Derivatives of 4-phenylpyrimidine and pharmaceutical composition

 

(57) Abstract:

The invention relates to new derivatives of 4-phenylpyrimidine and their pharmaceutically acceptable acid additive salts, which possess the properties of receptor antagonists neirokinina(NK-1), and can be used to treat diseases, oposredstvovanii NK-1 receptor, for example, headache, Alzheimer's disease, multiple sclerosis, cardiovascular changes, oedema, chronic inflammatory diseases, etc. of Compounds of the invention correspond to the General formula

where R1means hydrogen or halogen, R2means hydrogen, halogen, lower alkyl or lower alkoxy, R1and R2together with the two carbon atoms of the cycle can mean the group-CH=CH-CH=CH-, R3means halogen, trifluoromethyl, lower alkyl or lower alkoxy, R4/R4’independently from each other and each means hydrogen or lower alkyl, R5means lower alkyl, lower alkoxy, amino, phenyl, hydroxy(lower)alkyl, cyano(lower)alkyl, carbarnoyl(lower)alkyl, pyridyl, pyrimidyl, -(CH2)n-piperazinil, optionally substituted by one or two lower alkyl groups or a hydroxy(lower)alkylsulfonyl, lower alkylsulfonyl, benzylamino, -NH-(CH2)n+1N(R4’)2, -(CH2)n+1N(R4’)2, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl or-O-(CH2)n+1N(R4’)2where R4’means hydrogen or lower alkyl, and n denotes 0 to 2,X is-C(O)N(R4’)- or-N(R4’)C(O)-. The invention also relates to pharmaceutical compositions. 2 N. and 9 C.p. f-crystals.

The present invention relates to compounds of General formula

where

R1means hydrogen or halogen,

R2means hydrogen, halogen, lower alkyl or lower alkoxy,

R1and R2together with the two carbon atoms of the cycle can mean the group-CH=CH-CH=CH-,

R3means halogen, trifluoromethyl, lower alkyl or lower alkoxy,

R4/R4’independently from each other and each means hydrogen or lower alkyl,

R5means lower alkyl, lower alkoxy, amino, phenyl, hydroxy(ness.)alkyl, cyano(ness.)alkyl, carbarnoyl(ness.)alkyl, pyridyl, pyrimidyl, -(CH2)n-piperazinil, optionally substituted by one or two lower alkyl groups-imidazolyl, (ness.)alkylsulfanyl, (ness.)alkylsulfonyl, benzylamino, -NH-(CH2)n+1N(R4’)2-(CH2)n+1N(R4’)2, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl or-O-(CH2)n+1N(R4’)2where R4’means hydrogen or (ness.)alkyl, and

n means 0-2,

X is-C(O)N(R4’)- or-N(R4’)C(O)-;

and their pharmaceutically acceptable acid additive salts.

The compounds of formula I and their salts differ valuable therapeutic properties. With the invention it has been unexpectedly found that compounds of the present invention are antagonists of the receptor neirokinina 1 (NK-1, substance P). Substance P is a naturally occurring undecapeptide belonging to the peptides of the family of tachykinins, the latter so called because of the rapid contractile action on extravascular tissue of smooth muscles.

The receptor for substance P is a representative of the superfamily-related G protein receptors.

Neuropeptide receptors substance P (NK-1) are widely distributed in the nervous system of mammals (before the duodenum and jejunum), and they are involved in the regulation of numerous biological processes.

It is established that the Central and peripheral action tachykinin mammals, i.e., substance P, is associated with numerous inflammatory conditions, including migraine, rheumatoid arthritis, asthma and inflammatory bowel disease, and identified its role as mediator gag reflex and modulator of disorders of the Central nervous system (CNS), such as Parkinson's disease (Neurosci. Res. 7, 187-214, 1996), anxiety (Can. J. Phys., 75, 612-621, 1997) and depression (Science, 281, 1640-1645,1998).

Data about the possibility of using antagonists of the receptor tachykinin for the treatment of pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation syndrome waiver of morphine, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial Hyper-reactivity and other respiratory diseases including allergic rhinitis, inflammatory bowel disease, including ulcerative colitis and Crohn's disease, eye injury and ocular inflammatory diseases, sum the RA neirokinina 1 develop for the treatment of numerous disorders, associated with an excess or imbalance of tachykinins, especially substance P. Examples of conditions that are associated with substance P, include disorders of the Central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).

Antagonists of the receptor neirokinina-1, in addition, can be used to treat a condition of sickness and induced drug vomiting.

In addition, in the journal The New England Journal of Medicine, volume 34, No. 3, 190-195, 1999 described the reduction of cisplatin-induced vomiting, using selective antagonists of the receptor neirokinina-1.

In the patent US 5972938 also described is a method of treatment psychoimmunological or psychosomatic disorders by introducing receptor antagonist tachykinin, such as receptor NK-1.

Objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts, the method of obtaining the above-mentioned compounds containing medicines and the method of their manufacture, as well as the application of the above compounds for the treatment and prevention of illnesses, especially of illnesses and disorders of the above, or to produce relevant by such which include disorders of the Central nervous system, such as the need for treatment or prevention of certain depressive States or vomiting with the introduction of the antagonists of NK-1 receptor. The main attack of depression is defined as a period of at least two weeks, during which, for most of the days or nearly every day, there is depressed mood or loss of interest or lack of satisfaction from any or almost any kind of activity.

Common terms used in the context of the present invention, have the following meanings, regardless of apply these terms individually or in various combinations.

Used in the description of the term "(ness.)alkyl" means a linear or branched alkyl group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc., Preferred (ness.)alkyl groups containing from 1 to 4 carbon atoms.

The term "(ness.)alkoxy" means a group in which the alkyl residues have the meanings indicated above, and the alkyl is attached via an oxygen atom.

The term "halogen" means chlorine, iodine, fluorine and IIR acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, paratoluenesulfonyl acid, etc.,

Preferred are compounds in which X is-C(O)N(R4’)-, where R4’means methyl, a R5means piperazinil, optionally substituted by one or two methyl groups, for example, the following connections:

(3,5-bis-trifloromethyl)methylamide 4-(2-bromophenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide(3R,5S)-4-(2-bromophenyl)-2-(3,5-dimethylpiperazine-1-yl)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-bromophenyl)-2-piperazine-1-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide(3R,5S)-4-(2-chlorophenyl)-2-(3,5-dimethylpiperazine-1-yl)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-piperazine-1-risperidon-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide(3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-o-tolylboronic-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 2-piperazine-1-yl-4-o-tolylboronic-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-methoxyphenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide(3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-(2-methoxyphenyl)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-methoxyphenyl)-2-piperazine-1-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(4-forfinal)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-forfinal)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide(3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-(2-forfinal)pyrimidine-5-carboxylic acid,

(3,5-bis-trip)formatives)methylamide 4-(4-forfinal)-2-piperazine-1-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(4-fluoro-2-were)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid,

(3,5-bis-triptorelin the bis-trifloromethyl)methylamide 4-(4-fluoro-2-were)-2-piperazine-1-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 2-(4-methylpiperazin-1-yl)-4-naphthalene-1-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide(3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-naphthalene-1-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-naphthalene-1-yl-2-piperazine-1-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid and

(3,5-bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-piperazine-1-Yeremey-5-carboxylic acid.

In addition, preferred compounds in which X is-C(O)N(R4’)-, where R4’means methyl, a R5means morpholinyl or-O(CH2)2-morpholinyl.

Examples of such compounds are:

(3,5-bis-trifloromethyl)methylamide 4-(2-bromophenyl)-2-morpholine-4-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-morpholine-4-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-(2-morpholine-4-ylethoxy)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)metiram is oxyphenyl)-2-morpholine-4-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(4-fluoro-2-were)-2-morpholine-4-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 2-morpholine-4-yl-4-naphthalene-1-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-morpholine-4-Yeremey-5-carboxylic acid.

In addition, preferred compounds in which X means

-C(O)N(R4’)-, R4’means methyl, a R5means-NH(CH2)2N(CH3)2, -O(CH2)2N(CH3)2or-O(CH2)3N(CH3)2for example the following compounds:

(3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-(2-diethylaminoethylamine)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-(2-dimethylaminoethoxy)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-(3-dimethylaminopropoxy)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 2-(2-dimethylaminoethoxy)-4-o-tolylboronic-5-carboxylic acid, or

(3,5-bis-trifloromethyl)methylamide 2-(3-dimethylaminopropoxy)-4-o-tolylboronic-P>4’)C(O)-, R4’means methyl, and R5means morpholinyl or piperazinil, optionally substituted by a group of lower alkyl, for example, the following connections:

2-(3,5-bis-triptoreline)-N-methyl-N-[2-(4-methylpiperazin-1-yl)-4-o-tolylboronic-5-yl] isobutyramide and

2-(3,5-bis-triptoreline)-N-methyl-N-(2-morpholine-4-yl-4-o-tolylboronic-5-yl) isobutyramide.

These compounds of formula I and their pharmaceutically acceptable salts can be obtained by known in the art methods, for example as described below, which includes

a) interaction of the compounds of formula

with the compound of the formula

with the formation of the compounds of formula

where R1-R5and n have the meanings indicated above, or (b) the interaction of the compounds of formula

with the compound of the formula

with the formation of the compounds of formula

where R1-R5and n have the meanings stated above, or

C) modifying one or more substituents R1-R5with the values specified above, and, if necessary, translation of the compounds obtained in the II, for example methyl [6-(4-methylpiperazin-1-yl)-4-o-tolylboronic-3-yl] amine and compounds of formula III, for example, 2-(3,5-bis-triptoreline)-2-methylpropionyl-chloride, added DIPEA (N-ethyldiethanolamine) and the mixture is stirred at a temperature of from 35 to 40°C. the Desired compound of formula I-1 is obtained after purification with high yield.

Method b) describes the interaction of the compounds of formula IV with the compound of the formula V with the formation of the compounds of formula I-2. The reaction is carried out under normal conditions, for example, in a solvent such as dichloromethane, in the presence of triethylamine, EDCI (hydrochloride N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide) and NOT (1-hydroxybenzotriazole). The resulting mixture was stirred at 20°C for 12 hours

Getting salt is carried out at room temperature according to known in the art methods. However, there is due to salts with inorganic and organic acids. Examples of such salts are hydrochloride, hydrobromide, sulfates, nitrates, citrates, acetates, maleate, succinate, methanesulfonate, para-toluensulfonate etc.

The following figures 1-6 illustrate in more detail the methods of making compounds of formula I. the starting materials of formula V, VIII, X, XIVP>

In the diagrams the following abbreviations are used:

THF - tetrahydrofuran

DIPEA IS N-ethyldiethanolamine

NAVT - 1-hydroxybenzotriazole

EDCI hydrochloride N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide

m-HNBK - meta-chlormadinone acid

DFFA - diphenylphosphinite

DMF - dimethylformamide

The tea - triethylamine

Scheme 1

The substituents have the meanings specified above.

Scheme 2

Y=halogen

R4”(ness.)alkyl

The substituents have the meanings specified above.

Scheme 3

R’ means (ness.)alkyl, Y represents halogen, a represents the amino group, such as-N(R4)2, piperazinil, morpholinyl, piperidinyl or imidazolyl. The remaining substituents have the meanings specified above.

Scheme 4

The substituents have the meanings specified above.

Scheme 5

The type of reaction described in journal Bioorg. and Med. Chem., vol.5, №2, 437-444 (1997).

R1-R4and n have the meanings indicated above, means (ness.)alkoxy, -O-(CH2)n+1N(R4)2, -O-(CH2)n+1n+1N(R4)2.

Scheme 6

R1-R4and n have the meanings indicated above, means (ness.)alkoxy, -O-(CH2)n+1N(R4)2-O-(CH2)n+1-morpholinyl or-O-(CH2)n+1-piperidinyl, and’ means an amino group such as-N(R4)2, optionally substituted piperazinil, morpholinyl, piperidinyl, imidazolyl, benzylamine or-NH-(CH2)n+1N(R4)2.

As noted previously, the compounds of formula I and their pharmaceutically acceptable additive salts have valuable pharmacological properties. It is established that the compounds of the present invention are antagonists of the receptor neirokinina 1 (NK-1, substance P).

The compounds of formula I were investigated using the following tests.

The affinity of test compounds to NK1the receptor was evaluated using the human NK1receptors in Cho cells infected with human PC1receptor (using the expression system of the virus Semliki) and in the presence of radioactively labeled with [3CA (bovine serum albumin) (0,04%), leupeptin (8 µg/ml), MnCl2(3 mm) and phosphoramidon (2 μm). In experiments on the binding used 250 μl of the suspension membrane (1,25×105cells/tube for analysis), a 0.125 µl of buffer, including the replacement agent, and 125 μl of [3N]-substance P. To obtain the curves of substitution used at least 7 concentrations of compounds. Tubes for analysis were incubated for 60 min at room temperature, after which the contents of the tubes were rapidly filtered under vacuum through a filter type GF/C, which previously within 60 min, soaked PEI (0,3%) with two washings, each of which used 2 ml of HEPES buffer (50 mm, pH 7.4). The radioactivity remaining on the filters was assessed using the acquired scintillation counter. All experiments were performed in triplicate in at least two different experiments.

For preferred compounds their affinity for PC1-receptor, expressed in terms of the values PKiwas $ 8.00-9,20. Examples of such compounds are:

The compounds of formula I and their pharmaceutically acceptable acid salt additive can be used as medicines, for example, in the form of pharmaceutical compositions. Firmowych capsules with hard or soft coating, solutions, emulsions or suspensions. However, the introduction can also be carried out rectally, for example in the form of suppositories, or parenterally, e.g. in the form of injectable solutions.

The compounds of formula I and their pharmaceutically acceptable acid additive salts can be processed with pharmaceutically inert inorganic or organic excipients for the preparation of tablets, filmtabletten, tablets and gelatin capsules with a hard surface. As such excipients for preparation of, for example, tablets, coated tablets and gelatin capsules with solid floor can be used lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc.

Acceptable excipients for preparation of gelatin capsules with a soft coating are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols etc.,

Acceptable excipients for preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

Acceptable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

In addition, the pharmaceutical compositions can contain preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, corrigentov, salts for modifying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.

The dose can vary within wide limits and, of course, must be chosen depending on the individual requirements in each particular case. In General, in the case of oral administration, the daily dose for a patient may be in the range of from about 10 to 1000 mg of the compounds of formula I, optionally, however, the upper limit may be exceeded.

Below the present invention is illustrated by the examples, without limiting its scope.

Example 1

(3,5-bis-trifloromethyl)methylamide 2-methyl-4-phenylpyrimidine-5-carboxylic acid

a) 3,5-bis-triptoreline 2-metal-4-phenylpyrimidine-5-carboxylic acid

To a solution of 0.50 g (2,33 mmole) of 2-methyl-4-phenylpyrimidine-5-carboxylic acid, of 0.65 ml (4,47 mmole) of triethylamine, of 0.44 g (2,33 mmole) 1-hydrox the/SUB> added 0.68 g (2.8 mmole) of 3,5-bis-triphtalocyaninine and the reaction mixture was stirred for 16 hours Then the reaction mixture was diluted with 20 ml of CH2Cl2off , washed with 50 ml of 0.5 N. Hcl, 50 ml of N2On and held back extraction of the aqueous layer with 50 ml of CH2Cl2. The combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2, ethyl acetate), was obtained 0,80 g (78%) of 3,5-bis-triptoreline 2-methyl-4-phenylpyrimidine-5-carboxylic acid as a colourless solid, tPL188,5-189,5°C.

b) (3,5-Bis-tripteroides)methylamide 2-methyl-4-phenylpyrimidine-5-carboxylic acid

To a solution of 0.67 g (1.52 mmole) of 3,5-bis-triptoreline 2-methyl-4-phenylpyrimidine-5-carboxylic acid in 10 ml of N,N-dimethylformamide was added 0.08 g (1.98 mmole) of sodium hydride (60% dispersion in mineral oil) and the reaction mixture was stirred for 1 h and Then at 0°C was added 0.15 ml (2.4 mmole) under the conditions and the reaction mixture was stirred at room temperature (CT) within 3 hours the Reaction mixture was distributed between 50 ml of N2About 50 ml of saline solution and 50 ml of CH2CL2. The phases were separated and the aqueous SL is whether and evaporated. The obtained residue was purified by chromatography (SiO2, ethyl acetate/hexane, 4:1), was obtained 0.50 g (72%) of (3,5-bis-trifloromethyl)methylamide 2-methyl-4-phenylpyrimidine-5-carboxylic acid as a colourless oil, MC(EI):453 (M+).

Example 2

(3,5-Dichlorobenzyl)methylamide 2-metal-4-phenylpyrimidine-5-carboxylic acid

In the same way as described in example 1A), from 2-methyl-4-phenylpyrimidine-5-carboxylic acid and 3,5-dichloraniline received a 3.5-dichlorbenzene 2-methyl-4-phenylpyrimidine-5-carboxylic acid as a colourless solid, tPL194-195°C, which has metilirovanie same way as described in example 1B), received (3,5-dichlorobenzyl)methylamide 2-methyl-4-phenylpyrimidine-5-carboxylic acid as a colourless oil, MC(EI):385 (M+).

Example 3

(3,5-Bis-trifloromethyl)methylamide 4-(2-bromophenyl)-2-methylpyrimidin-5-carboxylic acid

a) Ethyl ester of 2-(2-bromobenzoyl)-3-dimethylaminoethanol acid

To a solution of 25.9 g (95,5 mmole) ethyl ester of 3-(2-bromophenyl)-3-oxopropanoic acid in 200 ml of toluene for 1 h was added 18,21 g (152 mmole) of dimethylacetal N,N-dimethylformamide dissolved in 100 ml of toluene, and reactionaries (SiO2CH2Cl2/MeOH, 40:1), received 25 g (80%) of the ethyl ester of 2-(2-bromobenzoyl)-3-dimethylaminoethanol acid in the form of a solid light brown color.

b) Ethyl ester of 4-(2-bromophenyl)-2-methylpyrimidin-5-carboxylic acid

To a freshly prepared solution of sodium alcoholate [obtained from 0,77 g (33,7 mmole) of sodium added to 100 ml of ethanol] was added 3,18 g (33,7 mmole) of the hydrochloride of acetamidine. After 10 min the solution was added 10.0 g (30,6 mmole) ethyl ester 2-(2-bromobenzoyl)-3-dimethylaminoethanol acid in 120 ml of ethanol and the reaction mixture was heated at 80°C for 16 hours the Solvent is evaporated, the residue was distributed between 100 ml of N2About 100 ml of CH2CL2. The aqueous phase was twice extracted with 100 ml of CH2CL2. The combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/MeOH, 40:1), when it got to 8.3 g (84%) of ethyl ester of 4-(2-bromophenyl)-2-methylpyrimidin-5-carboxylic acid in the form of butter, light brown.

b) 4-(2-bromophenyl)-2-methylpyrimidin-5-carboxylic acid

To a solution of 8.3 g (from 25.8 mmole) ethyl ester 4-(2-bromophenyl)-2-methylpr Uchenie 1 h, the reaction mixture was washed with 100 ml of diethyl ether. The aqueous phase was acidified 25% Hcl to pH 1 and was twice extracted with 200 ml of CH2Cl2. The combined organic extracts were dried (MgSO4), filtered and evaporated, to receive 7.0 g (92%) of 4-(2-bromophenyl)-2-methylpyrimidin-5-carboxylic acid in the form of foam a light yellow color.

g) (3,5-Bis-triptoreline)methylamide 4-(2-bromophenyl)-2-methylpyrimidin-5-carboxylic acid

To a solution of 0.5 g (1,71 mmole) 4-(2-bromophenyl)-2-methylpyrimidin-5-carboxylic acid, of 0.47 ml (3,41 mmole) of triethylamine, 0.26 g (1,71 mmole) of 1-hydroxybenzotriazole and 0.32 g (1,71 mmole) of the hydrochloride of N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide in 40 ml of CH2CL2added 0.52 g (2.0 mmole) of (3,5-bis-trifloromethyl)methylamine and the reaction mixture was stirred for 16 hours Then the reaction mixture was diluted with 20 ml of CH2CL2off , washed with 50 ml of 0.5 N. Hcl, 50 ml of N2On and held back extraction of the aqueous layer with 50 ml of CH2Cl2. The combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2, ethyl acetate), was obtained 0.7 g (77%) of (3,5-bis-trifloromethyl)methylamide 4-(2-bromophenyl)-2-methylpyrimidin-5-carboxylic acid as a colourless solid fuel is>-(2-bromophenyl)-2-methylpyrimidin-5-carboxylic acid

To a solution of 0.5 g (1,71 mmole) 4-(2-bromophenyl)-2-methylpyrimidin-5-carboxylic acid, of 0.47 ml (3,41 mmole) of triethylamine, 0.26 g (1,71 mmole) of 1-hydroxybenzotriazole and 0.32 g (1,71 mmole) of the hydrochloride of N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide in 40 ml of CH2Cl2added 0,49 g (2.05 mmole) of 3,5-bis-triphtalocyaninine and the reaction mixture was stirred for 16 hours Then the reaction mixture was diluted with 20 ml of CH2CL2off , washed with 50 ml of 0.5 N. Hcl, 50 ml of N2On and held back extraction of the aqueous layer with 50 ml of CH2Cl2. The combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/MeOH), was obtained 0.4 g (45%) of 3,5-bis-triptoreline 4-(2-bromophenyl)-2-methylpyrimidin-5-carboxylic acid as a colourless solid, tPL137,5-138,5°C.

Example 5

(3,5-Bis-trifloromethyl)methylamide 2,4-diphenylpyridine-5-carboxylic acid

In the same way as described in example 1A), from 2,4-diphenylpyridine-5-carboxylic acid and 3,5-bis-triphtalocyaninine received 3,5-bis-triptoreline 2,4-diphenylpyridine the ANO in example 1B), it was received (3,5-bis-trifloromethyl)methylamide 2,4-diphenylpyridine-5-carboxylic acid as a colourless oil, MC(ISP):516,2 (M+H+).

Example 6

(3,5-Dichlorobenzyl)methylamide 2,4-diphenylpyridine-5-carboxylic acid

In the same way as described in example 1A), from 2,4-diphenylpyridine-5-carboxylic acid and 3,5-dichloraniline received a 3.5-dichlorbenzene 2,4-diphenylpyridine-5-carboxylic acid as a colourless solid, tPL>220°C, which has metilirovanie as described in example 1B), received (3,5-dichlorobenzyl)methylamide 2,4-diphenylpyridine-5-carboxylic acid as a colourless oil, MC(ISP):448 (M+H+).

Example 7

(3,5-Dichlorobenzyl)methylamide 4-phenyl-2-propylpyrimidine-5-carboxylic acid

In the same way as described in example 1A), from 4-phenyl-2-propylpyrimidine-5-carboxylic acid and 3,5-dichloraniline received a 3.5-dichlorbenzene 4-phenyl-2-propylpyrimidine-5-carboxylic acid as a colourless solid, tPL183°C, which has metilirovanie as described in example 1B), received (3,5-dichlorobenzyl)methylamide 4-phenyl-2-propylpyrimidine-5-carboxylic acid as colorless oil, MS(EI):413 (Mwho, as described in example 3b), ethyl ester of 2-benzoyl-3-dimethylaminoethanol acid and hydrochloride of butyramide, followed by hydrolysis as described in example 3b), 4-phenyl-2-propylpyrimidine-5-carboxylic acid.

Example 8

(3,5-Bis-trifloromethyl)methylamide 4-phenyl-2-propylpyrimidine-5-carboxylic acid

In the same way as described in example 1A), from 4-phenyl-2-propylpyrimidine-5-carboxylic acid and 3,5-bis-triphtalocyaninine received 3,5-bis-triptoreline 4-phenyl-2-propylpyrimidine-5-carboxylic acid as a colourless solid, tPL194-195°C, which has metilirovanie as described in example 1B), received (3,5-bis-trifloromethyl)methylamide 4-phenyl-2-propylpyrimidine-5-carboxylic acid as a colourless oil, MC(ISP):482,3 (M+H+).

Example 9

(3,5-Bis-trifloromethyl)metagamed 4-phenyl-2-pyridine-4-Yeremey-5-carboxylic acid

In the same way as described in example 3 g), 4-phenyl-2-pyridine-4-Yeremey-5-carboxylic acid and (3,5-bis-trifloromethyl) of methylamine were obtained (3,5-bis-trifloromethyl)methylamide 4-phenyl-2-pyridine-4-Yeremey-5-carboxylic acid as a colourless solid vessel same as described in example 3b), ethyl ester of 2-benzoyl-3-dimethylaminoethanol acid and hydrochloride of isonicotinamide, followed by hydrolysis as described in example 3b), 4-phenyl-2-pyridine-4-Yeremey-5-carboxylic acid.

Example 10

(3,5-Bis-trifloromethyl)methylamide 4-phenyl [2,2’] bipyridinyl-5-carboxylic acid

In the same way as described in example 3 g), 4-phenyl-[2,2’] bipyridinyl-5-carboxylic acid and (3,5-bis-trifloromethyl) of methylamine were obtained (3,5-bis-trifloromethyl)methylamide 4-phenyl- [2,2’]bipyridinyl-5-carboxylic acid as a colourless solid, tPL172-173°C.

The original connection, 4-phenyl[2,2’]bipyridinyl-5-carboxylic acid was obtained in the same way as described in example 3b), ethyl ester of 2-benzoyl-3-dimethylaminoethanol acid and hydrochloride pyrimidine-2-carboxamidine, followed by hydrolysis as described in example 3b), 4-phenyl[2,2’]bipyridinyl-5-carboxylic acid.

Example 11

3,5-Bis-cryptomaterial 2-methyl-4-naphthalene-1-Yeremey-5-carboxylic acid

In the same way as described in example 1A), from 2-methyl-4-naphthalene-1-Yeremey-5-carboxylic acid and 3,5-howl acid as a colourless solid, tPL146,7-146,9°C.

The original connection, 2-methyl-4-naphthalene-1-Yeremey-5-carboxylic acid was obtained in the same way as described in example 3A)-3C) of ethyl ester of 3-naphthalene-1-yl-3-oxopropanoic acid and dimethylacetal N,N-dimethylformamide.

Example 12

(3,5-Bis-trifloromethyl)methylamide 2-methyl-4-naphthalene-1-Yeremey-5-carboxylic acid

In the same way as described in example 1B), from 3,5-bis-triptoreline 2-methyl-4-naphthalene-1-Yeremey-5-carboxylic acid and under the conditions received (3,5-bis-trifloromethyl)methylamide 2-methyl-4-naphthalene-1-Yeremey-5-carboxylic acid as a colourless solid, tPL164,9-165,2°C.

Example 13

(3,5-Bis-trifloromethyl)methylamide 4-(2-methoxyphenyl)-2-methylpyrimidin-5-carboxylic acid

In the same way as described in example 3 g), 4-(2-methoxyphenyl)-2-methylpyrimidin-5-carboxylic acid and (3,5-bis-trifloromethyl) of methylamine were obtained (3,5-bis-trifloromethyl)methylamide 4-(2-methoxyphenyl)-2-methylpyrimidin-5-carboxylic acid as a colourless solid, tPL140-141°C.

The original compound, 4-(2-methoxyphenyl)-2-methylpyrimidin-5-carboplatino acid and dimethylacetal N,N-dimethylformamide.

Example 14

(3,5-Bis-tripteroides)methylamide 2-methylsulfanyl-4-phenylpyrimidine-5-carboxylic acid

To a solution of 3 g (12,18 mmole) 2-methylsulfanyl-4-phenylpyrimidine-5-carboxylic acid, of 3.32 ml (24,36 mmole) of triethylamine, 1.84 g (12,18 mmole) of 1-hydroxybenzotriazole and of 2.33 g (12,81 mmole) of the hydrochloride of N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide in 170 ml of CH2CL2added 3,76 g (14,62 mmole) of (3,5-bis-trifloromethyl) methylamine and the reaction mixture was stirred for 16 hours Then the reaction mixture was diluted with 100 ml of CH2CL2off , washed with 100 ml of 0.5 N. Hcl, 100 ml of N2On and held back extraction of the aqueous layer with 100 ml of CH2CL2. The combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2CL2/ethyl acetate), was obtained 4.15 g (67%) of (3,5-bis-trifloromethyl)methylamide 2-methylsulfanyl-4-phenylpyrimidine-5-carboxylic acid as a colourless solid, tPL119,1-119,8°C.

Example 15

(3,5-Bis-trifloromethyl)methylamide 2-methylsulphonyl-4-phenylpyrimidine-5-carboxylic acid

To a solution of 4.15 g (85,5 mmole) of (3,5-bis-trifloromethyl)IU the g (21,4 mmole) 3-chlormadinone acid (70%) and the reaction mixture was stirred at RT for 3 hours Then added 150 ml of a saturated solution of Panso3the layers were separated, the organic phase was washed with saturated solution of NaHCO3, dried (PA2SO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/methanol 40:1), to receive 4,20 g (95%) of (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-phenylpyrimidine-5-carboxylic acid as colorless solids, MC(EI):517 (M+).

Example 16

(3,5-Bis-trifloromethyl)methylamide 2-(4-methylpiperazin-1-yl)-4-phenylpyrimidine-5-carboxylic acid

To a solution of 0.5 g (0.97 mmole) of (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-phenylpyrimidine-5-carboxylic acid in 10 ml of dioxane was added with 0.27 ml (2,42 mmole) of 1-methylpiperazine and the reaction mixture was stirred for 16 hours After evaporation of the solvent the residue was distributed between 50 ml of CH2CL2and 50 ml of N2O. the Aqueous layer was extracted with 50 ml of CH2CL2combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2CL2/methanol, 9:1), was obtained 0.4 g (77%) of (3,5-bis-trifloromethyl)methylamide 2-(4-m="ptx2">Example 17

(3,5-Bis-trifloromethyl)methylamide 2 benzylamino-4-phenylpyrimidine-5-carboxylic acid

To a solution of 0.4 g (0.77 mmole) of (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-phenylpyrimidine-5-carboxylic acid in 10 ml of dioxane was added to 0.21 ml (1,923 mmole) of benzylamine and the reaction mixture was stirred for 16 hours After evaporation of the solvent the residue was distributed between 50 ml of CH2CL2and 50 ml of N2O. the Aqueous layer was extracted with 50 ml of CH2Cl2combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2CL2/methanol 40:1), was obtained 0.2 g (47%) of (3,5-bis-trifluoromethyl-benzyl)methylamine 2 benzylamino-4-phenylpyrimidine-5-carboxylic acid as a colourless solid, tPL117,2-118,1°C.

Example 18

(3,5-Bis-triptoreline)methylamide 2-morpholine-4-yl-4-phenylpyrimidine-5-carboxylic acid

To a solution of 0.4 g (0.77 mmole) of (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-phenylpyrimidine-5-carboxylic acid in 10 ml of dioxane was added 0.17 ml (1,93 mmole) of the research and the reaction mixture was stirred for 16 hours After cypriani the 50 ml of CH2CL2combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2CL2/methanol 40:1), was obtained 0.21 g (52%) of (3,5-bis-trifloromethyl)methylamide 2-morpholine-4-yl-4-phenylpyrimidine-5-carboxylic acid as a colourless solid, tPL168,1-168,4°C.

Example 19

(3,5-Bis-trifloromethyl)methylamide 4-fined-2-piperazine-1-Yeremey-5-carboxylic acid

To a solution of 0.5 g (0.96 mmole) of (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-phenylpyrimidine-5-carboxylic acid in 10 ml of dioxane was added 0,208 g (2,15 mmole) piperazine and the reaction mixture was stirred for 16 hours After evaporation of the solvent the residue was distributed between 50 ml of CH2Cl2and 50 ml of N2O. the Aqueous layer was extracted with 50 ml of CH2CL2combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2CL2/methanol 40:1), it was received at 0.42 g (83%) of (3,5-bis-trifloromethyl)methylamide 4-phenyl-2-piperazine-1-Yeremey-5-carboxylic acid as a colourless oil, MC(ISP):524,1 (M+H+).

To a solution of 0.5 g (0.96 mmole) of (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-phenylpyrimidine-5-carboxylic acid in 10 ml of dioxane was added 0,276 g (2,15 mmole) of CIS-2,6-dimethylpiperazine and the reaction mixture was stirred for 16 hours After evaporation of the solvent the residue was distributed between 50 ml of CH2Cl2and 50 ml of N2O. the Aqueous layer was extracted with 50 ml of CH2CL2combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2CL2/methanol 40:1), was obtained 0.51 g (96%) of (3,5-bis-trifloromethyl)methylamide (2R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-phenylpyrimidine-5-carboxylic acid as a colourless oil, MC(ISP):552,1 (M+H+).

Example 21

(3,5-Bis-trifloromethyl)methylamide 2-(2-diethylaminoethylamine)-4-phenylpyrimidine-5-carboxylic acid

To a solution of 0.4 g (0.77 mmole) of (3,5-bis-trifloromethyl)methylamide-methylsulphonyl-4-phenylpyrimidine-5-carboxylic acid in 10 ml of dioxane was added 0,211 ml of 1.93 mmole) of 2-diethylaminoethylamine and the reaction mixture was stirred for 16 hours After evaporation of the solvent the residue was distributed between 50 ml of CH2Cl2and 50 ml 4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/methanol/NH4OH, 140:10:1), to receive 0,22 g (54%) of (3,5-bis-trifloromethyl)methylamide 2-(2-diethylaminoethylamine)-4-phenylpyrimidine-5-carboxylic acid as a colourless solid, tPL109,5-110,3°C.

Example 22

(3,5-Bis-cryptomelane)methylamide 4-phenyl-2-piperidine-1-Yeremey-5-carboxylic acid

To a solution of 0.5 g (0.96 mmole) of (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-phenylpyrimidine-5-carboxylic acid in 10 ml of dioxane was added 0,183 g (2,15 mmole) of piperidine and the reaction mixture was stirred for 16 hours After evaporation of the solvent the residue was distributed between 50 ml of CH2CL2and 50 ml of N2O. the Aqueous layer was extracted with 50 ml of CH2CL2combined organic extracts were dried (MgS4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2CL2/ethyl acetate, 20:1), when it got to 0.48 g (95%) of (3,5-bis-trifloromethyl)methylamide 4-phenyl-2-piperidine-1-Yeremey-5-carboxylic acid in the form of a waxy substance, light yellow, MC(ISP):523,2 (M+H+).

Primeval acid

To a solution of 0.5 g (0.96 mmole) of (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-phenylpyrimidine-5-carboxylic acid in 10 ml of dioxane was added 0.28 g (2,15 mmole) of N-(2-hydroxyethyl)piperazine and the reaction mixture was stirred for 16 hours After evaporation of the solvent the residue was distributed between 50 ml of CH2Cl2and 50 ml of N2O. the Aqueous layer was extracted with 50 ml of CH2CL2combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/MeOH, 6:1), to receive 0,43 g (78%) of (3,5-bis-trifluoromethyl-benzyl)methylamine-[4-(2-hydroxyethyl)piperazine-1-yl]-4-phenylpyrimidine-5-carboxylic acid in the form of a waxy substance light yellow color. MC(ISP):568,2 (M+H+).

Example 24

(3,5-Bis-trifloromethyl)methylamide 2-(2-morpholine-4-ylethoxy)-4-phenylpyrimidine-5-carboxylic acid

To a solution of 0.5 g (0.96 mmole) of (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-phenylpyrimidine-5-carboxylic acid in 20 ml of acetonitrile was added 0.15 g (1.16 mmole) of N-(2-hydroxyethyl)the research, of 1.57 g (a 4.83 mmole) Cs2CO3and the reaction mixture was stirred for 16 hours After evaporation dissolveCl2combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/MeOH, 40:1), to receive 0.39 g (68%) of (3,5-bis-trifloromethyl)methylamide 2-(2-morpholine-4-ylethoxy)-4-phenylpyrimidine-5-carboxylic acid in the form of oil is light yellow in color, MC(ISP):569,2 (M+H+).

Example 25

(3,5-Bis-triptoreline)methylamide 4-phenyl-2-(2-piperidine-1-ylethoxy)pyrimidine-5-carboxylic acid

To a solution of 0.5 g (0.96 mmole) of (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-phenylpyrimidine-5-carboxylic acid in 20 ml of acetonitrile was added 0.15 g (1.16 mmole) of N-(2-hydroxyethyl)piperidine, of 1.57 g (a 4.83 mmole) Cs2CO3and the reaction mixture was stirred for 16 hours After evaporation of the solvent the residue was distributed between 50 ml of CH2Cl2and 50 ml of N2O. the Aqueous layer was extracted with 50 ml of CH2Cl2combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/MeOH/NH4OH, 200:10:1), when it got to 0.47 g (85%) of (3,5-bis-trifloromethyl)methylamide 4-phenyl-2-(2-piperidine-1-ylethoxy)pyrimidine-5-carboncalculator)methylamide 2-(2-dimethylaminoethoxy)-4-phenylpyrimidine-5-carboxylic acid

To a solution of 0.5 g (0.96 mmole) of (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-phenylpyrimidine-5-carboxylic acid in 20 ml of acetonitrile was added 0.10 g (1.16 mmole) of 2-dimethylaminoethanol, of 1.57 g (a 4.83 mmole) Cs2CO3and the reaction mixture was stirred for 16 hours

After evaporation of the solvent the residue was distributed between 50 ml of CH2CL2and 50 ml of N2O. the Aqueous layer was extracted with 50 ml of CH2Cl2combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/MeOH/NH4OH, 110:10:1), to receive 0,43 g (82%) of (3,5-bis-trifloromethyl)methylamide-(2-dimethylaminoethoxy)-4-phenylpyrimidine-5-carboxylic acid in the form of oil is light yellow in color, MC(ISP):527,2 (M+N+).

Example 27

(3,5-Bis-trifloromethyl)methylamide 2-(3-dimethylaminopropoxy)-4-phenylpyrimidine-5-carboxylic acid

To a solution of 0.5 g (0.96 mmole) of (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-phenylpyrimidine-5-carboxylic acid in 20 ml of acetonitrile was added to 0.14 ml (1.16 mmole) 2-dimethylaminopropanol, of 1.57 g (a 4.83 mmole) Cs2CO3and the reaction mixture was stirred for 2O. the Aqueous layer was extracted with 50 ml of CH2Cl2combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/MeOH/NH4OH, 110:10:1), was obtained 0.50 g (95%) of (3,5-bis-trifloromethyl)methylamide 2-(3-dimethylaminopropoxy)-4-phenylpyrimidine-5-carboxylic acid in the form of oil is light yellow in color, MC(ISP):541,2 (M+H+).

Example 28

(3,5-Bis-trifloromethyl)methylamide 2-methoxy-4-phenylpyrimidine-5-carboxylic acid

To a suspension of 0.4 g (0.77 mmole) of (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-phenylpyrimidine-5-carboxylic acid in 10 ml of methanol was added 0.10 g (1,93 mmole) of methanolate sodium (95%) and the reaction mixture was stirred for 16 hours After evaporation of the solvent the residue was distributed between 50 ml of CH2CL2and 50 ml of N2O. the Aqueous layer was extracted with 50 ml of CH2Cl2combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/MeOH, 40:1), was obtained 0.23 g (63%) of (3,5-bis-trifloromethyl)methylamide 2-methoxy-4-phenylpyrimidine-5-carboxylic acid in the form of bestv lamed 2-carbamoylmethyl-4-phenylpyrimidine-5-carboxylic acid

In the same way as described in example 3 g), 2-carbamoylmethyl-4-phenylpyrimidine-5-carboxylic acid and (3,5-bis-trifloromethyl) of methylamine were obtained (3,5-bis-trifloromethyl)methylamide 2-carbamoylmethyl-4-phenylpyrimidine-5-carboxylic acid as a colourless solid, tPL161-163°C.

The original connection, 2-carbamoylmethyl-4-phenylpyrimidine-5-carboxylic acid was obtained in the same way as described in example 3b), ethyl ester of 2-benzoyl-3-dimethylaminoethanol acid and hydrochloride of malonamide, followed by hydrolysis as described in example 3b), up to 2-carbamoylmethyl-4-phenylpyrimidine-5-carboxylic acid.

Example 30

(3,5-Bis-trifloromethyl)methylamide 2-cyanomethyl-4-phenylpyrimidine-5-carboxylic acid

To a solution of 0.50 g (a 1.01 mmole) of (3,5-bis-trifloromethyl)methylamide 2-carbamoylmethyl-4-phenylpyrimidine-5-carboxylic acid and 0.17 ml of pyridine in 10 ml of dioxane was added 0.15 ml (1,06 mmole) of anhydride triperoxonane acid and the resulting reaction mixture was stirred at 50°C for 1 h Then the reaction mixture was poured into a mixture of ice water and was extracted three times with 50 ml of CH2Cl2. The combined organic extracts sushi is/SUB>/MeOH, 30:1), was obtained 0.25 g (51%) of (3,5-Bis-trifloromethyl)methylamide-cyanomethyl-4-phenylpyrimidine-5-carboxylic acid as a colourless solid, tPL114-116°C.

Example 31

(3,5-Bis-triptoreline)methylamide 2-hydroxymethyl-4-phenylpyrimidine-5-carboxylic acid

In the same way as described in example 3 g), 2-hydroxymethyl-4-phenylpyrimidine-5-carboxylic acid and (3,5-bis-trifloromethyl) of methylamine were obtained (3,5-bis-trifloromethyl)methylamide 2-hydroxymethyl-4-phenylpyrimidine-5-carboxylic acid as colorless oil, MS(EI):469 (M+).

The original connection, 2-hydroxymethyl-4-phenylpyrimidine-5-carboxylic acid was obtained in the same way as described in example 3b), ethyl ester of 2-benzoyl-3-dimethylaminoethanol acid hydrochloride and 2-hydroxyazetidine, followed by hydrolysis as described in example 3b), up to 2-hydroxymethyl-4-phenylpyrimidine-5-carboxylic acid.

Example 32

(3,5-Bis-triptoreline)metagamed 2-dimethylaminomethyl-4-phenylpyrimidine-5-carboxylic acid

a) 5-[(3,5-Bis-trifloromethyl)methylcarbamoyl]-4-phenylpyrimidine-2-ymetray ether methanesulfonate acid

To the slots and at 1.17 ml (8,44 mmole) of triethylamine in 30 ml of CH2Cl2when 0°With the added 0,479 ml (to 6.19 mmole) of methanesulfonamide and the reaction mixture was stirred for 16 hours Then the reaction mixture was poured into a saturated solution Panso3and thrice was extracted with 50 ml of CH2Cl2. The combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2CL2/ethyl acetate, 8:1), to receive 2,30 g(74%) 5-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4-phenylpyrimidine-2-ymetray ether methanesulfonate acid as a viscous colorless oil, MC(ISP):548,1 (M+N+).

b) (3,5-Bis-trifloromethyl)methylamide 2-dimethylaminomethyl-4-phenylpyrimidine-5-carboxylic acid

To a solution of 0.40 g (0.73 mmole) of 5-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4-phenylpyrimidine-2-Eletropaulo ether methanesulfonate acid in 5 ml of CH2CL2added 1 ml of 5.6 M solution of dimethylamine in ethanol and the reaction mixture was stirred at RT for 16 h Then the reaction mixture was poured into H2About three times and was extracted with 50 ml of CH2CL2. The combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO is nametil-4-phenylpyrimidine-5-carboxylic acid as a colourless oil, MC(ISP):497,2 (M+N+).

Example 33

(3,5-Bis-trifloromethyl)methylamide 2-morpholine-4-helmeted-4-phenylpyrimidine-5-carboxylic acid

To a solution of 0.40 g (0.73 mmole) of 5-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4-phenylpyrimidine-2-Eletropaulo ether methanesulfonate acid in 5 ml of CH2CL2added 0,095 ml (1,10 mmole) of the research and the reaction mixture was stirred at RT for 16 h Then the reaction mixture was poured into H2About three times and was extracted with 50 ml of CH2Cl2. The combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/MeOH, 10:1), was obtained 0.33 g (88%) of (3,5-bis-trifloromethyl)methylamide 2-morpholine-4-ylmethyl-4-phenylpyrimidine-5-carboxylic acid in the form of a waxy solid of light yellow color, MC(ISP):to 539.3 (M+H+).

Example 34

(3,5-Bis-trifloromethyl)methylamide 2-(4-methylpiperazin-1-ylmethyl)-4-phenylpyrimidine-5-carboxylic acid

To a solution of 0.40 g (0.73 mmole) of 5-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4-phenylpyrimidine-2-Eletropaulo ether methanesulfonate acid in 5 ml of CH2Cl2added to 0.12 ml (1.1 mmole) of N-METI Aravali 50 ml of CH2Cl2. The combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/MeOH, 10:1), was obtained 0.31 g (77%) of (3,5-bis-trifloromethyl)methylamide 2-(4-methylpiperazin-1-ylmethyl)-4-phenylpyrimidine-5-carboxylic acid in the form of a waxy solid of light yellow color, MC(ISP):552,2 (M+H+).

Example 35

(3,5-Bis-trifloromethyl)metagamed 4-phenyl-2-piperidine-1-iletilerimde-5-carboxylic acid

To a solution of 0.40 g (0.73 mmole) of 5-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4-phenylpyrimidine-2-Eletropaulo ether methanesulfonate acid in 5 ml of CH2Cl2added to 0.11 ml (1.1 mmole) of piperidine. The reaction mixture was stirred at RT for 16 h, then was poured into H2About three times and was extracted with 50 ml of CH2CL2. The combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/MeOH, 10:1), was obtained 0.32 g (81%) of (3,5-bis-trifloromethyl)methylamide 4-phenyl-2-piperidine-1-iletilerimde-5-carboxylic acid in the form of a waxy solid of light yellow color, MC(IS-5-carboxylic acid

To a solution of 0.40 g (0.73 mmole) of 5-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4-phenylpyrimidine-2-Eletropaulo ether methanesulfonate acid and 0.04 g (0,80 mmole) of methanolate of sodium in 15 ml of N,N-dimethylformamide was added 0,59 g (from 0.88 mmole) of imidazole, and the resulting mixture was stirred at RT for 16 h Then the reaction mixture was evaporated and the residue was distributed between H2Oh and CH2CL2. The aqueous layer was twice extracted with 50 ml of CH2Cl2combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/MeOH, 10:1), was obtained 0.24 g (63%) of (3,5-bis-trifloromethyl)methylamide 2-imidazol-1-ylmethyl-4-phenylpyrimidine-5-carboxylic acid in the form of a solid of light yellow color, MC(ISP):520.2 (M+H+).

Example 37

(3,5-Bis-triptoreline)methylamide 4-(2-bromophenyl)-2-methylsulfonylamino-5-carboxylic acid

a) Ethyl ester of 4-(2-bromophenyl)-2-methylsulfonylamino-5-carboxylic acid

To a suspension 3,81 g (46,54 mmole) of sodium acetate and 6,47 g (23,27 mmole) sulfate S-methylisothiazoline in 100 ml of N,N-dimethylformamide one portion was added a solution of 6.90 g (to 21.15 mmole) atrovaginata at 90°C for 16 hours The solvent is then evaporated, the residue was distributed between 100 ml of CH2Cl2and 100 ml of N2O. the Aqueous phase was twice extracted with 100 ml of CH2Cl2combined organic extracts were dried (MgSO4), filtered and evaporated.

The obtained residue was purified by chromatography (SiO2CH2CL2), it was received 5.20 g (69%) of ethyl ester of 4-(2-bromophenyl)-2-methylsulfonylamino-5-carboxylic acid in the form of oil is light green in color.

b) 4-(2-Bromophenyl)-2-methylsulfonylamino-5-carboxylic acid

To a solution of 5.10 g (14.4 mmole) of ethyl ester of 4-(2-bromophenyl)-2-methylsulfonylamino-5-carboxylic acid in 10 ml of ethanol was added 10 ml of 2 n NaOH solution. After stirring for 1 h, the yellow solution was added 50 ml of N2About 50 ml of CH2Cl2, the aqueous phase was acidified 25% Hcl to pH 1. The phases were separated and the aqueous phase was twice extracted with 200 ml of CH2CL2. The combined organic extracts were dried (MgSO4), filtered and evaporated, to receive 4,60 g (98%) of 4-(2-bromophenyl)-2-methylsulfonylamino-5-carboxylic acid in the form of a solid off-white color.

in) (3,5-Bis-trifloromethyl)methylamide 4-(2-brompheniramine-5-carboxylic acid, 1,71 ml (12.3 mmole) of triethylamine, 0,94 g (x 6.15 mmole) of 1-hydroxybenzotriazole and 1,17 g (x 6.15 mmole) of the hydrochloride of N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide in 70 ml of CH2CL2added 1.63 g (6,34 mmole) of (3,5-bis-trifloromethyl) methylamine and the reaction mixture was stirred for 16 hours Then the reaction mixture was diluted with 50 ml of CH2CL2off , washed with 50 ml of 0.5 N. Hcl, 50 ml of N2Oh, and held back extraction of the aqueous layers 75 ml of CH2CL2. The combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/MeOH, 40:1), was obtained 3.0 g (86%) of (3,5-bis-trifloromethyl) methylamide 4-(2-bromophenyl)-2-methylsulfonylamino-5-carboxylic acid in the form of a white foam, MC(ISP):566, 564 (M+N+).

Example 38

(3,5-Bis-trifloromethyl)metagamed 4-(2-bromophenyl)-2-methanesulfonamido-5-carboxylic acid

In the same way as described in example 15 from (3,5-bis-trifloromethyl) methylamide 4-(2-bromophenyl)-2 - methylsulfonylamino-5-carboxylic acid and 3-chlormadinone acid was obtained (3,5-bis-trifloromethyl)methylamide 4-(2-bromophenyl)-2-methanesulfonamido-5-carboxylic cyclotronic 2-amino-4-(2-bromophenyl)pyrimidine-5-carboxylic acid

Through a solution of 0.42 g (0.7 mmole) of (3,5-bis-trifloromethyl)methylamide 4-(2-bromophenyl)-2-methylsulfonylamino-5-carboxylic acid in 30 ml of N,N-dimethylformamide missed NH3within 10 min and the reaction mixture was stirred for 4 h Then the solvent is evaporated, the residue was distributed between 20 ml of CH2Cl2and 20 ml of N2O. the Aqueous phase was extracted twice with 30 ml of CH2CL2combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/MeOH/NH4HE, 140:10:1), to receive 0,29 g (77%) of (3,5-bis-trifloromethyl)methylamide 2-amino-4-(2-bromophenyl)pyrimidine-5-carboxylic acid in the form of a white foam, MC(ISP):535,1, 533,1 (M+N+).

Example 40

(3,5-Bis-trifloromethyl)methylamide 4-(2-bromophenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid

In the same way as described in example 16 from (3,5-bis-trifloromethyl)methylamide 4-(2-bromophenyl)-2-methylsulfonylamino-5-carboxylic acid and 1-methylpiperazine received (3,5-bis-trifloromethyl)methylamide 4-(2-bromophenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid in the form of a white foam, MC(ISP):618,1, the t (3,5-bis-trifloromethyl)methylamide 4-(2-bromophenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid (1:1), tPL179-180°C.

Example 41

(3,5-Bis-trifloromethyl)methylamide(3R,5S)-4-(2-bromophenyl)-2-(3,5-dimethylpiperazine-1-yl)pyrimidine-5-carboxylic acid

In the same way as described in example 20 from (3,5-bis-trifluoromethyl-benzyl)methylamine 4-(2-bromophenyl)-2-methylsulfonylamino-5-carboxylic acid and CIS-2,6-dimethylpiperazine received (3,5-bis-trifloromethyl)methylamide (3R,5S)-4-(2-bromophenyl)-2-(3,5-dimethylpiperazine-1-yl)pyrimidine-5-carboxylic acid in the form of a white foam, MC(ISP):632,0, 630,0 (M+N+).

Example 42

(3,5-Bis-trifloromethyl)methylamide 4-(2-bromfenac)-2-piperazine-1-Yeremey-5-carboxylic acid

In the same way as described in example 19, from (3,5-bis-trifloromethyl)methylamide 4-(2-bromophenyl)-2-methylsulfonylamino-5-carboxylic acid and piperazine was obtained (3,5-bis-trifloromethyl)methylamide 4-(2-bromophenyl)-2-piperazine-1-Yeremey-5-carboxylic acid in the form of a white foam, MC(ISP):603,9, 601,9 (M+N+).

Example 43

(3,5-Bis-trifloromethyl)methylamide 4-(2-bromophenyl)-2-morpholine-4-epirubicin-5-Karanovo acid

In the same way as described in example 18 from (3,5-bis-trifluoromethyl-benzyl)methylamine 4-(2-bromophenyl)-2-ompany)-2-morpholine-4-Yeremey-5-carboxylic acid in the form of a white foam, MC(ISP):605, 603 (M+N+).

Example 44

(3,5-Bis-triftoratsetilatsetonom 4-(2-chlorphenyl)-2-methylsulfonylamino-5-carboxylic acid

In the same way as described in example 37V), 4-(2-chlorophenyl)-2-methylsulfonylamino-5-carboxylic acid and (3,5-bis-trifloromethyl)of methylamine were obtained (3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-methylsulfonylamino-5-carboxylic acid in the form of a white foam, MC(EI):519 (M+).

The original compound, 4-(2-chlorophenyl)-2-methylsulfonylamino-5-carboxylic acid was obtained in the same way as described in example 37A), (b), of the ethyl ester of 2-(2-chlorobenzoyl)-3-dimethylaminoethanol acid and sulfate S-methylisothiazoline, with subsequent hydrolysis to 4-(2-chlorophenyl)-2-methylsulfonylamino-5-carboxylic acid obtained in the form of a white foam.

Example 45

(3,5-Bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-methanesulfonamido-5-carboxylic acid

In the same way as described in example 15 from (3,5-bis-trifluoromethyl-benzyl)methylamine 4-(2-chlorophenyl)-2-methylsulfonylamino-5-carboxylic acid and 3-chlormadinone acid was obtained (3,5-bis-trifloromethyl)methylamide 4-(2-ptx2">Example 46

(3,5-Bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid

In the same way as described in example 16 from (3,5-bis-trifluoromethyl-benzyl)methylamine 4-(2-chlorophenyl)-2-methylsulfonylamino-5-carboxylic acid and 1-methylpiperazine received (3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid in the form of a white foam, MC(ISP):572,1 (M+H+), from which after interaction by a known method with fumaric acid was obtained fumarate (3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid (1:1), tPL174,8-175,8°C.

Example 47

(3,5-Bis-tripteroides)methylamide (3R,5S)-4-(2-chlorophenyl)-2-(3,5-dimethylpiperazine-1-yl)pyrimidine-5-carboxylic acid

In the same way as described in example 20 from (3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-methylsulfonylamino-5-carboxylic acid and CIS-2,6-dimethylpiperazine received (3,5-bis-trifloromethyl)methylamide (3R,5S)-4-(2-chlorophenyl)-2-(3,5-dimethylpiperazine-1-yl)pyrimidine-5-carboxylic acid in the form of a white foam, MC(ISP):586,1 (M+N+).

Example 48

In the same way as described in example 19, from (3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-methylsulfonylamino-5-carboxylic acid and piperazine was obtained (3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-piperazine-1-Yeremey-5-carboxylic acid in the form of a white foam, MC(ISP):558,2 (M+N+), from which after interaction by a known method with fumaric acid was obtained fumarate (3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-piperazine-1-Yeremey-5-carboxylic acid (1:1), tPL123-126°C.

Example 49

(3,5-Bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-morpholine-4-Yeremey-5-carboxylic acid

In the same way as described in example 18 from (3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-methylsulfonylamino-5-carboxylic acid and the research received (3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-morpholine-4-Yeremey-5-carboxylic acid in the form of a white foam, MC(ISP):559,1 (M+H+).

Example 50

(3,5-Bis-tripteroides)methylamide 4-(2-chlorophenyl)-2-(2-diethylaminoethylamine)pyrimidine-5-carboxylic acid

In the same way as described in example 21 from (3,5-bis-trifloromethyl)methylamide rmatively)methylamide 4-(2-chlorophenyl)-2-(2-diethylaminoethylamine)pyrimidine-5-carboxylic acid in the form of a white foam, MC(ISP):560,2 (M+H+).

Example 51

(3,5-Bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-(2-morpholine-4-ylethoxy)pyrimidine-5-carboxylic acid

In the same way as described in example 24, (3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-methylsulfonylamino-5-carboxylic acid and N-(2-hydroxyethyl) the research was obtained (3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-(2-morpholine-4-ylethoxy)pyrimidine-5-carboxylic acid in the form of a white foam, MC(ISP):603,0 (M+H+).

Example 52

(3,5-Bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-(2-dimethylaminoethoxy)pyrimidine-5-carboxylic acid

In the same way as described in example 26 from (3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-methylsulfonylamino-5-carboxylic acid and 2-dimethylaminoethanol received (3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-(2-dimethylaminoethoxy)pyrimidine-5-carboxylic acid as a colourless oil, MC(ISP):561,2 (M+H+).

Example 53

(3,5-Bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-(3-dimethylaminopropoxy)pyrimidine-5-carboxylic acid

In the same way as described in example 27, from (3,5-bis-trifloromethyl)methylmetacrylate)methylamide 4-(2-chlorophenyl)-2-(3-dimethylaminopropoxy)pyrimidine-5-carboxylic acid as a colourless oil, MC(ISP):575,1 (M+H+).

Example 54

(3,5-Bis-trifloromethyl)methylamide 2-methylsulfanyl-4-o-tolylboronic-5-carboxylic acid

In the same way as described in example 37V), 2-methylsulfanyl-4-o-tolylboronic-5-carboxylic acid and (3,5-bis-trifloromethyl) of methylamine were obtained (3,5-bis-trifluoromethyl-benzyl)methylamide 2-methylsulfanyl-4-o-tolylboronic-5-carboxylic acid in the form of a white foam, MS(EI):499 (M+).

The original connection, 2-methylsulfanyl-4-o-tolylboronic-5-carboxylic acid was obtained in the same way as described in example 37A), (b), of the ethyl ester of 2-(2-methylbenzoyl)-3-dimethylaminoethanol acid and sulfate S-methylisothiazoline, with subsequent hydrolysis to 2-methylsulfanyl-4-o-tolylboronic-5-carboxylic acid obtained in the form of a white foam.

Example 55

(3,5-Bis-trifloromethyl)methylamide 2-methylsulfanyl-4-o-tolylboronic-5-carboxylic acid

In the same way as described in example 15 from (3,5-bis-trifloromethyl)methylamide 2-methylsulfanyl-4-o-tolylboronic-5-carboxylic acid and 3-chlormadinone acid was obtained (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-o-tolylboronic-5-Amativeness)methylamide 2-(4-methylpiperazin-1-yl)-4-o-tolylboronic-5-carboxylic acid

In the same way as described in example 16 from (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-o-tolyl-pyrimidine-5-carboxylic acid and 1-methylpiperazine received (3,5-bis-trifloromethyl)methylamide 2-(4-methylpiperazin-1-yl)-4-o-tolylboronic-5-carboxylic acid in the form of a white foam, MC(ISP):552,1 (M+N+), which when interacting with fumaric acid according to the method received fumarate (3,5-bis-trifloromethyl)methylamide 2-(4-methylpiperazin-1-yl)-4-o-tolylboronic-5-carboxylic acid (1:1), tPL151,5-152,5°C

Example 57

(3,5-Bis-tripteroides)methylamide(3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-o-tolylboronic-5-carboxylic acid

In the same way as described in example 20 from (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-o-tolylboronic-5-carboxylic acid and CIS-2,6-dimethylpiperazine received (3,5-bis-trifloromethyl)methylamide (3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-o-tolylboronic-5-carboxylic acid in the form of a white foam, MC(ISP):566,3 (M+H+), which when interacting with fumaric acid according to the method received fumarate (3,5-bis-trifloromethyl)methylamide(3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-o-tolylboronic-5-card 2-piperazine-1-yl-4-o-todepending-5-carboxylic acid

In the same way as described in example 19, from (3,5-bis-trifloromethyl)methylamide-methylsulphonyl-4-o-tolylboronic-5-carboxylic acid and piperazine was obtained (3,5-bis-trifloromethyl)methylamide 2-piperazine-1-yl-4-o-tolylboronic-5-carboxylic acid in the form of a white foam, MC(ISP): 538,3 (M+N+), which when interacting with fumaric acid according to the method received fumarate (3,5-bis-trifloromethyl)methylamide-piperazine-1-yl-4-o-tolylboronic-5-carboxylic acid (1:1), tPLAt 149.5-151,5°C.

Example 59

(3,5-Bis-trifloromethyl)metagamed 2-morpholine-4-yl-4-o-tolylboronic-5-carboxylic acid

In the same way as described in example 18 from (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-o-tolylboronic-5-carboxylic acid and the research received (3,5-bis-trifloromethyl)methylamide 2-morpholine-4-yl-4-o-tolylboronic-5-carboxylic acid in the form of a white foam, MC(EI):538 (M+).

Example 60

(3,5-Bis-trifloromethyl)methylamide 2-(2-dimethylaminoethoxy)-4-o-tolylboronic-5-carboxylic acid

In the same way as described in example 26 from (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-o-tolylboronic is ethoxy)-4-o-tolylboronic-5-carboxylic acid as a colourless oil, MC(ISP):541,2 (M+H+).

Example 61

(3,5-Bis-trifloromethyl)methylamide 2-(3-dimethylaminopropoxy)-4-o-tolylboronic-5-carboxylic acid

In the same way as described in example 27, from (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-o-tolylboronic-5-carboxylic acid and 2-dimethylaminopropanol received (3,5-bis-trifloromethyl)methylamide 2-(3-dimethylaminopropoxy)-4-o-tolylboronic-5-carboxylic acid as a colourless oil, MC(ISP):555,2 (M+N+).

Example 62

(3,5-Bis-trifloromethyl)metagamed 4-(2-methoxyphenyl)-2-methylsulfonylamino-5-carboxylic acid

In the same way as described in example 37V), 4-(2-methoxyphenyl)-2-methylsulfonylamino-5-carboxylic acid and (3,5-bis-trifloromethyl) of methylamine were obtained (3,5-bis-trifloromethyl)methylamide 4-(2-methoxyphenyl)-2-methylsulfonylamino-5-carboxylic acid in the form of a white foam, MC(EI):515 (M+).

The original compound, 4-(2-methoxyphenyl)-2-methylsulfonylamino-5-carboxylic acid was obtained in the same way as described in example 37A), (b), of the ethyl ester of 2-(2-methoxybenzoyl)-3-dimethylaminoethanol acid and sulfate S-methylisothiazoline with posleduyushego color.

Example 63

(3,5-Bis-tripteroides)methylamide 4-(2-methoxyphenyl)-2-methylsulfonylamino-5-carboxylic acid

In the same way as described in example 15 from (3,5-bis-trifloromethyl)methylamide 4-(2-methoxyphenyl)-2-methylsulfonylamino-5-carboxylic acid and 3-chlormadinone acid was obtained (3,5-bis-trifloromethyl)-methylamide 4-(2-methoxyphenyl)-2-methylsulfonylamino-5-carboxylic acid in the form of a white foam, MC(ISP):548,1 (M+H+).

Example 64

(3,5-Bis-trifloromethyl)methylamide 4-(2-methoxyphenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid

In the same way as described in example 16 from (3,5-bis-trifloromethyl)methylamide 4-(2-methoxyphenyl)-2-methylsulfonylamino-5-carboxylic acid and 1-methylpiperazine received (3,5-bis-trifloromethyl)methylamide 4-(2-methoxyphenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid in the form of a white foam, MC(ISP):568,5(M+H+).

Example 65

(3,5-Bis-trifloromethyl)methylamide(3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-(2-methoxyphenyl)pyrimidine-5-carboxylic acid

In the same way as described in example 20 from (3,5-bis-trifloromethyl)methylamide 4-(2-methoxy who benzyl)-methylamide (3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-(2-methoxyphenyl)pyrimidine-5-carboxylic acid in the form of a white foam, MC(ISP):582,2 (M+H+).

Example 66

(3,5-Bis-trifloromethyl)methylamide 4-(2-methoxyphenyl)-2-piperazine-1-epirubicin-5-carboxylic acid

In the same way as described in example 19, from (3,5-bis-trifloromethyl)methylamide 4-(2-methoxyphenyl)-2-methylsulfonylamino-5-carboxylic acid and piperazine was obtained (3,5-bis-trifloromethyl)methylamide 4-(2-methoxyphenyl)-2-piperazine-1-Yeremey-5-carboxylic acid in the form of a white foam, MC(ISP):554,2(M+N+).

Example 67

(3,5-Bis-trifloromethyl)methylamide 4-(2-methoxyphenyl)-2-morpholine-4-Yeremey-5-carboxylic acid

In the same way as described in example 18 from (3,5-bis-trifloromethyl)methylamide 4-(2-methoxyphenyl)-2-methylsulfonylamino-5-carboxylic acid and the research received (3,5-bis-trifloromethyl)methylamide 4-(2-methoxyphenyl)-2-morpholine-4-Yeremey-5-carboxylic acid in the form of a white foam, tPL190,8-192,0°C.

Example 68

(3,5-Bis-trifloromethyl)methylamide 4-(4-forfinal)-2-methylsulfonylamino-5-carboxylic acid

In the same way as described in example 37V), from 4-(4-forfinal)-2-methylsulfonylamino-5-carboxylic acid and (3,5-bis-triptoreline acid in the form of a white foam, MS(EI):503 (M+).

Example 69

(3,5-Bis-trifloromethyl)methylamide 4-(4-forfinal)-2-methylsulfonylamino-5-carboxylic acid

In the same way as described in example 15 from (3,5-bis-trifloromethyl)methylamide 4-(4-forfinal)-2-methylsulfonylamino-5-carboxylic acid and 3-chlormadinone acid was obtained (3,5-bis-trifloromethyl)methylamide 4-(4-forfinal)-2-methylsulfonylamino-5-carboxylic acid in the form of a white foam, MC(EI):535 (M+).

Example 70

(3,5-Bis-trifloromethyl)methylamide 4-(4-forfinal)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid

In the same way as described in example 16 from (3,5-bis-trifloromethyl) methylamide 4-(4-forfinal)-2-methylsulfonylamino-5-carboxylic acid and 1-methylpiperazine received (3,5-bis-trifloromethyl)methylamide 4-(4-forfinal)-2-(4-methylpiperazin-1-yl) pyrimidine-5-carboxylic acid in the form of a white foam, MS(E1):555 (M+), which when interacting with fumaric acid according to the method received fumarate (3,5-bis-trifloromethyl)methylamide 4-(4-forfinal)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid (1:1), tPL144,5-145,5°C

Example 71

In the same way as described in example 20 from (3,5-bis-trifloromethyl)methylamide 4-(4-forfinal)-2-methylsulfonylamino-5-carboxylic acid and CIS-2,6-dimethylpiperazine received (3,5-bis-trifloromethyl)methylamide(3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-(4-forfinal)pyrimidine-5-carboxylic acid in the form of a white foam, MC(ISP):570,2 (M+N+), which when interacting with fumaric acid according to the method received fumarate (3,5-bis-trifloromethyl)methylamide (3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-(4-forfinal)pyrimidine-5-carboxylic acid (1:0.5) with tPL220-223°C

Example 72

(3,5-Bis-trifloromethyl)methylamide 4-(4-forfinal)-2-piperazine-1-Yeremey-5-carboxylic acid

In the same way as described in example 19, from (3,5-bis-trifloromethyl) methylamide 4-(4-forfinal)-2-methylsulphonyl-pyrimidine-5-carboxylic acid and piperazine was obtained (3,5-bis-trifloromethyl)methylamide 4-(4-forfinal)-2-piperazine-1-Yeremey-5-carboxylic acid in the form of a white foam, MS (ISP):542,2 (M+N+), which when interacting with fumaric acid according to the method received fumarate (3,5-bis-trifloromethyl) methylamide 4-(4-forfinal)-2-piperazine-1-Yeremey-5-carb-forfinal)-2-morpholine-4-Yeremey-5-carboxylic acid

In the same way as described in example 18 from (3,5-bis-trifloromethyl) methylamide 4-(4-forfinal)-2-methylsulfonylamino-5-carboxylic acid and the research received (3,5-bis-trifloromethyl)methylamide 4-(4-forfinal)-2-morpholine-4-Yeremey-5-carboxylic acid in the form of a white foam, MC(ISP):543,2 (M+N+).

Example 74

(3,5-Bis-trifloromethyl)methylamide 4-(2-forfinal)-2-methylsulfonylamino-5-carboxylic acid

In the same way as described in example 37V), 4-(2-forfinal)-2-methylsulfonylamino-5-carboxylic acid and (3,5-bis-trifloromethyl) of methylamine were obtained (3,5-bis-trifloromethyl)methylamide 4-(2-forfinal)-2-methylsulfonylamino-5-carboxylic acid in the form of solids in white, tPL109,5-110°C.

The original compound, 4-(2-forfinal)-2-methylsulfonylamino-5-carboxylic acid, obtained as described in example 37A), (b), of the ethyl ester of 2-(2-perbenzoic)-3-dimethylaminoethanol acid and sulfate S-methylisothiazoline with subsequent hydrolysis to 4-(2-forfinal)-2-methylsulfonylamino-5-carboxylic acid obtained in the form of a white foam.

Example 75

(3,5-Bis-trifloromethyl)methylamide 4-( 15, from (3,5-bis-trifloromethyl)methylamide 4-(2-forfinal)-2-methylsulfonylamino-5-carboxylic acid and 3-chlormadinone acid was obtained (3,5-bis-trifloromethyl)methylamide 4-(2-forfinal)-2-methylsulfonylamino-5-carboxylic acid in the form of a white foam, MC(ISP):536,2 (M+N+).

Example 76

(3,5-Bis-trifloromethyl)methylamide 4-(2-forfinal)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid

In the same way as described in example 16 from (3,5-bis-trifloromethyl)methylamide 4-(2-forfinal)-2-methylsulfonylamino-5-carboxylic acid and 1-methylpiperazine received (3,5-bis-trifloromethyl) methylamide 4-(2-forfinal)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid in the form of a white foam, MC(ISP):556,1 (M+N+).

Example 77

(3,5-Bis-trifloromethyl)methylamide(3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-(2-forfinal)pyrimidine-5-carboxylic acid

In the same way as described in example 20 from (3,5-bis-trifloromethyl)methylamide 4-(2-forfinal)-2-methylsulfonylamino-5-carboxylic acid and CIS-2,6-dimethylpiperazine received (3,5-bis-trifloromethyl)methylamide (3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-(2-forfinal)pyrimidine-5-carboxylic acid for pH 4-(4-forfinal)-2-piperazine-1-Yeremey-5-carboxylic acid

In the same way as described in example 19, from (3,5-bis-trifloromethyl)methylamide 4- (2-forfinal)-2-methylsulfonylamino-5-carboxylic acid and piperazine was obtained (3,5-bis-trifloromethyl)methylamide 4-(4-forfinal)-2-piperazine-1-Yeremey-5-carboxylic acid in the form of a white foam, MS (ISP):542,2 (M+N+), which when interacting with fumaric acid according to the method received fumarate (3,5-bis-trifloromethyl)methylamide 4-(2-forfinal)-2-piperazine-1-Yeremey-5-carboxylic acid (1:1), tPLOf 124.8-125,1°C.

Example 79

(3,5-Bis-tripteroides)metagamed 4-(2-forfinal)-2-morpholine-4-Yeremey-5-carboxylic acid

In the same way as described in example 18 from (3,5-bis-trifloromethyl)methylamide 4-(2-forfinal)-2-methylsulfonylamino-5-carboxylic acid and the research received (3,5-bis-trifloromethyl)methylamide 4-(2-forfinal)-2-morpholine-4-Yeremey-5-carboxylic acid in the form of a white foam, MS(EI):542 (M+).

Example 80

(3,5-Bis-trifloromethyl)methylamide 4-(4-fluoro-2-were)-2-methylsulfonylamino-5-carboxylic acid

In the same way as described in example 37V), from 4-(4-fluoro-2-were)-2-meilaender)methylamide 4-(4-fluoro-2-were)-2-methylsulfonylamino-5-carboxylic acid in the form of a solid white color, MS(EI):517 (M+). The original compound, 4-(4-fluoro-2-were)-2-methylsulfonylamino-5-carboxylic acid was obtained in the same way as described in example 37A), (b), of the ethyl ester of 2-(4-fluoro-2-methylbenzoyl)-3-dimethylaminoethanol acid and sulfate S-methylisothiazoline with subsequent hydrolysis to 4-(4-fluoro-2-were)-2-methylsulfonylamino-5-carboxylic acid obtained in the form of a white foam.

Example 81

(3,5-Bis-trifloromethyl)metagamed 4-(4-fluoro-2-were)-2-methylsulfonylamino-5-carboxylic acid

In the same way as described in example 15 from (3,5-bis-trifloromethyl)methylamide 4-(4-fluoro-2-were)-2-methylsulfonylamino-5-carboxylic acid and 3-chlormadinone acid was obtained (3,5-bis-trifloromethyl)-methylamide 4-(4-fluoro-2-were)-2-methylsulfonylamino-5-carboxylic acid in the form of a white foam, MS(EI):549 (M+).

Example 82

(3,5-Bis-trifloromethyl)methylamide 4-(4-fluoro-2-were)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid

In the same way as described in example 16 from (3,5-bis-trifloromethyl)methylamide 4-(4-fluoro-2-were)2-methylsulfonylamino-5-carboxylic acid and 1-IU is one-5-carboxylic acid in the form of a white foam, MC(ISP):570,2 (M+H+), which when interacting with fumaric acid according to the method received fumarate (3,5-bis-trifloromethyl)methylamide 4-(4-fluoro-2-were)-2-piperazine-1-Yeremey-5-carboxylic acid (1:1), tPLTo 185.0-186,5°C.

Example 83

(3,5-Bis-trifloromethyl)methylamide (3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-(4-fluoro-2-were)pyrimidine-5-carboxylic acid

In the same way as described in example 20 from (3,5-bis-trifloromethyl)methylamide 4-(4-fluoro-2-were)-2-methylsulfonylamino-5-carboxylic acid and CIS-2,6-dimethylpiperazine received (3,5-bis-trifloromethyl)-methylamide(3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-(4-fluoro-2-were)pyrimidine-5-carboxylic acid in the form of a white foam, MC(ISP):548,1 (M+H+), which when interacting with fumaric acid according to the method received fumarate (3,5-bis-trifloromethyl)methylamide (3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-(4-fluoro-2-were)pyrimidine-5-carboxylic acid (1:0.5) with tPL228-230°C.

Example 84

(3,5-Bis-trifloromethyl)methylamide 4-(4-fluoro-2-methylphenyl)-2-piperazine-1-Yeremey-5-carboxylic acid

In the same way as described in example 19, from (3,5-bis-triptime and (3,5-Bis-trifloromethyl)methylamide 4-(4-fluoro-2-were)-2-piperazine-1-Yeremey-5-carboxylic acid in the form of a white foam, MC(ISP):556,1 (M+N+), which when interacting with fumaric acid according to the method received fumarate (3,5-bis-trifloromethyl)methylamide 4-(4-fluoro-2-were)-2-piperazine-1-Yeremey-5-carboxylic acid (1:1), tPL143-145°C

Example 85

(3,5-Bis-trifloromethyl) methylamide 4-(4-fluoro-2-were)-2-morpholine-4-Yeremey-5-carboxylic acid

In the same way as described in example 18 from (3,5-bis-trifloromethyl)methylamide 4-(4-fluoro-2-were)-2-methylsulfonylamino-5-carboxylic acid and the research received (3,5-bis-trifloromethyl)methylamide 4-(4-fluoro-2-were)-2-morpholine-4-Yeremey-5-carboxylic acid in the form of a white foam, MC(ISP):557,1 (M+H+).

Example 86

(3,5-bis-trifloromethyl)methylamide 2-methylsulfanyl-4-naphthalene-1-Yeremey-5-carboxylic acid

In the same way as described in example 37V), 2-methylsulfanyl-4-naphthalene-1-Yeremey-5-carboxylic acid and (3,5-bis-trifloromethyl) of methylamine were obtained (3,5-bis-trifloromethyl)methylamide 2-methylsulfanyl-4-naphthalene-1-Yeremey-5-carboxylic acid in the form of a white foam, MS(EI):535 (M+).

The original connection, 2-methylsulfanyl-4-on the ester of 3-dimethylamino-2-(naphthalene-1-carbonyl)acrylic acid and sulfate S-methylisothiazoline with subsequent hydrolysis to 2-methylsulfanyl-4-naphthalene-1-Yeremey-5-carboxylic acid, obtained in the form of a white foam.

Example 87

(3,5-Bis-trifloromethyl)methylamide 2-methylsulfonyl-4 - naphthalene-1-Yeremey-5-carboxylic acid

In the same way as described in example 15 from (3,5-bis-trifloromethyl)methylamide 2-methylsulfanyl-4-naphthalene-1-Yeremey-5-carboxylic acid and 3-chlormadinone acid was obtained (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-naphthalene-1-Yeremey-5-carboxylic acid in the form of a white foam, MC(ISP):568,1 (M+H+).

Example 88

(3,5-Bis-trifloromethyl)methylamide 2-(4-methylpiperazin-1-yl)-4-naphthalene-1-Yeremey-5-carboxylic acid

In the same way as described in example 16 from (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-naphthalene-1-Yeremey-5-carboxylic acid and 1-methylpiperazine received (3,5-bis-trifloromethyl) methylamide 2-(4-methylpiperazin-1-yl)-4-naphthalene-1-Yeremey-5-carboxylic acid in the form of solids in white, tPL170,6-To 170.9°C.

Example 89

(3,5-Bis-trifloromethyl)methylamide (3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-naphthalene-1-Yeremey-5-carboxylic acid

In the same way as described in example 20 from (3,5-bis-trip the azina received (3,5-bis-trifloromethyl) methylamide (3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-naphthalene-1-Yeremey-5-carboxylic acid in the form of a white foam, MC(ISP):602,1 (M+H+), which when interacting with fumaric acid according to the method received fumarate (3,5-bis-trifloromethyl)methylamide (3R,5S)-2-(3,5-dimethylpiperazine-1-yl)-4-naphthalene-1-Yeremey-5-carboxylic acid (1:0.5) with tPL247-249°C.

Example 90

(3,5-Bis-trifloromethyl)methylamide 4-naphthalene-1-yl-2-piperazine-1-Yeremey-5-carboxylic acid

In the same way as described in example 19, from (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-naphthalene-1-Yeremey-5-carboxylic acid and piperazine was obtained (3,5-bis-trifloromethyl) methylamide 4-naphthalene-1-yl-2-piperazine-1-Yeremey-5-carboxylic acid in the form of a white foam, MS (ISP):574,2 (M+N+), which when interacting with fumaric acid according to the method received fumarate (3,5-bis-trifloromethyl)methylamide 4-naphthalene-1-yl-2-piperazine-1-Yeremey-5-carboxylic acid (1:1), tPL176-178°C.

Example 91

(3,5-Bis-trifloromethyl)methylamide 2-morpholine-4-yl-4-naftalin-1-Yeremey-5-carboxylic acid

In the same way as described in example 18 from (3,5-bis-trifloromethyl)methylamide 2-methylsulphonyl-4-naphthalene-1-Yeremey-5-carboxylic acid and the slots in the form of a white foam, MC(ISP):575,1 (M+N+).

Example 92

(3,5-Bis-trifloromethyl)methylamide 4-phenyl-2-pyridin-3-Yeremey-5-carboxylic acid

In the same way as described in example 3 g), 4-phenyl-2-pyridin-3-Yeremey-5-carboxylic acid and (3,5-bis-trifloromethyl) of methylamine were obtained (3,5-bis-trifloromethyl)methylamide 4-phenyl-2-pyridin-3-Yeremey-5-carboxylic acid as a colourless solid, tPL127-128°C

The original connection, 4-phenyl-2-pyridin-3-Yeremey-5-carboxylic acid was obtained in the same way as described in example 3b), ethyl ester of 2-benzoyl-3-dimethylaminoethanol acid hydrochloride and 3-amidinopropane followed by hydrolysis as described in example 3b), 4-phenyl-2-pyridin-3-Yeremey-5-carboxylic acid, MS(E1):277 (M+).

Example 93

(3,5-Bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-methylsulfonylamino-5-carboxylic acid

In the same way as described in example 37V), 4-(2-chloro-4-forfinal)-2-methylsulfonylamino-5-carboxylic acid and (3,5-bis-trifloromethyl) of methylamine were obtained (3,5-bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-methylsulfonylamino-5-carbonatesulphide-5-carboxylic acid, received in the same way as described in example 37A), (b), of the ethyl ester of 2-(2-chloro-4-perbenzoic)-3-dimethylaminoethanol acid and sulfate S-methylisothiazoline with subsequent hydrolysis to 4-(2-chloro-4-forfinal)-2-methylsulfonylamino-5-carboxylic acid obtained in the form of a white foam.

Example 94

(3,5-Bis-trifloromethyl)methylamide 4-(2-chloro-4-forfend)-2-methylsulfonylamino-5-carboxylic acid

In the same way as described in example 15 from (3,5-bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-methylsulfonylamino-5-carboxylic acid and 3-chlormadinone acid was obtained (3,5-bis-trifloromethyl)-methylamide 4-(2-chloro-4-forfinal)-2-methylsulfonylamino-5-carboxylic acid in the form of a white foam, MC(ISP):570,1 (M+H+).

Example 95

(3,5-Bis-tripteroides)methylamide 4-(2-chloro-4-forfinal)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid

In the same way as described in example 16 from (3,5-bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-methylsulfonylamino-5-carboxylic acid and 1-methylpiperazine received (3,5-bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-(4-methylpiperazin-1-yl)pyrimidine-5-Amativeness)methylamide 4-(2-chloro-4-forfinal)-2-morpholine-4-Yeremey-5-carboxylic acid

In the same way as described in example 18 from (3,5-bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-methylsulfonylamino-5-carboxylic acid and the research received (3,5-bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-morpholine-4-Yeremey-5-carboxylic acid in the form of a white foam, MC(ISP):577,0 (M+H+).

Example 97

(3,5-Bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-piperazine-1-Yeremey-5-carboxylic acid

In the same way as described in example 19, from (3,5-bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-methylsulfonylamino-5-carboxylic acid and piperazine was obtained (3,5-bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2 - piperazine-1-Yeremey-5-carboxylic acid in the form of a white foam, MC(ISP):576,0 (M+N+).

Example 98

(3,5-Bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-(2-dimethylaminoethoxy)pyrimidine-5-carboxylic acid

In the same way as described in example 26 from (3,5-bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-methylsulfonylamino-5-carboxylic acid and 2-dimethylaminoethanol received (3,5-bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-(2-SS="ptx2">(3,5-Bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-(3-dimethylaminopropoxy)pyrimidine-5-carboxylic acid

In the same way as described in example 27, from (3,5-bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-methylsulfonylamino-5-carboxylic acid and 2-dimethylaminopropanol received (3,5-bis-trifloromethyl) methylamide 4-(2-chloro-4-forfinal)-2-(3-dimethylaminopropoxy)pyrimidine-5-carboxylic acid as a colourless oil, MC(ISP):593,1 (M+H+).

Example 100

(3,5-Bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-(2-morpholine-4-ylethoxy)pyrimidine-5-carboxylic acid

In the same way as described in example 24, (3,5-bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-methylsulfonylamino-5-carboxylic acid and N-(2-hydroxyethyl)-the research was obtained (3,5-bis-trifloromethyl)methylamide 4-(2-chloro-4-forfinal)-2-(2-morpholine-4-ylethoxy)pyrimidine-5-carboxylic acid in the form of oil is light yellow in color, MC(ISP):621,0 (M+N+).

Example 101

(3,5-Dimethoxybenzyl)methylamide 2-methylsulfanyl-4-o-tolylboronic-5-carboxylic acid

To a solution of 3.00 g (to 11.52 mmole) 2-methylsulfanyl-4-o-tolylboronic-5-carboxylic acid in 70 ml of CH22CL2. washed with 100 ml of 0.5 N. Hcl, 100 ml of N2On and held back extraction of the aqueous layer with 100 ml of CH2CL2. The combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/MeOH), received 4,20 g (86%) of (3,5-dimethoxybenzyl)methylamide 2-methylsulfanyl-4-o-tolylboronic-5-carboxylic acid as a colourless oil, MC(ISP):424,1 (M+H+).

Example 102

(3,5-Dimethoxybenzyl)methylamide 2-methanesulfonyl-4-o-tolylboronic-5-carboxylic acid

To a solution of 4.00 g (9,44 mmole) of (3,5-dimethoxybenzyl)methylamide 2-methylsulfanyl-4-o-tolylboronic-5-carboxylic acid in 100 ml of CH2CL2at 5°With the added of 5.82 g (23,61 mmole) 3-chlormadinone acid (70%) 30 and the reaction mixture was stirred at RT for 3 hours After adding 100 ml of a saturated solution of Panso3the layers were separated, the organic phase is washed with a saturated solution Panso3, dried (Na2SO4), filtered and evaporated. The obtained residue was purified chromatographically-4-o-tolylboronic-5-carboxylic acid as a colourless foam, MC(ISP):456,5 (M+H+).

Example 103

(3,5-Dimethoxybenzyl)methylamide 2-(4-methylpiperazin-1-yl)-4-o-teleperedachi-5-carboxylic acid

In the same way as described in example 16 from (3,5-dimethoxybenzyl) methylamide 2-methanesulfonyl-4-o-tolylboronic-5-10 carboxylic acid and 1-methylpiperazine received (3,5-dimethoxybenzyl)methylamide 2-(4-methylpiperazin-1-yl)-4-o-tolylboronic-5-carboxylic acid as a colourless oil, MC(ISP):476,3 (M+H+).

Example 104

(3,5-Dimethoxybenzyl)methylamide 2-morpholine-4-yl-4-o-tolylboronic-5-carboxylic acid

In the same way as described in example 18 from (3,5-dimethoxybenzyl) methylamide 2-methanesulfonyl-4-o-tolylboronic-5-carboxylic acid and the research received (3,5-dimethoxybenzyl)methylamide 2-morpholine-4-yl-4-o-tolylboronic-5-carboxylic acid in 20 colorless foam, MC(ISP):463,3 (M+H+).

Example 105

(3,5-Dimethoxybenzyl)methylamide 2-(2-diethylaminoethylamine)-4-o-tolylboronic-5-carboxylic acid

In the same way as described in example 21 from (3,5-dimethoxybenzyl) methylamide 2-methanesulfonyl-4-o-tolylboronic-5-carboxylic acid and 2-diethylaminoethylamine received (3,5-dimethoxybenzyl)methylamide the 2+).

Example 106

(3,5-Dimethoxybenzyl)methylamide 2-(2-dimethylaminoethoxy)-4-o-teleperedachi-5-carboxylic acid

In the same way as described in example 26 from (3,5-dimethoxybenzyl)methylamide 2-methanesulfonyl-4-o-tolylboronic-5-carboxylic acid and 2-dimethylaminoethanol received (3,5-dimethoxybenzyl)methylamide 2-(2-dimethylaminoethoxy)-4-o-tolylboronic-5-carboxylic acid in the form of oil is light yellow; MS(EI):465,3 (M+H+).

Example 107

(3,5-Dimethylbenzyl)methylamide 2-methylsulfanyl-4-o-tolylboronic-5-carboxylic acid

To a solution 2,60 g (9,99 mmole) 2-methylsulfanyl-4-o-tolylboronic-5-carboxylic acid, 2,78 ml (19,98 mmole) of triethylamine, 1,34 g (9,99 mmole) of 1-hydroxybenzotriazole and 1,91 g (9,99 mmole) of the hydrochloride of N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide in 70 ml of CH2Cl2added 1.78 g (11,99 mmole) of (3,5-dimethoxybenzyl) methylamine, and the reaction mixture was stirred for 16 hours Then the reaction mixture was diluted with 100 ml of CH2Cl2off , washed with 100 ml of 0.5 N. Hcl, 100 ml of N2On and held back extraction of the aqueous layer with 100 ml of CH2Cl2. The combined organic extracts were dried (MgSO4), filtered and evaporated. Received esterilidad 2-methylsulfanyl-4-o-tolylboronic-5-carboxylic acid in the form of oil is light yellow in color, MC(EI):391 (M+).

Example 108

(3,5-Dimethylbenzyl)methylamide 2-methanesulfonyl-4-o-tolyl-pyrimidine-5-carboxylic acid

To a solution 3,20 g (8,17 mmole) of (3,5-dimethylbenzyl)methylamide 2-methylsulfanyl-4-o-tolylboronic-5-carboxylic acid in 70 ml of CH2Cl2at 5°C was added to 3.52 g (20,43 mmole) 3-chlormadinone acid (70%) and the reaction mixture was stirred at RT for 3 hours After adding 100 ml of a saturated solution of Panso3the layers were separated, the organic phase is washed with a saturated solution Panso3, dried (Na2SO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/ethyl acetate, 4:1), when it got to 2.55 g (73%) of (3,5-dimethylbenzyl)methylamide 2-methanesulfonyl-4-o-tolylboronic-5-carboxylic acid as a colourless foam, MC(EI):423 (M+).

Example 109

(3,5-Dimethylbenzyl)methylamide 2-(4-methylpiperazin-1-yl)-4-o-tolylboronic-5-carboxylic acid

In the same way as described in example 16 from (3,5-dimethylbenzyl) methylamide 2-methanesulfonyl-4-o-tolylboronic-5-carboxylic acid and 1-methylpiperazine received (3,5-dimethylbenzyl)methylamide 2-(4-methylpiperazin-1-yl)-4-o-tolyl-pyrimidine-5-carbon the MFA 2-morpholine-4-yl-4-o-tolylboronic-5-carboxylic acid

In the same way as described in example 18 from (3,5-dimethylbenzyl) methylamide 2-methanesulfonyl-4-o-tolylboronic-5-carboxylic acid and the research received (3,5-dimethylbenzyl)-methylamide 2-morpholine-4-yl-4-o-tolylboronic-5-carboxylic acid as a colourless foam, MC(EI):430 (M+).

Example 111

(3,5-Dimethylbenzyl)methylamide 2-(2-dimethylaminoethoxy)-4-o-tolylboronic-5-carboxylic acid

In the same way as described in example 26 from (3,5-dimethylbenzyl) methylamide 2-methanesulfonyl-4-o-tolylboronic-5-carboxylic acid and 2-dimethylaminoethanol received (3,5-dimethylbenzyl) methylamide 2-(2-dimethylaminoethoxy)-4-o-tolylboronic-5-carboxylic acid in the form of oil is light yellow in color, MC(ISP):433,5 (M+N+).

Example 112

2-(3,5-Bis-triptoreline)-N-methyl-N-(2-methylsulfanyl-4-o-tolylboronic-5-yl)isobutyramide

a) Tert-botilony ether (2-methylsulfanyl-4-o-tolylboronic-5-yl)carbamino acid

To a solution of 2.33 g (8,95 mmole) 2-methylsulfanyl-4-o-tolylboronic-5-carboxylic acid, 1.25 ml of triethylamine (8,95 mmole) and by 1.68 ml (17.9 mmole) of tert-butanol in 30 ml of THF was added 1.97 ml (8,95 mmole) diphenylphosphinite and the resulting solution boiled with reverse you can see the>the. The aqueous phase was twice extracted with CH2Cl2combined organic extracts were dried (Na2SO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/ethyl acetate 15:1), to receive 1,95 g (65%) of tert-butyl methyl ether (2-methylsulfanyl-4-o-tolylboronic-5-yl)carbamino acid as a colourless solid, MC(TSP):331 (M+).

b) Tert-butyl methyl ether(2-methylsulfanyl-4-o-tolylboronic-5-yl)carbamino acid

To a solution of 1.9 g (5,73 mmole) of tert-butyl methyl ether (2-methylsulfanyl-4-o-tolylboronic-5-yl)carbamino acid in 15 ml of N,N-dimethylformamide was added to 0.29 g (7,45 mmole) of sodium hydride (60% dispersion in mineral oil) and the reaction mixture was stirred for 1 h After adding 0°From 0.57 ml (9,17 mmole) under the conditions of the reaction mixture was stirred for 3 h Then the reaction mixture was distributed between 75 ml of N2Oh, 75 ml of saline solution and 75 ml of CH2Cl2. The phases were separated and the aqueous layer was washed twice with 75 ml of CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2the one-5-yl)carbamino acid in the form of a colorless oil, MC(TSP):345 (M+).

b) Methyl(2-methylsulfanyl-4-o-teleperedachi-5-yl)Amin

A solution of 1.95 g (5,64 mmole) of tert-butyl methyl ether(2-methylsulfanyl-4-o-tolylboronic-5-yl)carbamino acid in 30 ml of 30 Meon/2 N. Hcl was stirred at 50°C for 3 hours After evaporation of the solvent the residue was distributed between 40 ml of 1 N. NaOH and 40 ml of CH2Cl2. The phases were separated, the aqueous layer was twice washed with 50 ml of CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/ethyl acetate, 10:1), to receive of 1.30 g (94%) of methyl(2-methylsulfanyl-4-o-tolylboronic-5-yl)amine in the form of solid white, MS(EI):245 (M+).

g) 2-(3.5-Bis-triptoreline)-N-methyl-N-(2-methylsulfanyl-4-o-tolylboronic-5-yl)isobutyramide

To a solution of 1.30 g (5.3 mmole) of methyl(2-methylsulfanyl-4-o-tolylboronic-5-yl)amine and 1.36 ml (7.95 mmole) of N-ethyldiethanolamine in 15 ml of CH2Cl2was added a solution of 1.30 g (5.3 mmole) of 2-(3,5-bis-triptoreline)-2-methylpropionitrile in 5 ml of CH2Cl2and the reaction mixture was stirred at RT for 24 h Then the reaction mixture was poured into 50 ml of 0.5 N. N (Na2SO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/ethyl acetate, 10:1), to receive 2.30 g (82%) of 2-(3,5-bis-triptoreline)-N-methyl-N-(2-methylsulfanyl-4-o-tolylboronic-5-yl)isobutyramide in a solid white color, tPL124-125°C, MC(TSP):528,2 (M+H+).

Example 113

2-(3,5-Bis-triptoreline)-N-(2-methanesulfonyl-4-o-teleperedachi-5-yl)-N-methylisoleucine

To a solution of 2.20 g (4,17 mmole) of (3,5-bis-trifloromethyl)methylamide 2-methylsulfanyl-4-phenylpyrimidine-5-carboxylic acid in 50 ml of CH2Cl2at 5°C was added to 2.57 g (10.43 mmole) 3-chlormadinone acid (70%) and the reaction mixture was stirred at RT for 3 hours After adding 100 ml of a saturated solution of Panso3the layers were separated, organicheskoi phase was washed with saturated solution of NaHCO3, dried (Na2SO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/ethyl acetate, 10:1), to receive 2.30 g (98%) of 2-(3,5-bis-triptoreline)-N-(2-methanesulfonyl-4-o-tolylboronic-5-yl)-N-methylisobutyl in the form of a colorless foam, MC(ISP):560,2 (M+H+).

Example 114

2-(3,5-Bis-triformis) 2-(3,5-bis-triptoreline)-N-(2-methanesulfonyl-4-o-tolylboronic-5-yl)-N-methylisobutyl in 10 ml of dioxane was added 0.25 ml (2,23 mmole) of 1-methylpiperazine and the reaction mixture was stirred for 16 hours After evaporation of the solvent the residue was distributed between 50 ml of CH2Cl2and 50 ml of N2O. the Aqueous layer was extracted with 50 ml of CH2Cl2combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/MeOH/NH4OH, 110:10:1), to receive and 0.37 g (71%) of 2-(3,5-bis-triptoreline)-N-methyl-N-(2-(4-methylpiperazin-1-yl)-4-o-tolylboronic-5-yl]isobutyramide in the form of a colorless solid, tPL149-151°C, MC(ISP):580,1 (M+H+).

Example 115

2-(3,5-Bis-triptoreline)-N-methyl-N-(2-morpholine-4-yl-4-o-tolylboronic-5-yl)isobutyramide

To a solution of 0.4 g (of 0.71 mmole) of 2-(3,5-bis-triptoreline)-N-(2-methanesulfonyl-4-o-tolylboronic-5-yl)-N-methyl-isobutyramide in 10 ml of dioxane was added to 0.19 ml (2,14 mmole) of the research and the reaction mixture was stirred for 16 hours After evaporation of the solvent the residue was distributed between 50 ml of CH2Cl2and 50 ml of N2O. the Aqueous layer was extracted with 50 ml of CH2Cl2combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/ethyl acetate), thus received is to maintain solids, tPL151-152°C, MC(ISP):567,1 (M+H+).

Example 116

2-(3,5-Bis-trifloromethyl)-N-[2-(2-dimethylaminomethylene)-4-o-tolylboronic-5-yl]-N-metaliterature

To a solution of 0.35 g (to 0.63 mmole) of 2-(3,5-bis-triptoreline)-N-(2-methanesulfonyl-4-o-tolylboronic-5-yl)-N-methylisobutyl in 10 ml of dioxane was added to 0.20 ml (a 1.88 mmole) of 2-diethylaminoethylamine and the reaction mixture was stirred for 16 hours After evaporation of the solvent the residue was distributed between 50 ml of CH2CL2and 50 ml of N2O. the Aqueous layer was extracted with 50 ml of CH2Cl2combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/MeOH/NH4OH), it was given to 0.23 g (64%) of 2-(3,5-bis-triptoreline)-N-[2-(2-diethylaminoethylamine)-4-o-tolylboronic-5-yl]-N-methylisobutyl in the form of a colorless solid, tPL143-144°C, MC(ISP):568,3 (M+H+).

Example 117

2-(3,5-Bis-triptoreline)-N-[2-(2-dimethylaminoethoxy)-4-o-teleperedachi-5-yl]-N-methylisoleucine

To a solution of 0.4 g (of 0.71 mmole) of 2-(3,5-bis-triptoreline)-N-(2-methanesulfonyl-4-o-tolylboronic-5-yl)-N-methylisobutyl in 15 ml acetonic massively for 16 PM After evaporation of the solvent the residue was distributed between 40 ml of CH2Cl2and 40 ml of N2O. the Aqueous layer was extracted with 40 ml of CH2CL2combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified by chromatography (SiO2CH2Cl2/MeOH/NH4OH, 110:10:1), was obtained 0.36 g (88%) of 2-(3,5-bis-triptoreline)-N-[2-(2-dimethylaminoethoxy)-4-o-tolylboronic-5-yl]-N-methylisobutyl in the form of a colorless solid, tPL140-141°C, MC(ISP):569,2 (M+H+).

Example 118

2-(3,5-Bis-triptoreline)-N-methyl-N-[2-(2-morpholine-4-ylethoxy)-4-o-tolylboronic-5-yl] isobutyramide

To a solution of 0.4 g (of 0.71 mmole) of 2-(3,5-bis-triptoreline)-N-(2-methanesulfonyl-4-o-tolylboronic-5-yl)-N-methylisobutyl in 15 ml of acetonitrile was added 0.12 g (0,93 mmole) of N-(2-hydroxymethyl)of the research, 1,17 g (3,57 mmole) Cs2CO3and the reaction mixture was stirred for 16 hours After evaporation of the solvent the residue was distributed between 40 ml of CH2CL2and 40 ml of N2O. the Aqueous layer was extracted with 40 ml of CH2Cl2combined organic extracts were dried (MgSO4), filtered and evaporated. The obtained residue was purified chromyl)-N-methyl-N-[2-(2-morpholine-4-ylethoxy)-4-o-tolylboronic-5-yl]isobutyramide in the form of a colorless foam, MC(ISP):611,1 (M+H+).

Example

Tablets of the following composition are prepared in a conventional method, mg/table:

Active substance 5

Lactose 45

Corn starch 15

Microcrystalline cellulose 34

Magnesium stearate 1

Weight tablets 100

Example B

Prepare capsules of the following composition (mg/caps.:

Active substance 10

Lactose 155

Corn starch 30

Talc 5

The weight of the contents of the capsules 200

The active ingredient, lactose and corn starch are first mixed in the mixer, and then treated in the grinding machine. The mixture back into the mixer, add the powder and mix thoroughly. The mixture through the machine fill gelatin capsules with a hard surface.

The Example In

Prepare suppositories of the following composition (mg/suppose.:

Active substance 15

The mass of filler suppository 1285

Just 1300

A lot of filler suppository is melted in a glass or steel vessel, mix thoroughly and cooled to 45°C. Then there was added connoisseurship desired size, allow to cool, then suppositories are removed from the molds and wrap individually in waxed paper or metal foil.

1. Compounds of General formula

where R1means hydrogen or halogen;

R2means hydrogen, halogen, lower alkyl or lower alkoxy;

R1and R2together with the two carbon atoms of the cycle can mean the group-CH=CH-CH=CH-;

R3means halogen, trifluoromethyl, lower alkyl or lower alkoxy;

R4, R4’independently from each other and each means hydrogen or lower alkyl,

R5means lower alkyl, lower alkoxy, amino, phenyl, hydroxy(lower)alkyl, cyano(lower)alkyl, carbarnoyl(lower)alkyl, pyridyl, pyrimidyl, -(CH2)n-piperazinil, optionally substituted by one or two lower alkyl groups or a hydroxy(lower)alkyl, -(CH2)n-morpholinyl, -(CH2)n-piperidinyl, -(CH2)n+1-imidazolyl lowest alkylsulfanyl, lower alkylsulfonyl,benzylamino,-NH-(CH2)n+1N(R4’)2, -(CH2)n+1N(R4’)2, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl and the ASS="ptx2">X is-C(O)N(R4’)- or-N(R4’)C(O)-,

and their pharmaceutically acceptable acid additive salt.

2. Connection on p. 1, in which X is-C(O)N(R4’)-; R4’means methyl, and R5means piperazinil, optionally substituted by one or two methyl groups.

3. Connection on p. 2, which means

(3,5-bis-trifloromethyl)methylamide 4-(2-bromophenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide (3R,5S)-4-(2-bromophenyl)-2-(3,5-dimethylpiperazine-1-yl)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-bromophenyl)-2-piperazine-1-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide (3R,5S)-4-(2-chlorophenyl)-2-(3,5-dimethylpiperazine-1-yl)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-piperazine-1-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 2-(4-methylpiperazin-1-yl)-4-o-tolylboronic-5-carboxylic acid,

(3,5-bis-triftormetilfullerenov)methylamide 2-piperazine-1-yl-4-o-tolylboronic-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-methoxyphenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide (3R,5R)-2-(3,5-dimethylpiperazine-1-yl)-4-(2-methoxyphenyl) pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-methoxyphenyl)-2-piperazine-1-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(4-forfinal)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-forfinal)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide (3R,5R)-2-(3,5-dimethylpiperazine-1-yl)-4-(2-forfinal)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(4-forfinal)-2-piperazine-1-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(4-fluoro-2-were)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl) methylamide (3R,5R)-2-(3,5-dimethylpiperazine-1-yl)-4-(4-fluoro-2-were)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(4-fluoro-2-were)-2-piperazine-1-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide (3R,5S)-2-(3,5-dimethyle-perazin-1-yl)-4-naphthalene-1-Yeremey-5-carboxylic acid and

(3,5-bis-trifloromethyl)methylamide 4-naphthalene-1-yl-2-piperazine-1-Yeremey-5-carboxylic acid.

4. Connection on p. 1, in which X is-C(O)N(R4’)-, R4’means methyl, and R5means morpholinyl or-O(CH2)2-morpholinyl.

5. Connection on p. 4, which means:

(3,5-bis-trifloromethyl)methylamide 4-(2-bromophenyl)-2-morpholine-4-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-morpholine-4-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-(2-morpholine-4-ylethoxy)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 2-morpholine-4-yl-4-o-tolylboronic-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-methoxyphenyl)-2-morpholine-4-Yeremey-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(4-fluoro-2-were)-2-morpholine-4-Yeremey-5-carboxylic acid and

(3,5-bis-trifloromethyl)methylamide 2-morpholine-4-yl-4-naphthalene-1-Yeremey-5-carbon the/SUP> means-NH(CH2)2N(CH3)2, -O(CH2)2N(CH3)2or-O(CH2)3N(CH3)2

7. Connection on p. 6, which means

(3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-(2-diethylaminoethylamine)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-(2-dimethylaminoethoxy)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 4-(2-chlorophenyl)-2-(3-dimethylaminopropoxy)pyrimidine-5-carboxylic acid,

(3,5-bis-trifloromethyl)methylamide 2-(2-dimethylaminoethoxy)-4-o-tolylboronic-5-carboxylic acid, or

(3,5-bis-trifloromethyl)methylamide 2-(3-dimethylaminopropoxy)-4-o-tolylboronic-5-carboxylic acid.

8. Connection on p. 1, in which X is-N(R4’)C(O)-, R4’means methyl, and R5means morpholinyl or piperazinil, optionally substituted lower alkyl.

9. Connection on p. 8, which means

2-(3,5-bis-triptoreline)-N-methyl-N-[2-(4-methylpiperazin-1-yl)-4-o-tolylboronic-5-yl]isobutyramide and

2-(3,5-bis-triptoreline)-N-methyl-N-(2-morpholine-4-yl-4-o-tolylboronic-5-yl)Sobota one or more compounds according to any one of paragraphs.1-9 and pharmaceutically acceptable excipients.

11. The pharmaceutical composition according to p. 10 for medicines for the treatment of diseases mediated NK-1 receptor.



 

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