Derivatives of 5-phenylpyrimidine and pharmaceutical composition

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

 

The present invention relates to compounds of General formula

where

R1means hydrogen or halogen;

R2means hydrogen, halogen, (ness.)alkyl or (ness.)alkoxygroup;

R3means halogen, trifluoromethyl, (ness.)alkoxygroup or (ness.)alkyl;

R4/R4’mean independently from each other hydrogen or (ness.)alkyl;

R5means (ness.)alkyl, (ness.)alkoxygroup, amino group, hydroxyl group, hydroxy(ness.)alkyl, -(CH2)n-piperazinil, optionally substituted lower alkyl, -(CH2)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (ness.)alkylsulfanyl, (ness.)alkylsulfonyl, benzylamino, -NH-(CH2)n+1N(R4”)2, -(C2)n-NH-(C2)n+1N(R4”)2, -(CH2)n+1N(R4”)2or-O-(CH2)n+1N(R4”)2where R4means hydrogen or (ness.)alkyl;

R6means hydrogen;

R2and R6or R1and R6together with the two carbon atoms of the ring to represent-CH=CH-CH=CH-, provided that n for R1equals 1;

n means independently 0-2; and

X is-C(O)N(R4") -or-N(R4”)C(O)-;

and their pharmaceutically priemel the most 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 (primarily in the brain and spinal ganglia), the circulatory system and peripheral tissues (primarily in the duodenum and jejunum), and they participate 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 bol is in June of 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, summarized in the article "Tachykinin Receptor and Tachykinin Receptor Antagonists" J. Auton. PharmacoL, 13, 23-93, 1993.

In addition, antagonists of the receptor neirokinina I develop for the treatment of numerous physiological 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.

Chrome is also 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.

Objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts, obtaining the above-mentioned compounds containing their medicines and their preparation and the use of the above compounds for the treatment or prevention of illnesses, especially of illnesses and disorders of the previously mentioned types, or for the manufacture of the drugs.

The most preferred indications in accordance with the present invention are indications, which include diseases of the Central nervous system, for example, the treatment or prevention of certain depressive disorders or vomiting by introducing 5 antagonists of the receptor NK-1. It is established that serious bout of depression lasts for at least two weeks, during which during the greater part of the day and almost every day there is depressed mood or loss of interest in all or pleasure in all, or almost complete loss of activity.

The following definitions of common terms used in this description, apply regardless of whether these terms separately or in to the munali. As used here, the term "(ness.)alkyl" means an alkyl group with straight or branched chain, containing from 1 to 7 carbon atoms, for example, methyl, 15 ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like.

Preferred lower alkyl groups are groups with 1-4 carbon atoms.

The term "(ness.)alkoxygroup" means a group in which the alkyl residues are as defined above, and which is attached via an oxygen atom.

The term "halogen" means chlorine, iodine, fluorine and bromine.

The term "pharmaceutically acceptable acid additive salts" includes salts with inorganic and organic 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, p-toluensulfonate and the like acid.

Preferred, for example, compounds in which X means 30-C(O)N(R4”)-, where R4”means methyl and R5means -(CH2)n-piperazinil, optionally substituted stands, and n means 0 or 1, for example, the following connections:

[3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxylic acid,

[3,5-bis(Tr is permitil)benzyl]methylamide 5-(4-fluoro-2-were)-2-(4-methyl-piperazine-1-yl)pyrimidine-4-carboxylic acid or [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(4-methylpiperazin-1-ylmethyl)pyrimidine-4-carboxylic acid.

Further preferred are compounds, in which X is-C(O)N(R4”)-, where R4”is stands, and R5means-O(CH2)2-morpholinyl.

An example of such compound is [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(2-morpholine-4-yl-ethoxy)pyrimidine-4-carboxylic acid.

Preferred further compounds in which X is-C(O)N(R4")-, R4"means methyl and R5means-NH(CH2)n+1N(CH3)2,

-(CH2)n-NH(CH2)n+1N(CH3)2or-O(CH2)n+1N(CH3)2where n is 1 or 2, for example, the following connections:

[3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(2-dimethylamino-ethylamino)pyrimidine-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-diethylaminoethylamine)-5-o-tolylboronic-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-20, diethylaminoethylamine)-5-(2-methoxyphenyl)pyrimidine-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-diethylaminoethylamine)-5-(4-forfinal)pyrimidine-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-diethylaminoethylamine)-5-(4-fluoro-2-were)pyrimidine-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(3-dimethylamino-propoxy)pyrimidine-4-carbon is th acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(2-dimethylamino-ethoxy)pyrimidine-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-dimethylaminoethoxy)-5-o-tolyl-pyrimidine-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(3-dimethylaminopropoxy)-5-o-tolyl-pyrimidine-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-dimethylaminopropoxy)-5-(2-methoxyphenyl)pyrimidine-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(3-dimethylaminopropoxy)-5-(4-fluoro-2-were)pyrimidine-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-dimethylaminoethoxy)-5-(4-fluoro-2-were)pyrimidine-4-carboxylic acid, or

[3,5-bis(trifluoromethyl)benzyl] methylamide 5 -(2-chlorophenyl)-2-[(2-dimethylamino-ethylamino)methyl]pyrimidine-4-carboxylic acid.

In addition, preferred compounds in which X is-CON(R4")2and R4"means methyl, and R5means S3for example, the following connections:

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-methylsulfanyl-5-o-tolyl-pyrimidine-4-carboxylic acid, or

[3,5-bis(trifluoromethyl)benzyl]methylamide 5-(4-fluoro-2-were)-2-methyl-sulfanilamide-4-carboxylic acid.

Other preferred compounds are those in which X is-CON(R4”and R4"means methyl,and R 2and R6or R1and R6together with the two carbon atoms of the ring are-CH=CH-CH=CH-, for example, the following connections:

[3,5-bis(trifluoromethyl)benzyl] methylamide 2-(4-methylpiperazin-1-yl)-5-naphthalene-1-Yeremey-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-diethylaminoethylamine)-5-naphthalene-1-Yeremey-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl] methylamide 2-(2-dimethylaminoethoxy)-5-naphthalene-1-Yeremey-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl] methylamide 2-(2-morpholine-4-ylethoxy)-5-naphthalene-1-Yeremey-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(3-dimetilaminoboran)-5-naphthalene-1-Yeremey-4-carboxylic acid.

Further preferred are those compounds where X is-N(R4”)C(O)-, R4”is lower alkyl and R5means (CH2)n-piperazinil, optionally substituted lower alkyl, -(CH2)n-morpholinyl, -NH-(CH2)n+1N(CH3)2or-O-(CH2)n+1N(CH3)2for example, the following connections:

2-[3,5-bis(trifluoromethyl)phenyl]-N-methyl-N-[2-(4-methylpiperazin-1-yl)-5-o-tolyl-pyrimidine-4-yl]isobutyramide,

2-[3,5-bis(trifluoromethyl)phenyl]-N-methyl-N-(2-piperazine-1-yl)-o-tolyl-pyrimidine-4-yl)isobutyramide,

2-[3,5-bis(trifluoromethyl)phenyl]-N-methyl-N-(2-morpholine-4-yl-5-o-tolyl-iremedi-4-yl)isobutyramide,

2-[3,5-bis(trifluoromethyl)phenyl]-N-[2-(2-diethylaminoethylamine)-5-o-tolyl-pyrimidine-4-yl]-N-methylisoleucine,

2-[3,5-bis(trifluoromethyl)phenyl]-N-[2-(2-dimethylaminoethoxy)-5-o-tolyl-pyrimidine-4-yl]-N-methylisoleucine,

2-[3,5-bis(trifluoromethyl)phenyl]-N-[5-(2-chlorophenyl)-2-(4-methylpiperazin-1-yl)-pyrimidine-4-yl]-N-methylisoleucine or

2-[3,5-bis(trifluoromethyl)phenyl]-N-[5-(2-chlorophenyl)-2-(2-dimethylamino-ethylamino)pyrimidine-4-yl]-N-methylisoleucine.

Presents the compounds of formula I and their pharmaceutically acceptable salts can be obtained well-known in this area by, for example, the methods described below, providing

a) interaction of the compounds of formula

with the compound of the formula

with the formation of compounds of the formula

where R1-R5and n have the above values,

or

b) interaction of the compounds of formula

with the compound of the formula

with the formation of compounds of the formula

where R1-R5and n have the above meanings, or

C) modifying one or more substituents R1-R5within the above values and, if desirable is, the conversion of the compounds obtained into pharmaceutically acceptable acid additive salt.

In accordance with a variant of the method a) compound of formula II, for example, [5-(2-chlorophenyl)-2-methylsulfonylamino-4-yl]methylamine is subjected to removal of the protective groups when processing KHMDS (hexamethyldisilazide potassium) in tetrahydrofuran (THF) at 0°C for 1 h and added the compound of formula III, for example 2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropionate, and the mixture is stirred at room temperature. A typical solvent is N,N-dimethylformamide. The desired compound of formula I-1 is obtained with good yields.

Variant of the method b) describes the reaction of the compound 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 in the usual way, for example, in a solvent, such as dichloromethane, in the presence of been certified with qi net3, EDCl (hydrochloride of N-(3-dimethylamino-propyl)-N’-ethylcarbodiimide) and NOT (1-hydroxybenzotriazole). The mixture is stirred for about 12 h at room temperature. The desired product is obtained after purification with good outputs.

The salt formation occurs at room temperature in accordance with methods known in themselves and are familiar to any person skilled in the art. Were submitted for consideration not only salts with inorganic acid and, but also salts with organic acids. Examples of such salts are hydrochloride, hydrobromide, sulfates, nitrates, citrates, acetates, maleate, succinate, methanesulfonate, p-toluene-sulfonates and the like salts.

The following schemes 1-6 describe how to obtain compounds of formula I in more detail. The initial compounds of formulae III, VIII, IX, XII, XIII, XIV, XVII and XXII are known compounds and can be obtained in accordance with known in this field means.

In the diagrams we used the following abbreviations:

THF tetrahydrofuran

DIPEA N-ethyldiethanolamine

HOBT 1-hydroxybenzotriazole

EDCl N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide, hydrochloride

m-CPBA m chloroperbenzoic acid

DPPA diphenylphosphoryl

DMF dimethylformamide

Net3the triethylamine

KHMDS hexamethyldisilazide potassium

Scheme 1

Values of the substituents R1-R6are shown above.

And means related to amines group, as, for example, an amino group, piperazinil, optional the tion substituted lower alkyl, morpholinyl, imidazolyl, piperidinyl, benzylamino or-NH-(CH2)n+1N(R4”)2and means (ness.)alkoxygroup, -O-(CH2)n+1-morpholinyl,-O-(CH2)n+1-piperidinyl or-O-(CH2)n+1N(R4”)2.

Scheme 2

Values of the substituents listed above.

Scheme 3

Values of the substituents R1-R6above.

And means related to amines group, as, for example, an amino group, piperazinil, optionally substituted lower alkyl, morpholinyl, imidazolyl, piperidinyl, benzylamino or-NH-(CH2)n+1N(R4”)2

Scheme 4

Values of the substituents R1-R6are shown above.

And means related to amines group, as, for example, an amino group, piperazinil, optionally substituted lower alkyl, morpholinyl, imidazolyl, piperidinyl, benzylamino or-NH-(CH2)n+1N(R4”)2and means (ness.)alkoxygroup, -O-(CH2)n+1-morpholinyl,-O-(CH2)n+1-piperidinyl or-O-(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 receptor antagonist neirokinina 1 (NK-1, substance P). The compounds of formula I studied using the following tests.

The affinity of test compounds to NK1the receptor was evaluated using the human NK1receptors in Cho-cells infected by human NK1receptor (using the expression system of the virus Semliki) and in the presence of radioactiveman with [3H]-substance P (final concentration of 0.6 nm). Experiments on the binding was performed in HEPES-buffer (50 mm, pH 7.4)containing BSA (bovine serum albumin) (0,04%), leupeptin (8 µg/ml), MnCl2(3 mm) and phosphoramidon (2 μm). In experiments on the binding is of 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 [3H]-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 to the NK1-receptor, expressed in terms of the values PKiwas $ 8.00-9 : 30 a.m. Examples of such compounds are:

Table
(3,5-bistrifluormethylbenzene)methylamide 5-(2-chlorophenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxylic acid8,21
(3,5-bistrifluormethylbenzene)methylamide 2-(2-dimethylaminoethoxy)-5-ortho-tolylboronic-4-carboxylic acid8,66
(3,5-bistrifluormethylbenzene)methylamide 2-(4-methylpiperazin-1-yl)-5-naphthalene-1-iler midin-4-carboxylic acid 8,43
(3,5-bistrifluormethylbenzene)methylamide 2-(2-diethylaminoethylamine)-5-(4-fluoro-2-were) pyrimidine-4-carboxylic acid8,84
2-(3,5-bistrifluormethylbenzene)-N-[2-(2-dimethylaminoethoxy)-5-ortho-tolylboronic-4-yl]-N-methylisoleucine9,18

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. 5 Pharmaceutical compositions can be administered orally, for example in the form of tablets, filmtabletten, pills, gelatin capsules, soft or hard surface 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 a hard coating, can be used lactose, corn starch and 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.

Acceptable excipients for suppositories are, for example, natural or hydrogenated oils, waxes, fats, semi-solid or liquid polyols.

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 one patient may be in the range from 10 to 1000 mg of the compounds of formula I, but in which neobhodimosti the upper limit may be exceeded.

Below the invention is illustrated in the examples, not limiting its scope. All temperatures are given in degrees Celsius.

Example 1

[3,5-Bis(trifluoromethyl)benzyl] methylamide 2-methylsulfanyl-5-20 phenyl-pyrimidine-4-carboxylic acid

a) 3,5-Bis(trifluoromethyl)benzylamine 5-bromo-2-methylsulfonylamino-4-carboxylic acid

To a solution of 3.54 g (14,21 mmol) 5-bromo-2-methylsulfonylamino-4-carboxylic acid, to 3.92 ml (28, 24 mmol) of triethylamine, 2.17 g 25 (14,21 mmol) of 1-hydroxybenzotriazole and of 2.72 g (14, 21 mmol) of the hydrochloride of N-(3-dimethyl-aminopropyl)-N'-ethylcarbodiimide in 200 ml dichloromethane was added 3.80 g (15,63 mmol) 3,5-bis(trifluoromethyl)benzylamine. The reaction mixture was stirred for 16 hours. The reaction mixture was washed with 100 ml of 0.5 N. hydrochloric acid and 100 ml of water. The aqueous layers was extracted again with 100 ml of dichloromethane. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane), received 4,70 g (69%) of 3,5-bis(trifluoromethyl)benzylamine 5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid as colorless solid.

b) [3,5-Bis(trifluoromethyl)benzyl]methylamide 5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid

To a solution and 4.40 g (9.28 are mmol) 3,5-bis(trifluoromethyl)benzylamine 5-bromo-2-methylsulfonylamino-4-carboxylic acid in 50 ml N-dimethyl-formamide was added to 0.48 g (12,06 mmol) of sodium hydride (60% dispersion in mineral oil) and the reaction mixture was stirred for 1 hour. After addition of 0.92 ml (14,85 mmol) methyl iodide at 0°the reaction mixture was stirred 3 h at room temperature. The reaction mixture was distributed between 100 ml of water, 100 ml of brine and 100 ml of dichloromethane. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ ethyl acetate 40:1), received 3.50 g (77%) of [3,5-bis(trifluoromethyl)benzyl]methylamide 5-bromo-2-methylsulfonylamino-4-carboxylic acid as a colourless oil.

in) [3,5-Bis(trifluoromethyl)benzyl]methylamide 2-methylsulfanyl-5-phenyl-pyrimidine-4-carboxylic acid

To a suspension of 3.50 g (7,17 mmol) of [3,5-bis(trifluoromethyl)benzyl] methylamide 5-bromo-2-methylsulfonylamino-4-carboxylic acid, 0,213 g (0.2 mmole) tetrakis(triphenylphosphine)palladium and 0.96 g (7.89 mmol) of phenylboric acid in 40 ml of 1,2-dimethoxyethane was added a solution of 0.83 g (7.89 mmol) of sodium carbonate in 15 ml of water. The resulting reaction mixture is boiled under reflux for 16 hours. After evaporation 1,2-dimethoxyethane the aqueous phase was twice extracted with 50 ml dichloromethane. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ ethyl acetate 40:1) and was led, received 2.4 g (69%) of [3,5-bis(trifluoromethyl)benzylmethylamine 2-methyl-effect-free remedy 5-phenyl-pyrimidine-4-carboxylic acid in the form of crystals is not quite white, tPL109,7-to 110.7°C.

Example 2

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-methanesulfonyl-5-phenyl-pyrimidine-4-carboxylic acid

To a solution of 2.30 g (4,74 mmol) of [3,5-5 bis(trifluoromethyl)benzyl]methylamine 2-methylsulfanyl-5-phenylpyrimidine-4-carboxylic acid in 90 ml of dichloromethane was added of 2.92 g (11.4 mmol) 3-chloroperbenzoic acid (70%) at 5°and the reaction mixture was stirred for 3 h at room temperature. After addition of 100 ml of saturated solution of bicarbonate 10 sodium layers were separated, the organic phase is washed with saturated sodium bicarbonate solution, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SIO, SIS2, dichloromethane/ methanol 40:1), received 2,30 g (94%) of [3,5-bis(trifluoromethyl)benzyl]methylamine 2-methanesulfonyl-5-phenylpyrimidine-4-carboxylic acid as a colourless solid, mass spectra (MS) with ionization by electron impact (EI):517(M+).

Example 3

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-morpholine-4-yl-5-20 phenyl-pyrimidine-4-carboxylic acid

To a solution of 0.3 g (of 0.58 mmole) of [3,5-bis(trifluoromethyl)benzyl]methylamine 2-methanesulfonyl-5-phenylpyrimidine-4-carboxylic acid in 10 ml of dioxane was added to 0.12 ml (1,45 mmole) of the research. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml dichlo the methane and 50 ml of water. The aqueous layer was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgS4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ ethyl acetate 9:1), was obtained 0.16 g (53%) of [3,5-30 bis(trifluoromethyl)benzyl]methylamine 2-morpholine-4-yl-5-phenylpyrimidine-4-carboxylic acid in the form of not quite white solids, tPL154,0-155, 0°C.

Example 4

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2 benzylamino-5-phenyl-pyrimidine-4-carboxylic acid

To a solution of 0.3 g (of 0.58 mmole) of [3,5-bis(trifluoromethyl)benzyl]methylamine 2-methanesulfonyl-5-phenylpyrimidine-4-carboxylic acid in 10 ml of dioxane was added 0.16 ml (1,45 mmole) of benzylamine. The reaction mixture was stirred for 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of dichloromethane and 50 ml of water. The aqueous layer was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgS4), filtered and evaporated. The residue was purified by chromatography (SIO, SIS2, dichloromethane/ methanol 50:1), was obtained 0.14 g (44%) [3,5-bis(trifluoromethyl)benzyl]methylamine 2 benzylamino-5-phenylpyrimidine-4-carboxylic acid in the form of not quite white solids, tPL128,5-129,5°C.

Example 5

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-(4-methylpiperazin-1-yl)-5-phenylpyrimidine-4-carboxylic acid

To a solution of 0.3 g(of 0.58 mmole) of [3,5-bis(trifluoromethyl)benzyl]methylamine 2-methanesulfonyl-5-phenylpyrimidine-4-carboxylic acid in 10 ml of di water added 0.16 ml (1,45 mmole) of 1-methylpiperazine. The reaction mixture was stirred for 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of dichloromethane and 50 ml of water. The aqueous layer was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgS4), filtered and evaporated. The residue was purified by chromatography (SIO, SIS2, dichloromethane/ methanol/ ammonium hydroxide 140:10:1), was obtained 0.15 g (48%) of [3,5-bis(trifluoromethyl)benzyl]methylamine 2-(4-methylpiperazin-1-yl)-5-phenyl-pyrimidine-4-carboxylic acid in the form of not quite white solids, tPL162,0-162,8°C.

Example 6

[3,5-Bis(trifluoromethyl)benzyl] methylamide 2-(2-diethylaminoethylamine)-5-phenylpyrimidine-4-carboxylic acid

To a solution of 0.3 g (of 0.58 mmole) of [3,5-bis(trifluoromethyl)benzyl]methylamine 2-methanesulfonyl-5-phenylpyrimidine-4-carboxylic acid in 10 ml of dioxane was added 0.16 ml (1,45 mmole) of 2-diethylaminoethylamine. The reaction mixture was stirred for 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of dichloromethane and 50 ml of water. The aqueous layer was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgS4), filtered and evaporated. The residue was purified by chromatography (SIO, SIS2, dichloromethane/ methanol/ ammonium hydroxide 130:10:1), was obtained 0.05 g (16%) [3,5-bis(trifluoromethyl)benzyl]methylamine 2-(2-diethylaminoethylamine)-5-phenylboron the DIN-4-carboxylic acid in the form of not quite white solids, tPL108,5-109,5°C.

Example 7

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-hydroxy-5-phenylpyrimidine-4-carboxylic acid

To a solution of 0.3 g (of 0.58 mmole) of [3,5-bis(trifluoromethyl)benzyl] methylamine 2-methanesulfonyl-5-phenylpyrimidine-4-carboxylic acid in 10 ml of dioxane/water was added 5 ml of 2 n sodium hydroxide solution. The reaction mixture was stirred for 3 hours. Then pH of the reaction solution was brought to 4 with 25% hydrochloric acid. The aqueous layer three times was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgS4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ methanol 9:1), was obtained 0.20 g (75%) of [3,5-bis(trifluoromethyl)benzyl]methylamine 2-hydroxy-5-phenylpyrimidine-4-carboxylic acid in the form of not quite white solids, tPL218,5-to 219.5°C.

Example 8

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-amino-5-phenylpyrimidine-4-carboxylic acid

In a solution of 0.3 g (of 0.58 mmole) of [3,5-bis(trifluoromethyl)benzyl]methylamine 2-methanesulfonyl-5-phenylpyrimidine-4-carboxylic acid in 20 ml of N,N-dimethylformamide was passed a stream of gaseous ammonia for 10 minutes. The reaction mixture was poured into 100 ml of water. The aqueous layer was extracted three times with 50 ml dichloromethane, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified using XP is matography (SiO 2, dichloromethane/ methanol/ ammonium hydroxide 140:10:1), was obtained 0.17 g (65%) of [3,5-bis(trifluoromethyl)benzyl]methylamine-amino-5-phenylpyrimidine-4-carboxylic acid in the form of not quite white solids, tPL181,5-182,5°C.

Example 9

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-methoxy-5-phenylpyrimidine-4-carboxylic acid

To a solution of 0.45 g (of 0.87 mmole) of [3,5-20 bis(trifluoromethyl)benzyl]methylamine 2-methanesulfonyl-5-phenylpyrimidine-4-carboxylic acid in 15 ml of methanol was added 0,123 g (2,17 mmole) of sodium methylate (95%) at room temperature and the reaction solution was stirred for 12 hours. The reaction mixture was distributed between 100 ml of water and 100 ml dichloromethane. The aqueous layer was extracted three times with 50 ml dichloromethane, the combined organic layers were dried (MgS4), filtered and evaporated. The residue was purified by chromatography (SIO, SIS2, dichloromethane/ methanol 40:1), received 0,30 g (73%) of [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methoxy-5-phenylpyrimidine-4-carboxylic acid in the form of not quite white solids, tPL97,5-98,5°C.

Example 10

[3,5-Bis(trifluoromethyl) benzyl]methylamide 2-methyl-5-phenylpyrimidine-4-carboxylic acid

a) 3,5-Bis(trifluoromethyl)benzylamine 5-bromo-2-methylpyrimidin-4-carboxylic acid

To a solution of 2.17 g (10 mmol) 5-bromo-2-methylpyrimidin-4-carboxylic acid, 3,18 ml (24 mmol) of triethylamine, of 1.62 g, 12 mmol) 1-hydroxybenzotriazole and 1,91 g (12 mmol) of the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide in 100 ml of dichloromethane was added only 2.91 g (12 mmol) of 3,5-bis(trifluoromethyl)benzylamine. The reaction mixture was stirred for 16 hours. The reaction mixture was washed with 100 ml of 0.5 N. hydrochloric acid and 100 ml of water. The aqueous layers were again subjected to extraction with 100 ml dichloromethane. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane), received 2,95 g (67%) of 3,5-bis(trifluoromethyl)benzylamine 5-bromo-2-methylpyrimidin-4-carboxylic acid in the form of a solid pale yellow color.

b) [3,5-Bis(trifluoromethyl)benzyl]methylamide 5-bromo-2-methylpyrimidin-4-carboxylic acid

To a solution of 2.28 g (5 mmol) of 3,5-bis(trifluoromethyl)benzylamine 5-bromo-2-methylpyrimidin-4-carboxylic acid in 20 ml of N,N-dimethylformamide was added 0.26 g (5.5 mmol) of sodium hydride (60% dispersion in mineral oil) and the reaction mixture was stirred for 1 hour. After addition of 0.4 ml (6.5 mmol) of methyl iodide at 0°the reaction mixture was stirred 3 hours at room temperature. The reaction mixture was distributed between 80 ml of water, 80 ml of saline solution and 80 ml of dichloromethane. The phases were separated, the aqueous layer was twice washed with 80 ml of dichloromethane. The combined organic layers were dried (MgS4), filtered and evaporated. The residue was purified by chromatography (SIO, SIS2, dichloromethane/ methanol 19:1)were 1.98 g (87%) of [3,5-bis(trifluoromethyl)benzyl]methylamide 5-bromo-2-methylp rimidine-4-carboxylic acid in the form of a waxy solid.

in) [3,5-Bis(trifluoromethyl)benzyl]methylamide 2-methyl-5-phenylpyrimidine-4-carboxylic acid

To a suspension 0,456 g (1 mmole) of [3,5-bis(trifluoromethyl)benzyl]methylamide 5-bromo-2-methylpyrimidin-4-carboxylic acid, 0,034 g (0.2 mmole) tetrakis(triphenylphosphine)palladium and 0,121 g(1 mmole) of phenylboric acid in 20 ml of 1,2-dimethoxyethane was added a solution 0,105 g (1 mmole) of sodium carbonate in 8 ml of water. The resulting reaction mixture is boiled under reflux for 16 hours. After evaporation 1,2-dimethoxyethane the aqueous phase was twice extracted with 50 ml dichloromethane. The combined organic layers were dried (MgS4), filtered and evaporated. The residue was purified by chromatography (SIO, SIS2, dichloromethane/ methanol 40:1) and subjected to crystallization (ethanol)was obtained 0,258 g (57%) [3,5-bis(trifluoromethyl)benzyl]-methylamide 2-methyl-5-phenylpyrimidine-4-carboxylic acid as off-white crystals, tPL149-152°C.

Example 11

[3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl')-2-methyl-sulfanilamide-4-carboxylic acid

a) Ethyl ester 5-(2-chlorophenyl')-2-methylsulfonylamino-4-carboxylic acid

To a solution 3,20 g (11,55 mmol) ethyl ester 5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid in 40 ml of N,N-dimethylformamide was added 2.70 g (17,32 mmol) 2-chloraniline acid, 4,82 ml (34,64 mmol) of triethyl is in, 0,077 g (0.35 mmole) of palladium acetate (2) and 0.167 g (0.72 mmole) of triphenylphosphine and the resulting reaction mixture was heated for 4 hours at 105°C. the Reaction mixture was evaporated and the residue was dissolved in 100 ml of dichloromethane. The organic phase is washed with 80 ml of 0.5 n sodium hydroxide solution, 80 ml of water and 80 ml of brine. The organic phase was dried (MgS4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane)were 3.00 g (84%) ethyl ester 5-(2-chlorophenyl)-2-methylsulfonylamino-4-carboxylic acid in the form of oil pale brown color.

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

To a solution of 3.00 g (9,72 mmol) ethyl ester 5-(2-chlorophenyl)-2-methyl-sulfanilamide-4-carboxylic acid in 15 ml of ethanol was added at room temperature a solution of 0.58 g (14, 5 mmol) sodium hydroxide in 15 ml water and the reaction solution was stirred for 1 hour. Then brought the pH of the solution to 1 by addition of 25% hydrochloric acid. The resulting solution was twice extracted with 100 ml dichloromethane/methanol 2:1. The combined organic phases were dried (MgS4), filtered and evaporated. The residue is suspended in 20 ml of diisopropyl ether, filtered and dried, received 2,40 g (88%) of 5-(2-chlorophenyl)-2-methylsulfonylamino-4-carboxylic acid in the form of not quite white t is ejogo substances.

in) [3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-methyl-sulfanilamide-4-carboxylic acid

To a suspension of 2.40 g (8,55 mmol) 5-(2-chlorophenyl)-2-methylsulfonylamino-4-carboxylic acid, 2.38 ml (17.1 mmol) of triethylamine, 1.30 grams (8,55 mmol) of 1-hydroxybenzotriazole and 1.63 g (8, 55 mmol) of the hydrochloride of N-(3-dimethylamino-propyl)-N'-ethylcarbodiimide in 80 ml dichloromethane was added to 2.41 g (8, 55 mmol) of [3,5-bis(trifluoromethyl)benzyl]methylamine. The reaction mixture was stirred for 16 hours. The reaction mixture was washed with 50 ml of 0.5 N. hydrochloric acid and 50 ml of water. The aqueous layers were again subjected to extraction with 50 ml of dichloromethane. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane), received 3.80 g (85%) of [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-methylsulfonylamino-4-carboxylic acid as a white foamy substance, MS ionization by electrocapillary with the formation of positive ions (IS):520,1(M+N)+

Example 12

[3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl-(2-methyl-sulfanilamide-4-carboxylic acid

To a solution 3,70 g (7,12 mmol) of [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-methylsulfonylamino-4-carboxylic acid in 100 ml dichloromethane was added at 5°With 4.38 g (17, 8 mmol) 3-globe the benzoic acid (70%) and the reaction mixture was stirred 2 hours at room temperature. The solution was washed with 80 ml of saturated sodium bicarbonate solution, 80 ml of a diluted solution of sodium bisulfite and 80 ml of water. The organic phase was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/methanol 100:1), received 3,10 g (97%) of [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-methyl-sulfanilamide-4-carboxylic acid as a white foamy substance, MS (ISP): 551,9 (M+N)+.

Example 13

[3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(4-methyl-piperazine-1-yl)pyrimidine-4-carboxylic acid

To a solution of 0.40 g (0.72 mmole) of [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-methylsulfonylamino-4-carboxylic acid in 10 ml of dioxane was added to 0.20 ml (1,81 mmole) of 1-methylpiperazine. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of dichloromethane and 50 ml of water. The aqueous layer was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ methanol/ ammonium hydroxide 110:10:1), received 0,37 g (89%) of [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxylic acid as a white foamy substance, MS (ISP):572,1 (M+H+).

Example 14

[3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(2-dimethyl-aminoethylamino)pyrimidine-4-carboxylic acid

To a solution of 0.56 g (0.10 mmole) of [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-methylsulfonylamino-4-carboxylic acid in 10 ml of dioxane was added with 0.27 ml (figure 2.54 mmole) of 2-diethylaminoethylamine. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of dichloromethane and 50 ml of water. The aqueous layer was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ methanol/ ammonium hydroxide 140:10:1), received 0,49 g (86%) of [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(2-dimethylamino-ethylamino)pyrimidine-4-carboxylic acid as a white foamy substance, MS (ISP): 560,2 (M+N)+

Example 15

[3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(3-dimethylaminopropoxy)pyrimidine-4-carboxylic acid

To a solution of 0.5 g (of 0.91 mmole) of [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-methylsulfonylamino-4-carboxylic acid in 20 ml of acetonitrile was added to 0.14 ml (1,18 mmole) 2-dimethylaminopropanol and 1.47 g (a 4.53 mmole) Cs2CO3. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 midichlorian and 50 ml of water. The aqueous layer was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/methanol/ ammonium hydroxide 110:10:1), was obtained 0.40 g (77%) of [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(3-dimethylaminopropoxy)pyrimidine-4-carboxylic acid as colorless oil, MS (ISP): 575,1 (M+N)+

Example 16

[3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(2-dimethyl-aminoethoxy)pyrimidine-4-carboxylic acid

To a solution of 0.50 g (of 0.91 mmole) of [3,5-5 bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-methylsulfonylamino-4-carboxylic acid in 20 ml of acetonitrile was added amount of 0.118 ml (1,18 mmole) of 2-dimethylaminoethanol and 1.47 g (a 4.53 mmole) Cs2CO3. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of dihormati and 50 ml of water. The aqueous layer was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/methanol/ ammonium hydroxide 110:10:1), was obtained 0.40 g (77%) of [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(2-dimethylaminoethoxy)pyrimidine-4-carboxylic acid in the form of not-quite-white solid, MS (ISP): 561,3 (M+N)+

Example 17

[35-Bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(2-morpholine-4-ylethoxy)pyrimidine-4-carboxylic acid

To a solution of 0.50 g (of 0.91 mmole) of [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-methylsulfonylamino-4-carboxylic acid in 20 ml of acetonitrile was added 0,143 ml (1,18 mmole) of N-(2-hydroxyethyl)the research and 1.47 g (a 4.53 mmole) Cs2CO3. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of dichloromethane and 50 ml of water. The aqueous layer was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/methanol/ ammonium hydroxide 140:10:1), was obtained 0.40 g (73%) of [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(2-morpholine-4-ylethoxy)pyrimidine-4-carboxylic acid in the form of not quite white foamy substance, MS (ISP): 603,0 (M+N)+

Example 18

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-methylsulfanyl-5-o-tolyl-pyrimidine-4-carboxylic acid

By the way, is similar to that described in example 11 (a)of the ethyl ester of 5-bromo-2-methylsulfonylamino-4-carboxylic acid and o-tolylboronic acid was obtained ethyl ester 2-methylsulfanyl-5-o-tolylboronic-4-carboxylic acid, which omilami as described in example 11 (b), and subjected to reaction with [3,5-bis(trifluoromethyl)benzyl]methylamine to obtain, as described in example 11 in), [3,5-bis(trifluoromethyl)benzyl]methylamine 2-meth is sulfanyl-5-o-tolylboronic-4-carboxylic acid as a white foamy substance, MS (ISP):500,2(M+N)+

Example 19

[3.5-Bis(trifluoromethyl)benzyl]methylamide 2-methanesulfonyl-5-o-tolyl-pyrimidine-4-carboxylic acid

By the way, is similar to that described in example 12, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methylsulfanyl-5-o-tolylboronic-4-carboxylic acid and 3-chloroperbenzoic acid was obtained [3,5-bis(trifluoromethyl)benzyl]-methylamide 2-methylsulphonyl-5-o-tolylboronic-4-carboxylic acid as a white foamy substance, MS (EI): 531 (M+).

Example 20

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-(2-diethylaminoethylamine)-5-o-tolylboronic-4-carboxylic acid

By the way, is similar to that described in example 14, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methylsulphonyl-5-o-tolylboronic-4-carboxylic acid and 2-diethylaminoethylamine received [3,5-bis(trifluoromethyl)benzyl]-methylamide 2-(2-diethylaminoethylamine)-5-o-tolylboronic-4-carboxylic acid as a white foamy substance, MS (ISP): 540,3 (M+N)+

Example 21

[3,5-Bis(trifluoromethyl)benzyl] methylamide 2-(2-dimethylaminoethoxy')-5-o-tolylboronic-4-carboxylic acid

By the way, is similar to that described in example 16, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methylsulphonyl-5-o-tolylboronic-4-carboxylic acid and 2-dimethylaminoethanol received [3,5-bis(trifluoromethyl)benzyl]-methylamide 2-(2-dimethylaminoethoxy)-5-o-tol is pyrimidin-4-carboxylic acid as a white foamy substance, MS (ISP):541,2(M+H)+which was treated with Hcl in ethanol accepted way and got hydrochloride [3,5-bis(trifluoromethyl)benzyl]methylamine 2-(2-dimethylaminoethoxy)-5-o-tolyl-pyrimidine-4-carboxylic acid, tPL147-149°C.

Example 22

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-(3-dimethylaminopropoxy)-5-o-tolylboronic-4-carboxylic acid in a Manner analogous to the one described in example 15, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methylsulphonyl-5-o-tolylboronic-4-carboxylic acid and 2-dimethylaminopropanol received [3,5-bis(trifluoromethyl)benzyl]-methylamide 2-(3-dimethylaminopropoxy)-5-o-tolylboronic-4-carboxylic acid as a white foamy substances, MS (ISP):555,2(M+N)+

Example 23

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-methylsulfanyl-5-naphthalene-1-Yeremey-4-carboxylic acid

By the way, is similar to that described in example 11 (a)of the ethyl ester of 2-bromo-5-methylsulfonylbenzoyl acid and 1-afterborn acid was obtained ethyl ester 2-methylsulfanyl-5-naphthalene-1-Yeremey-4-carboxylic acid, which omilami as described in example 11 (b), and subjected to reaction with [3,5-bis(trifluoromethyl)benzyl]methylamine to obtain, as described in example 11 in), [3,5-bis(trifluoromethyl)benzyl]methylamine 2-methylsulfanyl-5-naphthalene-1-Yeremey-4-carboxylic acid in the form of a foamy substance below the color, MS (EI): 535 (M+).

Example 24

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-methanesulfonyl-5-naphthalene-1-Yeremey-4-carboxylic acid

By the way, is similar to that described in example 12, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methanesulfonyl-5-naphthalene-1-Yeremey-4-carboxylic acid and 3-chloroperbenzoic acid was obtained [3,5-bis(trifluoromethyl)benzyl]-methylamide 2-methanesulfonyl-5-naphthalene-1-Yeremey-4-carboxylic acid in the form of a foamy substance white, MS (EI): 567 (M+).

Example 25

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-(4-methylpiperazin-1-yl)-5-naphthalene-1-Yeremey-4-carboxylic acid

By the way, is similar to that described in example 13, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methanesulfonyl-5-naphthalene-1-Yeremey-4-carboxylic acid and 1-methylpiperazine received [3,5-bis(trifluoromethyl)benzyl]methylamide 2-(4-methylpiperazin-1-yl)-5-naphthalene-1-Yeremey-4-carboxylic acid in the form of a foamy substance white, MS (ISP):588,2(M+N)+.

Example 26

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-(2-diethylaminoethylamine)-5-naphthalene-1-Yeremey-4-carboxylic acid

By the way, is similar to that described in example 14, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methanesulfonyl-5-naphthalene-1-Yeremey-4-carboxylic acid and 2-diethylaminoethylamine received [3,5-bis(trifluoromethyl)benzo is l]-methylamide 2-(2-diethylaminoethylamine)-5-naphthalene-1-Yeremey-4-carboxylic acid in the form of a foamy substance white, MS (ISP): 576,2 (M+N)+

Example 27

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-(2-dimethylaminoethoxy)-5-naphthalene-1-Yeremey-4-carboxylic acid

By the way, is similar to that described in example 16, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methanesulfonyl-5-naphthalene-1-Yeremey-4-carboxylic acid and 2-dimethylaminoethanol received [3,5-bis(trifluoromethyl)benzyl]-methylamide 2-(2-dimethylaminoethoxy)-5-naphthalene-1-Yeremey-4-carboxylic acid in the form of a foamy substance white, MS ionization by thermocapillary with the formation of positive ions (TSP): 576 (M)+

Example 28

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-(2-morpholine-4-ylethoxy)-5-naphthalene-1-Yeremey-4-carboxylic acid

By the way, is similar to that described in example 17, from [3,5-bis(trifluoromethyl)-benzyl] methylamide 2-methanesulfonyl-5-naphthalene-1-Yeremey-4-carboxylic acid and N-(2-hydroxyethyl)the research received [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-(2-morpholine-4-ylethoxy)-5-naphthalene-1-Yeremey-4-carboxylic acid in the form of a foamy substance white, MS (ISP):619,2 (M+N)+

Example 29

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-(3-dimethylaminopropoxy)-5-naphthalene-1-Yeremey-4-carboxylic acid

By the way, is similar to that described in example 15, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methanesulfonyl-5-naphthalene-1-yl is eremein-4-carboxylic acid and 2-dimethylaminopropanol received [3,5-bis(trifluoromethyl)benzyl]-methylamide 2-(3-dimethylaminopropoxy)-5-naphthalene-1-Yeremey-4-carboxylic acid in the form of a foamy substance white, MS (ISP):to $ 591.1(M+N)+.

Example 30

[3.5-Bis(trifluoromethyl)benzyl]methylamide 5-(2-methoxyphenyl)-2-methyl-sulfanilamide-4-carboxylic acid

By the way, is similar to that described in example 11 (a)of ethyl 5 ester 5-bromo-2-methylsulfonylamino-4-carboxylic acid and 2-methoxyflavone acid was obtained ethyl ester 5-(2-methoxyphenyl)-2-methylsulfanyl-pyrimidine-4-carboxylic acid, which omilami as described in example 11 (b), and subjected to reaction with [3,5-bis(trifluoromethyl)benzyl]methylamine to obtain, as described in example 11 in), [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-methoxyphenyl)-2-methylsulfonylamino-4-carboxylic acid, MS (EI): 515 (M+).

Example 31

[3.5-Bis(trifluoromethyl)benzyl]methylamide 2-methanesulfonyl-5-(2-methoxyphenyl)pyrimidine-4-carboxylic acid

By the way, is similar to that described in example 12, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methanesulfonyl-5-(2-methoxyphenyl)pyrimidine-4-carboxylic acid and 3-chloroperbenzoic acid was obtained [3,5-bis(trifluoromethyl)benzyl]methylamide 2-methanesulfonyl-5-(2-methoxyphenyl)-pyrimidine-4-carboxylic acid in the form of a foamy substance white, MS (TSP): 547 (M+).

Example 32

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-(2-diethylaminoethylamine)-5-(2-methoxyphenyl)pyrimidine-4-carboxylic acid

By the way, is similar to that described in PR is least 14, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methanesulfonyl-5-(2-methoxyphenyl)pyrimidine-4-carboxylic acid and 2-diethylaminoethylamine received [3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-diethylaminoethylamine)-5-(2-methoxy-phenyl)pyrimidine-4-carboxylic acid in the form of a foamy substance white, MS (ISP): 556,1(M+H)+.

Example 33

[3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(2-methoxyphenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxylic acid

By the way, is similar to that described in example 13, from [3,5-5 bis(trifluoromethyl)-benzyl]methylamide 2-methanesulfonyl-5-(2-methoxyphenyl)pyrimidine-4-carboxylic acid and 1-methylpiperazine received [3,5-bis(trifluoromethyl)-benzyl]methylamide 5-(2-methoxyphenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxylic acid in the form of a foamy substance white, MS (ISP):557,2(M+N)+

Example 34

[3.5-Bis(trifluoromethyl)benzyl]methylamide 2-(2-dimethylaminoethoxy)-5-(2-methoxyphenyl)pyrimidine-4-carboxylic acid

By the way, is similar to that described in example 16, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methanesulfonyl-5-(2-methoxyphenyl)pyrimidine-4-carboxylic acid and 2-dimethylaminoethanol received [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-(2-dimethylaminoethoxy)-5-(2-methoxyphenyl)pyrimidine-4-carboxylic acid in the form of a foamy substance white, MS (ISP): 557,2 (M+H)+.

Example 35

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-(2-dimethylaminopropoxy)-5-(2-methoxyphenyl)pyrimidine-4-carboxylic acid

By the way, is similar to that described in example 15, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methanesulfonyl-5-(2-methoxyphenyl)pyrimidine-4-carboxylic acid and 2-dimethylaminopropanol received [3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-dimethylaminopropoxy)-5-(2-methoxyphenyl)pyrimidine-4-carboxylic acid in the form of a foamy substance white, MS (ISP): 571,1 (M+H)+.

Example 36

[3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(2-methoxyphenyl)-2-(2-morpholine-4-ylethoxy)pyrimidine-4-carboxylic acid

By the way, is similar to that described in example 17, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methanesulfonyl-5-(2-methoxyphenyl)pyrimidine-4-carboxylic acid and N-(2-hydroxyethyl)the research received [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-methoxyphenyl)-2-(2-morpholine-4-ylethoxy)pyrimidine-4-carboxylic acid in the form of a foamy substance white, MS (ISP): 599,1 (M+H)+.

Example 37

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-methylsulfanyl-5-naphthalene-2-Yeremey-4-carboxylic acid

By the way, is similar to that described in example 11 (a)of the ethyl ester of 5-bromo-2-methylsulfonylamino-4-carboxylic acid and 2-afterborn acid was obtained ethyl ester 2-methylsulfanyl-5-naphthalene-2-Yeremey-4-CT is about acid, which omilami as described in example 11 (b), and subjected to reaction with [3,5-bis(trifluoromethyl)benzyl]methylamine to obtain, as described in example 11 in), [3,5-bis(trifluoromethyl)benzyl]methylamine 2-methyl-effect-free remedy 5-naphthalene-2-Yeremey-4-carboxylic acid in the form of a foamy substance white, MS (ISP): 536,2 (M+N+).

Example 38

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-methanesulfonyl-5-naphthalene-2-Yeremey-4-carboxylic acid

By the way, is similar to that described in example 12, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methanesulfonyl-5-naphthalene-2-Yeremey-4-carboxylic acid and 3-chloroperbenzoic acid was obtained [3,5-bis(trifluoromethyl)benzyl]-methylamide 2-methanesulfonyl-5-naphthalene-2-Yeremey-4-carboxylic acid in the form of a foamy substance white, MS (TSP): 567 (M+).

Example 39

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-(4-methylpiperazin-1-yl)-5-naphthalene-2-Yeremey-4-carboxylic acid

By the way, is similar to that described in example 13, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methanesulfonyl-5-naphthalene-2-Yeremey-4-carboxylic acid and 1-methylpiperazine received [3,5-bis(trifluoromethyl)benzyl]methylamide 2-(4-methylpiperazin-1-yl)-5-naphthalene-2-Yeremey-4-carboxylic acid in the form of a foamy substance white, MC(ISP): 588,3 (M+H)+.

Example 40

[3,5-Bis(trifluoromethyl)benzyl]IU is ilamed 2-(2-diethylaminoethylamine)-5-naphthalene-2-Yeremey-4-carboxylic acid

By the way, is similar to that described in example 14, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methanesulfonyl-5-naphthalene-2-Yeremey-4-carboxylic acid and 2-diethylaminoethylamine received [3,5-bis(trifluoromethyl)benzyl]-methylamide 2-(2-diethylaminoethylamine)-5-naphthalene-2-Yeremey-4-carboxylic acid in the form of a foamy substance white, MS (ISP):576,1 (M+H)+.

Example 41

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-(2-dimethylaminoethoxy)-5-naphthalene-2-Yeremey-4-carboxylic acid

By the way, is similar to that described in example 16, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-methanesulfonyl-5-naphthalene-2-Yeremey-4-carboxylic acid and 2-dimethylaminoethanol received [3,5-bis(trifluoromethyl)benzyl]-methylamide 2-(2-dimethylaminoethoxy)-5-naphthalene-2-Yeremey-4-carboxylic acid in the form of a foamy substance white, MS (ISP): 577,1 (M+H)+.

Example 42

[3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(4-forfinal)-2-methyl-sulfanilamide-4-carboxylic acid

By the way, is similar to that described in example 11 (a)of the ethyl ester of 5-bromo-2-methylsulfonylamino-4-carboxylic acid and 4-forborne acid was obtained ethyl ester 5-(4-forfinal)-2-methylsulfonylamino-4-carboxylic acid, which omilami as described in example 11 (b), and subjected to reaction with [3,5-bis(trifluoromethyl)benzyl] methylamine to receive the deposits, as described in example 11 in), [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(4-forfinal)-2-methylsulfonylamino-4-carboxylic acid in the form of a foamy substance white, MS (EI):503 (M+).

Example 43

[3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(4-forfinal)-2-methyl-sulfanilamide-4-carboxylic acid

By the way, is similar to that described in example 12, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 5-(4-forfinal)-2-methylsulfonylamino-4-carboxylic acid and 3-chloroperbenzoic acid was obtained [3,5-bis(trifluoromethyl)benzyl]-methylamide 5-(4-forfinal)-2-methylsulfonylamino-4-carboxylic acid in the form of a foamy substance white, MS (EI):535 (M+).

Example 44

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-(3-dimethylaminopropoxy)-5-(4-forfinal)pyrimidine-4-carboxylic acid

By the way, is similar to that described in example 15, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 5-(4-forfinal)-2-methylsulfonylamino-4-carboxylic acid and 2-dimethylaminopropanol received [3,5-bis(trifluoromethyl)benzyl]-methylamide 2-(3-dimethylaminopropoxy)-5-(4-forfinal)pyrimidine-4-carboxylic acid in the form of a foamy substance white, MS (ISP):559,3 (M+H)+.

Example 45

[3,5-Bis(trifluoromethyl)benzyl] methylamide 2-(2-dimethylaminoethoxy)-5-(4-forfinal)pyrimidine-4-carboxylic acid

By the way, is similar to that described in the example 16, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 5-(4-forfinal)-2-methylsulfonylamino-4-carboxylic acid and 2-dimethylaminoethanol received [3,5-bis(trifluoromethyl)benzyl]-methylamide 2-(2-dimethylaminoethoxy)-5-(4-forfinal)pyrimidine-4-carboxylic acid in the form of a foamy substance white, MS (ISP):545,2 (M+H)+.

Example 46

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-(2-diethylaminoethylamine)-5-(4-forfinal)pyrimidine-4-carboxylic acid

By the way, is similar to that described in example 14, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 5-(4-forfinal)-2-methylsulfonylamino-4-carboxylic acid and 2-diethylaminoethylamine received [3,5-bis(trifluoromethyl)benzyl]-methylamide 2-(2-diethylaminoethylamine)-5-(4-forfinal)pyrimidine-4-carboxylic acid in the form of a foamy substance white, MS (ISP):544,2 (M+H)+.

Example 47

[3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(4-forfinal)-2-(2-morpholine-4-ylethoxy)pyrimidine-4-carboxylic acid

By the way, is similar to that described in example 17, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 5-(4-forfinal)-2-methylsulfonylamino-4-carboxylic acid and N-(2-hydroxyethyl)the research received [3,5-bis(trifluoromethyl)-benzyl]methylamide 5-(4-forfinal)-2-(2-morpholine-4-ylethoxy)pyrimidine-4-carboxylic acid in the form of a foamy substance white, MS (ISP):587,2 (M+H)+.

Example 48

[3,5-Bis(thrift rmutil)benzyl]methylamide 5-(4-fluoro-2-were)-2-methylsulfonylamino-4-carboxylic acid

By the way, is similar to that described in example 11 (a)of the ethyl ester of 5-bromo-2-methylsulfonylamino-4-carboxylic acid and 4-fluoro-2-were-boric acid was obtained ethyl ester 5-(4-fluoro-2-were)-2-methyl-sulfanilamide-4-carboxylic acid, which omilami as described in example 11 (b), and subjected to reaction with [3,5-bis(trifluoromethyl)benzyl]methylamine to obtain, as described in example 11 in), [3,5 bis(trifluoromethyl)-benzyl]methylamide 5-(4-fluoro-2-were)-2-methylsulfonylamino-4-carboxylic acid in the form of a foamy substance white, MS (EI): 517 (M+).

Example 49

[3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(4-fluoro-2-were)-2-methylsulfonylamino-4-carboxylic acid

By the way, is similar to that described in example 12, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 5-(4-fluoro-2-were)-2-methylsulfonylamino-4-carboxylic acid and 3-chloroperbenzoic acid was obtained [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(4-fluoro-2-were)-2-methylsulphonyl-pyrimidine-4-carboxylic acid in the form of a foamy substance white, MS (EI): 549 (M+).

Example 50

[3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(4-fluoro-2-were)-2-(2-morpholine-4-ylethoxy)pyrimidine-4-carboxylic acid

By the way, is similar to that described in example 17, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 5-(4-fluoro-2-were)-2-methyl shall sulfanilamide-4-carboxylic acid and N-(2-hydroxyethyl)the research received [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(4-fluoro-2-were)-2-(2-morpholine-4-ylethoxy)pyrimidine-4-carboxylic acid in the form of a foamy substance white, MS (ISP):601,1 (M+N)+

Example 51

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-(3-dimethylaminopropoxy)-5-(4-fluoro-2-were)pyrimidine-4-carboxylic acid

By the way, is similar to that described in example 15, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 5-(4-fluoro-2-were)-2-methylsulfonylamino-4-carboxylic acid and 2-dimethylaminopropanol received [3,5-bis(trifluoromethyl)benzyl]methylamide 2-(3-dimethylaminopropoxy)-5-(4-fluoro-2-were)pyrimidine-4-carboxylic acid in the form of a foamy substance white, MS (ISP):573,1 (M+H)+.

Example 52

[3,5-Bis(trifluoromethyl)benzyl]methylamide 2-(2-dimethylaminoethoxy)-5-(4-fluoro-2-were)pyrimidine-4-carboxylic acid

By the way, is similar to that described in example 16, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 5-(4-fluoro-2-were)-2-methylsulfonylamino-4-carboxylic acid and 2-dimethylaminoethanol received [3,5-bis(trifluoromethyl)-benzyl]methylamide 2-(2-dimethylaminoethoxy)-5-(4-fluoro-2-were)pyrimidine-4-carboxylic acid in the form of a foamy substance white, MS (ISP):559,2 (M+H)+.

Example 53

[3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(4-fluoro-2-were)-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxylic acid

By the way, is similar to that described in example 13, from [3,5-bis(trifluoromethyl)-benzyl]methylamide 5-(4-fluoro-2-were)-2-methylsulfonylamino the Jn-4-carboxylic acid and 1-methylpiperazine received [3,5-bis(trifluoromethyl)-benzyl]methylamide 5-(4-fluoro-2-methyl phenyl)-2-(4-methylpiperazin-1-yl)-pyrimidine-4-carboxylic acid in the form of a foamy substance white, MS (ISP): 570, 2 (M+H)+.

Example 54

[3,5-Bis(trifluoromethyl)benzyl] methylamide 2-(2-diethylaminoethylamine)-5-(4-fluoro-2-were)pyrimidine-4-carboxylic acid

By the way, is similar to that described in example 14, from [3,5-bis(trifluoromethyl)-benzyl] methylamide 5-(4-fluoro-2-were)-2-methylsulfonylamino-4-carboxylic acid and 2-diethylaminoethylamine received [3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-diethylaminoethylamine)-5-(4-fluoro-2-were)pyrimidine-4-carboxylic acid in the form of a foamy substance white, MS (ISP):558,3 (M+H)+.

Example 55

[3,5-Bis(trifluoromethyl)benzyl] methylamide 5-(2-chlorophenyl)-2-hydroxyethylpyrrolidine-4-carboxylic acid

a) Ethyl ester of 5-bromo-2-hydroxyethylpyrrolidine-4-carboxylic acid

A solution of 4.2 g (18,02 mmol) 5-bromo-2-hydroxyethylpyrrolidine-4-carboxylic acid in 50 ml of 5 N. HCl/EtOH was stirred 5 hours at room temperature. After evaporation of the solvent the residue was distributed between 50 ml of dichloromethane and 30 ml of water. The organic phase was washed with saturated sodium bicarbonate solution and saline. The combined organic phases were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography, received 3.80 g (80%) ethyl ester 5 bromo-2-hydroxyethylpyrrolidine-4-carboxylic acid as a pale yellow solid.

b) Atila the initial ester 5-(2-chlorophenyl)-2-hydroxyethylpyrrolidine-4-carboxylic acid

To a solution 3,70 g (14,17 mmol) ethyl ester 5-bromo-2-hydroxymethyl-pyrimidine-4-carboxylic acid in 50 ml of N,N-dimethylformamide was added of 3.32 g (21.6 mmole) 2-chloraniline acid, of 5.92 ml (42,52 mmole) of triethylamine, 0,095 g (0.43 mmole) of palladium acetate (2) and 0.223 g of 0.85 mmole) of triphenylphosphine and the resulting reaction mixture was heated for 4 hours at 105°C. the Reaction mixture was evaporated and the residue was dissolved in 100 ml of dichloromethane. The organic phase is washed with 80 ml of 0.5 n sodium hydroxide solution, 80 ml of water and 80 ml of brine. The organic phase was dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ ethyl acetate), was obtained 3,40 g (82%) ethyl ester 5-(2-chlorophenyl)-2-hydroxyethylpyrrolidine-4-carboxylic acid as pale brown oil.

C) 5-(2-Chlorophenyl)-2-hydroxyethylpyrrolidine-4-carboxylic acid

To a solution of 3.40 in g (11.6 mmol) ethyl ester 5-(2-chlorophenyl)-2-hydroxy-methylpyrimidin-4-carboxylic acid in 15 ml of ethanol was added to 0.69 g (17,42 mmol) of sodium hydroxide in 15 ml water and the mixture was stirred for 1 hour. Brought the pH of the solution to 1 and the solid residue was filtered, was obtained after drying 2,80 g (91%) of 5-(2-chlorophenyl)-2-hydroxyethylpyrrolidine-4-carboxylic acid in the form of a solid pale brown color.

g) [3,5-Bis(trifluoromethyl)benzyl]met lamed 5-(2-chlorophenyl)-2-hydroxymethyl-pyrimidine-4-carboxylic acid

To a suspension 2,80 g (of 10.58 mmol) 5-(2-chlorophenyl)-2-hydroxyethylpyrrolidine-4-carboxylic acid in 70 ml of dichloromethane, to 2.94 ml (to 21.2 mmole) of triethylamine, 1,62 g (of 10.58 mmol) of 1-hydroxybenzotriazole and 2.02 g (of 10.58 mmol) of the hydrochloride of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide was added to 2.99 g (11,64 mmol) of [3,5-bis(trifluoromethyl)benzyl]methylamine. The reaction mixture was stirred for 16 hours. The reaction mixture was washed with 50 ml of 0.5 N. hydrochloric acid and 50 ml of water. The aqueous layers were again subjected to extraction with 50 ml of dichloromethane. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ methanol 19:1), received 3.80 g (71%) [3,5-bis(trifluoromethyl)-benzyl]methylamide 5-(2-chlorophenyl)-2-hydroxyethylpyrrolidine-4-carboxylic acid as a pale brown oil, MC(ISP): 504,2 (M+N+).

Example 56

[3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(4-methyl-piperazine-1-ylmethyl)pyrimidine-4-carboxylic acid

a) 4-[(3,5-Bis(trifluoromethyl)benzyl)methylcarbamoyl]-5-(2-5 chlorophenyl)pyrimidine-2-ymetray broadcast methanesulfonate and [3,5-bis(trifluoromethyl)benzyl]-methylamide 2-chloromethyl-5-(2-chlorophenyl)pyrimidine-4-carboxylic acid

To a solution of 3.80 g (7,54 mmol) of [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-hydroxyethylpyrrolidine-4-carboxylic acid and 1.57 ml (11,31 mmol) of t is ethylamine in 80 ml dichloromethane was added at 0° With to 0.645 ml (8.30 mmol) of methanesulfonamide. The reaction mixture was stirred 16 hours. The reaction mixture was poured into saturated sodium bicarbonate solution and was extracted three times with 50 ml dichloromethane. The combined organic layers were dried (MgSO4), filtered and evaporated.

The residue was purified by chromatography (SiO2, dichloromethane/ ethyl acetate 8:1), received 2.70 g (61%) of 4-[(3,5-bis(trifluoromethyl)benzyl)methylcarbamoyl]-5-(2-chlorophenyl)pyrimidine-2-Eletropaulo ether methanesulfonate in the form of a pale brown oil, MS (ISP): 582,0 (M+N+), and 0.90 g (22%) [3,5-bis(trifluoromethyl)benzyl]methylamine 2-chloromethyl-5-(2-chlorophenyl)pyrimidine-4-carboxylic acid as a pale brown oil, MC (ISP):522,1 (M+N+).

b) [3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(4-methyl-piperazine-1-ylmethyl)pyrimidine-4-carboxylic acid

To a solution of 0.39 g (0.75 mmole) of [3,5-bis(trifluoromethyl)benzyl]methylamine 2-chloromethyl-5-(2-chlorophenyl)pyrimidine-4-carboxylic acid in 10 ml of dichloromethane was added to 0.20 ml (to 1.87 mmole) of N-methylpiperazine. The reaction mixture was stirred 16 hours at room temperature and then poured into water and three times was extracted with 50 ml dichloromethane. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ methanol/ ammonium hydroxide 110:10:1), p is were given 0.27 g (61%) of [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(4-methylpiperazin-1-ylmethyl)pyrimidine-4-carboxylic acid as a colourless oil, MC(ISP): 586,1 (M+N+).

Example 57

[3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-morpholine-4-iletilerimde-4-carboxylic acid

To a solution of 0.58 g (1,11 mmole) of [3,5-bis(trifluoromethyl)benzyl]methylamine 2-chloromethyl-5-(2-chlorophenyl)pyrimidine-4-carboxylic acid in 10 ml of dichloromethane was added to 0.24 ml (2,78 mmole) of the research. The reaction mixture was stirred 16 hours at room temperature and then poured into water and three times was extracted with 50 ml dichloromethane. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ methanol/ ammonium hydroxide 200:10:1), was obtained 0.40 g (62%) of [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-morpholine-4-iletilerimde-4-carboxylic acid as colorless foamy substance, MC (ISP):573,1 (M+H+).

Example 58

[3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-[(2-diethylaminoethylamine)methyl]pyrimidine-4-carboxylic acid

To a solution of 0.62 g (1,07 mmole) 4-[(3,5-bis(trifluoromethyl)benzyl)methylcarbamoyl]-5-(2-chlorophenyl)pyrimidine-2-Eletropaulo ether methanesulfonate in 10 ml of dichloromethane was added to 0.29 ml (2,66 mmole) of 2-diethylaminoethylamine. The reaction mixture was stirred 16 hours at room temperature and then poured into water and three times was extracted with 50 ml dichloromethane. The combined organization is organic layers were dried (MgSO 4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane /methanol/ ammonium hydroxide 110:10:1), received 0,22 g (36%) [3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-[(2-diethylaminoethylamine)methyl]pyrimidine-4-carboxylic acid as a colourless oil, MC (ISP): 574,1 (M+N+).

Example 59

[3,5-Bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-dimethylaminomethylene-4-carboxylic acid

To a solution of 0.62 g (1,07 mmole) 4-[(3,5-bis(trifluoromethyl)benzyl)methylcarbamoyl]-5-(2-chlorophenyl)pyrimidine-2-Eletropaulo ether methanesulfonate in 10 ml of dichloromethane was added 1,53 ml (charged 8.52 mmol) of 5.6 M solution of dimethylamine. The reaction mixture was stirred 16 hours at room temperature and then poured into water and three times was extracted with 50 ml dichloromethane. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ methanol/ ammonium hydroxide 200:10:1), was obtained 0.40 g (70%) of [3,5-bis(tri permitil)benzyl] methylamide 5-(2-chloro phenyl)-2-dimethylaminomethylene-4-carboxylic acid as a colourless oil, MC (ISP): 531,1 (M+N+).

Example 60

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

To a suspension of 0.30 g (1.15 mmole) 2-methylsulfanyl-5-o-tolylboronic-4-carboxylic acid is in 20 ml of dichloromethane, of 0.32 ml (2.3 mmol) of triethylamine, 0.17 g (1.15 mmole) of 1-hydroxybenzotriazole and 0.22 g (1.15 mmole) of the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide was added 0.20 g (1,38 mmole) of (3,5-dimethylbenzyl)methylamine. The reaction mixture was stirred 16 hours. The reaction mixture was washed with 50 ml of 0.5 N. hydrochloric acid and 50 ml of water. The aqueous layers were again subjected to extraction with 50 ml of dichloromethane. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane), was obtained 0.36 g (79%) of (3,5-dimethylbenzyl)methylamide 2-methylsulfanyl-5-o-tolylboronic-4-carboxylic acid in the form of a foamy substance white, MS (EI):391 (M+).

Example 61

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

To a solution of 0.36 g (to 0.92 mmole) of (3,5-dimethylbenzyl)methylamide 2-methylsulfanyl-5-o-tolylboronic-4-carboxylic acid in 20 ml of dichloromethane was added at 5°With 0.56 g (0,23 mmole) of 3-chloroperbenzoic acid (70%) and the reaction mixture was stirred for 3 hours at room temperature. After addition of 50 ml of saturated sodium bicarbonate solution, the layers were separated, the organic phase is washed with saturated sodium bicarbonate solution, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2di is Loretan/ methanol 40:1), got to 0.29 g (74%) of (3,5-dimethylbenzyl)methylamide 2-methanesulfonyl-5-o-tolylboronic-4-carboxylic acid as colorless foamy substance, MS (EI): 423 (M+).

Example 62

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

To a solution of 0.28 g (0,66 mmole) of (3,5-dimethylbenzyl)methylamide 2-methanesulfonyl-5-o-tolylboronic-4-carboxylic acid in 10 ml of dioxane was added to 0.18 ml (1.65 mmole) of 1-methylpiperazine. The reaction mixture was stirred for 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of dichloromethane and 50 ml of water. The aqueous layer was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ methanol/ ammonium hydroxide 110: 10:1), was obtained 0.18 g (61%) of (3,5-dimethylbenzyl)methylamide 2-(4-methylpiperazin-1-yl)-5-o-tolylboronic-4-carboxylic acid as colorless foamy substance, MS (ISP): 444,5 (M+N+).

Example 63

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

To a solution of 0.21 g (0,49 mmole) of (3,5-dimethylbenzyl)methylamide 2-methanesulfonyl-5-o-tolylboronic-4-carboxylic acid in 10 ml of dioxane was added to 0.13 ml (1.48 mmole) of the research. The reaction mixture was stirred for 16 hours. After you is Ariane of the solvent the residue was distributed between 50 ml of dichloromethane and 50 ml of water. The aqueous layer was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ methanol 100:1), was obtained 0.17 g (78%) of (3,5-dimethylbenzyl)methylamide 2-morpholine-4-yl-5-o-tolylboronic-4-carboxylic acid as colorless foamy substance, MS (ISP): 431,5 (M+H+).

Example 64

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

To a suspension of 0.30 g (1.15 mmole) 2-methylsulfanyl-5-o-tolylboronic-4-carboxylic acid in 20 ml of dichloromethane, of 0.32 ml (2.3 mmol) of triethylamine, 0.17 g (1.15 mmole) of 1-hydroxybenzotriazole and 0.22 g (1.15 mmole) of the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide was added 0.25 g (1,38 mmole) of (3,5-dimethoxybenzyl)methylamine. The reaction mixture was stirred 16 hours. The reaction mixture was washed with 50 ml of 0.5 N. hydrochloric acid and 50 ml of water. The aqueous layers were again subjected to extraction with 50 ml of dichloromethane. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ methanol 40:1), was obtained 0.45 g (92%) of (3,5-dimethoxybenzyl)methylamide 2-methylsulfanyl-5-o-tolylboronic-4-carboxylic acid in the form of a foamy substance white, MS (EI): 423 (M+).

Example 65

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

To a solution of 0.45 g (of 1.06 mmole) of (3,5-dimethoxybenzyl)methylamide 2-methyl-effect-free remedy 5-o-tolylboronic-4-carboxylic acid in 20 ml of dichloromethane was added at 5°With 0.65 g (of 0.26 mmole) of 3-chloroperbenzoic acid (70%) and the reaction mixture was stirred 3 hours at room temperature. After addition of 50 ml of saturated sodium bicarbonate solution layers were separated, the organic phase is washed with saturated sodium bicarbonate solution, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ methanol 40:1), was obtained 0.20 g (41%) (3,5-dimethoxybenzyl)methylamide-methanesulfonyl-5-o-tolylboronic-4-carboxylic acid as colorless foamy substance, MS (EI): 455 (M+).

Example 66

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

To a solution of 0.18 g (0.4 mmole) of (3,5-dimethoxybenzyl)methylamide 2-methane sulfonyl-5-o-tolylboronic-4-carboxylic acid in 10 ml of dioxane was added to 0.11 ml (0.99 mmole) of 1-methylpiperazine. The reaction mixture was stirred for 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of dichloromethane and 50 ml of water. The aqueous layer was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO 2, dichloromethane/ methanol/ammonium hydroxide 110:10:1), was obtained 0.16 g (85%) of (3,5-dimethoxybenzyl)methylamide 2-(4-methylpiperazin-1-yl)-5-o-tolyl-pyrimidine-4-carboxylic acid as colorless foamy substance, MS (ISP): 476,3 (M+H+).

Example 67

3,5-Dichloraniline 2-methylsulfanyl-5-o-tolylboronic-4-carboxylic acid

To a solution of 1.2 g (4.6 mmol) of 2-methylsulfanyl-5-o-tolylboronic-4-carboxylic acid in 30 ml of dichloromethane, to 1.28 ml (9.2 mmol) of triethylamine, and 0.62 g (4.6 mmol) of 1-hydroxybenzotriazole and 0.88 g (4.6 mmol) of the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide was added to 1.05 g (6 mmol) of 3,5-dichloroaniline. The reaction mixture was stirred 16 hours. The reaction mixture was diluted with 20 ml dichloromethane, washed with 50 ml of 0.5 N. hydrochloric acid and 50 ml of water. The aqueous layers were again subjected to extraction with 50 ml of dichloromethane. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SIO, SIS2, dichloromethane/ methanol 100:1)were 1.64 g (85%) of 3,5-dichlorobenzamide 2-methylsulfanyl-5-o-tolyl-pyrimidine-4-carboxylic acid as colorless foamy substance, MS (ISP): 418,1, 420,1 (M+H+).

Example 68

3,5-Dichloraniline 2-methanesulfonyl-5-o-tolylboronic-4-carboxylic acid

To a solution of 0.3 g (of 0.71 mmole) of 3,5-dichlorobenzamide 2 - methylsulfanyl-5-o-tolylboronic the-4-carboxylic acid in 25 ml dichloromethane was added at 5° From 0.44 g (1,79 mmole) of 3-chloroperbenzoic acid (70%) and the reaction mixture was stirred 3 hours at room temperature. After addition of 20 ml saturated sodium bicarbonate solution layers were separated, the organic phase is washed with saturated sodium bicarbonate solution, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ methanol 125:1), received 0,305 g (94%) of 3,5-dichlorobenzamide 2-methanesulfonyl-5-o-tolylboronic-4-carboxylic acid as colorless foamy substance, MS (ISP): 450,2, 452,2 (M+H+).

Example 69

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

To a solution 0,19 g (0,435 mmole) of 3,5-dichlorobenzamide 2-methanesulfonyl-5-o-tolylboronic-4-carboxylic acid in 5 ml of dioxane was added to 0.12 ml (1,08 mmole) of 1-methylpiperazine. The reaction mixture was stirred for 16 hours. After evaporation of the solvent the residue was distributed between 5 ml of dichloromethane and 25 ml of water. The aqueous layer was extracted with 20 ml dichloromethane, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ methanol 9:1), was obtained 0.18 g (88%) of 3,5-dichlorobenzamide 2-(4-methylpiperazin-1-yl)-5-o-tolylboronic-4-carboxylic acid as colorless oil, MS (ISP): 470,2, 472,2 (M+H+ ).

Example 70

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

To a solution of 0.6 g (1, 43 mmole) of 3,5-dichlorobenzamide 2-methylsulfanyl-5-o-tolylboronic-4-carboxylic acid in 10 ml of N,N-dimethylformamide was added 0,073 g (of 1.85 mmole) of sodium hydride (60% dispersion in mineral oil) and the reaction mixture was stirred for 1 hour. After addition of 0.14 ml of methyl iodide at 0°the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was distributed between 50 ml water, 50 ml brine and 50 ml of dichloromethane. The phases were separated and the aqueous layer was washed twice with 50 ml dichloromethane. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ ethyl acetate 40:1), received 0,57 g (92%) of (3,5-dichlorobenzyl)methylamide 2-methylsulfanyl-5-o-tolylboronic-4-carboxylic acid as colorless oil, MS (ISP): 432,2, 434,2 (M+H+).

Example 71

(3,5-Dichlorobenzyl)methylamide 2-methylsulphonyl-5-o-tolylboronic-4-carboxylic acid

To a solution of 0.57 g (1,31 mmole) of (3,5-dichlorobenzyl)methylamide 2-methylsulfanyl-5-o-tolylboronic-4-carboxylic acid in 50 ml dichloromethane was added at 5°From 0.81 g (3,29 mmole) of 3-chloroperbenzoic acid (70%) and the reaction mixture was stirred 3 hours at room Tempe is the atur. After addition of 40 ml of saturated sodium bicarbonate solution, the layers were separated, the organic phase is washed with saturated sodium bicarbonate solution, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography using SiO2, dichloromethane/ methanol 100:1)were of 0.58 g (94%) of (3,5-dichlorobenzyl)methylamide 2-methylsulphonyl-5-o-tolylboronic-4-carboxylic acid as colorless foamy substance, MS (EI): 463, 465 (M+).

Example 72

(3,5-Dichlorobenzyl)methylamide 2-(4-methylpiperazin-1-yl)-5-o-tolyl-pyrimidine-4-carboxylic acid

To a solution of 0.25 g (0,538 mmole) of (3,5-dichlorobenzyl)methylamide 2-methylsulphonyl-5-o-tolylboronic-4-carboxylic acid in 5 ml of dioxane was added 0.15 ml (1.34 mmole) of 1-methylpiperazine. The reaction mixture was stirred for 16 hours. After evaporation of the solvent the residue was distributed between 25 ml of dichloromethane and 25 ml of water. The aqueous layer was extracted with 20 ml dichloromethane, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ methanol/ ammonium hydroxide 9:1), received 0,116 g (44%) (3,5-dichlorobenzyl)methylamide 2-(4-methylpiperazin-1-yl)-5-o-tolylboronic-4-carboxylic acid as colorless oil, MS (ISP): 484,3, 486,3 (M+N+).

Example 73

2-[3,5-Bis(trifluoromethyl)phenyl]-N-methyl-N-(2-matilal panel-5-o-tolyl-pyrimidine-4-yl)isobutyramide

a) tert-Butyl ether (2-methylsulfanyl-5-o-tolylboronic-4-yl)-carbamino acid

The solution to 2.29 g (8.8 mmol) of 2-methylsulfanyl-5-o-tolylboronic-4-carboxylic acid, of 1.26 ml of triethylamine (8.8 mmol) and of 1.66 ml (17.6 mmol) of butyl alcohol in 30 ml of tetrahydrofuran was added 1.90 ml (8.8 mmol) diphenylphosphinite and the resulting solution was boiled under reflux for 12 hours. After evaporation of the solvent the residue was distributed between dichloromethane and water. The aqueous phase was twice extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ ethyl acetate 19:1), were of 2.45 g (84%) of tert-butyl methyl ether (2-methylsulfanyl-5-o-tolylboronic-4-yl)carbamino acid as colorless solid, MS (TSP): 331 (M+).

b) tert-Butyl methyl ether(2-methylsulfanyl-5-o-tolylboronic-4-yl)-carbamino acid

To a solution of 2.45 g (7,40 mmol) tert-butyl ether (2-methylsulfanyl-5-o-tolylboronic-4-yl)carbamino acid in 30 ml of N,N-dimethylformamide was added to 0.44 g (11,09 mmol) of sodium hydride (60% dispersion in mineral oil) and the reaction mixture was stirred for 1 hour. After the addition of 0.74 ml (11,83 mmol) methyl iodide at 0°the reaction mixture was paramesh the Wali 3 hours. The reaction mixture was distributed between 75 ml of water, 75 ml of saline solution and 75 ml of dichloromethane. The phases were separated, the aqueous layer was washed twice with 75 ml of dichloromethane. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ ethyl acetate 19:1), received 2.50 g (98%) of tert-butyl methyl ether(2-methylsulfanyl-5-o-tolylboronic-4-yl)carbamino acid in the form of a colorless oil, MS (TSP): 345 (M+).

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

A solution of 2.66 g (7.7 mmol) of tert-butyl methyl ether(2-methylsulfanyl-5-o-tolylboronic-4-yl)carbamino acid in 30 ml Meon/Hcl (2 BC) was stirred at 50°C for 3 hours. After evaporation of the solvent the residue was distributed between 40 ml of 1 n sodium hydroxide and 40 ml of dichloromethane. The phases were separated, the aqueous layer was twice washed with 50 ml of dichloromethane. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane), was obtained 1.48 g (78%) of methyl(2-methylsulfanyl-5-o-tolylboronic-4-yl)amine in the form of solid white, MS(El): 245 (M+).

g) 2-(3,5-Bis(trifluoromethyl)phenyl]-N-methyl-N-(2-methylsulfanyl-5-o-tolyl-pyrimidine-4-yl)isobutyramide

To a solution of 1.48 g (6.0 mmol) of methyl(2-methylsulfanyl-5-o-tolyl eremein-4-yl)amine in 10 ml of N,N-dimethylformamide was added at 0° With 6.4 ml of a 1M solution hexamethyldisilazide potassium (6.4 mmol) in tetrahydrofuran. After 1 hour, was added 2.3 g (7.22 mmol) of 2-[3,5-bis(trifluoromethyl)phenyl]-2-methyl-Propionaldehyde in 5 ml of tetrahydrofuran and the reaction mixture was stirred 24 hours at room temperature. The reaction mixture was poured into 50 ml of 0.5 n sodium hydroxide solution. After addition of ethyl acetate were separated phases, the aqueous layer was twice washed with 50 ml of ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ethyl acetate 10:1), was obtained 1.20 g (37%) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-methyl-N-(2-methylsulfanyl-5-o-tolylboronic-4-yl)isobutyramide in the form of a foamy substance white, MS (ISP): 528,2 (M+N+).

Example 74

2-[3,5-Bis(trifluoromethyl)phenyl]-M-(2-methanesulfonyl-5-o-tolyl-pyrimidine-4-yl)-N-methylisoleucine

To a solution of 1.20 g (2.27 mmol) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-methyl-(2-methylsulfanyl-5-o-tolylboronic-4-yl)isobutyramide in 50 ml of dichloromethane was added at 5°With a 1.46 g (5,91 mmol) 3-chloroperbenzoic acid (70%) and the reaction mixture was stirred 3 hours at room temperature. After addition of 100 ml saturated sodium bicarbonate solution layers were separated, the organic phase is washed with saturated sodium bicarbonate solution, dried (Na2SO 4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane)were 1.10 g (86%) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-(2-methanesulfonyl-5-o-tolylboronic-4-yl)-N-methyl-isobutyramide in the form of a colorless foamy substance, MS (EI): 559 (M+N+).

Example 75

2-[3,5-Bis(trifluoromethyl)phenyl]-N-methyl-N-[2-(4-methylpiperazin-1-yl)-5-o-tolylboronic-4-yl]isobutyramide

To a solution of 0.2 g (of 0.36 mmole) 2-[3,5-bis(trifluoromethyl)phenyl]-N-(2-methanesulfonyl-5-o-tolylboronic-4-yl)-N-methylisobutyl in 10 ml of dioxane was added and 0.09 ml (0,89 mmole) of 1-methylpiperazine. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of dichloromethane and 50 ml of water. The aqueous layer was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2MeOH/ NH4OH 140:10:1), was obtained 0.08 g (36%) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-methyl-N-[2-(4-methylpiperazin-1-yl)-5-o-tolylboronic-4-yl]isobutyramide in the form of a colorless foamy substance, MS (ISP): 580,1 (M+N+).

Example 76

2-[3,5-Bis(trifluoromethyl)phenyl]-N-methyl-N-(2-piperazine-1-yl-5-o-tolylboronic-4-yl)isobutyramide

To a solution of 0.2 g (of 0.36 mmole) 2-[3,5-bis(trifluoromethyl)phenyl]-N-(2-methanesulfonyl-5-o-tolylboronic-4-yl)-N-methylisobutyl the 10 ml of dioxane was added 0.1 g (0,89 mmole) piperazine. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of dichloromethane and 50 ml of water. The aqueous layer was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2CH2CL2/ MeOH/ NH4OH 110:10:1), was obtained 0.18 g (89%) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-methyl-N-(2-piperazine-1-yl-5-o-tolylboronic-4-yl)isobutyramide in the form of a colorless foamy substance, MS (ISP): 556,2 (M+H+).

Example 77

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

To a solution of 0.2 g (of 0.36 mmole) 2-[3,5-bis(trifluoromethyl)phenyl]-N-(2-methanesulfonyl-5-o-tolylboronic-4-yl)-N-methylisobutyl in 10 ml of dioxane was added 0.08 g (0,89 mmole) of the research. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of dichloromethane and 50 ml of water. The aqueous layer was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ methanol 90:1), was obtained 0.18 g (89%) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-methyl-N-(2-morpholine-4-yl-5-o-tolylboronic-4-yl)isobutyramide in the form of a colorless foamy substance, MS (ISP): 567,2 (M+N+).

Example 78

2-3,5-Bis(trifluoromethyl)phenyl]-N-[2-(2-diethylaminoethylamine)-5-o-tolylboronic-4-yl]-N-methylisoleucine

To a solution of 0.2 g (of 0.36 mmole) 2-[3,5-bis(trifluoromethyl)phenyl]-N-(2-methanesulfonyl-5-o-tolylboronic-4-yl)-N-methylisobutyl in 10 ml of dioxane was added and 0.09 ml (0,89 mmole) of 2-diethylaminoethylamine. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of dichloromethane and 50 ml of water. The aqueous layer was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/ Meon/ NH4OH 140:10:1), was obtained 0.15 g (77%) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[2-(2-diethylaminoethylamine)-5-o-tolylboronic-4-yl]-N-methylisobutyl in the form of a colorless foamy substance, MS (ISP): 568,3 (M+N+).

Example 79

2-[3,5-Bis(trifluoromethyl)phenyl]-N-[2-(2-dimethylaminoethoxy)-5-o-tolyl-pyrimidine-4-yl]-N-methylisoleucine

To a solution of 0.3 g (0.54 mmole) 2-[3,5-bis(trifluoromethyl)phenyl]-N-(2-methanesulfonyl-5-o-tolylboronic-4-yl)-N-methylisobutyl in 10 ml of acetonitrile was added 0.08 ml (0.8 mmole) of 2-dimethylaminoethanol and 0.97 g (2.68 mmole) of cesium carbonate. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 40 ml of dichloromethane and 40 ml of water. The aqueous layer was extracted with 40 ml of dichloromethane, the combined organic layers were dried (MgSO4), filtered and evaporated. The remainder of ciali using chromatography (SiO 2CH2Cl2/ MeOH/NH4OH 140:10:1), was obtained 0.27 g (88%) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[2-(2-dimethylaminoethoxy)-5-o-tolylboronic-4-yl]-N-methylisobutyl in the form of a colorless solid, MS (ISP):569,2 (M+N+).

Example 80

2-[3,5-Bis(trifluoromethyl)phenyl]-N-[5-(2-chlorophenyl)-2-methylsulfanyl-pyrimidine-4-yl]-N-methylisoleucine

a) tert-Butyl ether [5-(2-chlorophenyl)-2-methylsulfonylamino-4-yl]-carbamino acid

To a solution of 2.50 g (8.9 mmol) of 5-(2-chlorophenyl)-2-methylsulfonylamino-4-carboxylic acid, 1,24 ml of triethylamine (8.9 mmol) and 1.67 ml (17.8 mmol) of butyl alcohol in 30 ml of tetrahydrofuran was added at 1.91 ml (8.9 mmol) diphenylphosphinite and the resulting solution was boiled under reflux for 12 hours. After evaporation of the solvent the residue was distributed between dichloromethane and water. The aqueous phase was twice extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ ethyl acetate 19:1), received 2.20 g (70%) of tert-butyl ester [5-(2-chlorophenyl)-2-methylsulfonylamino-4-yl]carbamino acid as colorless solid, MS (EI):351 (M+).

b) tert-Butyl ether [5-(2-chlorophenyl)-2-methylsulfonylamino-4-yl]-methylcarbamyl acids

RA is Toru 2.0 g (of 5.68 mmol) tert-butyl ether [5-(2-chlorophenyl)-2-methyl-sulfanilamide-4-yl]carbamino acid in 30 ml of N,N-dimethylformamide was added 0.34 g (8,53 mmol) of sodium hydride (60% dispersion in mineral oil) and the reaction the mixture was stirred for 1 hour. After addition at 0°From 0.56 ml (a 9.09 mmol) methyl iodide, the reaction mixture was stirred for 3 hours. The reaction mixture was distributed between 75 ml of water, 75 ml of saline solution and 75 ml of dichloromethane. The phases were separated, the aqueous layer was washed twice with 75 ml of dichloromethane. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ethyl acetate 19:1), was obtained 2.0 g (96%) of tert-butyl ester [5-(2-chlorophenyl)-2-methylsulfonylamino-4-yl]methylcarbamate acid in the form of a pale yellow oil, MS (EI): 365 (M+).

C) [5-(2-Chlorophenyl)-2-methylsulfonylamino-4-yl] methylamine

A solution of 2.40 g (6.5 mmol) of tert-butyl ester [5-(2-chlorophenyl)-2-methyl-sulfanilamide-4-yl]methylcarbamate acid in 30 ml Meon/Hcl (2 BC) was stirred 3 hours at 55°C. After evaporation of the solvent the residue was distributed between 40 ml of 1 n sodium hydroxide and 40 ml of dichloromethane. The phases were separated, the aqueous layer was twice washed with 50 ml of dichloromethane. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ ethyl acetate 19:1)were 1.70 g (97%) [5-(2-chlorophenyl)-2-methylsulfonylamino-4-yl] methylamine in the form of solid white, MS(EI): 265 (M +).

g) 2-[3.5-Bis(trifluoromethyl)phenyl]-N-[5-(2-chlorophenyl)-2-methylsulfanyl-pyrimidine-4-yl]-N-methylisoleucine

To a solution 0,70 g (2.6 mmol) [5-(2-chlorophenyl)-2-methylsulfonylamino-4-yl]methylamine in 4 ml of N,N-dimethylformamide was added at 0°2.6 ml of 1 M solution hexamethyldisilazide potassium (2.6 mmole) in tetrahydrofuran. After 1 h was added to 0.92 g (2.6 mmole) 2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropionamide in 2 ml of tetrahydrofuran and the reaction mixture was stirred 24 hours at room temperature. The reaction mixture was poured into 50 ml of 0.5 n sodium hydroxide solution. After adding ethyl acetate, the phases were separated, the aqueous layer was twice washed with 50 ml of ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ethyl acetate 19:1), received 0,85 g (58%) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[5-(2-chlorophenyl)-2-methylsulfonylamino-4-yl]-N-methylisobutyl in the form of a white foamy substance, MS (EI): 547 (M+).

Example 81

2-[3,5-Bis(trifluoromethyl)phenyl]-N-[5-(2-chlorophenyl)-2-methanesulfonyl-pyrimidine-4-yl]-N-methylisoleucine

To a solution of 0.8 g (1,64 mmole) 2-[3,5-bis(trifluoromethyl)phenyl]-N-[5-(2-chlorophenyl)-(2-methylsulfonylamino-4-yl]-N-methylisobutyl in 50 ml of dichloromethane was added at 5°0,89 g (3.65 mmole) of 3-chloroperbenzoic acid (0%) and the reaction mixture was stirred 3 hours at room temperature. After addition of 100 ml saturated sodium bicarbonate solution layers were separated, the organic phase is washed with saturated sodium bicarbonate solution, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, dichloromethane/ ethyl acetate), was obtained 0.73 g (86%) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[5-(2-chlorophenyl)-2-methanesulfonamido-4-yl]-N-methylisobutyl in the form of a colorless foamy substance, MS (ISP): 580,0 (M+N+).

Example 82

2-[3,5-Bis(trifluoromethyl)phenyl]-N-[5-(2-chlorophenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-4-yl]-N-methylisoleucine

To a solution of 0.3 g (0,52 mmole) 2-[3,5-bis(trifluoromethyl)phenyl]-N-[5-(2-chlorophenyl)-2-methanesulfonamido-4-yl]-N-methylisobutyl in 10 ml of dioxane was added to 0.14 ml (1,29 mmole) of 1-methylpiperazine. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of dichloromethane and 50 ml of water. The aqueous layer was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2Meon/ NH4OH 140:10:1), was obtained 0.25 g (80%) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[5-(2-chlorophenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-4-yl]-N-methylisobutyl in the form of a colorless foamy substance, MS (ISP): 600,1 (M+N+).

Example 83

-[3,5-Bis(trifluoromethyl)phenyl]-N-[5-(2-chlorophenyl)-2-(2-dimethylamino-ethylamino)pyrimidine-4-yl]-N-methylisoleucine

To a solution of 0.4 g (0,69 mmole) 2-[3,5-bis(trifluoromethyl)phenyl]-N-[5-(2-chlorophenyl)-2-methanesulfonamido-4-yl]-N-methylisobutyl in 10 ml of dioxane was added to 0.19 ml (1,72 mmole) of 2-diethylaminoethylamine. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of dichloromethane and 50 ml of water. The aqueous layer was extracted with 50 ml dichloromethane, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2CH2CL2/Meon/ NH4OH 110:10:1), received 0,30 g (74%) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[5-(2-chlorophenyl)-2-(2-diethylaminoethylamine)pyrimidine-4-yl]-N-methyl-isobutyramide in the form of a colorless foamy substance, MS (ISP): 588,2 (M+H+).

Example

Tablets of the following composition are prepared in the usual method:

mg/tablet

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/capsule

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 return the mixer, add talc 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/suppository

active substance 15

the mass of filler suppository 1285

total: 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 finely ground active substance is added and stirred until complete dispersion. The mixture fills the mold for suppositories 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)alkoxygroup;

R3means halogen, trifluoromethyl, (lower)alkoxygroup or (lower)alkyl;

R4/R4’mean independently from each other hydrogen or (lower)alkyl;

R5means (lower)alkyl, (lower)alkoxygroup, amino group, hydroxyl group, hydroxy(lower)alkyl, -(CH2)n-piperazinil, optionally substituted Nissi is an alkyl, -(CH2)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)alkylsulfonyl, (lower)alkylsulfonyl, benzylamino, -NH-(CH2)n+1N(R4’)2, -(CH2)n-NH-(CH2)n+1N(R4’)2, -(CH2)n+1N(R4’)2or-O-(CH2)n+1N(R4’)2where R4’means hydrogen or (lower)alkyl;

R6means hydrogen;

R2and R6or R1and R6together with the two carbon atoms of the ring to represent-CH=CH-CH=CH-, provided that n for R1equals 1;

n means independently 0-2; and

X is-C(O)N(R4’)- or-N(R4’)C(O)-;

or their pharmaceutically acceptable acid additive salt.

2. The compound according to claim 1, where X is-C(O)N(R4’)-, R4’means methyl and R5means -(CH2)n-piperazinil, optionally substituted stands, and n means 0 or 1.

3. The compound according to claim 2, which is

[3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 5-(4-fluoro-2-were)-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxylic acid, or

[3,5-bis(triptime who yl)benzyl]methylamide 5-(2-chlorophenyl)-2-(4-methylpiperazin-1-ylmethyl)pyrimidine-4-carboxylic acid.

4. The compound according to claim 1, in which X is-C(O)N(R4’)-, R4’means methyl and R5means-O(CH2)2-morpholinyl.

5. The compound according to claim 4, which means [3,5-bis(trifluoromethyl)benzyl]-methylamide 5-(2-chlorophenyl)-2-(2-morpholine-4-ylethoxy)pyrimidine-4-carboxylic acid.

6. The compound according to claim 1, in which X is-C(O)N(R4’)-, R4’means methyl and R5is-NH(CH2)n+1N(CH3)2,-(CH2)n-NH(CH2)n+1N(CH3)2or-O(CH2)n+1N(CH3)2where n is 1 or 2.

7. The connection according to claim 6, which means

[3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(2-dimethylamino-ethylamino)pyrimidine-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-diethylaminoethylamine)-5-o-tolylboronic-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-diethylaminoethylamine)-5-(2-methoxyphenyl)pyrimidine-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-diethylaminoethylamine)-5-(4-forfinal)pyrimidine-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-diethylaminoethylamine)-5-(4-fluoro-2-were)pyrimidine-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(3-dimethylaminopropoxy)pyrimidine-4-carboxylic sour is s,

[3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-(2-dimethylaminoethoxy)pyrimidine-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-dimethylaminoethoxy)-5-o-tolylboronic-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(3-dimethylaminopropoxy)-5-o-tolyl-pyrimidine-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-dimethylaminopropoxy)-5-(2-methoxyphenyl)pyrimidine-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(3-dimethylaminopropoxy)-5-(4-fluoro-2-were)pyrimidine-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-dimethylaminoethoxy)-5-(4-fluoro-2-were)pyrimidine-4-carboxylic acid, or

[3,5-bis(trifluoromethyl)benzyl]methylamide 5-(2-chlorophenyl)-2-[(2-diethylaminoethylamine)methyl]pyrimidine-4-carboxylic acid.

8. The compound according to claim 1, where X is-CON(R4’)2, R4’means methyl and R5means S3.

9. The connection of claim 8, which is a

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-methylsulfanyl-5-o-tolylboronic-4-carboxylic acid, or

[3,5-bis(trifluoromethyl)benzyl]methylamide 5-(4-fluoro-2-were)-2-methylsulfonylamino-4-carboxylic acid.

10. The compound according to claim 1, where X is-CON(R4’)2, R4’OSN which denotes methyl and R 2and R6or R1and R6together with the two carbon atoms of the ring are-CH=CH-CH=CH-.

11. The connection of claim 10, which means

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(4-methylpiperazin-1-yl)-5-naphthalene-1-Yeremey-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-diethylaminoethylamine)-5-naphthalene-1-Yeremey-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-dimethylaminoethoxy)-5-naphthalene-1-Yeremey-4-carboxylic acid,

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(2-morpholine-4-ylethoxy)-5-naphthalene-1-Yeremey-4-carboxylic acid, or

[3,5-bis(trifluoromethyl)benzyl]methylamide 2-(3-dimethylaminopropoxy)-5-naphthalene-1-Yeremey-4-carboxylic acid.

12. The compound according to claim 1, where X is-N(R4’)C(O)-, R4’means (lower)alkyl and R5means (CH2)n-piperazinil, optionally substituted (lower)alkyl, -(CH2)n-morpholinyl, -NH-(CH2)n+1N(CH3)2or-O-(CH2)n+1N(CH3)2.

13. The connection section 12, which means

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

2-[3,5-bis(trifluoromethyl)phenyl]-N-methyl-N-(2-piperazine-1-yl-5-o-tolylboronic-4-yl)isobutyramide,

2-[3,5-bis(triform the Teal)phenyl]-N-methyl-N-(2-morpholine-4-yl-5-o-tolylboronic-4-yl)isobutyramide,

2-[3,5-bis(trifluoromethyl)phenyl]-N-[2-(2-diethylaminoethylamine)-5-o-tolylboronic-4-yl]-N-methylisoleucine,

2-[3,5-bis(trifluoromethyl)phenyl]-N-[2-(2-dimethylaminoethoxy)-5-o-tolyl-pyrimidine-4-yl]-N-methylisoleucine,

2-[3,5-bis(trifluoromethyl)phenyl]-N-[5-(2-chlorophenyl)-2-(4-methylpiperazin-1-yl)-pyrimidine-4-yl]-N-methylisoleucine or

2-[3,5-bis(trifluoromethyl)phenyl]-N-[5-(2-chlorophenyl)-2-(2-diethylaminoethylamine)pyrimidine-4-yl]-N-methylisoleucine.

14. Pharmaceutical composition having the properties of antagonists of the receptor NK-1, containing one or more compounds according to any of claims 1 to 13, and pharmaceutically acceptable excipients.

15. The pharmaceutical composition according to 14 for medicinal products for treatment of diseases associated with the antagonists of the receptor NK-1.



 

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