (1H, d, J=2.2 Hz).

Example 44b

To a suspension of tert-butyl 4-bromo-2-(5-vinylpyridin-3-carboxamido)benzoate (0.10 g) in toluene (2.1 ml) was added ethanol (0,62 ml), water (0,31 ml), sodium carbonate (70 mg), 2-ftorhinolonovy acid (37 mg) and tetrakis(triphenylphosphine)palladium(0) (13 mg)and then heated under reflux in nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then was added a 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated in the conditions of reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 91-85% hexane/ethyl acetate] to obtain tert-butyl 4-(2-forfinal)-2-(5-vinylpyridin-3-carboxamido)benzoate.

To the obtained tert-butyl 4-(2-forfinal)-2-(5-vinylpyridin-3-carboxamido)benzoate was added triperoxonane acid (3.0 ml)and then stirred at room temperature for 1 hour and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid is collected by filtration. To the obtained solid substance was added dioxane (3.0 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,041 ml)and then stirred at room temperature for 1 hour. To the reaction mixture were added 10% aqueous citric acid solution, and collecting the solid by filtration to obtain 36 mg of 4-(2-forfinal)-2-(5-vinylpyridin-3-carboxamido)benzoic acid as a white solid.

To the obtained 4-(2-forfinal)-2-(5-vinylpyridin-3-carboxamido)benzoic acid (36 mg), was added ethanol (1.5 ml) and 1 mol/l aqueous solution of sodium hydroxide (0,087 ml)and then stirred at room temperature for 3 hours. The solid substance was collected by filtration to obtain 22 mg of 4-(2-forfinal)-2-(5-phenyl what iridin-3-carboxamido)sodium benzoate as a white solid.

1H-NMR (DMSO-d6) δ: 7,21 (1H, DDD, J=8.0 a, 1,8, 1.8 Hz), 7,30-7,38 (2H, m), 7,41-7,53 (2H, m), 7,53-to 7.61 (3H, m), 7,81-7,87 (2H, m), 8,13 (1H, d, J=8.0 Hz), 8,61 (1H, DD, J=2,2, 2,1 Hz), 8,90-to 8.94 (1H, m), which is 9.09 (1H, d, J=2.2 Hz), 9,18 (1H, d, J=2.1 Hz).

Example 45b

To a solution of tert-butyl 4-bromo-2-(5-vinylpyridin-3-carboxamido)benzoate (0.10 g) in toluene (2.1 ml) was added ethanol (0,62 ml), water (0,31 ml), sodium carbonate (70 mg), 1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (55 mg) and tetrakis(triphenylphosphine)palladium(0) (13 mg)and then heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, then added to it sodium carbonate (23 mg), 1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (46 mg) and tetrakis(triphenylphosphine)palladium(0) (13 mg)and then heated under reflux in nitrogen atmosphere for 3 hours and 30 minutes. The reaction mixture was cooled to room temperature, then was added a toluene (1.0 ml), ethanol (0,31 ml) and water (0.16 ml), and then was heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and then was added a 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and evaporated the solvent under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-85% hexane/ethyl acetate] to obtain 71 mg of tert-butyl 4-(1-methyl-1H-pyrrol-2-yl)-2-(5-vinylpyridin-3-carboxamido)benzoate as a pale yellow solid.

To the obtained tert-butyl 4-(1-methyl-1H-pyrrol-2-yl)-2-(5-vinylpyridin-3-carboxamido)benzoate (71 mg) was added methanol (1.5 ml), dioxane (1.5 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,24 ml)and then stirred at 50-55°C for 2 hours. The reaction mixture was cooled to room temperature, and then was added a 10% aqueous solution of citric acid. The solid substance was collected by filtration to obtain 50 mg of 4-(1-methyl-1H-pyrrol-2-yl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: with 3.79 (3H, s), x 6.15 (1H, DD, J=3,0, 3.0 Hz), 6,38-to 6.43 (1H, m), 6,97 (1H, DD, J=2.1 a, 2.1 Hz), was 7.36 (1H, DD, J=8,3, 1,6 Hz), 7,47-7,53 (1H, m), 7,54-to 7.61 (2H, m), 7,81-7,87 (2H, m), 8,07 (1H, d, J=8,3 Hz), 8,54 (1H, DD, J=2.1 a, 2.1 Hz), 8,84 (1H, d, J=1.6 Hz), 9,13 (1H, d, J=2.1 Hz), to 9.15 (1H, d, J=2.1 Hz), 12,37 (1H, s).

Example 46b

To a solution of tert-butyl 4-bromo-2-(5-vinylpyridin-3-carboxamido)benzoate (80 mg) in dimethyl ether of ethylene glycol (2.0 ml) was added water (0.6 ml), sodium carbonate (47 mg), 3-tiefenbronn acid (27 mg) and dichloride bis(triphenylphosphine)palladium(II) (2.5 mg)and then heated with a back hall is dildocam in nitrogen atmosphere for 2 hours and 10 minutes. The reaction mixture was cooled to room temperature and then added to it the ethyl acetate and 10% aqueous citric acid solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-85% hexane/ethyl acetate] to obtain tert-butyl 2-(5-vinylpyridin-3-carboxamido)-4-(thiophene-3-yl)benzoate.

To the obtained tert-butyl 2-(5-vinylpyridin-3-carboxamido)-4-(thiophene-3-yl)benzoate was added triperoxonane acid (4.0 ml)and then stirred at room temperature for 1 hour and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid substance was collected by filtration to obtain 47 mg of 2-(5-vinylpyridin-3-carboxamido)-4-(thiophene-3-yl)benzoic acid as a white solid.

To the suspension obtained 2-(5-vinylpyridin-3-carboxamido)-4-(thiophene-3-yl)benzoic acid (47 mg) in ethanol (4.0 ml) at room temperature was added 1 mol/l aqueous sodium hydroxide solution (0.10 ml)and then stirred at the same temperature for 1 hour and 10 minutes. The solvent is evaporated under reduced pressure, and added to p is obtained residue ethanol and water. The solid substance was collected by filtration to obtain 40 mg of 2-(5-vinylpyridin-3-carboxamido)-4-(thiophene-3-yl)sodium benzoate as a white solid.

1H-NMR (DMSO-d6) δ: of 7.36-7,42 (1H, m), 7,46-rate of 7.54 (2H, m), 7,54-to 7.61 (2H, m), 7,65-of 7.70 (1H, m), 7,81-7,87 (3H, m), 8,04-8,10 (1H, m), 8,59-8,64 (1H, m), 9,01-9,05 (1H, m), the remaining 9.08-9,12 (1H, m), 9,17-of 9.21 (1H, m).

Example 47b

The following compound was obtained as described in Example 46b.

4-(4-(Deformedarse)phenyl)-2-(5-vinylpyridin-3-carboxamido)sodium benzoate

1H-NMR (DMSO-d6) δ: 7,12-7,53 (5H, m), 7,54 to 7.62 (2H, m), 7,72 for 7.78 (2H, m), 7,81-7,87 (2H, m), 8,13 (1H, d, J=7.8 Hz), 8,59-8,65 (1H, m), 9,01-9,05 (1H, m), 9,11 (1H, d, J=1.5 Hz), 9,20 (1H, d, J=1.5 Hz).

Example 48b

To a suspension of tert-butyl 2-(5-bromopyridin-2-carboxamido)-4-phenylbenzoate (0.12 g) in dimethyl ether of ethylene glycol (1.2 ml) was added sodium carbonate (55 mg), phenylboronic acid (38 mg), water (0.35 ml) and dichloride bis(triphenylphosphine)palladium(II) (3.7 mg)and then heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, then added to it sodium carbonate (55 mg), phenylboronic acid (38 mg) and dichloride bis(triphenylphosphine)palladium(II) (3.7 mg)and then heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature is, and added to it the ethyl acetate and water. Insoluble substances were removed by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-80% hexane/ethyl acetate] to obtain 0.11 g of tert-butyl 4-phenyl-2-(5-vinylpyridin-2-carboxamido)benzoate as a white solid.

To the obtained tert-butyl-4-phenyl-2-(5-vinylpyridin-2-carboxamido)benzoate (0.11 g) was added triperoxonane acid (5 ml)and then stirred at room temperature for 4 hours. The solvent is evaporated under reduced pressure, and was added to the obtained residue, ethyl acetate and water. After adjusting the pH to 6.5 by the addition of saturated aqueous sodium bicarbonate solution the organic layer was separated, sequentially washed with water and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 90 mg of 4-phenyl-2-(5-vinylpyridin-2-carboxamido)benzoic acid in view of the white solid.

1H-NMR (DMSO-d6) δ: 7,44-of 7.60 (7H, m), 7,73-7,79 (2H, m), a 7.85 to $ 7.91 (2H, m), 8,15 (1H, d, J=8.1 Hz), 8,29 (1H, d, J=8,3 Hz), 8,40 (1H, DD, J=8,2, 2.3 Hz), the remaining 9.08 (1H, d, J=2.0 Hz), 9,26 (1H, d, J=1.7 Hz), 13,23 (1H, s).

Example 49b

To a solution of tert-butyl 4-bromo-2-(5-vinylpyridin-3-carboxamido)benzoate (0.15 g) in dimethyl ether of ethylene glycol (2.0 ml) was added water (0,60 ml), sodium carbonate (88 mg), tert-butylmethyl-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (0,13 g) dichloride and bis(triphenylphosphine)palladium(II) (5.0 mg)and then heated under reflux in a nitrogen atmosphere at for 1 hour. The reaction mixture was cooled to room temperature, and then was added a 10% aqueous citric acid solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-85% hexane/ethyl acetate] to obtain 0.16 g of tert-butyl 4-(4-((tert-butoxycarbonyl)(methyl)amino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate as a white solid.

To the obtained tert-butyl 4-(4-((tert-butoxycarbonyl)(methyl)amino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate (0.16 g) was added triperoxonane acid (4.0 ml), and then per Merivale at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid is collected by filtration, and was added to the obtained solid substance ethanol and water. After adjusting the pH to 5.5 by adding 1 mol/l aqueous solution of sodium hydroxide, the solid was collected by filtration to obtain 0.11 g of 4-(4-(methylamino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 2,74 (3H, s), 6,65-of 6.71 (2H, m), 7,43-to 7.61 (6H, m), 7,81-7,87 (2H, m), with 8.05 (1H, d, J=8,3 Hz), 8,53-8,58 (1H, m), 8,97 (1H, d, J=1.5 Hz), 9,11-9,18 (2H, m), KZT 12.39 (1H, s).

Example 50b

The following compound was obtained as described in Example 49b.

4-(Indolin-5-yl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid

1H-NMR (DMSO-d6) δ: to 3.02 (2H, t, J=8,4 Hz), 3,51 (2H, t, J=8,4 Hz), is 6.61 (1H, d, J=8,3 Hz), 7,37 (1H, d, J=8,3 Hz), 7,40-of 7.48 (2H, m)to 7.50 (1H, DD, J=7,3, 7,3 Hz), 7,54 to 7.62 (2H, m), 7,80-7,89 (2H, m), with 8.05 (1H, d, J=8,3 Hz), 8,56 (1H, s), 8,97 (1H, s), 9,07-9,23 (2H, m), 12,46 (1H, s).

Example 51b

The following compound was obtained as described in Example 49b.

4-(3-(Dimethylamino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid

1H-NMR (DMSO-d6) δ: 2,99 (6H, s), 6,79-6,87 (1H, m), 6,95? 7.04 baby mortality (2H, m), 7,34 (1H, DD, J=8,2, 8,2 Hz), 7,47-7,63 (4H, m), 7,81-7,89 (2H, m)to 8.12 (1H, d, J=8,3 Hz), 8,56 (1H, DD, =2,1, and 2.1 Hz), 8,98 (1H, d, J=1.7 Hz), 9,11-9,19 (2H, m), 12,35 (1H, s).

Example 52b

To a solution of N,N-diethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (83 mg) in dimethyl ether of ethylene glycol (1.0 ml) was added tert-butyl 4-bromo-2-(5-vinylpyridin-3-carboxamido)benzoate (0.11 g), sodium carbonate (64 mg), water (0,30 ml) and dichloride bis(triphenylphosphine)palladium(II) (3.5 mg)and then heated under reflux in nitrogen atmosphere for 2 hours 40 minutes. The reaction mixture was cooled to room temperature and then added to her water and chloroform. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 90-70% hexane/ethyl acetate] to obtain 0.12 g of tert-butyl 4-(3-(diethylamino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate as a yellow solid.

To the obtained tert-butyl 4-(3-(diethylamino)phenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate (0.12 g) was added triperoxonane acid (1.0 ml)and then stirred at room temperature for 1 hour and 10 minutes. The solvent is evaporated under reduced pressure, and was added to the obtained residue, methanol (2.0 ml). After adjusting the pH to 12.7 by adding 2 mol/l aqueous solution guide is sodium oxide solid substance was collected by filtration to obtain 99 mg of 4-(3-(diethylamino)phenyl)-2-(5-vinylpyridin-3-carboxamido)sodium benzoate as a white solid.

1H-NMR (DMSO-d6) δ: 1,15 (6H, t, J=7,0 Hz)to 3.41 (4H, q, J=7.0 Hz), 6,70 (1H, DD, J=8,4, and 2.3 Hz), for 6.81-6,92 (2H, m), 7,21-7,31 (2H, m), 7,46 to 7.62 (3H, m), 7,81-7,89 (2H, m), of 8.09 (1H, d, J=7.8 Hz), 8,59-8,65 (1H, m), 8,98 (1H, d, J=1.7 Hz), which is 9.09 (1H, d, J=2.0 Hz), 9,19 (1H, d, J=2.0 Hz).

Example 53b

The following compound was obtained as described in Example 52b.

4-Phenyl-2-(5-(pyridin-3-yl)pyridine-3-carboxamido)sodium benzoate

1H-NMR (DMSO-d6) δ: 7,34 (1H, DD, J=8,0, 1.8 Hz), 7,37-the 7.43 (1H, m), 7,47-rate of 7.54 (2H, m), 7,60 (1H, DD, J=8.0 a, a 4.9 Hz), 7,66-7,72 (2H, m)to 8.12 (1H, d, J=8.0 Hz), compared to 8.26 (1H, DDD, J=8.0 a, 2,0, 2,0 Hz), 8,67 (1H, DD, J=2,2, 2,2 Hz), to 8.70 (1H, DD, J=4,9, 1,4 Hz), 9,03 (1H, d, J=1.7 Hz), 9,05 (1H, d, J=1.9 Hz), 9,17 (1H, d, J=2.2 Hz), 9,24 (1H, d, J=2.0 Hz).

Example 54b

The following compound was obtained as described in Example 52b.

4-Phenyl-2-(5-(pyridin-4-yl)pyridine-3-carboxamido)sodium benzoate

1H-NMR (DMSO-d6) δ: 7,31 and 7.36 (1H, m), of 7.36-the 7.43 (1H, m), 7,47-rate of 7.54 (2H, m), 7,66-7,72 (2H, m), 7,87-a 7.92 (2H, m)to 8.12 (1H, d, J=8.1 Hz), 8,71-8,78 (3H, m), 9,00-9,04 (1H, m), of 9.21-9,24 (1H, m), 9,26-of 9.30 (1H, m).

Example 55b

To a suspension of tert-butyl 4-bromo-2-(5-vinylpyridin-3-carboxamido)benzoate (0.10 g) in dimethyl ether of ethylene glycol (2.0 ml) was added water (0.6 ml), sodium carbonate (58 mg), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (85 mg) and dichloride bis(triphenylphosphine)palladium(II) (3.0 mg)and then heated under reflux in the atmosphere is fere nitrogen for 1 hour. The reaction mixture was cooled to room temperature and then added to it the ethyl acetate and 10% aqueous citric acid solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 95-80% hexane/ethyl acetate] to obtain tert-butyl 4-(3-(tert-butoxycarbonyl)oxyphenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate.

To the obtained tert-butyl 4-(3-(tert-butoxycarbonyl)oxyphenyl)-2-(5-vinylpyridin-3-carboxamido)benzoate was added triperoxonane acid (4.0 ml)and then stirred at room temperature for 1 hour and 15 minutes. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid substance was collected by filtration to obtain 70 mg of 4-(3-hydroxyphenyl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid as a pale yellow solid.

To the obtained 4-(3-hydroxyphenyl)-2-(5-vinylpyridin-3-carboxamido)benzoic acid (70 mg), was added ethanol (4.0 ml) and 1 mol/l aqueous solution of sodium hydroxide (0.17 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated in terms of the reduced pressure, and was added to the obtained residue, ethanol and water. The solid substance was collected by filtration to obtain 26 mg of 4-(3-hydroxyphenyl)-2-(5-vinylpyridin-3-carboxamido)sodium benzoate as a white solid.

1H-NMR (DMSO-d6) δ: 6,76-6,83 (1H, m), 7,08-7,14 (2H, m), 7,25-7,33 (2H, m), 7,46-7,53 (1H, m), 7,54 to 7.62 (2H, m), 7,81-7,87 (2H, m), 8,10 (1H, d, J=8.1 Hz), 8,61 (1H, DD, J=2,2, 2,1 Hz), of 9.00 (1H, d, J=1.7 Hz), 9,10 (1H, d, J=2.2 Hz), 9,18 (1H, d, J=2.1 Hz), 9,59 (1H, s).

Example 56b

The following compound was obtained as described in Example 31b.

4-(2-Hydroxyphenyl)-2-(5-vinylpyridin-3-carboxamido)sodium benzoate

1H-NMR (DMSO-d6) δ: 6,90 (1H, DD, J=7,4, 7,4 Hz), of 6.96 (1H, d, J=8.0 Hz), 7,14-7,26 (2H, m), 7,26-to 7.32 (1H, m), 7,49 (1H, DD, J=7,3, 7,3 Hz), 7,54-to 7.61 (2H, m), 7,80-7,87 (2H, m), with 8.05 (1H, d, J=8.0 Hz), at 8.60 (1H, DD, J=2.1 and and 2.1 Hz), 8,88 (1H, d, J=1.4 Hz), which is 9.09 (1H, d, J=2.0 Hz), 9,17 (1H, d, J=1.7 Hz), 9,54 (1H, s).

Example 57b

The following compound was obtained as described in Example 55b.

4-(Furan-3-yl)-2-(5-vinylpyridin-3-carboxamido)sodium benzoate

1H-NMR (DMSO-d6) δ: 6,91 (1H, s), 7,31 (1H, d, J=8.0 Hz), 7,45-7,63 (3H, m), 7,76-7,89 (3H, m), of 8.06 (1H, d, J=7.8 Hz), 8,17 (1H, s), 8,61 (1H, s), 8,91 (1H, s), 9,10 (1H, s), 9,19 (1H, s).

Example 58b

To a solution of tert-butyl 4-bromo-2-(5-vinylpyridin-3-carboxamido)benzoate (0.10 g) in toluene (3.0 ml) was added tribalistas (0.12 g), 1-(tert-butoxycarbonyl)-1H-pyrrol-2-Boro the OIC acid (56 mg), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (1 mg) and palladium(II) acetate (1 mg)and then heated under reflux in nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, added to it tribalistas (47 mg), 1-(tert-butoxycarbonyl)-1H-pyrrol-2-Bronevoy acid (47 mg), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (1 mg) and palladium(II) acetate (1 mg)and then heated under reflux in nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and added to it the ethyl acetate and 10% aqueous citric acid solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was sequentially added dioxane (1.5 ml), methanol (1.5 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,29 ml)and then stirred at 50°C for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then was added a 10% aqueous citric acid solution and ethyl acetate. The solid substance was collected by filtration to obtain 39 mg of 2-(5-vinylpyridin-3-carboxamido)-4-(1H-pyrrol-2-yl)benzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 6,18-6,24 (1H, m), 6,63-6,69 (1H, is), 6,95-7,01 (1H, m), 7,46-rate of 7.54 (2H, m), 7,54 to 7.62 (2H, m), 7,81-7,88 (2H, m), 8,03 (1H, d, J=8,3 Hz), 8,56 (1H, DD, J=2.1 a, 2.1 Hz), of 8.90 (1H, d, J=1.7 Hz), 9,12-9,17 (2H, m), of 11.61 (1H, s), 12,38 (1H, s), 13,50-13,82 (1H, broadened).

Example 59b

To a solution of tert-butyl 2-(4-chloropyridin-2-carboxamido)-4-phenylbenzoate (60 mg) in toluene (1.2 ml) was added phenylboronic acid (21 mg), tribalistas (69 mg), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (1.2 mg) and palladium(II) acetate (1.3 mg)and then heated under reflux in nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, then added to it phenylboronic acid (5.4 mg), tribalistas (16 mg), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (1.2 mg) and palladium(II) acetate (1.3 mg)and then heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature and then added to it the ethyl acetate and 10% aqueous citric acid solution. Insoluble substances were removed by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 100-85% hexane/ethyl acetate] receipt is m 65 mg of tert-butyl 4-phenyl-2-(4-vinylpyridin-2-carboxamido)benzoate as a colorless oily substance.

To the obtained tert-butyl-4-phenyl-2-(4-vinylpyridin-2-carboxamido)benzoate (64 mg) was added triperoxonane acid (5 ml)and then stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the obtained residue, ethyl acetate and water. After adjusting the pH to 6.5 by the addition of saturated aqueous sodium bicarbonate solution the organic layer was separated, sequentially washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and collecting the solid by filtration to obtain 50 mg of 4-phenyl-2-(4-vinylpyridin-2-carboxamido)benzoic acid as a white solid.

1H-NMR (DMSO-d6) δ: 7,44-7,51 (1H, m), 7,51 to 7.62 (6H, m), 7,73 for 7.78 (2H, m), 7,89-7,94 (2H, m), of 8.04 (1H, DD, J=5,1, 1.9 Hz), 8,15 (1H, d, J=8,3 Hz), 8,48 (1H, d, J=1.2 Hz), 8,82 (1H, d, J=5,1 Hz), 9,27 (1H, d, J=1.7 Hz), 13,20 (1H, s).

Example 60b

To a suspension of tert-butyl 2-(6-chloropyridin-3-carboxamido)-4-phenylbenzoate (80 mg) in toluene (1.6 ml) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (48 mg), tribalistas (91 mg), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (1.6 mg) and palladium(II) acetate (1.8 mg)and then heated with reverse what holodilniki in nitrogen atmosphere for 2 hours 30 minutes. The reaction mixture was cooled to room temperature, then added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (48 mg), tribalistas (91 mg), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (1.6 mg) and palladium(II) acetate (1.8 mg)and then heated under reflux in nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, then added to it 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (1.6 mg) and palladium(II) acetate (1.8 mg)and then heated under reflux in nitrogen atmosphere for 2 hours. After cooling the reaction mixture to room temperature, the solvent evaporated under reduced pressure, and was added to the residue chloroform and water. Insoluble substances were removed by filtration. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-15% hexane/ethyl acetate] to obtain 25 mg of tert-butyl 4-phenyl-2-(6-(pyridin-4-yl)pyridine-3-carboxamido)benzoate as a pale yellow solid.

To the obtained tert-butyl-4-phenyl-2-(6-(pyridin-4-yl)pyridine-3-carboxamido)benzoate (25 mg) was added three is torakusu acid (5 ml), and then was stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the obtained residue, water. After adjusting the pH to 5.5 by the addition of saturated aqueous sodium bicarbonate solution, the solid was collected by filtration to obtain 20 mg of 4-phenyl-2-(6-(pyridin-4-yl)pyridine-3-carboxamido)benzoic acid as a yellow solid.

To the obtained 4-phenyl-2-(6-(pyridin-4-yl)pyridine-3-carboxamido)benzoic acid (20 mg) was added dioxane (2 ml), methanol (2 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,025 ml)and the solvent evaporated under reduced pressure. To the obtained residue was added acetone. The solid substance was collected by filtration to obtain 17 mg of 4-phenyl-2-(6-(pyridin-4-yl)pyridine-3-carboxamido)sodium benzoate as a yellow solid.

1H-NMR (DMSO-d6) δ: 7,30-the 7.43 (2H, m), 7,46-rate of 7.54 (2H, m), 7,66-7,72 (2H, m), 8,08-to 8.20 (3H, m), 8,32 is 8.38 (1H, m), 8,49-8,55 (1H, m), 8,73-8,80 (2H, m), 9,00-9,04 (1H, m), a 9.35 (1H, s).

Example 61b

To a solution of tert-butyl 4-bromo-2-(5-vinylpyridin-3-carboxamido)benzoate (0.10 g) in toluene (2.5 ml) was added cesium carbonate (0.14 g), aniline (0,030 ml), Tris(dibenzylideneacetone)dipalladium(0) (2 mg), palladium(II) acetate (1 mg) and 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (5 mg), and then n is gravely under reflux in a nitrogen atmosphere at 1 hour 10 minutes. The reaction mixture was cooled to room temperature and then added to it the ethyl acetate and 10% aqueous citric acid solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 91-80% hexane/ethyl acetate] to obtain tert-butyl-4-aniline-2-(5-vinylpyridin-3-carboxamido)benzoate.

To the obtained tert-butyl-4-aniline-2-(5-vinylpyridin-3-carboxamido)benzoate was added triperoxonane acid (3.0 ml)and then stirred at room temperature for 1 hour and 30 minutes. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid is collected by filtration. To the obtained solid substance was sequentially added dioxane (3.0 ml) and 2 mol/l aqueous solution of sodium hydroxide (0,068 ml)and then stirred at room temperature for 1 hour and 30 minutes. To the reaction mixture were added 10% aqueous citric acid solution, and collecting the solid by filtration to obtain 73 mg of 4-aniline-2-(5-vinylpyridin-3-carboxamido)benzoic acid as a yellow solid.

1H-NMR (DMSO-d6) δ: to 6.80 (1H, is d, J=an 8.8 and 2.2 Hz), 7,00-7,07 (1H, m), 7,22-7,28 (2H, m), 7,33-7,40 (2H, m), 7,46-7,52 (1H, m), 7,53-of 7.60 (2H, m), 7,80-7,86 (2H, m), to $ 7.91 (1H, d, J=8,8 Hz), 8,48-charged 8.52 (1H, m), 8,55 (1H, d, J=2.2 Hz), of 9.00 (1H, ), 9,10 (1H, d, J=1.7 Hz), 9,13 (1H, d, J=2.0 Hz), 12,67 (1H, s), 13,14-of 13.27 (1H, broadened).

Example 62b

To a solution of tert-butyl 4-bromo-2-(5-vinylpyridin-3-carboxamido)benzoate (0.10 g) in toluene (3.0 ml) was added cesium carbonate (0.14 g), morpholine (0,029 ml), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (5 mg), Tris(dibenzylideneacetone)dipalladium(0) (2 mg) and palladium(II) acetate (1 mg)and then heated under reflux in nitrogen atmosphere for 1 hours. The reaction mixture was cooled to room temperature, then added to it morpholine (0,029 ml)and then heated under reflux in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, then added to it, cesium carbonate (72 mg), morpholine (0,029 ml), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (5 mg), Tris(dibenzylideneacetone)dipalladium(0) (2 mg) and palladium(II) acetate (1 mg)and then heated under reflux in nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature and then added to it the ethyl acetate and 10% aqueous citric acid solution. The organic layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous self the volume of magnesium, and the solvent evaporated under reduced pressure. The obtained residue was purified by the method of column chromatography on silica gel [eluent: 85-70% hexane/ethyl acetate] to obtain tert-butyl-4-morpholino-2-(5-vinylpyridin-3-carboxamido)benzoate.

To the obtained tert-butyl-4-morpholino-2-(5-vinylpyridin-3-carboxamido)benzoate was added triperoxonane acid (3.0 ml)and then stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and was added to the obtained residue diisopropyl ether. The solid is collected by filtration, successively added to the obtained solid substance ethanol (2.5 ml) and 1 mol/l aqueous sodium hydroxide solution (of 0.44 ml)and then stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and was added to the obtained residue, water. The solid substance was collected by filtration to obtain 35 mg of 4-morpholino-2-(5-vinylpyridin-3-carboxamido)sodium benzoate as a white solid.

1H-NMR (DMSO-d6) δ: 3,13-is 3.21 (4H, m), of 3.73-3,81 (4H, m), 6,62 (1H, DD, J=8,8, and 2.6 Hz), 7,46-7,52 (1H, m), 7,54-to 7.61 (2H, m), 7,80-7,86 (2H, m), of 7.90 (1H, d, J=8,8 Hz), of 8.37 (1H, d, J=2.6 Hz), 8,59 (1H, DD, J=2.1 a, 2.2 Hz), the remaining 9.08 (1H, d, J=2.2 Hz), 9,17 (1H, d, J=2.1 Hz).

Example 63b

The following compound was obtained, ka is described in Example 62b.

2-(5-Vinylpyridin-3-carboxamido)-4-(piperidine-1-yl)benzoate sodium

1H-NMR (DMSO-d6) δ: 1,53-to 1.67 (6H, m), 3,18-of 3.25 (4H, m), to 6.57 (1H, DD, J=8,9, and 2.1 Hz), 7,46-7,53 (1H, m), 7,53-to 7.61 (2H, m), 7,79-7,87 (3H, m), a 8.34 (1H, d, J=2.4 Hz), 8,58-8,63 (1H, m), 9,07 (1H, d, J=2.2 Hz), 9,16 (1H, d, J=2.0 Hz).

Applicability in an industrial environment

Because a derived N-acylanthranilic acid of the present invention or its salt has an inhibitory effect on collagen production, it is applicable to the prevention, treatment and the like, and diseases associated with excessive production of collagen, such as pulmonary fibrosis, scleroderma, nephrosclerosis and cirrhosis of the liver.

1. The derived N-acylanthranilic acid represented by the following General formula, or its pharmaceutically acceptable salt:
[Formula 1]

in which
R1represents an optionally protected carboxyl group or 1H-tetrazol-5-ilen group;
R2represents a hydrogen atom, halogen atom, optionally protected hydroxyl group, or alkoxygroup;
R3represents an optionally substituted aryl group or optionally substituted heterocyclic group;
X1represents a carbonyl group;
X2that is the link;
X3that is the link;
X4A represents a group represented by the following General formula:
[Formula 2]

in which
R4represents a hydrogen atom or a protective group of a phenolic hydroxyl;
one of R5, R6, R7and R8represents a group represented by the General formula-Y-R9,
in which
R9represents a halogen atom, a nitro-group, optionally protected hydroxyl group, amino group, alkylamino, optionally substituted by dialkylamino, alkyl group, alkoxygroup, aryl group, alloctype, optionally substituted heterocyclic group, optionally substituted heterocyclic oxygraph, acyl group, or alloctype;
Y represents alkylenes group communication, the group represented by the General formula -(CH2)m-O-(CH2)n-,
in which m is an integer from 0 to 1; and n is an integer from 1 to 3, or the General formula -(CH2)m-NR10-(CH2)n-,
in which R10represents a hydrogen atom or a lower alkyl group; and m and n have the same aforesaid meanings, and
each of the other represents a hydrogen atom; or
each of R5and R8predstavljaet a hydrogen atom, and
each R6and R7together with the carbon atoms to which they are linked, represent a 5-7-membered heterocyclic group, or
the group represented by the following General formula:
[Formula 3]

in which
one of the Z1, Z2, Z3, Z4and Z5represents a nitrogen atom,
one of the remaining four is a group represented by the General formula (C-R11,
in which R11represents an optionally substituted aryl group, nitrogen-containing 6-membered aromatic heterocyclic group or oxygen-containing 5-membered aromatic heterocyclic group,
each of the remaining three is a group represented by the General formula (C-R12,
in which R12represents a hydrogen atom;
in which the substituents for aryl groups and heterocyclic groups, R3represent one or more selected from the group consisting of a halogen atom, nitro, optionally protected amino, alkylamino and hydroxyl groups, and alkyl, alkoxy, alkylamino, dialkylamino groups which may be substituted by one or more halogen atoms;
deputies to dialkylamino R9represent one or more hydroxyl groups;
the mandated the prevalence for heterocyclic group and heterocyclic actigraphy R 9represent one or more selected from the group consisting of acyl groups, alkylsulfonyl group, carbonyl group, amino group, hydroxyl group, and alkyl, alkylamino and dialkylamino, which can be substituted by one or more hydroxyl groups;
the substituents for the aryl group, R11represent one or more selected from the group consisting of halogen atoms;
carboxylamide group include alkyl group, aryl group, aracelio group, arylalkyl group, alltoallw group, arylsulfonyl group, oxygen-containing heterocyclic group, alkylsulphonyl group, aryloxyalkyl group, nitrogen-containing heterocyclic alkyl group, cycloalkyl group, alkoxyalkyl group, kalkylarksmall group, alkylthiomethyl group, alkenylphenol group and a substituted silyl group;
the protective group of a phenolic hydroxyl includes acyl group, alkyl group, alkenylphenol group, aracelio group, oxygen-containing heterocyclic group, a sulfur-containing heterocyclic group, alkoxyalkyl group, alkylsulfonyl group, arylsulfonyl group and a substituted silyl group;
aminosidine group includes an acyl group, allyloxycarbonyl the second group, aracelikarsaalyna group, aryloxyalkyl group, aracelio group, alkoxyalkyl group, kalkylarksmall group, killigrew, alkylsulfonyl group, arylsulfonyl group and a substituted silyl group;
and hydroxylamine group includes an acyl group, allyloxycarbonyl group, aracelikarsaalyna group, heterocyclic oxycarbonyl group, alkyl group, alkenylphenol group, aracelio group, oxygen-containing heterocyclic group, a sulfur-containing heterocyclic group, alkoxyalkyl group, kalkylarksmall group, alkylsulfonyl group, arylsulfonyl group and a substituted silyl group.

2. The derived N-acylanthranilic acid or its pharmaceutically acceptable salt according to claim 1, in which a represents a group represented by the following General formula:
[Formula 4]

in which
R4represents a hydrogen atom or a protective group of a phenolic hydroxyl;
one of R5, R6, R7and R8represents a group represented by the General formula-Y-R9,
in which
R9represents a halogen atom, a nitro-group, optionally protected hydroxyl group, amino group, alkylamino, optionally substituted d is alkylamino, alkyl group, alkoxygroup, aryl group, alloctype, optionally substituted heterocyclic group, optionally substituted heterocyclic oxygraph, acyl group, or alloctype;
Y represents alkylenes group communication, the group represented by the General formula -(CH2)m-O-(CH2)n-,
in which m is an integer from 0 to 1; and n is an integer from 1 to 3, or
the group represented by the General formula -(CH2)m-NR10-(CH2)n-,
in which R10represents a hydrogen atom or a lower alkyl group; and m and n have the same aforesaid meanings, and
each of the other represents a hydrogen atom; or
each of R5and R8represents a hydrogen atom, and
each R6and R7together with the carbon atoms to which they are linked, represent a 5-7-membered heterocyclic group;
in which the substituents for dialkylamino, heterocyclic group and heterocyclic actigraphy R9protective group of a phenolic hydroxyl and hydroxylamine the group defined in claim 1.

3. The derived N-acylanthranilic acid or its pharmaceutically acceptable salt according to claim 2, in which X4represents an oxygen atom, aminogroup or link.

4. About svodnoe N-acylanthranilic acid or its pharmaceutically acceptable salt according to claim 2 or 3, in which R1represents an optionally protected carboxyl group;
in which carboxylterminal the group defined in claim 1.

5. The derived N-acylanthranilic acid or its pharmaceutically acceptable salt according to any one of claim 2 to 3, in which R2represents a hydrogen atom or a halogen atom.

6. The derived N-acylanthranilic acid or its pharmaceutically acceptable salt according to any one of claim 2 to 3, in which R3represents an optionally substituted phenyl group or fornillo group;
in which the substituents for the phenyl group, R3represent one or more selected from the group consisting of a halogen atom, nitro, optionally protected amino, alkylamino and hydroxyl groups, and alkyl, alkoxy, alkylamino, dialkylamino groups which may be substituted by one or more halogen atoms; and
aminosidine group and hydroxylamine the group defined in claim 1.

7. The derived N-acylanthranilic acid or its pharmaceutically acceptable salt according to any one of claim 2 to 3, in which R4represents a hydrogen atom.

8. The derived N-acylanthranilic acid or its pharmaceutically acceptable salt according to any one of claim 2 to 3, in which X4that is the link.

9. The derived N-acylanthranilic acid or its headlight is asepticheski acceptable salt according to any one of claim 2 to 3, in which
one of R5, R6, R7and R8represents a group represented by the General formula-Ya-R9a,
in which
R9arepresents a halogen atom, a nitro-group, optionally protected hydroxyl group, amino group, alkylamino, optionally substituted by dialkylamino, alkyl group, alkoxygroup, aryl group, alloctype, optionally substituted heterocyclic group, optionally substituted heterocyclic oxygraph, acyl group, or alloctype; and
Yarepresents alkylenes group communication, the group represented by the General formula-O-(CH2)n-,
in which n is an integer from 1 to 3, or a group represented by the General formula NR10a-(CH2)n-,
in which R10arepresents a lower alkyl group; and n has the same meaning as above, and
each of the other remaining represents a hydrogen atom;
in which the substituents for dialkylamino R9arepresent one or more hydroxyl groups;
the substituents for the heterocyclic group and heterocyclic actigraphy R9arepresent one or more selected from the group consisting of acyl groups, alkylsulfonyl group, a carbonyl group, and is kinogruppy, hydroxyl group, and alkyl, alkylamino and dialkylamino, which can be substituted by one or more hydroxyl groups;
and hydroxylamine the group defined in claim 1.

10. The derived N-acylanthranilic acid or its pharmaceutically acceptable salt according to any one of claim 2 to 3, in which
each R5, R6and R8represents a hydrogen atom, and
R7represents a group represented by the General formula-Yb-R9b,
in which
R9brepresents an optionally substituted heterocyclic group; and
Ybrepresents alkylenes group, a relationship or a group represented by the General formula-O-(CH2)n-,
in which n is an integer from 1 to 3;
in which the substituents for the heterocyclic group, R9brepresent one or more selected from the group consisting of acyl groups, alkylsulfonyl group, carbonyl group, amino group, hydroxyl group, and alkyl, alkylamino and dialkylamino, which can be substituted by one or more hydroxyl groups.

11. The derived N-acylanthranilic acid or its pharmaceutically acceptable salt according to any one of claim 2 to 3, in which
each R5, R6and R8represents a hydrogen atom, and
R7is with the battle group, represented by the General formula-Yc-R9c,
in which
R9crepresents a heterocyclic group which may be substituted by a lower alkyl group; and
Ycrepresents a methylene group, a relationship or a group represented by the General formula-O-(CH2)2-.

12. The derived N-acylanthranilic acid or its pharmaceutically acceptable salt according to claim 1, in which a represents a group represented by the following General formula:
[Formula 5]

in which
one of the Z1, Z2, Z3, Z4and Z5represents a nitrogen atom,
one of the remaining four is a group represented by the General formula (C-R11,
in which R11represents an optionally substituted aryl group, nitrogen-containing 6-membered aromatic heterocyclic group or oxygen-containing 5-membered aromatic heterocyclic group, and
each of the remaining three is a group represented by the General formula (C-R12,
in which R12represents a hydrogen atom;
in which the substituents for the aryl group, R11defined in claim 1.

13. The derived N-acylanthranilic acid or its pharmaceutically acceptable salt according to clause 12, in which X4is an atom KIS is aroda, aminogroup or link.

14. The derived N-acylanthranilic acid or its pharmaceutically acceptable salt according to item 12 or 13, in which R1represents an optionally protected carboxyl group;
in which carboxylterminal the group defined in claim 1.

15. The derived N-acylanthranilic acid or its pharmaceutically acceptable salt according to any one of PP-13, in which R2represents a hydrogen atom or a halogen atom.

16. The derived N-acylanthranilic acid or its pharmaceutically acceptable salt according to clause 12, in which X4that is the link.

17. The derived N-acylanthranilic acid or its pharmaceutically acceptable salt according to any one of p, 13 or 16, in which R3represents an optionally substituted phenyl group or fornillo group;
in which the substituents for the phenyl group, R3represent one or more selected from the group consisting of a halogen atom, nitro, optionally protected amino, alkylamino and hydroxyl groups, and alkyl, alkoxy, alkylamino, dialkylamino groups which may be substituted by one or more halogen atoms; and
aminosidine group and hydroxylamine the group defined in claim 1.

18. The derived N-acylanthranilic acid or its pharmaceutically acceptable salt of either is from PP, 13 or 16, in which
Z1represents CH,
Z2represents a nitrogen atom,
Z3represents CH,
Z4represents a group represented by the General formula (C-R11a,
in which R11arepresents an optionally substituted aryl group, nitrogen-containing 6-membered aromatic heterocyclic group or oxygen-containing 5-membered aromatic heterocyclic group, and
Z5represents CH;
in which the substituents for the aryl group, R11arepresent one or more halogen atoms.

19. The derived N-acylanthranilic acid or its pharmaceutically acceptable salt according to any one of p, 13 or 16, in which
Z1represents CH,
Z2represents a nitrogen atom,
Z3represents CH,
Z4represents a C-C6H5and
Z5represents CH.

20. Inhibitor of collagen production, containing the derived N-acylanthranilic acid represented by the following General formula, or its pharmaceutically acceptable salt, and a carrier or excipient:
[Formula 6]

in which
R1represents an optionally protected carboxyl group or 1H-tetrazol-5-ilen group;
R2is an atom of odor is Yes, halogen atom, optionally protected hydroxyl group, or alkoxygroup;
R3represents an optionally substituted aryl group or optionally substituted heterocyclic group;
X1represents a carbonyl group;
X2represents an optionally substituted alkylenes group, alkenylamine group or Association;
X3that is the link;
X4represents a group represented by the General formula-X5-X6or X6-X5- (assuming that the link on the left side of each General formula associated with R3), in which
X5represents an oxygen atom, aminogroup or communication; and
X6represents alkylenes group or Association; and
But is an optionally substituted phenyl group or optionally substituted heterocyclic group;
in which the substituents for aryl groups and heterocyclic groups, R3represent one or more selected from the group consisting of a halogen atom, nitro, optionally protected amino, alkylamino and hydroxyl groups, and alkyl, alkoxy, alkylamino, dialkylamino, cyclic amino, and heterocyclic groups which may be substituted by one or more halogen atoms;
substituents for the alkyl is a new group of X 2represent one or more phenyl groups;
the substituents for the phenyl group and the heterocyclic group are one or more selected from the group consisting of a halogen atom, nitro, optionally substituted amino and hydroxyl groups, and optionally substituted alkyl, alkoxy, phenyl, cyclic amino, and heterocyclic groups;
carboxylamide group include alkyl group, aryl group, aracelio group, arylalkyl group, alltoallw group, arylsulfonyl group, oxygen-containing heterocyclic group, alkylsulphonyl group, aryloxyalkyl group, nitrogen-containing heterocyclic alkyl group, cycloalkyl group, alkoxyalkyl group, kalkylarksmall group, alkylthiomethyl group, alkenylphenol group and a substituted silyl group;
the protective group of a phenolic hydroxyl includes acyl group, alkyl group, alkenylphenol group, aracelio group, oxygen-containing heterocyclic group, a sulfur-containing heterocyclic group, alkoxyalkyl group, alkylsulfonyl group, arylsulfonyl group and a substituted silyl group;
aminosidine group includes an acyl group, allyloxycarbonyl group, aracelikarsaalyna g is the SCP, aryloxyalkyl group, aracelio group, alkoxyalkyl group, kalkylarksmall group, killigrew, alkylsulfonyl group, arylsulfonyl group and a substituted silyl group;
and hydroxylamine group includes an acyl group, allyloxycarbonyl group, aracelikarsaalyna group, heterocyclic oxycarbonyl group, alkyl group, alkenylphenol group, aracelio group, oxygen-containing heterocyclic group, a sulfur-containing heterocyclic group, alkoxyalkyl group, kalkylarksmall group, alkylsulfonyl group, arylsulfonyl group and a substituted silyl group.

21. Inhibitor of collagen production according to claim 20, in which
R1represents an optionally protected carboxyl group,
R2represents a hydrogen atom, and
R3represents an optionally substituted phenyl group, optionally substituted monocyclic heterocyclic group, or a bicyclic heterocyclic group;
in which the substituents for the phenyl group, and a monocyclic heterocyclic group, R3represent one or more selected from the group consisting of a halogen atom, nitro, optionally protected amino, alkylamino and hydroxyl groups, and alkyl,alkoxy, alkylamino, dialkylamino, cyclic amino, and heterocyclic groups which may be substituted by one or more halogen atoms.

22. Inhibitor of collagen production according to any one of p or 21, in which X4represents an oxygen atom, alkylenes group or Association.

23. Inhibitor of collagen production according to any one of p or 21, in which
But is an optionally substituted phenyl group or optionally substituted heterocyclic group, and
R3represents an optionally substituted phenyl group or a bicyclic heterocyclic group;
in which the substituents for the phenyl group and the heterocyclic group As defined in claim 20; and the substituents for the phenyl group, R3defined in item 21.

24. Inhibitor of collagen production according to item 23, in which
X2is a relationship
X3that is the link, and
X4that is the link.

25. Inhibitor of collagen production according to paragraph 24, in which
But is an optionally substituted phenyl group or optionally substituted pyridyloxy group, and
R3represents an optionally substituted phenyl group;
in which the substituents for peredelnoj group And represent one or more groups selected from phenyl, cyclic amine and heterocyclic groups, which may be substituted by one or more halogen atoms;
the substituents for the phenyl group As defined in claim 20;
and the substituents for the phenyl group, R3defined in item 21.

26. For the treatment of diseases associated with excessive production of collagen containing derived N-acylanthranilic acid represented by the following General formula, or its pharmaceutically acceptable salt, and a carrier or excipient:
[Formula 7]

in which
R1represents an optionally protected carboxyl group or 1H-tetrazol-5-ilen group;
R2represents a hydrogen atom, halogen atom, optionally protected hydroxyl group, or alkoxygroup;
R3represents an optionally substituted aryl group or optionally substituted heterocyclic group;
X1represents a carbonyl group;
X2represents an optionally substituted alkylenes group, alkenylamine group or Association;
X3that is the link;
X4represents a group represented by the General formula-X5-X6or X6-X5- (assuming that the link on the left side of each General formula associated with R3), in which
X5is an atom sour the ode, aminogroup or communication; and
X6represents alkylenes group or Association; and
But is an optionally substituted phenyl group or optionally substituted heterocyclic group;
in which the substituents for aryl groups and heterocyclic groups, R3represent one or more selected from the group consisting of a halogen atom, nitro, optionally substituted amino, alkylamino and hydroxyl groups, and alkyl, alkoxy, alkylamino, dialkylamino, cyclic amino, and heterocyclic groups which may be substituted by one or more halogen atoms;
the substituents for alkilinity groups X2represent one or more phenyl groups;
the substituents for the phenyl group and the heterocyclic group are one or more selected from the group consisting of a halogen atom, nitro, optionally substituted amino and hydroxyl groups, and optionally substituted alkyl, alkoxy, phenyl, cyclic amino, and heterocyclic groups;
carboxylamide group include alkyl group, aryl group, aracelio group, arylalkyl group, alltoallw group, arylsulfonyl group, oxygen-containing heterocyclic group, alkylsulphonyl group, acyloxy lilou group, nitrogen-containing heterocyclic alkyl group, cycloalkyl group, alkoxyalkyl group, kalkylarksmall group, alkylthiomethyl group, alkenylphenol group and a substituted silyl group;
the protective group of a phenolic hydroxyl includes acyl group, alkyl group, alkenylphenol group, aracelio group, oxygen-containing heterocyclic group, a sulfur-containing heterocyclic group, alkoxyalkyl group, alkylsulfonyl group, arylsulfonyl group and a substituted silyl group;
aminosidine group includes an acyl group, allyloxycarbonyl group, aracelikarsaalyna group, aryloxyalkyl group, aracelio group, alkoxyalkyl group, kalkylarksmall group, killigrew, alkylsulfonyl group, arylsulfonyl group and a substituted silyl group;
and hydroxylamine group includes an acyl group, allyloxycarbonyl group, aracelikarsaalyna group, heterocyclic oxycarbonyl group, alkyl group, alkenylphenol group, aracelio group, oxygen-containing heterocyclic group, a sulfur-containing heterocyclic group, alkoxyalkyl group, kalkylarksmall group, alkylsulfonyl group, arylsulfonyl group and a substituted silyl group is at.

27. For the treatment of diseases associated with excessive production of collagen, p, in which
R1represents an optionally protected carboxyl group,
R2represents a hydrogen atom, and
R3represents an optionally substituted phenyl group, optionally substituted monocyclic heterocyclic group, or a bicyclic heterocyclic group;
in which the substituents for the phenyl group, and a monocyclic heterocyclic group, R3represent one or more selected from the group consisting of a halogen atom, nitro, optionally substituted amino, alkylamino and hydroxyl groups, and alkyl, alkoxy, alkylamino, dialkylamino, cyclic amino, and heterocyclic groups which may be substituted by one or more halogen atoms.

28. For the treatment of diseases associated with excessive production of collagen according to any one of p or 27, in which X4represents an oxygen atom, alkylenes group or Association.

29. For the treatment of diseases associated with excessive production of collagen according to any one of p or 27, in which
But is an optionally substituted phenyl group or optionally substituted heterocyclic group, and
R 3represents an optionally substituted phenyl group or a bicyclic heterocyclic group;
in which the substituents for the phenyl group and the heterocyclic group As defined in p; and the substituents for the phenyl group, R3defined in item 27.

30. For the treatment of diseases associated with excessive production of collagen, in clause 29, which
X2is a relationship
X3that is the link, and
X4that is the link.

31. For the treatment of diseases associated with excessive production of collagen, item 30, in which
But is an optionally substituted phenyl group or optionally substituted pyridyloxy group, and
R3represents an optionally substituted phenyl group;
in which the substituents for peredelnoj group And represent one or more groups selected from phenyl, cyclic amino, and heterocyclic groups which may be substituted by one or more halogen atoms;
the substituents for the phenyl group As defined in b;
and the substituents for the phenyl group, R3defined in item 27.

32. Inhibitor of collagen production, containing the derived N-acylanthranilic acid or its pharmaceutically acceptable salt according to any one of claims 1, 2, 3, 12, 13 or 16, the media or excipient.

33. For the treatment of diseases associated with excessive production of collagen containing derived N-acylanthranilic acid or its pharmaceutically acceptable salt according to any one of claims 1, 2, 3, 12, 13, or 16, and the carrier or excipient.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a photoinitiator, a method for production and use thereof and a coating composition. The photoinitiator is a compound of formula: (PI-Sp)n-BB (I), where PI is a thioxanthone group, optionally including additional substitutes in the Sp group; Sp is a spacer link selected from a group consisting of or , BB is a backbone chain link selected from a group consisting of

The method of producing the photoinitiator includes the following steps: (a) optionally substituted thioxanthone, containing at least one hydroxy group, reacts with epichlorohydrin or haloacetic acid ester; (b) the compound from step (a) reacts with the corresponding backbone chain link containing a functional group, or the compound from step (a) reacts with a compound containing a functional group, and the obtained intermediate then reacts with the corresponding backbone chain link; optionally (c) obtaining derivatives of the compounds from step (b). The photoinitiator is used to cure a coating composition, preferably printing ink containing a polymerisable component.

EFFECT: invention enables to obtain a photoinitiator with good curing activity, faint odour and good compatibility with other components of the composition.

10 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula

,

wherein: each of R1, R2, R4, R5, R6, R7, R8 R9, R10, R11, R12, R13, R14, R15 R16 and R17 is independently specified in a group consisting of deuterium or hydrogen; and R3 is independently specified in a group consisting of CD3 and CH3; provided R3 represents CH3, at least one of the groups R1, R2, R4, R5, R6, R7, R8 R9, R10, R11, R12, R13, R14, R15 R16 and R17 represents deuterium; and R18 represents hydrogen. The invention also refers to a drug on the basis of the above compound for treating a condition causing pain.

EFFECT: there are prepared new compounds inhibiting MMPs (metalloproteinases) which show the high activity, metabolic stability and/or lower toxicity in relation to the currently known MMP inhibitors for treating pain and other diseases, such as cancer.

16 cl, 2 dwg, 14 tbl, 136 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 6-substituted isoquinoline and isoquinolinone derivatives of formula or to its stereoisomer and/or tautomer forms and/or a pharmaceutically acceptable salt, wherein R1 represents H, OH or NH2; R3 represents H; R4 represents H, a halogen atom, CN or (C1-C6)alkylene-(C6-C10)aryl; R5 represents H, a halogen atom, (C1-C6)alkyl; R7 represents H, a halogen atom, (C1-C6)alkyl, O-(C1-C6)alkyl; R8 represents H; R9 and R6 are absent; R10 represents (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C6)hetrocycloalkyl, (C1-C6)alkylene-(C3-C8)cycloalkyl, (C1-C6)alkylene-(C6-C10)aryl, (C1-C6)alkylene-(C6)heterocycloalkyl; R11 represents H; R12 represents (C1-C6)alkyl, (C3-C8)cycloalkyl, (C5)heteroaryl or (C6-C10)aryl; R13 and R14 independently represent H, (C1-C6)alkyl, (C1-C6)alkylene-R'; n is equal to 0; m is equal to 2 or 3; s is equal to 1 or 2; r is equal to 1; L represents O or NH; R' represents (C3-C8)cycloalkyl, (C6-C10)aryl; wherein in the rests, R10, R12-R14 alkyl or alkylene are unsubstituted or optionally substituted by one or more OCH3; wherein in the rests, R10, R12-R14 alkyl or alkylene are unsubstituted or optionally substituted by one or more halogen atoms; wherein (C1-C8)heteroaryl group means (C1-C8)alkyl groups, wherein at least one carbon atom is substituted by O;. (C6)heterocycloalkyl group means a monocyclic carbon ring system containing 6 ring atoms wherein one carbon atom can be substituted by 1 oxygen atom or 1 sulphur atom which can be optionally oxidated; (C5)heteroaryl means a monoring system wherein one or more carbon atoms can be substituted by 1 nitrogen atom or 1 sulphur atom or a combination of various heteroatoms. Also, the invention refers to using the compound of formula (I) and to a therapeutic agent based on the compound of formula (I).

EFFECT: there are prepared new compounds effective for treating and/or preventing diseases associated with Rho-kinase and/or mediated by Rho-kinase by phosphorylation of myosin light chain phosphatase, and the compositions containing these compounds.

32 cl, 111 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula or to its therapeutically acceptable salt, where A1 represents N or C(A2); A2 represents H; B1 represents H, OR1 or NHR1; D1 represents H; E1 represents H; Y1 represents CN, NO2, F, Cl, Br, I, R17 or SO2R17; R1 represents R4 or R5; Z1 represents R26 or R27; Z2 represents R30; Z1A and Z2A both are absent; L1 represents R37; R26 represents phenylene; R27 represents indolyl; R30 represents piperasinyl; R37 represents R37A; R37A represents C2-C4 alkylene; Z3 represents R38, R39 or R40; R38 represents phenyl; R39 represents benzodioxilyl; R40 represents C4-C7cycloalkenyl, heterocycloalkyl, which represents monocyclic six- or seven-member ring, containing one heteroatom, selected from O, and zero of double bonds, or azaspiro[5.5]undec-8-ene; the remaining values of radicals are given in i.1 of invention formula. Invention also relates to pharmaceutical composition, based on claimed compound.

EFFECT: novel compounds, which can be applied in medicine for treatment of diseases, in the process of which anti-apoptotic Bcl-2 protein is expressed, are obtained.

8 cl, 2 tbl, 411 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compounds can find application for preventing or treating cancer, lung cancer, non-small cells lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cells lung cancer. In formula (I) -X-: group of formula , A represents chlorine, ethyl or isopropyl; R1 represents phenyl wherein carbon in the 4th position is substituted by the group -W-Y-Z, and carbon in the 3rd position can be substituted by a group specified in a group consisting of halogen, R00 and -O-R00; R00: lower alkyl which can be substituted by one or more halogen atoms; -W-: a bond, piperidine-1,4-diyl or piperazine-1,4-diyl; -Y- represents a bond; Z represents a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more substitutes R00; R2 represents (i) an optionally bridged saturated C3-10cycloalkyl which can be substituted by one or more groups specified in -N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or (ii) a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more groups specified in a group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzene; and RZB: phenyl which can be substituted by a group consisting of halogen and -O-lower alkyl; R3 represents -H.

EFFECT: invention refers to new compounds of formula or their pharmaceutically acceptable salts possessing the properties of a selective inhibitor of EML4-ALK hybrid protein kinase activity.

16 cl, 201 tbl, 582 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to methods of treating or relieving severity of disease in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease. Methods include introduction of effective amount of N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide or pharmaceutical composition, containing said compound, to patient.

EFFECT: treatment of relief of disease severity in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease.

16 cl, 15 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel fungicidally active 5-fluoropyrimidines of general formula I. In compounds of formula , R1 is -N(R3)R4; R2 is -OR21; R3 is: H; C1-C6-alkyl, optionally substituted with 1-3 groups R5; C2-C6-alkenyl, optionally substituted with 1-3 groups R5; a 5- or 6-member heteroaromatic cycle, selected from a group consisting of furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, triazolyl; wherein each heteroaromatic cycle is optionally substituted with 1-3 R29 groups; 3H-isobenzofuran-1-oyl; -C(=O)R6; -C(=S)R6; -C(=S)NHR8; -(=O)N(R8)R10; -OR7; -P(O)(OR15)2; -S(O)2R8;-SR8; -Si(R8)3; -N(R9)R10; -(CHR24)mOR29 or -C(=NR16)SR16; where m equals an integer from 1 to 3; R4 is: H; C1-C6-alkyl, optionally substituted with 1-3 R5 groups; or -C(=O)R6; alternatively, R3 and R4 together can form: a 5- or 6-member saturated or unsaturated cycle containing 1-2 heteroatoms selected from N and O, where each cycle can be optionally substituted with 1-3 R11 groups; =C(R12)N(R13)R14 or =C(R15)OR15. The rest of the radicals are given in the claim.

EFFECT: obtaining novel fungicidally active 5-fluoropyrimidines of general formula I.

4 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-membered heterocyclic compounds of general formula (I), their prodrugs or pharmaceutically acceptable salts, which possess xanthine oxidase inhibiting activity. In formula (I) T represents nitro, cyano or trifluoromethyl; J represents phenyl or heteroaryl ring, where heteroaryl represents 6-membered aromatic heterocyclic group, which has one heteroatom, selected from nitrogen, or 5-membered aromatic heterocyclic group, which has one heteroatom, selected from oxygen; Q represents carboxy, lower alkoxycarbonyl, carbomoyl or 5-tetrasolyl; X1 and X2 independently represent CR2 or N, on condition that both of X1 and X2 do not simultaneously represent N and, when two R2 are present, these R2 are not obligatorily similar or different from each other; R2 represents hydrogen atom or lower alkyl; Y represents hydrogen atom, hydroxy, amino, halogen atom, perfluoro(lower alkyl), lower alkyl, lower alkoxy, optionally substituted with lower alkoxy; nitro, (lower alkyl)carbonylamino or (lower alkyl) sulfonylamino; R1 represents perfluoro(lower alkyl), -AA, -A-D-L-M or -A-D-E-G-L-M (values AA, A, D, E, G, L, M are given in i.1 of the invention formula).

EFFECT: invention relates to xanthine oxidase inhibitor and pharmaceutical composition, which contain formula (I) compound.

27 cl, 94 tbl, 553 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted pyrrolidine-2-carboxamides of formula I or their pharmaceutically acceptable salts, where values X, Y, R1, R2, R3, R3, R4, R5, R6 and R7 are given in item 1 of the formula. Compounds can be used in pharmaceutical composition, inhibiting interaction of MDM2-p53.

EFFECT: compounds can be used as anti-cancer medications.

46 cl, 4 dwg, 347 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel quinazoline derivatives of formula , where each of R1, R2 and R5, independently, represents H; one of R3 and R4 represents where n - 1 or 2; each Ra represents H, C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkoxy, C1-10alkansulfonyl carboxy-group, 5-6-membered monocyclic heterocycloalkyl, which has one or several heteroatoms, selected from O and N, where N atom can be substituted with C1-10alkyl, phenyl, optionally substituted with halogen, 5-6-membered monocyclic heteroaryl, which has one or several heteroatoms, selected from N and S, 7-membered bicyclic heterocycloalkyl, which has 2 N atoms; C2-10alkenyl; C2-10alkinyl; cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms; each of Rb and Rc, independently, represents H or C1-10alkyl, optionally substituted C1-10alkoxy, or Rb and Rc, together with atom of nitrogen, with which they are bound, form bicyclic ring of the following formula: , where each of m1, m2, m3, and m4 is 0, 1 or 2; A is CH; B is NR, where R is H or C1-10alkyl; and each of Ri, Rii, Riii, RiV, Rv, Rvi, Rvii and Rviii is H; or 6-7-membered monocyclic heterocycloalkyl, containing 1-2 N atoms, optionally substituted with substituent, selected from group, including hydroxy, C1-10alkyl, optionally substituted C1-10alkoxy, C1-10alkyl, optionally substituted with C3-6cycloalkyl; and each of Rd, Re, independently represents H, C2-10alkenyl; C2-10alkinyl; or C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkyloxy, hydroxy, CN, 5-6-membered monocyclic heterocycloalkyl, which has 1 or 2 N atoms, optionally substituted with C1-10alkyl, halogen or 5-6-membered heterocycloalkyl, which has 1 N atom, phenyl, optionally substituted with halogen, cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms, 5-6-membered monocyclic heteroaryl, which has one or 2 N atoms; or Rd and Re, together with nitrogen atom, with which they are bound, form 5-6-membered saturated heterocycloalkyl, which has 1-2 heteroatoms, selected from N and O, optionally substituted with substituent, selected from group, including C1-10alkyl (which is optionally substituted with C3-6cicloalkyl, C1-10alkoxy, halogen), 5-membered heterocycloalkyl, which has one N atom, halogen, C1-10alkansulfonyl, C1-10alkylcarbonyl, optionally substituted with halogen, or Rd and Re, together with nitrogen, with which they are bound, form 7-10-membered, saturated, bicyclic heterocycloalkyl, containing 1-2 heteroatoms, selected from N and O, optionally substituted with C1-10alkyl; and the other of R3 and R4 represents H, halogen or C1-10alkoxy; X represents NRf, where Rf represents phenyl, substituted with C2-4 alkinyl; and Z represents N. Invention also relates to particular quinazoline derivatives, based on it pharmaceutical composition, and to method of cancer treatment.

EFFECT: novel quinazoline derivatives, inhibiting EGFR activity are obtained.

11 cl, 171 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound of formula [I] or to its pharmaceutically acceptable salt, wherein A represents optionally substituted alkyl, wherein the substitute represents identical or different 1-3 groups specified in aryl optionally substituted by 1-3 groups specified in alkyl, halogen, alkoxy and alkanoyl; cycloalkyl optionally substituted by 1-3 groups specified in alkyl and halogen; hydroxy; alkoxy; halogen; an amino group and oxo; an optionally substituted carbocyclic group specified in a mono- and bicyclic group, wherein an aromatic ring and cycloalkyl are condensed; optionally substituted aryl, an optionally substituted completely saturated 5- or 6-merous monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, wherein the substitute of optionally substituted aryl, the optionally substituted carbocyclic group and the optionally substituted heterocyclic group for A represents identical or different 1-3 groups specified in alkyl, optionally substituted hydroxy, alkoxy, cycloalkyl or halogen; cycloalkyl optionally substituted by alkyl or alkoxy; alkoxy optionally substituted by halogen; halogen; hydroxy; oxo; heterocycle; alkyl sulphonyl; and mono- or dialkylcarbamoyl, optionally substituted amino, wherein the substitute represents identical or different 1 or 2 alkyl or aryl, or optionally substituted carbamoyl, wherein the substitute represents identical or different 1 or 2 alkyls optionally substituted by aryl, X represents optionally substituted methylene or -O-, wherein the substitute of optionally substituted methylene for X represents alkoxy or hydroxy, Q represents N or C-R4, L1 represents a single bond, methylene, -CH=CH-, -O-, -CO-, -NR11-, -NR11CO-, -CONR11- or -CH2NR11-, L2 represents a single bond, -CR6R7- or a bivalent 5- or 6-merous completely saturated monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, R1 and R2 are identical or different, and each represents hydrogen, alkyl or halogen, R3 and R4 are identical or different, and each represents hydrogen, alkyl, alkoxy, cyano or halogen, R1 and R3 are optionally bond thereby forming 5- or 6-merous cycloalkane, or a 5- or 6-merous aliphatic heterocycle containing oxygen atom, R5 represents a carboxyl group, an alkoxycarbonyl group or a bioisosteric group of the carboxyl group, R6 and R7 are identical or different, and each represents hydrogen or alkyl, or R6 and R7 are bond thereby forming cycloalkane, R8 represents hydroxy, alkanoylamino or alkyl sulphonylamino, R9 and R10 represent hydrogen or halogen, and R11 represents hydrogen or alkyl. Besides, the invention refers to specific compounds of formula [I], a drug based on the compound of formula [I], using the compound of formula [I], a method of treating based on using the compound of formula [I], and an intermediate compound of formula [II].

EFFECT: there are prepared new compounds possessing the agonist activity on thyroid hormone β receptor.

18 cl, 36 tbl, 344 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel compound of formula (1) or its pharmaceutically acceptable salt, possessing SNS inhibiting properties. In general formula R1 represents (1) hydrogen atom, (2) halogen atom, (3) C1-6alkyl group or (4) C1-6halogenalkyl group (whereR1 can be present in any substitutable position of benzene or pyridine ring); L represents (1) simple bond, (2) -O- or (3) -CH2O- (where L can be present in position 5 or 6 of condensed cycle); R2 represents (1) C6-10aryl group (C6-10aryl group is optionally condensed with C3-6cycloalkane), optionally substituted with substituent(s), X represents carbon atom or nitrogen atom. Other values of radicals are given in the invention formula.

EFFECT: obtaining compounds which can be used to prepare medication for treatment or prevention of such diseases as neuropathic pain, nociceptive pain, dysuria, disseminated sclerosis, etc.

19 cl, 47 tbl, 237 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula I , where R1 is a hydrogen atom, a lower alkyl, CD3, -(CH2)n-CHO, -(CH2)n-O-lower alkyl, -(CH2)n-OH, -(CH2)n-cycloalkyl or is a heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O); R2 is a hydrogen atom, a halogen atom, hydroxy, lower alkyl, di-lower alkyl, -OCH2-O-lower alkyl or lower alkoxy; or the piperidine ring along with R2 forms a spiro-ring selected from 4-aza-spiro[2,5]oct-6-yl; Ar is an aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), optionally having one, two or three substitutes selected from a halogen atom, lower alkyl, lower alkyl having as substitutes, a halogen atom, a lower alkoxy having as substitutes, a halogen atom, cycloalkyl, lower alkoxy, S-lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with N), or optionally having as substitutes, phenyl, optionally having R' as substitutes, and R' is a halogen atom, CF3, lower alkyl, lower alkoxy or a lower alkoxy having as substitutes, a halogen atom, or is a heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N and S); R is a lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O), aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), Where the aryl and heteroaryl optionally have as substitutes, one or two R'; n equals 0, 1, 2 or 3; or to a pharmaceutically acceptable acid addition salt, a racemic mixture or a corresponding enantiomer and/or optical isomer of said compound. The invention also relates to pharmaceutical compositions based on a glycine reuptake inhibitor of a compound of formula I.

EFFECT: obtaining novel compounds and a pharmaceutical composition based thereon, which can be used in medicine to treat neurological and psychoneurological disorders.

22 cl, 1 tbl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-membered heterocyclic compounds of general formula (I), their prodrugs or pharmaceutically acceptable salts, which possess xanthine oxidase inhibiting activity. In formula (I) T represents nitro, cyano or trifluoromethyl; J represents phenyl or heteroaryl ring, where heteroaryl represents 6-membered aromatic heterocyclic group, which has one heteroatom, selected from nitrogen, or 5-membered aromatic heterocyclic group, which has one heteroatom, selected from oxygen; Q represents carboxy, lower alkoxycarbonyl, carbomoyl or 5-tetrasolyl; X1 and X2 independently represent CR2 or N, on condition that both of X1 and X2 do not simultaneously represent N and, when two R2 are present, these R2 are not obligatorily similar or different from each other; R2 represents hydrogen atom or lower alkyl; Y represents hydrogen atom, hydroxy, amino, halogen atom, perfluoro(lower alkyl), lower alkyl, lower alkoxy, optionally substituted with lower alkoxy; nitro, (lower alkyl)carbonylamino or (lower alkyl) sulfonylamino; R1 represents perfluoro(lower alkyl), -AA, -A-D-L-M or -A-D-E-G-L-M (values AA, A, D, E, G, L, M are given in i.1 of the invention formula).

EFFECT: invention relates to xanthine oxidase inhibitor and pharmaceutical composition, which contain formula (I) compound.

27 cl, 94 tbl, 553 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel radiolabelled compounds of formula I in which R1 represents isopropoxy or 2,2,2-trifluoro-1-methyl-ethoxy; and R2 represents radiolabelled CH3 group, where radionuclide represents 3H or 11C. Invention also relates to pharmaceutical composition for diagnostic visualisation of GlyT1 transporter (glycine transporter type 1).

EFFECT: obtained are novel radiolabelled compounds, which can be applied in medicine as radioactive indicator in PET (positron emission tomography) for labeling and diagnostic molecular visualisation of functionality of glycine transporter type 1.

13 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-[2,4-dioxo-6-(tetrahydrofuran-2-yl)-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]methanesulphonamide and N-[6-(1-isopropoxyethyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H- quinazolin-3-yl] methanesulphonamide, having antagonistic activity on the AMPA receptor. The invention also relates to a pharmaceutical composition.

EFFECT: use of said compounds to produce drugs for treating AMPA mediated conditions and primarily for treating epilepsy or schizophrenia.

6 cl, 81 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a method for obtaining [1S-[1α,2α,3β(1S*,2R*),5β]]-3-[7-[2-(3,4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol of formula (I) .

EFFECT: improving yield of the compound of the formula and its high quality when recrystallisation is not available.

5 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I

or a pharmaceutically acceptable salt thereof, where R1 is H or R1 and R2 together with a nitrogen group can form where A, B, C and D are independently selected from a group consisting of CR1a and N; where at least one of A, B, C and D is CR1a; where R1a is selected from a group consisting of H, -ORi, -SRii, -S(O)Riii, -C(O)NRvRvi and CF3, where Ri is selected from a group consisting of methyl, ethyl, propyl, hydroxyethyl, hydroxypropyl, 2-oxo-2-phenylethyl, butyl, acetonitrile and benzyl; Rii, Riii and Riv denote methyl; Rv and Rvi are independently selected from a group consisting of H, methyl, ethyl, hydroxyethyl, hydroxypropyl, diethyalminoethyl, phenyl, pyridinyl, methoxyethyl, hydroxyethoxyethyl, benzyl, phenylethyl, 2-hydroxy-1-hydroxymethyl-2-phenylethyl and carbomoylethyl, or Rv and RVi together form morpholine or ethyl ester of piperazine; R2 is selected from a group consisting of phenyl, naphthyl, pyrazolyl and C1-C8alkylene phenyl; R3 is C1-C8alkylene; R4 is selected from a group consisting of H, C1-C8alkyl and -C=NH(NH2). The invention also relates to compounds of formulae I-A

I-B I-C

I-D I-E

values of radicals of which are given in the claim; a method of treating said pathological conditions, a pharmaceutical composition based on said compounds, a method of identifying a Trp-p8 agonist and specific compounds.

EFFECT: obtaining compounds which are useful as Trp-p8 modulators.

25 cl, 19 dwg, 8 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyranyl aryl methylbenzoquinazolinone compounds of formula (I), which are positive allosteric modulators of the M1 receptor and which can be used to treat diseases associated with the M1 receptor, such as Alzheimer's disease, schizophrenia, pain disorders or sleep disturbance. In formula (I) X-Y are selected from a group comprising (1) -O-CRARB-, (2) -CRARB-O-, (3) -CRARB-SRC-, (4) -CRARB-NRC- and (5) -NRC-CRARB-, where each RA and RB is a hydrogen atom, and RC is selected from a group comprising (a) hydrogen, (b) -C(=O)-C1-6alkyl, (c) -C1-6alkyl, (d) -C(=O)-CH2-C6H5, (e) -S(=O)2-C1-6 alkyl, R1 is a hydroxy group, R2 is selected from a group comprising (1) -phenyl, (2) - heteroaryl, where the phenyl or heteroaryl group R2 is optionally substituted; the rest of the values of the radicals are given in the claim.

EFFECT: obtaining novel pyranyl aryl methylbenzoquinazolinone compounds.

28 cl, 12 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 1,3-dihydroimidazole-2-thione derivatives of formula I: , in which R1, R2 and R3, identical or different, denote hydrogen or halogen; R4 denotes alkyl aryl; X denotes an oxygen atom; n equals 2 or 3; individual (R)-enantiomers thereof; or pharmaceutically acceptable salts thereof, where the term "alkyl" denotes straight or branched hydrocarbon chains which contain one to six carbon atoms; the term "aryl" denotes a phenyl or naphthyl group; the term "halogen" denotes fluorine, chlorine, bromine or iodine. The invention also relates to a method of producing said compounds, a pharmaceutical composition based on said compounds, having inhibiting action on dopamine-beta-hydroxylase, methods of treating different cardiovascular diseases such as hypertension and chronic heart failure, and use of compounds of formula 1 to produce drugs for treating said diseases.

EFFECT: improved properties of derivatives.

32 cl, 2 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new dihydroindenamide specified in compounds described by general formula II, or their pharmaceutically acceptable salts. In general formula II, R1 represents piperazinyl which can be optionally substituted by one R1a; R1a represents H, CH3, C(O)Rd or C(O)ORa; Y represents pyrimidyl; Z represents pyridyl or pyrimidyl; Ra represents tert-butyl and Rd represents CH3. The above compounds represent tert-butyl-4-{5-[({(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl}amino)carbonyl)-2,3-dihydro-1H-inden-1-yl}piperazine-1-carboxylate; N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-1-piperazin-1-yl-2,3-dihydro-1H-indene-5-carboxamide; 1-[4-acetylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide; (1R)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide; (1S)-N-[3-(4,5′-bipyrimidin-2-ylamino)-4-methylphenyl]-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxamide; (1R)-N-[3-(4,5′-bipyrimidin-2-ylamino)-4-methylphenyl]-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxamide; (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-4-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide and (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide sulphate.

EFFECT: compounds inhibit activity of protein kinases specified in Abl, c-Kit and PDGFR, and can find application for treating diseases related to disturbed activity of the above protein kinases, eg leukaemia and other cancers.

4 cl, 4 tbl, 16 ex

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