Derivatives of pyrimidine and methods for their production

 

(57) Abstract:

The invention relates to new pyrimidine derivative of the formula (I-1) and (I-2), where R1and R5that may be the same or different, independently represent hydrogen or C1-C3alkyl group or, taken together, form cyclopentene or tsiklogeksilnogo ring; a represents a group of formula (II) in which R1and R2represent independently from each other hydrogen or C1-C3alkyl group, and R3represents hydrogen, C1-C3alkyl group or halogen; B is 1-(substituted) -1,2,3,4-tetrahydroisoquinoline-2-yl of the formula (III-1) or 7-(substituted) -4,5,6,7-tetrahydrothieno(2,3-C)-pyridine-6-yl of the formula (III-2), where R6is hydrogen or C1-C3alkyl group, and their pharmaceutically acceptable salts, which have excellent antisecretory activity, to pharmaceutical compositions that contain the specified active ingredient, and a new intermediate compounds and methods for their preparation. 4 C. and 3 h.p. f-crystals, 3 PL.

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The invention relates to new pyrimidine derivatives and their pharmaceutically acceptable salts, which have excellent contrast ratio, the rate, their new intermediate compounds and methods for their preparation.

Background of the invention

For the treatment of peptic ulcer disease using various drugs such as antacid, an anticholinergic agent, an antagonist of H2-receptor and a proton pump inhibitor.

Recently the emergence of omeprazole, useful as a proton pump inhibitor, again caused the activity of research in this area.

However, it is noted that the inhibition of the proton pump omeprazole irreversibly, which can lead to side effects. In line with this, actively been various attempts to develop a reversible proton pump inhibitor. For example, in Heb.Pat. NN 322133 and 404322 disclosed derivatives hintline, Heb.Pat. N 259174 describes quinoline derivatives, WO 91/13337 offers pyrimidine derivatives as a reversible proton pump inhibitor. In addition, these inventors also reported quinoline derivatives in WO 94/14795.

The invention

These inventors conducted intensive research on the development of reversible proton pump inhibitor with high efficiency; and, in the result of the and pyrimidine nucleus, demonstrate excellent effect of proton pump inhibitor and have the ability to provide a reversible inhibition of the proton pump.

Accordingly, the main purpose of this invention is the development of new pyrimidine derivatives having tetrahydroisoquinoline group in the 2 - or 4-position of the pyrimidine nucleus, and their pharmaceutically acceptable salts.

Another objective of this invention is to develop a method of producing such compounds.

The next objective of this invention to provide pharmaceutical compositions containing these substances as active ingredients.

Another aim of the invention is to develop a new intermediate compounds useful for obtaining new pyrimidine derivatives.

Detailed description of the invention

In accordance with this invention, represented by new connection - pyrimidine derivatives of formula (I-1) and (I-2), including their pharmaceutically acceptable salts:

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where R4and R5that may be the same or different, independently represent hydrogen or C1-C3alkyl group, or together the image of the B> and R2represent, independently from each other, hydrogen or C1-C3alkyl group, a R3is hydrogen, C1-C3alkyl group or halogen; and

B represents a 1-(substituted)-1,2,3,4-tetrahydroisoquinoline-2-yl of the formula (III-1) or 7-(substituted)- 4,5,6,7-tetrahydrothieno[2,3-c] -pyridine-6-yl of the formula (III-2):

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where R6is hydrogen or C1-C3alkyl group.

Among the compounds of this invention are preferred compounds in which R1, R2and R6are independently hydrogen or methyl group; R3is hydrogen or fluorine; R4and R5that may be the same or different, represent independently, hydrogen or C1-C3alkyl group or together form cyclopentene or tsiklogeksilnogo ring.

In particular, the preferred compounds of this invention are:

(2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2 - yl) pyrimidine hydrochloride;

6-methyl-2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2- (4-forgenerating)pyrimidine

6-ethyl-2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

6-ethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2 - yl)pyrimidine hydrochloride;

6-ethyl-2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2 - yl)pyrimidine hydrochloride;

6-ethyl-2-(2-methylphenylimino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2 - yl)pyrimidine hydrochloride;

2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2 - yl)-6-propylpyrimidine hydrochloride;

4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-6-propyl-2- (4-forgenerating)pyrimidine hydrochloride;

2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) 6-propylpyrimidine hydrochloride;

5,6 - dimethyl-2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

(R)-5,6-dimethyl-2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

(S)-5,6-dimethyl-2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

(R)-5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochlo the>5,6-dimethyl-2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

(R)-5,6-dimethyl-2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

(S)-5,6-dimethyl-2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-2-(phenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2 - yl)pyrimidine hydrochloride;

(R)-5,6-dimethyl-2-(4-phenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

(S)-5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-2-(2-methylphenylimino)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-2-(4-methylphenylimino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride;

5-methyl-6-ethyl-2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

5-methyl-6-ethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

5-methyl-6-ethyl-2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)cyclopent[d]pyrimidine guide is;

2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) cyclopent[d]pyrimidine hydrochloride;

2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-5,6,7,8-tetrahydroquinazolin hydrochloride;

2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -5,6,7,8-tetrahydroquinazolin hydrochloride;

6-methyl-2-(2-methyl-4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

6-methyl-2-(4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride;

6-methyl-2-(N-methylpentylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride;

6-ethyl-2-(2-methyl-4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride;

6-ethyl-2-(4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride;

6-ethyl-2-(N-methylpentylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride;

6-ethyl-2-(2-methylphenylimino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride;

5,6-dimethyl-2-(2-methyl-4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-2-(4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride;

5,6-dimethyl-2-(N - methylpentylamino)-4-(1,2,3,4-tetrahydrothieno)pyrimidine hydrochloride;

5-methyl-6-ethyl-2-(4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride;

5-methyl-6-ethyl-2-(N-methylpentylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride;

2-(2-methyl-4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) cyclopent[d]pyrimidine hydrochloride;

2-(2-methyl-4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) -5,6,7,8-tetrahydroquinazolin hydrochloride;

2-(4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-5,6,7,8 - tetrahydroquinazolin hydrochloride;

2-(N-methylpentylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-5,6,7,8 - tetrahydroquinazolin hydrochloride;

2-(2-methylphenylimino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-5,6,7,8 - tetrahydroquinazolin hydrochloride;

6-methyl-2-(2-methyl-4-forgenerating)-4-(7-methyl-4,5,6,7-tetrahydrothieno [2,3-C]pyridine-6-yl)pyrimidine hydrochloride;

6-methyl-4-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-C] -pyridine-6-yl)-2- (4-forgenerating)pyrimidine hydrochloride;

6-methyl-2-(N-methylpentylamino)-4-(7-methyl-4,5,6,7-tetrahydrothieno [2,3-C] pyridine-6-yl)pyrimidine hydrochloride;

5,6-dimethyl-2-(2-methyl-4-forgenerating)-4-(7-methyl-4,5,6,7 - tetrahydrothieno[2,3-C]pyridine-6-yl)pyrimidine hydrochloride;

5-methyl-2-(2-methyl-4-forgenerating)-4-(7-methyl-4,5,6,7 - tetrahydrothieno[2,3-C]pyridine-6-yl)-6-is imidan hydrochloride;

6-methyl-4-(4-forgenerating)-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

6-methyl-4-(2-methyl-4-forgenerating)-2-(7-methyl-4,5,6,7-tetrahydrothieno [2,3-C]pyridine-6-yl)pyrimidine hydrochloride;

6-methyl-4-(4-forgenerating)-2-(7-methyl-4,5,6,7-tetrahydrothieno [2,3-C] pyridine-6-yl)pyrimidine hydrochloride;

6-ethyl-2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

6-ethyl-4-(2-methyl-4-forgenerating)-2-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

6-ethyl-4-(4-forgenerating)-2-(1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride;

6-ethyl-4-(N-methylpentylamino)-2-(1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride;

5,6-dimethyl-4-(2-methyl-4-forgenerating)-2-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

(R)-5,6-dimethyl-4-(2-methyl-4-forgenerating)-2-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

(S)-5,6-dimethyl-4-(2-methyl-4-forgenerating)-2-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-4-(4-forgenerating)-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

(R)-5,6-dimethyl-4-(4-forgenerating)-2-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;
methyl-4-(N-methylpentylamino)-2-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

(R)-5,6-dimethyl-4-(N-methylpentylamino)-2-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

(S)-5,6-dimethyl-4-(N-methylpentylamino)-2-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-4-(2-methyl-4-forgenerating)-2-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-4-(4-forgenerating)-2-(1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride;

5,6-dimethyl-4-(N-methylpentylamino)-2-(1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride;

5,6-dimethyl-4-(2-methyl-4-forgenerating)-2-(7-methyl-4,5,6,7 - tetrahydrothieno[2,3-C]pyridine-6-yl)pyrimidine hydrochloride;

5,6-dimethyl-2-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine-6-yl) -4-(4-forgenerating)pyridine hydrochloride;

5,6-dimethyl-4-(N-methylpentylamino)-2-(7-methyl-4,5,6,7-tetrahydrothieno [2,3-C]pyridine-6-yl)pyrimidine hydrochloride;

5-methyl-6-ethyl-4-(2-methyl-4-forgenerating)-2-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride;

4-(2-methyl-4-forgenerating)-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)cyclopent[d]pyrimidine hydrochloride;

2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-5,6,7,8-tetrahydroquinazolin hydrochloride and 4-(2-methyl-4-forgenerating) -2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-5,6,7,8 - can exist in the form of optical isomers, (R) or (S), or mixtures thereof. It was found that both types of isomeric compounds demonstrate excellent antisecretory activity.

Compounds of formula (I-1) and (I-2) can be obtained according to schemes 1 and 2, respectively, described below.

Circuit 1

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where A, B, R1, R2, R3, R4, R5, R6have the meanings given above.

In particular, the compound of formula (I-1) can be obtained by using a method that includes: the interaction of compounds of formula (IV) with the compound of the formula (V-1) or (V-2) to obtain the compounds of formula (VI-1); and the interaction of the compounds of formula (VI-1) with the compound of the formula (VII)

Scheme 2

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where A, B, R1, R2, R3, R4, R5and R6have the meanings given above.

Further, the compound of formula (I-2) can be obtained according to the method, which includes: the hydrolysis of the compound (IV) in the 4-position with obtaining the compounds of formula (VIII); the interaction of the compounds of formula (VIII) with the compound of the formula (V-1) or (V-2) to obtain the compounds of formula (IX); chlorination of compounds of formula (IX) in the 4-position with obtaining the compounds of formula (VI-2); and then the interaction of the compounds of formula (VI-2) with the compound of the formula (VII).

In procedure, for example, J. Heterocyclic Chem. , 28, 231 (1991); and Org. Synt., Coll. Vol 638/ and the compounds of formula (V-1) and (V-2) can be obtained according to the method, opened in Heb. Pat. N 230871. The compound of formula (VII) is industrially available (for example, from Aldrich. in the United States).

As shown in scheme 1 and scheme 2, pyrimidine compounds (IV) and (VIII) is subjected to interaction with compounds of the formula (V-1) or (V-2) in the presence of an aprotic solvent and substrate within 1-24 hours of receiving, respectively, compounds of formula (VI-1) or (VI-2). Suitable solvents for this reaction may include dichloromethane, acetone, acetonitrile and dimethylformamide. The reaction temperature preferably ranges from room temperature to 150oC. Suitable bases for this reaction include triethylamine, N,N-dimethylaniline and pyridine.

Substituted pyrimidine compounds of formula (VI-1 and VI-2), thus obtained, is then injected into the reaction with compounds of the formula (VII) in an aprotic solvent in 2-5 hours, obtaining compounds of the present invention of the formula (I-1) and (I-2), respectively. Suitable solvents for this reaction may include dimethylformamide, p-dioxane, dimethyl sulfoxide, etc., the reaction Temperature, predpochteniem formula (V-1) or (V-2), the compound of formula (IV) in the 4-position may selectively be either hydrolyzed using NaOH solution in an aprotic solvent. Suitable solvents for this reaction may include acetone, acetonitrile and tetrahydrofuran.

The compounds of formula (VI-2) are obtained from the compounds of formula (IX) using gloriouse agent such as phosphorus oxychloride.

The compounds of formula (VI-1 and VI-2), obtained as described above, are new and they are used as intermediates to obtain the pyrimidine compounds of formula (I-1) or (I-2). Therefore, this invention embraces in its scope the new compounds of formula (VI-1) or (VI-2) and methods for their preparation.

The compounds of this invention can be assigned to receive either orally or intraperitoneally, in an effective amount in the range from 0.1 to 500 mg/kg, preferably from 1.0 to 100 mg/kg patient per day.

Further, the present invention covers its scope pharmaceutically acceptable salts of compounds of formula (I-1) and (I-2). Non-toxic salts, which are covered by the scope of the present invention may include salts of inorganic acids such as hydrochloride, sulfate, phosphate and nitrate, and organic salt is but to receive according to known methods, for example, the interaction of the compounds of formula (I-1) or (I-2) with the above acid in the presence of a solvent, for example, ethanol, dichloromethane, ethyl acetate and diethyl ether.

This invention also includes within its scope pharmaceutical compositions comprising one or more of the inventive compounds as active ingredients together with pharmaceutically acceptable carrier, diluent and/or other additives, if necessary. The active ingredient present in the composition may be in the range from 0.1 to 99.9% by weight.

The following examples are given for illustration only and is not intended to limit their scope of the invention. 1-Methyl-1,2,3,4-tetrahydroisoquinoline, (R)-1-methyl-1,2,3,4-tetrahydroisoquinoline and (S)-1-methyl-1,2,3,4 - tetrahydroisoquinoline receive the same manner as described in Obtaining WO 94/14795.

Getting 1: Obtain 7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

Stage 1: 2-(3-thienyl)chlorate

Thionyl chloride (17 ml, 0.23 mol) is added dropwise to a mixture solution of 2-(3-thienyl)ethanol (22,4 ml, 0.2 mol) and chloroform (60 ml), maintaining the temperature of the reaction system below 10oC, followed by stirring at room is the cosmology vacuum getting 24 g of the named compound. (Output: 81,5%).

Stage 2: 7-methyl-6,7-dihydrothieno[2,3-C]pyridine

To a solution of 2-(3-thienyl)chlorethane (20 g, 136 mol), obtained in stage 1 above, and anhydrous acetonitrile (350 ml) was added tin chloride (IV) (20 ml, to 0.17 mol) at room temperature. The reaction mixture is refluxed for 16 hours and cooled, add water to the mixture to remove the excess chloride tin (IV). Then the reaction mixture was washed with dichloromethane. The aqueous layer was separated and alkalinized with an aqueous solution of K2CO3while cooling with ice and then extracted with dichloromethane. The combined dichloromethane layers are dried over magnesium sulfate and concentrated, obtaining 10,56 g of the named compound. (51% yield).

Stage 3: 7-methyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine

Sodium borohydride (4.4 g, 116 mmol) is added by portions at room temperature to a mixture solution of 7-methyl-6,7-dihydrothieno [2,3-C]pyridine (10.5 g, 69,4 mmol) obtained above in stage 2, and ethanol (100 ml). After stirring for 1 hour the reaction mixture is diluted with water and extracted with dichloromethane. The combined dichloromethane layers are dried over magnesium sulfate and concentrated, obtaining 10,34 g called soy is pyrimidine-4-one

To a solution of sodium methoxide (24 g, 0.44 mol) and ethanol (180 ml) was added thiourea (15,22 g, 0.2 mol) and methylpropionate (25 ml, 0.2 mol). After removal of the solvent slowly add water (200 ml) to the reaction mixture, which was then refluxed for 30 minutes. To the reaction mixture add activated charcoal, and then stirred for 5 minutes and filtered. The filtrate is cooled to room temperature and acidified with glacial acetic acid, the resulting solid is filtered off and dried, receiving 29 g of these compounds. (Yield: 93%).

Stage 2: 2,4-dihydroxy-6-ethylpyrimidine

The reaction mixture Chloroacetic acid (33.3 g, 0,352 mol), water (400 ml) and 2-mercapto-6-ethylpyrimidine-4-it (29 g, 0,186 mol) obtained above in stage 1, refluxed for 14 hours and cooled to room temperature. To the reaction mixture are added conc. HCl (95 ml) and the mixture refluxed for 1 day. Then the reaction mixture is cooled to room temperature and concentrated under reduced pressure, the residue diluted with water. After stirring for 2 hours, the resulting solid is filtered off and dried, obtaining 11,16 g Nazvanov is orakei phosphorus) (43 ml), N,N-dimethylaniline (6,6 ml) and 2,4-dihydroxy-6-ethylpyrimidine (11,12 g, 79.3 mmol) obtained above in Stage 2, refluxed for 6 hours. The reaction mixture is cooled to room temperature and diluted with dichloromethane. The diluted solution is added slowly to ice water, maintaining the reaction temperature below 10oC, and the mixture is extracted with dichloromethane. The combined dichloromethane layers are dried over magnesium sulfate and concentrated, obtaining 13,10 g of these compounds in oily form. (Output: 93,3%).

Receipt 3: Receipt of 2,4-d sodium dichloro-6-propylpyrimidine

In accordance with the same procedure as in getting 2, except that as starting substances used sodium methoxide (24 g, 0.44 mol), thiourea (15,22 g, 0.2 mol), ethyl butyrylacetate (31,6 ml, 0.2 mol) and ethanol (180 ml), receive a 10.5 g of these compounds in oily form.

Getting 4: Obtain 2,4-dichloro-5-methyl-6-ethylpyrimidine

In accordance with the same procedure as in getting 2, except that as starting substances used sodium methoxide (24 g, 0.44 mol), thiourea (15,22 g, 0.2 mol), ethyl 2-propionyl propionate (31,6 ml, 0.2 mol) and ethanol (180 ml), obtain 16.5 g ve named the quinoline-2-yl)pyrimidine hydrochloride

Stage 1: 4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2 - yl)-2 - chloropyrimidine

A mixture solution of 2,4-dichloropyrimidine (3.0 g, 20 mmol), 1-methyl-1,2,3,4-tetrahydroisoquinoline (3.3 g, 22 mmol), triethylamine (3.4 ml, 24.4 mmol) and N,N-dimethylformamide (20 ml) is stirred for 5 hours, diluted with dichloromethane, washed several times with water. The dichloromethane layer is separated, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel, obtaining 1.5 g of these compounds. (Output: 28,9%).

Stage 2: 2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

2-Methyl-4-ftoranila (1.1 ml, 10.2 mmol) are added to a solution mixture of 4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine (1.5 g, 5.8 mmol) and dimethylformamide (10 ml). The reaction mixture is stirred for 3 hours at 110-120oC, cooled to room temperature, diluted with dichloromethane and then washed with water. The dichloromethane layer is separated, alkalinized with an aqueous solution of sodium hydroxide, washed with water, dried and concentrated. The resulting residue is purified by column chromatography on silica gel, receive the CSO Foundation and ethyl ether added aqueous hydrochloric acid, and formed a named connection is filtered and dried in vacuum. Recrystallization from ethanol gives 1.2 g of the named compound as a white crystalline solid. (Output: 58,6%).

So pl. 160-163oC

1H NMR (DMSO-d6): for 1.49 (d, 3H), of 2.30 (s, 3H), 2,90 (m, 2H), 3.45 points (m, 1H), 4,20 (SHS, 1H), 5.40 to (CL, 1H), equal to 6.05 (d, 1H), 6,45 (s, 1H), 6.90 to (m, 2H), 7,18 (m, 4H), 7,88 (m, 4H), to 7.95 (d, 1H).

Example 2: Synthesis of 6-methyl-2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

Stage 1: 6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -2-chloropyrimidine

In accordance with the same technique as in stage 1 of example 1, except that as starting substances used 6-methyl-2,4-dichloropyrimidine (6,52 g, 40 mmol), 1-methyl-1,2,3,4-tetrahydroisoquinoline (6.6 g, 44 mmol), triethylamine (6.8 ml, 48.8 mmol) and N,N-dimethylformamide (30 ml), obtain 5.5 g of the named compound. (Yield: 50.2 per cent).

Stage 2: 6-methyl-2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 2-methyl-4-foronline (1.1 ml, 10.2 mmol) to a solution of a mixture of 6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine (1.5 g, 5.5 mmol) and dimethylformamide (10 ml), obtain 1.2 g of the named sueoC

1H NMR (DMSO-d6): the / of 1.42 (d, 3H), of 2.30 (s, 3H), 2,32 (s, 3H), 2,90 (m, 2H), 3,50 (square, 1H), 4,22 (square, 1H), 5,42 (square sq, 1H), 6,70 (s, 1H), 7,18 (m, 6H), 7,63 (m, 1H), 9,80 (s, 1H), 13,30 (SHS, 1H).

Example 3: Synthesis of 6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -2-(4-forgenerating)pyrimidine hydrochloride

After adding 4-foronline (0.8 ml, 8.4 mmol) to a solution of a mixture of 6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine (1.5 g, 5.5 mmol) and dimethylformamide (10 ml), obtain 1.5 g of the above compound in accordance with the same technique as in step 2 of example 1.

(Yield: 70.7 percent)

So pl. 194-196oC

1H NMR (DMSO-d6): of 1.50 (d, 3H), of 2.38 (s, 3H), 2,92 (CL, 2H), 3,50 (m, 1H), 4,30 (square sq, 1H), 5,58 (square sq, 1H), 6,70 (s, 1H), 7,1-7,40 (m, 6H), 7,60 (m, 2H), 10,50 (s, 1H), 13,10 (SHS, 1H).

Example 4: Synthesis of 6-methyl-2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding N-methylaniline (0.9 ml, 8.4 mmol) to a solution of a mixture of 6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine (1.5 g, 5.5 mmol) and dimethylformamide (10 ml), obtain 1.2 g of the above compound in accordance with the method of step 2 of example 1.

(Output: 57,3%)

So pl. 170-172oC

1H NMR (DMSO-d6): of 1.40 (d, 3H), of 2.38 (s, 3H), 2.95 and (m, 2H), to 3.58-2-(2-methyl-4-forgenerating)-4-(1-methyl-1, 2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

Stage 1: 6-ethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2 - chloropyrimidine

In accordance with the methodology stage 1 of example 1, except that as starting substances used 1-methyl-1,2,3,4-tetrahydroisoquinoline (4.1 g, 27.8 mmol), triethylamine (4,7 ml, or 33.7 mmol), N,N-dimethylformamide (20 ml) and 6-ethyl-2,4-dichloropyrimidine (4.9 g, 27.7 mmol), obtained in the Obtaining 2, get to 5.58 g of the above compound (yield: 70%).

Stage 2: 6-ethyl-2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 2-methyl-4-foronline (of 0.77 ml, 6,93 mmol) to a solution of a mixture of 6-ethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine (1.0 g, 3,47 mmol) and dimethylformamide (5 ml) gain of 0.92 g of the above compound in accordance with the method of step 2 of example 1.

(Yield: 64%)

So pl. 172 and 174oC

3H NMR (CDCl3): 1,38-1,60 (TT+DD, 6H), 2,43 (SS, 3H), 2,68-of 3.06 (m, 4H), 3,76 (m, 1H), 3,94 (m, 1H), 5,33 (square sq, 1H), 6,01 (SS, 1H), 6,85-7,30 (m, 6H), 7,58 (t, 1H), 9,83 (s, 1H), 14,00 (s, 1H).

Example 6: Synthesis of 6-ethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 4-foronline (0,38 ml, 4,01 mmol) to restorepolicy 0.17 g of the above compound in accordance with the method of step 2 of example 1.

(Yield: 22%)

So pl. 156-158oC

1H NMR (DMSO-d6): of 1.29 (t, 3H), 1,49 (d, 3H), 2,65 (kV, 2H), 2,93-2,96 (m, 2H), 3,70 (m, 1H), 4,05-4,60 (m, 1H), ceiling of 5.60 (QC, 1H), 7,10-of 7.55 (m, 6H), 7,60-the 7.65 (m, 2H), or 10.60 (s, 1H), 10,90 (s, 1H).

Example 7: Synthesis of 6-ethyl-2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding N-methylaniline (and 0.46 ml of 4.25 mmol) to a solution of a mixture of 6-ethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine (0,61 g, 2,12 mmol) and dimethylformamide (5 ml) to obtain 0.50 g of the above compound in accordance with the method of step 2 of example 1.

(Yield: 60%)

So pl. 109-111oC

1H NMR (DMSO-d6): to 1.22 (t, 3H), USD 1.43 (DD, 3H), 2,78 (kV, 2H), 2.95 points (s, 1H), 3,30 (m, 1H), 3,62 (s, 3H), 4,37 (mm, 1H), 5,70 (kV, 1H), 6,70 (s, 1H), 7,06-7,58 (m, 9H), 12,15 (s, 1H).

Example 8: Synthesis of 6-ethyl-2-(2-methylphenylimino)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 2-methylaniline (and 0.46 ml, or 4.31 mmol) to a solution of a mixture of 6-ethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine (0,61 g, 2,12 mmol) and dimethylformamide (5 ml) to obtain 0.52 g of the above compound in accordance with the method of step 2 of example 1.

(Yield: 62%)

So pl. 78-81oC

1H NMR (DMSO-d6): 1,80-2,20 (m, 6H), 2,90 (s, 3H), of 3.07 (s, 1Htx2">

Example 9: Synthesis of 2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)-6-propylpyrimidine hydrochloride

Stage 1: 4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-6 - propyl-2-chloropyrimidine

In accordance with the same procedure as in stage 1 of example 1, except that as starting substances used 1-methyl-1,2,3,4-tetrahydroisoquinoline (1.6 g, 10.9 mmol), triethylamine (1.6 ml, 11.5 mmol), N,N-dimethylformamide (20 ml) and 2,4-dichloro-6-propylpyrimidine (1.8 g, 9.4 mmol), obtained in the obtaining 3, get 1.6 g of the above compound (Yield: 56.4 per cent).

Stage 2: 2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)-6-propylpyrimidine hydrochloride

After adding 4-fluoro-2-methylaniline (0,35 ml of 3.15 mmol) to a solution of a mixture of 4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -6-propyl-2-chloropyrimidine (0.5 g, of 1.66 mmol) and dimethylformamide (5 ml), to obtain 0.2 g of the above compound in accordance with the method of step 2 of example 1.

(Output: 28,2%)

So pl. 95-97oC

1H NMR (DMSO-d6): and 1.00 (t, 3H), 1,50 (DD, 3H), 1,81 (sq. 2H), 2,35 (s, 3H), 2,70 (t, 2H), 2,94 (sm, 2H), 3,60 (mm, 1H), 4,30 (DD, 1H), 5,55 (DD, 1H), 6,70 (s, 1H), 7,22 (MS, 6H), 7,75 (SHS, 1H), 9,90 (s, 1H), 13,30 (SHS, 1H).

Example 10: Synthesis of 4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -6-ol is a mixture of 4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-6-propyl-2-chloropyrimidine (0.5 g, of 1.66 mmol) and dimethylformamide (5 ml), obtain 0.3 g of the above compound in accordance with the method of step 2 of example 1.

(Output: 43,8%)

So pl. 100-105oC

1H NMR (DMSO-d6): to 0.96 (t, 3H), and 1.54 (m, 3H), of 1.75 (q, 2H), 2,60 (t, 2H), 2,96 (m, 2H), 3,62 (mm, 1H), 4,35 (square sq, 1H), ceiling of 5.60 (square sq, 1H), 6,70 (d, 1H), 7,00-7,40 (m, 6H), a 7.62 (m, 2H).

Example 11: 2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-6-propylpyrimidine hydrochloride

After adding N-methylaniline (0,27 ml, 2.49 mmol) to a solution of a mixture of 4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)- 6-propyl-2-chloropyrimidine (0.5 g, of 1.66 mmol) and dimethylformamide (5 ml), to obtain 0.5 g of the above compound in accordance with the method of step 2 of example 1.

(Yield: 73.6 per cent)

So pl. 92-94oC

1H NMR (DMSO-d6) : to 0.96 (t, 3H), of 1.46 (DD, 3H), of 1.59 (q, 2H), 2.57 m (t, 2H), 2,90 (sm, 2H), 3,50 (mm+d, 4H), 4,35 (QC, 1H), 5.56mm (square, 1H), 6,65 (d, 1H), 7,00-of 7.70 (m, 9H).

Example 12: Synthesis of 5,6-dimethyl-2-(2-methyl-4-forgenerating)-4- (1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

Step 1: 5,6-Dimethyl-2,4-dichloropyrimidine

A solution of a mixture of 5,6-dimethyl-2,4-dihydroxypyrimidine (72 g, 0.51 mol), phosphorus oxychloride (250 ml) and N,N-dimethylaniline (41 ml) is refluxed for 3 hours. After about what the substance is filtered and recrystallized from dichloromethane, getting to 54.3 g of the named compound. (Yield: 60%).

Stage 2: 5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -2-chloropyrimidine

In accordance with the methodology stage 1 of example 1, except that as starting substances used 1-methyl-1,2,3,4-tetrahydroisoquinoline (3,9 g of 26.4 mmol) and 5,6-dimethyl-2,4-dichloropyrimidine (4.3 g, 24 mmol) obtained in the above stage 1, gain of 4.17 g of the named compound. (Output: 60,4%).

Stage 3: 5,6-Dimethyl-2-(2-methyl-4-forgenerating)-4- (1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 2-methyl-4-foronline (1.1 ml, 9.9 mmol) to a solution of a mixture of 5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2 - chloropyrimidine (1.4 g, 4.8 mmol) obtained in the above stage 2, and dimethylformamide (10 ml), obtain 1.35 g of the above compound in accordance with the method of step 2 of example 1.

(Yield: 68%)

So pl. 201-205oC

1H NMR (DMSO-d6) : was 1.58 (d, 3H), 2,17 (s, 3H), of 2.36 (s, 3H), 2,89 (sm, 1H), is 3.08 (m, 1H) and 3.59 (m, 1H), 4,19 (sm, 1H), 5,38 (K, 1H), 7,34 (m, 6H), 7,60 (m, 2H), the 10.40 (s, 1H).

Example 13: Synthesis of (R)-5,6-dimethyl-2-(2-methyl-4-forgenerating)-4- (1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-pyrimidine hydrochloride

Stage 1: (R)-5,6-Dimethyl-4-(1-methyl-1,2,3,4-tetr is, is it as a source of substances used (R)-1-methyl-1,2,3,4-tetrahydroisoquinoline (3,9 g of 26.4 mmol) and 5,6 - dimethyl-2,4-dichloropyrimidine (4.3 g, 24 mmol), obtain 4.35 g of the named compound. (Yield: 63%)

Stage 2: (R) -5, 6-Dimethyl-2-(2-methyl-4-forgenerating) -4- (1 - methyl-1, 2, 3, 4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride

After adding 2-methyl-4-foronline (1.1 ml, 9.9 mmol) to a solution of a mixture of (R)-5, 6-dimethyl-4-(1-methyl-1,2,3, 4 - tetrahydroisoquinoline-2-yl)-2-chloropyrimidine (1.4 g, 4.8 mmol) obtained in the above Stage 1, and dimethylformamide (10 ml), obtain 1.10 g of the above compound in accordance with the method of step 2 of example 1.

(Output: 55,5%)

So pl. 203-205oC

1H NMR (DMSO-d6) : was 1.58 (d, 3H), 2,17 (s, 3H), of 2.36 (s, 3H), 2,89 (sm, 1H), is 3.08 (m, 1H) and 3.59 (m, 1H), 4,19 (sm, 1H), 5,38 (kV, 1H), 7,34 (m, 6H), 7,60 (m, 2H), the 10.40 (s, 1H).

Example 14: Synthesis of (S)-5,6-dimethyl-2-(2-methyl-4-forgenerating)-4- (1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

Stage 1: (S)-5,6-Dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -2-chloropyrimidine

In accordance with the methodology stage 1 of example 1, except that as starting substances are used (S)-1-methyl-1,2,3,4-tetrahydroisoquinoline (3,9 g of 26.4 mmol) and 5,6-dimethyl-2,4-dichloropyrimidine (4,3 is 4- (1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 2-methyl-4-foronline (1.1 ml, 9.9 mmol) to a solution of a mixture of (S)-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2 - chloropyrimidine (1.4 g, 4.8 mmol) obtained in the above stage 1, and dimethylformamide (10 ml), gain of 0.90 g of the above compound in accordance with the method of step 2 of example 1.

(Output: 45,5%)

So pl. 202-204oC

1H NMR (DMSO-d6) : was 1.58 (d, 3H), 2,17 (s, 3H), of 2.36 (s, 3H), 2,89 (sm, 1H), is 3.08 (m, 1H) and 3.59 (m, 1H), 4,19 (sm, 1H), 5,38 (K, 1H), 7,34 (m, 6H), 7,60 (m, 2H), the 10.40 (s, 1H).

Example 15: Synthesis of 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl - 1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 4-foronline (1.0 ml, 10 mmol) to a solution mixture of 5, 6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine (1.4 g, 4.8 mmol) and dimethylformamide (10 ml), gain of 1.32 g of the above compound in accordance with the same procedure as in stage 2 of example 1.

(Yield: 69%)

So pl. 205-208oC

1H NMR (DMSO-d6): was 1.58 (d, 3H), 2,17 (s, 3H), of 2.36 (s, 3H), 2,89 (sm, 1H), is 3.08 (m, 1H) and 3.59 (m, 1H), 4,19 (sm, 1H), 5,38 (K, 1H), 7,34 (m, 6H), 7,60 (m, 2H), the 10.40 (s, 1H).

Example 16: Synthesis of (R)-5,6-dimethyl-2-(4-forgenerating)-4- (1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 4-feranil,8 mmol) and dimethylformamide (10 ml), obtain 1.20 g of the above compound in accordance with the same procedure as in stage 2 of example 1.

(Output: 62,7%)

So pl. 205-207oC

1H NMR (DMSO-d6): was 1.58 (d, 3H), 2,17 (s, 3H), of 2.36 (s, 3H), 2,89 (sm, 1H), is 3.08 (m, 1H) and 3.59 (m, 1H), 4,19 (sm, 1H), 5,38 (kV, 1H), 7,34 (m, 6H), 7,60 (m, 2H), the 10.40 (s, 1H).

Example 17: Synthesis of (S)-5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 4-foronline (1 ml, 10 mmol) to a solution of a mixture of (S)-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2 - chloropyrimidine (1.4 g, 4.8 mmol) and dimethylformamide (10 ml), obtain 1.50 g of the above compound in accordance with the method of step 2 of example 1.

(Yield: 78.3% of)

So pl. 204-206oC

1H NMR (DMSO-d6): was 1.58 (d, 3H), 2,17 (s, 3H), of 2.36 (s, 3H), 2,89 (sm, 1H), is 3.08 (m, 1H) and 3.59 (m, 1H), 4,19 (sm, 1H), 5,38 (kV, 1H), 7,34 (m, 6H), 7,60 (m, 2H), the 10.40 (s, 1H).

Example 18: Synthesis of 5,6-dimethyl-2-(N-methylpentylamino)-4-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding N-methylaniline (1.5 ml, 14 mmol) to a solution of a mixture of 5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2 - chloropyrimidine (1.9 g, 6.6 mmol) and dimethylformamide (10 ml), obtain 0.25 g of the above compound in accordance with the methodology stage 2 ol the (sm, 2H), 3,48 (m, 1H), 3,98 (s, 3H), 4.04 the (sm, 1H), 5,02 (m, 1H), to 6.88 (m, 1H), 7,16-7,42 (m, 5H), 7,58 (m, 3H), 13,42 (sm, 1H).

Example 19: Synthesis of (R)-5,6-dimethyl-2-(N-methylpentylamino)-4-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding N-methylaniline (1,04 ml, 9.6 mmol) to a solution of a mixture of (R)-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -2-chloropyrimidine (1.4 g, 4.8 mmol) and dimethylformamide (10 ml), obtain 0.55 g of the above compound in accordance with the method of step 2 of example 1.

(Yield: 29%)

So pl. 221-223oC

1H NMR (CDCl3): of 1.34 (d, 3H), 2,19 (s, 3H), 2,77 (s, 3H), 2,93 (sm, 2H), 3,48 (m, 1H), 3,98 (s, 3H), 4.04 the (sm, 1H), 5,02 (m, 1H), to 6.88 (m, 1H), 7,16-7,42 (m, 5H), 7,58 (m, 3H), 13,42 (sm, 1H).

Example 20: Synthesis of (S)-5,6-dimethyl-2-(N-methylpentylamino)-4-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding N-methylaniline (1,04 ml, 9.6 mmol) to a solution of a mixture of (S)-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -2-chloropyrimidine (1.4 g, 4.8 mmol) and dimethylformamide (10 ml), get 0,70 g of the above compound in accordance with the method of step 2 of example 1.

(Yield: 37%)

So pl. 220-223oC

1H NMR (CDCl3): of 1.34 (d, 3H), 2,19 (s, 3H), 2,77 (s, 3H), 2,93 (sm, 2H), 3,48 (m, 1H), 3,98 (s, 3H), 4.04 the (sm, 1H), 5,02 (m, 1H), to 6.88 (m, 1H), 7,16-7,42 (m, 5H), 7,58 (m, 3H), 13,42 hydrochloride

After addition of aniline (of 0.53 ml, 5.5 mmol) to a solution of a mixture of 5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine (to 0.72 g, 2.5 mmol) and dimethylformamide (5 ml), obtain 0.21 g of the above compound in accordance with the method of step 2 of example 1.

(Yield: 22%)

So pl. 243-245oC

1H NMR (DMSO-d6): was 1.58 (d, 3H), of 2.15 (s, 3H), of 2.34 (s, 3H), 2,90 (sm, 1H), 3,12 (m, 1H), to 3.64 (m, 1H), 4,25 (m, 1H), 5,42 (kV, 1H), 7,21 (m, 5H), the 7.43 (m, 2H), 7,56 (m, 2H), 10,30 (s, 1H), 13,35 (sm, 1H).

Example 22: Synthesis of (R)-5,6-dimethyl-2-(4-phenylamino)-4-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After addition of aniline (of 0.53 ml, 5.5 mmol) to a solution of a mixture of (R)-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2 - chloropyrimidine (to 0.72 g, 2.5 mmol) and dimethylformamide (5 ml), obtain 0.25 g of the above compound in accordance with the method of step 2 of example 1.

(Yield: 26%)

So pl. 243-246oC

1H NMR (DMSO-d6): was 1.58 (d, 3H), of 2.15 (s, 3H), of 2.35 (s, 3H), 2,89 (sm, 1H), 3,12 (m, 1H), to 3.64 (m, 1H), 4,25 (m, 1H), 5,42 (kV, 1H), 7,20 (m, 5H), the 7.43 (m, 2H), 7,56 (m, 2H), 10,30 (s, 1H), 13,35 (sm, 1H).

Example 23: Synthesis of (S)-5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After addition of aniline (of 0.53 ml, 5.5 mmol) to a solution of a mixture of (S)-5,6-Dima 0.20 g of the above compound in accordance with the method of step 2 of example 1.

(Yield: 21%)

So pl. 243-245oC

1H NMR (DMSO-d6): was 1.58 (d, 3H), of 2.15 (s, 3H), of 2.34 (s, 3H), 2,89 (sm, 1H), 3,12 (m, 1H), to 3.64 (m, 1H), 4,25 (m, 1H), 5,42 (kV, 1H), 7,20 (m, 5H), the 7.43 (m, 2H), 7,56 (m, 2H), 10,30 (s, 1H), 13,35 (sm, 1H).

Example 24: Synthesis of 5,6-dimethyl-2-(2-methylphenylimino)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 2-methylaniline (1.0 ml, 9.6 mmol) to a solution of a mixture of 5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine (1,34 g, 4.6 mmol) and dimethylformamide (5 ml), obtain 0.65 g of the above compound in accordance with the method of step 2 of example 1.

(Yield: 36%)

So pl. 94-96oC

1H NMR (DMSO-d6): of 1.52 (d, 3H), 2,17 (s, 3H), of 2.30 (s, 3H), is 2.37 (s, 3H), 2,82 (d, 1H), 3,01 (t, 1H), 3,54 (t, 1H), 4,15 (sm, 1H), 5,31 (t, 1H), to 7.15 (m, 5H), 7,30 (m, 2H), 7,73 (d, 1H), of 9.55 (s, 1H), 13,73 (sm, 1H).

Example 25: Synthesis of 5,6-dimethyl-2-(4-methylphenylimino)-4-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding p-toluidine (0.45 ml, 4.20 mmol) to a solution mixture of 5, 6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine (0,80 g, 2,78 mmol) and dimethylformamide (5 ml), gain of 0.30 g of the above compound in accordance with the method of step 2 of example 1.

(Yield: 27%)

So pl. 243-245oC

1H YAM IS H), and 10.20 (s, 1H), 14,10 (SHS, 1H).

Example 26: Synthesis of 5-methyl-6-ethyl-2-(2-methyl-4-forgenerating)-4- (1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

Stage 1: 5-Methyl-6-ethyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) -2-chloropyrimidine

In accordance with the methodology stage 1 of example 1, except that as starting substances used 1-methyl-1,2,3,4 - tetrahydroisoquinoline (2.3 g, 15.6 mmol) and 2,4-dichloro-5-methyl-6-ethylpyrimidine (2.7 g, 14.1 mmol), obtained in the obtaining 4, get 2.3 g of the named compound. (Yield: 54%)

Stage 2: 5-Methyl-6-ethyl-2-(2-methyl-4-forgenerating)-4-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 4-fluoro-2-methylaniline (0,55 ml of 4.95 mmol) to a solution mixture of 5-methyl-6-ethyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2 - chloropyrimidine (0,80 g, to 2.65 mmol) and dimethylformamide (5 ml), obtain 0.25 g of the above compound in accordance with the method of step 2 of example 1.

(Output: 22,1%)

So pl. 171-173oC

1H NMR (DMSO-d6) : of 1.20 (t, 3H), of 1.46 (d, 3H), of 2.16 (s, 3H), 2,22 (s, 3H), 2,68 (kV, 2H), 2.95 and (m, 1H), 3,48 (t, 1H), 4,12 (d, 2H), 5,20 (kV, 1H), 6.90 to-7,30 (m, 6H), 7,58 (m, 1H).

Example 27: Synthesis of 5-methyl-6-ethyl-2-(2-methyl-4-forgenerating)-4- (1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

(Output: 50,3%)

So pl. 198-200oC

1H NMR (DMSO-d6) : of 1.20 (t, 3H), and 1.56 (d, 3H), of 2.18 (s, 3H), of 2.56 (q, 2H), 2,81 (sm, 1H), 3,05 (m, 1H), to 3.58 (t, 1H), to 4.41 (d, 1H), 5,38 (kV, 1H), 7,00-7,40 (m, 6H), 7,58 (m, 2H).

Example 28: Synthesis of 5-methyl-6-ethyl-2-(N-methylpentylamino)-4-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding N-methylaniline (of 0.44 ml, 4,06 mmol) to a solution mixture of 5-methyl-6-ethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2 - chloropyrimidine (0,80 g, to 2.65 mmol) and dimethylformamide (5 ml), gain of 0.60 g of the above compound in accordance with the method of step 2 of example 1.

(Yield: 55.4 per cent)

So pl. 214-216oC

1H NMR (DMSO-d6) : 1,90 (t, 3H), of 1.46 (d, 3H), of 2.18 (s, 3H),

to 2.67 (2H square), 2,79 (CL, 2H), 2,90-3,18 (m, 1H), 3,40-3,60 (s+m, 4H), 4,18 (DD, 1H), 5.25-inch (sq. 1H), 7,05-7,20 (s, 4H), 7,32-7,58 (m, 5H).

Example 29; Synthesis of 2-(2-methyl-4-forgenerating)-4-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)cyclopent[d]pyrimidine hydrochloride

Stage 1: 2-Amino-4-hydroxycyclopent[d]pyrimidine

A solution of 2-ethoxycarbonylmethylene (114 ml, 0.77 mol) and N,N-dimethylformamide (40 ml) is added dropwise to the solution mixture of sodium methoxide is ukazannoi the reaction mixture is added a solution of salt HCl (81 g, 0.85 mol) and methanol (127 ml) and then refluxed for 14 hours. The reaction mixture is neutralized conc. HCl and the resulting solid filtered and dried under reduced pressure, getting 20,69 g of the named compound. (Yield: 18%)

Stage 2: 2,4-Dihydrocyclopenta[d]pyrimidine

To a solution of a mixture of 20% HCl (62 ml) and 2-amino-4-hydroxycyclopent[d]pyrimidine (20.6 g, 0,136 mol) obtained in the above stage 1, add an aqueous solution of sodium nitrate (19,4 g) for 4 hours, maintaining the temperature of the reaction system at 70oC. the Reaction mixture was cooled to 0oC and the resulting solid is filtered off, dried under reduced pressure, getting 15,43 g of the named compound. (Output: 74,6%).

Stage 3: 2,4-Dichlorocyclopentane[d]pyrimidine

A mixture solution of phosphorous oxychloride (49 ml), N,N-dimethylaniline (8.0 ml) and 2,4-dihydrocyclopenta[d]pyrimidine (to 15.4 g, 0.1 mol) obtained in the above stage 2, refluxed for 3 hours and cooled to room temperature. After dilution of the reaction mixture is diluted with dichloromethane, the solution is added to ice water, keeping the temperature of the reaction mixture below 10 C. the Reaction smashnova connection in the form of oil. (Yield: 15%).

Stage 4: 4-(1-Methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chlorocyclopentane [d]pyrimidine

In accordance with the methodology stage 1 of example 1, except that as starting substances used 1-methyl-1,2,3,4-tetrahydroisoquinoline (1.7 g, 11,55 mmol) and 2,4-dichlorocyclopentane[d]pyrimidine (2.0 g, 10.5 mmol) obtained above in stage 3, the gain of 1.95 g of the named compound. (Yield: 62%)

Stage 5: 2-(2-Methyl-4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)cyclopent[d]pyrimidine hydrochloride

After adding 4-fluoro-2-methylaniline (and 0.40 ml of 3.60 mmol) to a mixture solution of 4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chlorocyclopentane[d] pyrimidine (0.50 g, 1.70 mmol) and dimethylformamide (5 ml), obtain 0.15 g of the above compound in accordance with the method of step 2 of example 1.

(Output: 20.8 per cent)

So pl. 110-112oC

1H NMR (DMSO-d6) : 1,50 (t, 3H), 2,12 (m, 2H, in), 2.25 (s, 3H), 2,93 (sm, 3H), 3,10 (m, 2H), 3,42 (sm, 2H), 3,70 (sm, 1H), 4,40 (sm, 1H), 5,78 (sm, 1H), 7,22 (m, 6H), to 7.50 (m, 5H), 7,60 (m, 1H), 9,80 (s, 1H), 13,32 (sm, 1H).

Example 30: Synthesis of 2-(4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)cyclopent[d]pyrimidine hydrochloride

After adding 4-foronline (and 0.40 ml, 4.2 mmol) to a solution of a mixture of 4-(1-methyl-1,2,3, 4-tetrahydroisoquinoline is in accordance with the method of step 2 of example 1.

(Output: 13,4%)

So pl. 220-222oC

1H NMR (DMSO-d6) : was 1.58 (d, 3H), 2,10 (sm, 2H), 3,01 (sm, 4H), 3,18 (m, 2H), 3,60 (sm, 1H), 4,45 (sm, 1H), 5,64 (sm, 1H), 7,30 (m, 6H), a 7.62 (m, 2H), 10,42 (s, 1H), 13,15 (sm, 1H).

Example 31: Synthesis of 2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)cyclopent[d]pyrimidine hydrochloride

After adding N-methylaniline (0,20 ml, 1,90 mmol) to a solution of a mixture of 4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chlorocyclopentane[d] pyrimidine (0.51 g, 1.70 mmol) and dimethylformamide (5 ml), obtain 0.20 g of the above compound in accordance with the method of step 2 of example 1.

(Yield: 29%)

So pl. 105-107oC

1H NMR (DMSO-d6): 1,42 (sm, 3H), 2,10 (m, 2H), 2,87 (m, 3H), 3,10 (m, 2H), to 3.58 (s, 3H), of 4.38 (sm, 1H), of 5.53 (q, 1H), 7,21 (m, 4H), of 7.48 (m, 5H), br12.62 (sm, 1H).

Example 32: Synthesis of 2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)-5,6,7,8-tetrahydroquinazolin hydrochloride

Step 1: 2,4-Dihydroxy-5,6,7,8-tetrahydroquinazolin

The solution mixture of 2,4-dihydroxyindoline (39,2 g, 0.24 mol), platinum oxide (4 g) and triperoxonane acid hydronaut in the Parr reactor for 2 hours. Platinum is filtered, and the filtrate is concentrated, diluted with water and alkalinized 1N-NaOH solution. The resulting solid is shown that azalin

2,4-Dihydroxy-5,6,7,8-tetrahydroquinazolin (3.4 g, 20 mmol) obtained in the above stage 1, are suspended in a solution of a mixture of phosphorous oxychloride (10 ml) and N,N-dimethylaniline (0.8 ml). The reaction mixture is refluxed for 3 hours and cooled to room temperature. The reaction mixture was added to ice water, keeping the temperature of the reaction system below 10oC, and the resulting solid is filtered off, dried under reduced pressure, getting 3,26 g of the named compound. (Yield: 80%).

Stage 3: 4-(1-Methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloro - 5,6,7,8-tetrahydroquinazolin

The solution mixture of 1-methyl-1,2,3,4-tetrahydroisoquinoline (2.6 g, to 17.4 mmol), triethylamine (2.8 ml), N,N-dimethylformamide (20 ml) and 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (3.2 g, 15.8 mmol) obtained in the above stage 2, stirred at 80oC for 3 hours and cooled. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated. The residue is purified column chromatography on silica gel, obtaining 3.1 g of the named compound. (Output: 62,5%).

Stage 4: 2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahy mmol) to a solution of a mixture of 4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2 - chloro-5,6,7,8-tetrahydroquinazoline (0.75 g, is 2.40 mmol) and dimethylformamide (5 ml), gain of 0.58 g of the above compound in accordance with the method of step 2 of example 1.

(Yield: 55%)

So pl. 190-193oC

1H NMR (DMSO-d6): of 1.53 (d, 3H), 1.60-to a 1.96 (m, 3H), of 2.34 (s, 3H), 2,55 (sm, 2H), 2,75 (sm, 4H), 2,98 (m, 1H), 3,54 (m, 1H), 4,25 (sm, 1H), are 5.36 (q, 1H), 7,12-7,31 (m, 6H), 7,60 (m, 1H), RS 9.69 (s, 1H).

Example 33: Synthesis of 2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)-5,6,7,8-tetrahydroquinazolin hydrochloride

After adding N-methylalanine source (0.50 ml, 4.8 mmol) to a solution of a mixture of 4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloro - 5,6,7,8-tetrahydroquinazoline (0.75 g, is 2.40 mmol) and dimethylformamide (5 ml), obtain 0.26 g of the above compound in accordance with the method of step 2 of Example 1.

(Yield: 26%)

So pl. 207-210oC

1H NMR (DMSO-d6): of 1.42 (d, 3H), 1,53 is 1.96 (m, 3H), 2.57 m (sm, 1H), 2,80 (m, 5H), 2.95 and (m, 1H), 3,45 (sm, 1H), 3,60 (s, 3H), 4,18 (sm, 1H), 5.25-inch (kV, 1H), 7,16 (m, 3H), 7,50 (m, 6H), 12,10 (s, 1H).

Example 34: Synthesis of 6-methyl-2-(2-methyl-4-forgenerating)-4-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

Stage 1: 6-Methyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2 - chloropyrimidine

In accordance with the methodology stage 1 of example 1, except that as starting substances used 6-methyl-2,4-dichl formamid (10 ml), obtain 3.1 g of the named compound. (Yield: 59.7 per cent)

Stage 2: 6-Methyl-2-(2-methyl-4-forgenerating)-4-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 2-methyl-4-foronline (0.8 ml, 7.2 mmol) to a solution of a mixture of 6-methyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2 - chloropyrimidine (1.0 g, 3.8 mmol) and dimethylformamide (10 ml), gain of 0.85 g of the above compound in accordance with the method of step 2 of example 1.

Yield: 58%

So pl. 183-185oC

1H NMR (CDCl3): to 2.41 (s, 3H), 2,48 (d, 3H), 2,88 (t, 1H), to 3.02 (t, 1H, in), 3.75 (t, 1H), 3,91 (t, 1H), 4,67 (s, 1H), 4,78 (s, 1H), 6,00 (d, 1H), 6.90 to-7,30 (m, 5H), 7,58 (m, 1H), 9,75 (s, 1H), 14,20 (sm, 1H).

Example 35: Synthesis of 6-methyl-2-(4-forgenerating)-4-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 4-foronline (0.7 ml, 7.4 mmol) to a solution of a mixture of 6-methyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine (1.0 g, 3.8 mmol) and dimethylformamide (10 ml), obtain 0.6 g of the above compound in accordance with the method of step 2 of example 1.

Output: 42,6%

So pl. 238-240oC

1H NMR (CDCl3): 2,45 (d, 3H), 2,90-3,10 (m, 2H), 3,78 (t, 1H), of 4.05 (t, 1H), 4,70 (s, 1H), 4.92 in (t, 1H), equal to 6.05 (d, 1H), 6.90 to-7,30 (m, 6H), 7,60 (m, 2H), the 10.40 (s, 1H), 13,80 (SHS, 1H).

Example 36: Synthesis of 6-methyl-2-(N-methylpentylamino)-4-(1,2,3,4 - tetrahydrothieno-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine (0.95 g, 3.65 mmol) and dimethylformamide (10 ml), obtain 0.7 g of the above compound in accordance with the method of step 2 of example 1.

Yield: 52.3% of

So pl. 85-95oC

1H NMR (CDCl3): 2,75 (s, 3H), 2,99 (s, 3H), 3,70 (m, 2H), of 3.78 (s, 3H), 4,51 (s, 1H) and 4.65 (s, 1H), and 5.30 (SHS, 1H), between 6.08 (d, 1H), to 6.88 (d, 1H), 7,05-of 7.60 (m, 8H), of 13.05 (s, 1H).

Example 37: Synthesis of 6-Ethyl-2-(2-methyl-4-forgenerating)-4-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

Stage 1: 6-Ethyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine

In accordance with the methodology stage 1 of example 1, except that as starting substances use 1,2,3,4-tetrahydroisoquinoline (3.5 ml, 28 mmol), triethylamine (3.9 ml, 28 mmol), N,N-dimethylformamide (20 ml) and 6-ethyl-2,4-dichloropyrimidine (4.9 g, 27.7 mmol), obtained in the Obtaining 2, receive 5.0 g of the named compound. (Yield: 66%)

Stage 2: 6-Ethyl-2-(2-methyl-4-forgenerating)-4-(1,2,3,4 - tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride

After adding 2-methyl-4-foronline (or 0.57 ml, 5,13 mmol) to a solution of a mixture of 6-ethyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2 - chloropyrimidine (0.7 g, 2.56 mmol) and dimethylformamide (5 ml), obtain 0.55 g of the above compound in accordance with the method of step 2 of example 1.

Yield: 54%

So pl. 223-225oC

Example 38: Synthesis of 6-ethyl-2-(4-forgenerating)-4-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 4-foronline (0,50 ml, 5,28 mmol) to a solution of a mixture of 6-ethyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2 - chloropyrimidine (0.7 g, 2.56 mmol) and dimethylformamide (5 ml), gain of 0.41 g of the above compound in accordance with the method of step 2 of example 1.

Yield: 42%

So pl. 203 - 206oC

1H NMR (CDCl3): 1,42 (TT, 3H), 2,74 (QC, 2H), 3,02 (TT, 2H), 3,93 (TT, 2H), 4,82 (SS, 2H), 6,03 (SS, 2H), 7,00-to 7.32 (m, 6H), 7,54-to 7.64 (m, 2H), or 10.60 (s, 1H), 13,80 (s, 1H).

Example 39: Synthesis of 6-ethyl-2-(-methylphenylimino)-4-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding N-methylaniline (0.54 ml, 5,15 mmol) to a solution of a mixture of 6-ethyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine (0.7 g, 2.56 mmol) and dimethylformamide (5 ml), obtain 0.56 g of the above compound in accordance with the method of step 2 of example 1.

Yield: 57%

So pl. 98-100oC

1H NMR (CDCl3): 1,24-of 1.40 (m, 3H), 2,83 (TT, 2H), 3,16-3,24 (m, 2H), 3,65 (TT, 2H), with 3.89 (s, 3H), 4.53-in (SS, 2H), 6,00 (SS, 1H), 6,85 (d, 1H), 7,05-of 7.55 (m, 8H), 13,40 (s, 1H).

Example 40: Synthesis of 6-ethyl-2-(2-methylphenylimino)-4-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After doba (0.7 g, 2.56 mmol) and dimethylformamide (5 ml), get to 0.23 g of the above compound in accordance with the method of step 2 of example 1.

Yield: 24%

So pl. 153 to 155oC

1H NMR (CDCl3) : of 1.37 to 1.47 (m, 3H), of 2.50 (s, 3H), 2,74 was 2.76 (m, 2H), 2,97 (TT, 2H), a 3.87 (TT, 2H), 4,76 (SS, 2H), 5,98 (SS, 1H), 7,10-7,28 (m, 7H), of 7.70 (t, 1H), 9,82 (s, 1H), 14,17 (s, 1H).

Example 41: Synthesis of 5,6-dimethyl-2-(2-methyl-4-forgenerating)-4- (1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

Step 1: 5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2 - chloropyrimidine

In accordance with the methodology stage 1 of example 1, except that as starting substances use 1,2,3,4-tetrahydroisoquinoline (2,9 ml, 23 mmol) and 5,6-dimethyl-2,4-dichloropyrimidine (3.8 g, 21 mmol), obtained in stage 1 of example 12, the gain of 3.95 g of the named compound. (Yield: 68.7 per cent)

Stage 2: 5,6-Dimethyl-2-(2-methyl-4-forgenerating)-4-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 4-fluoro-2-methylaniline (0.8 ml, 7 mmol) to a solution of a mixture of 5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinoline - 2-yl)-2-chloropyrimidine (1.0 g, 3.6 mmol) and dimethylformamide (10 ml), gain of 0.58 g of the above compound in accordance with the method of step 2 of example 1.

Yield: 44%

So pl. 190-193oC

1H NMR (DM is the Example 42; Synthesis of 5,6-dimethyl-2-(4-forgenerating)-4-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 4-foronline (0.7 ml, 7.4 mmol) to a solution of a mixture of 5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine (1.0 g, 3.6 mmol) and dimethylformamide (5 ml), gain of 0.67 g of the above compound in accordance with the method of step 2 of example 1.

Yield: 48%

So pl. 251-253oC

1H NMR (DMSO-d6) : of 2.23 (s, 3H), 2,41 (s, 3H), to 3.02 (t, 2H), 3,94 (t, 2H), to 4.87 (s, 2H), 7,35 (m, 6H), the 7.65 (m, 2H), accounted for 10.39 (s, 1H), 13,20 (sm, 1H).

Example 43: Synthesis of 5,6-dimethyl-2-(N-methylpentylamino)-4-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding N-methylaniline (from 0.84 ml, 7.8 mmol) to a solution of a mixture of 5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2 - chloropyrimidine (1.0 g, 3.6 mmol) and dimethylformamide (5 ml), obtain 0.55 g of the above compound in accordance with the method of step 2 of example 1.

Yield: 39%

So pl. 58-60oC

1H NMR (DMSO-d6) : and 2.14 (s, 3H), of 2.45 (s, 3H), and 2.83 (t, 2H), to 3.64 (s, 3H), 3,71 (t, 2H), of 4.66 (s, 2H), 7,07-to 7.15 (m, 4H), 7,38-rate of 7.54 (m, 5H), 12,40 (s, 1H).

Example 44: Synthesis of 5-methyl-6-ethyl-2-(2-methyl-4-forgenerating)-4- (1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

Stage 1: 5-Methyl-6-Ethyl-4-(1,2,3,4-tetrahydroisoquinoline substances use 1,2,3,4-tetrahydroisoquinoline (3.5 ml, 28 mmol) and 2,4-dichloro-5-methyl-6-ethylpyrimidine (4.9 g, 27.7 mmol), obtained in the obtaining 4 receive 5.0 g of the named compound. (Yield: 66%)

Stage 2: 5-Methyl-6-ethyl-2-(2-methyl-4-forgenerating)-4-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 4-fluoro-2-methylaniline (0.5 ml, 3.6 mmol) to a solution mixture of 5-methyl-6-ethyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) -2-chloropyrimidine (0.7 g, 2.4 mmol) and dimethylformamide (5 ml), gain of 0.53 g of the above compound in accordance with the method of step 2 of example 1.

Output: 53.5% of

So pl. 192-194oC

1H NMR (DMSO-d6) : a 1.25 (t, 3H), 2,19 (s, 3H), of 2.28 (s, 3H), 2,68 (kV, 2H), 2,88 (t, 2H), 3,79 (t, 2H), and 4.75 (s, 2H), 7,15 (m, 6H), of 7.70 (m, 1H), 9,80 (s, 1H).

Example 45: Synthesis of 5-methyl-6-ethyl-2-(4-forgenerating)-4-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 4-foronline (0.45 ml, 3.6 mmol) to a solution mixture of 5-methyl-6-ethyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine (0.7 g, 2.4 mmol) and dimethylformamide (5 ml), obtain 0.50 g of the above compound in accordance with the method of step 2 of example 1.

Output: 52,2%

So pl. 235-238oC

1H NMR (CDCl3) : of 1.42 (t, 3H), of 2.25 (s, 3H), was 2.76 (q, 2H), 3.04 from (t, 2H), 3,90 (m, 2H), 4,80 (s, 2H), 6,95-7,35 (m, 6H), 7,55 (m, 2H), 10,50 (s, 1H), 13,80 (sm, 1H).

Output: 52,7%

So pl. 75-80oC

1H NMR (CDCl3) : of 1.32 (t, 3H), of 2.15 (s, 3H), 2,80 (t, 2H), 3,10 (m, 2H), 3,60 (m, 2H), 3,80 (s, 3H), 4,48 (s, 2H), 6,95 (m, 2H), 7,05-of 7.70 (m, 7H).

Example 47: Synthesis of 2-(2-methyl-4-forgenerating)-4-(1,2,3,4 - tetrahydroisoquinoline-2-yl)cyclopent[d]pyrimidine hydrochloride

Stage 1: 4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chlorocyclopentane[d] pyrimidine

In accordance with the methodology stage 1 of example 1, except that as starting substances use 1,2,3,4-tetrahydroisoquinoline (0.5 ml, 4 mmol) and 2,4-dichlorocyclopentane[d]pyrimidine (0,79 g, 4 mmol), obtained in stage 3 of example 29, gain of 0.58 g of the named compound. (Yield: 51%)

Stage 2: 2-(2-Methyl-4-forgenerating)-2-(1,2,3,4-tetrahydroisoquinoline-2-yl)cyclopent[d]pyrimidine hydrochloride

After adding 4-fluoro-2-methylaniline (0.25 ml, of 2.20 mmol) to a solution of a mixture of 4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-4 - chlorocyclopentane[d]pyrimidine (of 0.58 g, 2.0 mmol) and dimethylformamide (5 ml), obtain 0.34 g called with 1H NMR (DMSO-d6) : to 2.06 (m, 2H), and 2.26 (s, 3H), 2,90 (m, 4H), of 3.12 (t, 2H), of 3.97 (t, 2H), 4,90 (s, 2H), 7,11-7,21 (m, 6H), 9,78 (s, 1H), 13,25 (sm, 1H).

Example 48: Synthesis of 2-(2-methyl-4-forgenerating)-4-(1,2,3,4 - tetrahydroisoquinoline-2-yl)-5,6,7,8-tetrahydroquinazolin hydrochloride

Stage 1: 4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloro-5,6,7,8 - tetrahydroquinazoline hydrochloride

In accordance with the methodology stage 1 of example 1, except that as the original substances using a solution mixture of 1,2,3,4-tetrahydroisoquinoline (2.8 ml, 22 mmol), triethylamine (3.4 ml, 24 mmol), N,N-dimethylformamide (10 ml) and 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (4.0 g, 20 mmol) obtained in step 2 of Example 32, obtain 4.7 g of the named compound. (Yield: 78.4 per cent)

Stage 2: 2-(2-Methyl-4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-5,6,7,8 - tetrahydroquinazolin hydrochloride

After adding 4-fluoro-2-methylaniline (0.75 ml, 6.6 mmol) to a solution of a mixture of 4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloro-5,6,7,8 - tetrahydroquinazoline (from 0.90 g, 3.0 mmol) and dimethylformamide (5 ml), obtain 0.36 g of the above compound in accordance with the method of step 2 of example 1.

Yield: 28%

So pl. 191-193oC

1H NMR (DMSO-d6) : 1,62-1,80 (sm, 4H), and 2.26 (s, 3H), 2,65 (sm, 4H), 2,88 (t, 2H), 3,84 (t, 2H), 4,78 (s, 2H), 7,18 (m, 6H), to 7.67 (m, 1H),hydrogenation hydrochloride

After adding 4-foronline (of 0.60 ml, 6.3 mmol) to a solution of a mixture of 4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloro-5,6,7,8-tetrahydroquinazoline (from 0.90 g, 3.0 mmol) and dimethylformamide (5 ml), gain of 0.62 g of the above compound in accordance with the method of step 2 of example 1.

Yield: 50%

So pl. 215-218oC

1H NMR (DMSO-d6) : 1,62-1,74 (sm, 4H), 2,68 (m, 4H), 2.95 and (t, 2H), 3,90 (m, 2H), a 4.86 (s, 2H), 7,19-7,41 (m, 6H), EUR 7.57 (m, 2H), 10,42 (s, 1H), 11,40 (sm, 1H).

Example 50: Synthesis of 2-(N-methylpentylamino)-4-(1,2,3,4-tetrahydroisoquinoline - 2-yl)-5,6,7,8-tetrahydroquinazolin hydrochloride

After adding N-methylaniline (0,70 ml, 6.3 mmol) to a solution of a mixture of 4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloro-5,6,7,8-tetrahydroquinazoline (from 0.90 g, 3.0 mmol) and dimethylformamide (5 ml), gain of 0.48 g of the above compound in accordance with the method of step 2 of example 1.

Yield: 39%

So pl. 164-167oC

1H NMR (DMSO-d6): 1,59-1,74 (sm, 4H), of 2.64 (t, 2H), 2,78 (m, 4H), 3,51 (s, 3H), of 3.78 (t, 2H), 4.72 in (s, 2H), 7,19-7,17 (m, 4H), 7,38-to 7.50 (m, 5H), 12,18 (sm, 1H).

Example 51: Synthesis of 2-(2-methylphenylimino)-4-(1,2,3,4-tetrahydroisoquinoline - 2-yl)-5,6,7,8-tetrahydroquinazolin hydrochloride

After adding 2-methylaniline (0,30 ml, 2.7 mmol) to a solution of a mixture of 4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloro - 5,6,7,8-tetrahydro the wild stage 2 of example 1.

Yield: 49%

So pl. 173-175oC

1H NMR (DMSO-d6) : 1,63-1.77 in (sm, 4H), 2,32 (s, 3H), 2,65 (m, 4H), 2,88 (t, 2H), 3,85 (t, 2H), 4,80 (s, 2H), 7,09-to 7.32 (m, 7H), 7,72 (m, 1H), 9,67 (s, 1H), 13,43 (sm, 1H).

Example 52: Synthesis of 6-methyl-2-(2-methyl-4-forgenerating)-4-(7-methyl - 4,5,6,7-tetrahydrothieno[2,3-C]pyridine-6-yl) pyrimidine hydrochloride

Stage 1: 6-Methyl-4-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-C]-pyridine-6-yl) -2-chloropyrimidine

In accordance with the methodology stage 1 of example 1, except that as the original substances using 2,4-dichloro-6-methylpyrimidine (3.1 ml, 19 mmol) and 7-methyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine (2.9 g, 19 mmol) of a 1, obtain 2.2 g of the above compound in the form of white crystals. (Yield: 41%)

Stage 2: 6-Methyl-2-(2-methyl-4-forgenerating)-4-(7-methyl - 4,5,6,7 - tetrahydrothieno[2,3-C]pyridine-6-yl)-pyrimidine hydrochloride

After adding 4-fluoro-2-methylaniline (0.5 ml, 4.6 mmol) to a solution of a mixture of 6-methyl-4-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine-6-yl)-2 - chloropyrimidine (0.7 g, 2.5 mmol) and dimethylformamide (10 ml) to obtain 0.45 g of the above compound in accordance with the method of step 2 of example 1.

Output: 44.4% of

So pl. 120-121oC

1H NMR (CDCl3): and 1.54 (DD, 3H), 2.40 a (s, 3H), 2,48 (s, 3H), 2,68 (m, 1H), 2,80 (m, 1H), 3,30 (mm, 1H), 4,45 (DD, 1H), 5,48 (CL-4,5,6,7-tetrahydrothieno[2,3-C] pyridine-6-yl)-2-(4-forgenerating)pyrimidine hydrochloride

After adding 4-foronline (0.4 ml, 3.7 mmol) to a solution of a mixture of 6-methyl-4-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine-6-yl)-2 - chloropyrimidine (0.7 g, 2.5 mmol) and dimethylformamide (10 ml), obtain 0.7 g of the above compound in accordance with the method of step 2 of example 1.

Yield: 71.6% of

So pl. 210-212oC

1H NMR (CDCl3): 1,80 (DD, 3H), 2,42 (s, 3H), 2,80 (m, 2H), 3,40 (mm, 1H), 4,60 (DD, 1H), ceiling of 5.60 (mm, 1H), between 6.08 (d, 1H), 6,80 (m, 1H), was 7.08 (t, 2H), 7,21 (m, 1H), 7,55 (m, 2H), the 10.40 (s, 1H), 13,80 (s, 1H).

Example 54; Synthesis of 6-methyl-2-(N-methylpentylamino)-4-(7-methyl-4,5,6,7 - tetrahydrothieno[2,3-C]pyridine-6-yl)pyrimidine hydrochloride

After adding N-methylaniline (0.45 ml, of 4.05 mmol) to a solution of a mixture of 6-methyl-4-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine-6-yl)-2 - chloropyrimidine (0.75 g, 2.7 mmol) and dimethylformamide (10 ml), obtain 0.52 g of the above compound in accordance with the method of step 2 of example 1.

Output: 49,7%

So pl. 175-178oC

1H NMR (CDCl3): to 1.38 (DD, 3H), 2,50 (SHS, 1H), 2,68 was 3.05 (m, 4H), of 3.45 (m, 1H), 3,90 (s, 3H), 4,27 (DD,.1H), and 5.30 (kV,kV, 1H), 6,02 (d, 1H), 6,78 (d, 1H), 7,10-7,35 (m, 4H), 7,38 - of 7.55 (m, 2H), 13,50 (SHS, 1H).

Example 55: Synthesis of 5,6-dimethyl-2-(2-methyl-4-forgenerating)-4-(7-methyl - 4,5,6,7-tetrahydrothieno[2,3-C]pyridine-6-yl)pyrimidine hydrochloride

Step 1: 5,6-Dimethyl-4-(7-methyl-4,5,6 connection, as the original substances using N,N-dimethylformamide (20 ml), 5,6-dimethyl-2,4-dichloropyrimidine (2.8 g, 16 mmol) obtained in stage 1 of example 12, and 7-methyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine (2.7 g, 17.6 mmol) of receive 2 receive 1.85 g of the named compound. (Output: 39,4%)

Stage 2: 5,6-Dimethyl-2-(2-methyl-4-forgenerating)-4-(7-methyl - 4,5,6,7-tetrahydrothieno[2,3-C]pyridine-6-yl)pyrimidine hydrochloride

After adding 4-fluoro-2-methylaniline (0.5 ml, 4.6 mmol) to a solution of a mixture of 5,6-dimethyl-4-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-C[pyridine-6-yl)-2 - chloropyrimidine (0.68 g, 2.3 mmol) and dimethylformamide (5 ml), obtain 0.12 g of the above compound in accordance with the method of step 2 of example 1.

Output: 12,4%

So pl. > 240oC

1H NMR (CDCl3): to 1.60 (d, 3H), 2,22 (s, 3H), 2,43 (s, 3H),

to 2.55 (s, 1H), 2,72 (sm, 1H), 2,80 (m, 1H), 3,48 (m, 1H), 4,30 (m, 1H), 5,58 (kV, 1H), 6,76 (d, 1H), 6.90 to (m, 2H), 7,18 (d, 1H), 7,44 (m, 1H), of 9.55 (s, 1H), 14,36 (s, 1H).

Example 56: Synthesis of 5-methyl-2-(2-methyl-4-forgenerating)-4-(7-methyl - 4,5,6,7-tetrahydrothieno[2,3-C]pyridine-6-yl)-6-ethylpyrimidine hydrochloride

Stage 1: 5-Methyl-4-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-C]-pyridine-6-yl) -6-ethyl-2-chloropyrimidine

In accordance with the methodology stage 1 of example 1, except that as starting substances ispolzue 4, and 7-methyl-4,5,6,7 - tetrahydrothieno[2,3-C]pyridine (2.4 g, 15.7 mmol) of a 1, gain of 2.23 g of the named compound. (Output: 51,3%)

Stage 2: 5-Methyl-2-(2-methyl-4-forgenerating)-4-(7-methyl-4,5,6,7 - tetrahydrothieno[2,3-C]pyridine-6-yl)-6-ethylpyrimidine hydrochloride

After adding 4-fluoro-2-methylaniline (0.51 ml, 4,59 mmol) to a solution mixture of 5-methyl-4-(7-methyl-4,5,6,7-tetrahydrothieno [2,3-C]pyridine-6-yl)-6-ethyl-2-iloperidone (0.74 g, 2.4 mmol) and dimethylformamide (5 ml), obtain 0.15 g of the above compound in accordance with the method of step 2 of example 1.

Output: 14.4% of

So pl. 178-180oC

1H NMR (DMSO-d6+ TFA) with 1.07 (t, 3H), of 1.75 (d, 3H), of 1.95 (s, 3H), of 2.21 (s, 3H), 2,35 (m, 2H), 2,61 (kV, 2H), 3,34 (m, 2H), of 5.05 (m, 1H), for 6.81 (d, 1H), 6,83-7,20 (m, 3H), 7,50 (d, 1H).

Example 57: Synthesis of 6-methyl-4-(2-methyl-4-forgenerating)-2- (1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

Stage 1: 6-Methyl-2-chloro-4-hydroxypyrimidine

To a solution of a mixture of 6-methyl-2,4-dichloropyrimidine (25 g, 0,153 mol) in tetrahydrofuran (170 ml) is added a 1N-NaOH (420 ml) and stirred for 48 hours at room temperature. The reaction mixture is washed with ethyl ether to remove impurities, acidified with hydrochloric acid, and then extracted with ethyl acetate. Ethylacetate compound as a yellow solid. (Output: 66,7%)

Stage 2: 6-Methyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -4-hydroxypyrimidine

A solution of a mixture of 6-methyl-2-chloro-4-hydroxypyrimidine (6 g, 37.5 mmol) obtained in the above stage 1, 1-methyl-1,2,3,4-tetrahydroisoquinoline (11.6 g, of 78.8 mmol) and N,N-dimethylformamide (30 ml) was stirred at 120oC for 2 hours and cooled, getting solid. The obtained solid substance was dissolved in a solution mixture of dichloromethane and methanol, and nerastvorimaya substance is filtered off. The filtrate is washed repeatedly with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, obtaining of 7.1 g of the named compound. (Yield: 74.1 per cent).

Stage 3: 6-Methyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -4-chloropyrimidine

A solution of a mixture of 6-methyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-4 - hydroxypyrimidine (7.0 g, a 27.4 mmol) obtained in the above stage 2, phosphorous oxychloride (30 ml) and N,N-dimethylaniline (2.3 ml) was stirred at 90oC for 2 hours and cooled. The reaction mixture was added to chilled water and alkalinized with sodium bicarbonate and then extracted with ethyl ether. The layer of ethyl ether is dried over anhydrous sodium sulfate, and concentrate under ponot)-2-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

2-Methyl-4-ftoranila (1.1 ml, 10.2 mmol) are added to a solution mixture of 6-methyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-4 - chloropyrimidine (1.5 g, 5.5 mmol) and dimethylformamide (10 ml). The reaction solution is stirred for 3 hours and cooled to room temperature. The reaction mixture was diluted with dichloromethane and washed with water. The dichloromethane layer is separated, alkalinized with an aqueous solution of sodium hydroxide, washed with water, dried and concentrated in vacuo. The resulting residue is purified column chromatography on silica gel, getting a named connection in the form of a free base in the form of oil. A named connection in the form of a free base is dissolved in ethyl ether, then there is added hydrochloric acid. The formed solid is filtered off, dried under reduced pressure, obtaining 0.9 g of the named compound.

Yield: 41%

So pl. 157-160oC

1H NMR (DMSO-d6) : 1,42 (CL, 3H), of 2.25 (s, 3H), 2.40 a (s, 2H), 2,90 (CL, 2H), 3,55 (SHS, 1H), 4,40 (SHS, 1H), ceiling of 5.60 (SHS, 1H), 6,40 (s, 1H), 7,00-7,30 (m, 6H), 7,40 (SHS, 1H), or 10.60 (SHS, 1H), 12,35 (SHS, 1H).

Example 58: Synthesis of 6-methyl-4-(4-forgenerating)-2-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 4-foronline (0.8 ml, 8,4 formamide (10 ml), obtain 1.1 g of the above compound in accordance with the method of stage 4 of example 57.

Yield: 52%

So pl. 165-167oC

1H NMR (DMSO-d6): was 1.58 (d, 3H), of 2.50 (s, 3H), 3.00 and (CL, 2H), 3,60 (SHS, 1H), 4,50 (SHS, 1H), 5,75 (SHS, 1H), 6,38 (SHS, 1H), 7,00-to 7.50 (m, 6H), 7,75 (CL, 2H), 11,20 (SHS, 1H), 12,38 (SHS, 1H).

Example 59: Synthesis of 6-methyl-4-(2-methyl-4-forgenerating)-2-(7-methyl - 4,5,6,7-tetrahydrothieno[2,3-C]pyridine-6-yl)pyrimidine hydrochloride

Stage 1: 6-Methyl-2-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-C]-pyridine-6-yl) -4-hydroxypyrimidine

In accordance with the method of step 2 of example 57, except that as starting substances used 6-methyl-2-chloro-4-hydroxypyrimidine (6 g, 37.5 mmol), obtained in stage 1 of example 57, and 7-methyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine (12,07 g, 78,75 mmol) obtained in the obtaining 1, gain of 6.9 g of the named compound. (Yield: 70%)

Stage 2: 6-Methyl-2-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-C]-pyridine-6-yl) -4-chloropyrimidine

In accordance with the method of stage 3 of example 57, except that as the initial substance use 6-methyl-2-(7-methyl - 4,5,6,7-tetrahydrothieno[2,3-C] pyridine-6-yl)-4-hydroxypyrimidine (6.5 g, 24,9 mmol) obtained in the above stage 1, obtain 4.5 g of the named compound. (Yield: 70%)

Stage 3 After adding 2-methyl-4-foronline (0,38 ml, of 3.42 mmol) to a solution of a mixture of 6-methyl-2-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine-6-yl)-4 - chloropyrimidine (0.5 g, 1.8 mmol) and dimethylformamide (10 ml), obtain 0.35 g of the above compound in accordance with the method of stage 4 of example 57.

Yield: 48%

So pl. 135-137oC

1H NMR (CDCl3): / 1,43 (CL, 3H), 2,22 (s, 3H), 2,42 (s, 3H), 2,70 (CL, 2H), 3,36 (SHS, 1H) and 4.65 (m, 1H), 5,70 (m, 1H), 6,38 (SHS, 1H), 6,85 (d, 1H),? 7.04 baby mortality-7,30 (m, 2H), 7,34-to 7.50 (m, 2H), of 10.58 (SHS, 1H), 12,42 (SHS, 1H).

Example 60: Synthesis of 6-methyl-4-(4-forgenerating)-2-(7-methyl-4,5,6,7 - tetrahydrothieno[2,3-C]pyridine-6-yl)pyrimidine hydrochloride

After adding 4-foronline (of 0.26 ml, is 2.74 mmol) to a solution of a mixture of 6-methyl-2-(7-methyl-4,5,6,7-tetrahydrothieno[2, 3-C] pyridine-6-yl)-4-chloropyrimidine (0.5 g, 1.8 mmol) and dimethylformamide (10 ml), gain of 0.30 g of the above compound in accordance with the method of stage 4 of example 57.

Output: 42,6%

So pl. 245-247oC

1H NMR (DMSO-d6) : 1,58 (doctor 3H), 2,42 (s, 3H), of 2.81 (m, 2H), 3,48 (m, 1H), with 4.64 (m, 1H), of 5.75 (m, 1H), and 6.25 (s, 1H), 6.90 to (d, 1H), 7,30 (m, 3H), 7,42 (d, 2H), of 7.70 (m, 2H).

Example 61: Synthesis of 6-ethyl-2-(2-methyl-4-forgenerating)-4-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

Stage 1: 6-Ethyl-2-chloro-4-hydroxypyrimidine

In accordance with the methodology stage 1 of example 57, except the first in getting 2, obtain 14.6 g of the named compound. Output: 66,7%.

Stage 2: 6-Ethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-4 - hydroxypyrimidine

In accordance with the method of step 2 of example 57, except that as starting substances used 6-ethyl-2-chloro-4-hydroxypyrimidine (7.0 g, 37.5 mmol) obtained in the above stage 1, and 1-methyl-1,2,3,4-tetrahydroisoquinoline (11,04 g, 75 mmol), gain of 8.1 g of the named compound. Yield: 80%.

Stage 3: 6-Ethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -4-chloropyrimidine

In accordance with the method of stage 3 of example 57, except that as the initial substance use 6-ethyl-2-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)-4-hydroxypyrimidine (8.0 g, 29.7 mmol) obtained in the above step 2, obtain 4.9 g of the named compound. Output: 57.3 per cent.

Stage 4: 6-Ethyl-4-(2-methyl-4-forgenerating)-2-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 2-methyl-4-foronline (1.1 ml, 10.2 mmol) to a solution of a mixture of 6-Ethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-4-chloropyrimidine (2.0 g, 7.0 mmol) and dimethylformamide (10 ml), obtain 1.1 g of the above compound in accordance with the method of stage 4 of example 57.

Yield: 38%

of 6.45 (s, 1H), 7,08-7,52 (m, 7H), 10,61 (s, 1H), 12,27 (s, 1H).

Example 62: Synthesis of 6-ethyl-4-(2-methyl-4-forgenerating)-2-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

Stage 1: 6-Ethyl-2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-4 - hydroxypyrimidine

In accordance with the method of step 2 of example 57, except that as starting substances used 6-ethyl-2-chloro-4-hydroxypyrimidine (7.0 g, 37.5 mmol), obtained in stage 1 of example 59, and 1,2,3,4-tetrahydroisoquinoline (9.4 ml, 75 mmol), gain of 8.1 g of the named compound. Output: 84,6%.

Stage 2: 6-Ethyl-2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-4-chloropyrimidine

In accordance with the method of step 2 of example 57, except that as the initial substance use 6-ethyl-2-(1,2,3,4 - tetrahydroisoquinoline-2-yl)-4-hydroxypyrimidine (8.0 g, 31,3 mmol) obtained in the above stage 1, gain of 4.7 g of the named compound. (Yield: 55%)

Stage 3: 6-Ethyl-4-(2-methyl-4-forgenerating)-2-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After Dawley 2-methyl-4-foronline (0,35 ml of 3.15 mmol) to a solution of a mixture of 6-ethyl-2-(1, 2,3, 4-tetrahydroisoquinoline-2-yl)-4-chloropyrimidine (0.40 g, of 1.46 mmol) and dimethylformamide (10 ml), obtain 0.51 g of the above compound in accordance with the methodology, 3H), 2,74-2,95 (m, 4H), 3,88 (t, 2H), a 4.83 (s, 2H), 6,44 (s, 1H), 7,05-of 7.55 (m, 7H), to 10.62 (s, 1H), 12,30 (s, 1H).

Example 63: Synthesis of 6-ethyl-4-(4-forgenerating)-2-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 4-foronline (0,30 ml, 3,17 mmol) to a solution of a mixture of 6-ethyl-2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-4-chloropyrimidine (0.40 g, of 1.46 mmol) and dimethylformamide (10 ml), gain of 0.44 g of the above compound in accordance with the method of stage 4 of example 57.

Yield: 78%

So pl. 122-126oC

1H NMR (CDCl3): 1,41 (kV, 3H), 2,70-2,95 (m, 4H), 4,05 (CL, 2H), 4.95 points (s, 2H), 6,16 (s, 1H), 6,35-to 6.80 (t, 2H),? 7.04 baby mortality-7,14 (m, 4H), 7,66 to 7.75 (DD, 2H), 11,05 (s, 1H), 12,06 (s, 1H).

Example 64: Synthesis of 6-ethyl-4-(N-methylpentylamino)-2-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding N-methylaniline (0.10 ml, which 9.22 mmol) to a solution of a mixture of 6-ethyl-2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-4 - chloropyrimidine (1.20 g, of 4.38 mmol) and dimethylformamide (10 ml), get 0,22 g of the above compound in accordance with the method of stage 4 of example 57.

Yield: 13%

So pl. 130-132oC

1H NMR (CDCl3): to 1.15 (t, 3H), 2,97 is 3.15 (m, 4H), 3,55 (s, 3H), of 4.38 (CL, 2H), 5,10 (CL, 2H), 5,50 (s, 1H), 7,10-7,40 (m, 6H), 7,50-of 7.60 (m, 3H), 13,40 (s, 1H).

Example 65: Synthesis of 5,6-dimethyl-4-(2-methyl-4-forgenerating)-2-(1-methyl - 1,2,3,4-tetr is and 5,6-dimethyl-2,4-dihydroxypyrimidine (72 g, 0.51 mol), phosphorus oxychloride (250 ml) and N,N-dimethylaniline (41 ml) is refluxed for 3 hours and cooled to room temperature. The reaction mixture was added to ice water, and the resulting solid is filtered off and recrystallized from dichloromethane, getting 58.5 g of the named compound. (Yield: 64.7 per cent)

Stage 2: 5,6-Dimethyl-2-chloro-4-hydroxypyrimidine

In accordance with the methodology stage 1 of example 57, except that as the starting material using 5,6-dimethyl-2,4-dichloropyrimidine (50.0 g, 0.28 mmol) obtained in the above stage 1, obtain 24.4 g of the named compound. (Yield: 55%)

Stage 3: 5,6-Dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -4-hydroxypyrimidine

In accordance with the method of step 2 of example 57, except that as the starting material using 5,6-dimethyl-2-chloro-4 - hydroxypyrimidine (6.0 g, 37.8 mmol) obtained in the above step 2, obtain 7.6 g of the named compound. (Yield: 75%)

Stage 4: 5,6-Dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -4-chloropyrimidine

In accordance with the method of stage 3 of example 57, except that as the starting material using 5,6-dimethyl-2-(1-methyl - 1,2, of 3.9 g of the named compound. (Yield: 52%)

Stage 5: 5,6-Dimethyl-4-(2-methyl-4-forgenerating)-2-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 2-methyl-4-foronline (0.7 ml, 6.3 mmol) to a solution of a mixture of 5,6-Dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-4-chloropyrimidine of 0.85 g, 3.0 mmol) and dimethylformamide (10 ml), obtain 0.9 g of the above compound in accordance with the method of stage 4 of example 57.

Output: 72,6%

So pl. 208-211oC

1H NMR (DMSO-d6): of 1.28 (d, 3H), of 2.16 (s, 3H), of 2.18 (s, 3H), by 2.55 (s, 3H), 2,80 (sm, 2H), 3,42 (sm, 1H), 4,34 (sm, 1H), 5,44 (sm, 1H), 7,02 (sm, 1H), 7,24 (m, 6H), 9,65 (s, 1H), 12,30 (sm, 1H).

Example 66: Synthesis of (R)-5,6-dimethyl-4-(2-methyl-4-forgenerating)-2-(1 - methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-pyrimidine hydrochloride

Stage 1: (R)-5,6-Dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -4-hydroxypyrimidine

In accordance with the method of step 2 of example 57, except that as the original substances using 5,6-dimethyl-2-chloro-4 - hydroxypyrimidine (6.0 g, 37.8 mmol) obtained in example 60 and (R)-1-methyl-1,2,3,4-tetrahydroisoquinoline (11,7 g, 79.5 mmol), obtain 7.0 g of the named compound. (Yield: 68.8 per cent).

Stage 2: (R)-5,6-Dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -4-chloropyrimidine

In accordance with the IU shall ethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -4-hydroxypyrimidine (7.0 g, 26 mmol) obtained in the above stage 1, obtain 3.2 g of the named compound. (Output: 42,8%)

Stage 3: (R)-5,6-Dimethyl-4-(2-methyl-4-forgenerating)-2-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 2-methyl-4-foronline (0,82 ml of 7.35 mmol) to a solution of a mixture of (R)-5,6-dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -4-chloropyrimidine (1.0 g, 3.5 mmol) obtained in the above stage 2, and dimethylformamide (10 ml), obtain 1.2 g of the above compound in accordance with the method of stage 4 of example 57.

Yield: 83%

So pl. 207-209oC

1H NMR (DMSO-d6): of 1.28 (d, 3H), of 2.16 (s, 3H), of 2.18 (s, 3H), by 2.55 (s, 3H), 2,80 (sm, 2H), 3,42 (sm, 1H), 4,34 (sm, 1H), 5,44 (sm, 1H), 7,02 (sm, 1H), 7,24 (m, 6H), 9,65 (s, 1H), 12,30 (sm, 1H).

Example 67: Synthesis of (S)-5,6-Dimethyl-4-(2-methyl-4-forgenerating)-2- (1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-pyrimidine hydrochloride

Stage 1: (S)-5,6-Dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-4-hydroxypyrimidine

In accordance with the method of step 2 of example 57, except that as the original substances using 5,6-dimethyl-2-chloro-4-hydroxypyrimidine (6.0 g, 37.8 mmol) obtained in example 60, and (S)-1-methyl-1,2,3,4-tetrahydroisoquinoline (11,7 g, 79.5 mmol), obtain 6.6 g of the named compound. the accordance with the method of step 2 of example 57, except that as the initial substance use (S)-5,6-dimethyl-2-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)-4-hydroxypyrimidine (7.0 g, 26 mmol) obtained in the above stage 1, obtain 3.5 g of the named compound. (Output: 46,8%)

Stage 3: (S)-5,6-Dimethyl-4-(2-methyl-4-forgenerating)-2-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 2-methyl-4-foronline (0,82 ml of 7.35 mmol) to a solution of a mixture of (S)-5,6-dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -4-chloropyrimidine (1.0 g, 3.5 mmol) obtained in the above stage 2, and dimethylformamide (10 ml), obtain 1.0 g of the above compound in accordance with the method of stage 4 of example 57.

Output: 69,2%

So pl. 208-210oC

1H NMR (DMSO-d6): of 1.28 (d, 3H), of 2.16 (s, 3H), of 2.18 (s, 3H), by 2.55 (s, 3H), 2,80 (sm, 2H), 3,42 (sm, 1H), 4,34 (sm, 1H), 5,44 (sm, 1H), 7,02 (sm, 1H), 7,24 (m, 6H), 9,65 (s, 1H), 12,30 (sm, 1H).

Example 68: Synthesis of 5,6-dimethyl-4-(4-forgenerating)-2-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 4-foronline (0.6 ml, 6.3 mmol) to a solution mixture of 5, 6-dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-4-chloropyrimidine of 0.85 g, 3.0 mmol) and dimethylformamide (10 ml), gain of 0.62 g of the above compound in accordance with IU who 3H), to 2.18 (s, 3H), of 2.50 (s, 3H), 2,88 (sm, 2H), 3,42 (sm, 1H), 4,42 (sm, 1H), 5,62 (sm, 1H), 7,18 (m, 4H), 7,30 (m, 2H), 7,63 (kV, 2H), to 9.70 (s, 1H), 12,30 (sm, 1H).

Example 69: Synthesis of (R)-5,6-Dimethyl-4-(4-forgenerating)-2-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 4-foronline (0.6 ml, 6.3 mmol) to a solution of a mixture of (R)-5,6-dimethyl-2-(1-methyl-1,2,3,4-tetrahydro-isoquinoline-2-yl) -4-chloropyrimidine of 0.85 g, 3.0 mmol) obtained in step 2 of example 61, and dimethylformamide (10 ml), obtain 0.50 g of the above compound in accordance with the method of stage 4 of Example 57.

Output: 41,8%

So pl. 245-248oC

1H NMR (DMSO-d6): of 1.40 (d, 3H), of 2.18 (s, 3H), of 2.50 (s, 3H), 2,88 (sm, 2H), 3,42 (sm, 1H), 4,42 (sm, 1H), 5,62 (sm, 1H), 7,18 (m, 4H), 7,30 (m, 2H), 7,63 (kV, 2H), to 9.70 (s,1H), 12,30 (sm, 1H).

Example 70 Synthesis of (S)-5,6-dimethyl-4-(4-forgenerating)-2-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 4-foronline (0.6 ml, 6.3 mmol) to a solution of a mixture of (S)-5,6-dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-4 - chloropyrimidine of 0.85 g, 3.0 mmol) obtained in step 2 of example 62, and dimethylformamide (10 ml), obtain 0.55 g of the above compound in accordance with the method of stage 4 of example 57.

Yield: 46%

So pl. 245-247oC

1H NMR (DMSO-d6): 1,40 (D.

Example 71: Synthesis of 5,6-dimethyl-4-(N-methylpentylamino)-2-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding N-methylaniline (0.6 ml, 5 mmol) to a solution of a mixture of 5,6-dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-4-chloropyrimidine (0.7 g, 2.4 mmol) and dimethylformamide (10 ml), obtain 0.45 g of the above compound in accordance with the method of stage 4 of example 57.

Yield: 47%

So pl. 91-95oC

1H NMR (CDCl3): of 1.32 (s, 3H), of 1.64 (d, 3H), 1,90 (sm, 1H), 2,72 (s, 3H), 3,02 (sm, 1H), 3,25 (sm, 1H), of 3.56 (s, 3H), 3,70 (sm, 1H), of 5.05 (SHS, 1H), 5,78 (SHS, 1H), 7,20 (m, 6H), 7,42 (m, 3H), 13,44 (s, 1H).

Example 72; Synthesis of (R)-5,6-dimethyl-4-(N-methylpentylamino)-2-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding N-methylaniline (0.6 ml, 5 mmol) to a solution of a mixture of (R)-5,6-dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine (0.7 g, 2.4 mmol) obtained in step 2 of Example 61, and dimethylformamide (10 ml), obtain 0.50 g of the above compound in accordance with the method of stage 4 of example 57.

Output: 52,7%

So pl. 90-93oC

1H NMR (CDCl3): of 1.32 (s, 3H), of 1.64 (d, 3H), 1,90 (sm, 1H), 2,72 (s, 3H), 3,02 (sm, 1H), 3,25 (sm, 1H), of 3.56 (s, 3H), 3,70 (sm, 1H), of 5.05 (SHS, 1H), 5,78 (SHS, 1H), 7,20 (m, 6H), 7,42 (m, 3H), 13,44 (s, 1H).

Example 73: Synthesis of (S)-5,6-Dima is I N-methylaniline (0.6 ml, 5 mmol) to a solution of a mixture of (S)-5,6-dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-4 - chloropyrimidine (0.7 g, 2.4 mmol) obtained in step 2 of example 62, and dimethylformamide (10 ml), gain of 0.42 g of the above compound in accordance with the method of stage 4 of example 57.

Output: 44.4% of

So pl. 91-94oC

1H NMR (CDCl3): of 1.32 (s, 3H), of 1.64 (d, 3H), 1,90 (sm, 1H), 2,72 (s, 3H), 3,02 (sm, 1H), 3,25 (sm, 1H), of 3.56 (s, 3H), 3,70 (sm, 1H), of 5.05 (SHS, 1H), 5,78 (SHS, 1H), 7,20 (m, 6H), 7,42 (m, 3H), 13,44 (s, 1H).

Example 74: Synthesis of 5,6-dimethyl-4-(2-methyl-4-forgenerating)-2-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

Step 1: 5,6-Dimethyl-2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-4 - hydroxypyrimidine

In accordance with the method of step 2 of example 57, except that as the original substances using 5,6-dimethyl-2-chloro-4 - hydroxypyrimidine (6.0 g, 37.8 mmol) obtained in step 2 of example 65, and 1,2,3,4-tetrahydroisoquinoline (10 ml, 79,9 mmol), gain of 7.8 g of the named compound. (Yield: 81%).

Stage 2: 5,6-Dimethyl-2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-4-chloropyrimidine

In accordance with the method of stage 3 of example 57, except that as the starting material using 5,6-dimethyl-2-(1,2,3,4 - tetrahydroisoquinoline-2-yl)-4-hydroxypyrimidine (7.0 g, 26 maetel-4-(2-methyl-4-forgenerating)-2-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 2-methyl-4-foronline (0.3 ml, 2.7 mmol) to a solution mixture of 5, 6-dimethyl-2-(1,2,3,4-tetrahydroisoquinoline-2-yl) -4-chloropyrimidine (0,30 g, 1.0 mmol) and dimethylformamide (10 ml), obtain 0.12 g of the above compound in accordance with the method of stage 4 of example 57.

Yield: 30%

So pl. 117-120oC

1H NMR (DMSO-d6) : to 2.13 (s, 3H), of 2.16 (s, 3H), 2,52 (s, 3H), of 2.81 (t, 2H), 3,79 (t, 2H), 4,74 (s, 2H), 7,00 (sm, 1H), 7,09-7,34 (m, 6H), 9,16 (s, 1H), 12,35 (s, 1H).

Example 75: Synthesis of 5,6-dimethyl-4-(4-forgenerating)-2-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 4-foronline (of 0.24 ml, 2.5 mmol) to a solution of a mixture of 5,6-dimethyl-2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-4-chloropyrimidine (0.33 g, 1.2 mmol) and dimethylformamide (10 ml), obtain 0.31 g of the above compound in accordance with the method of stage 4 of example 57.

Yield: 67%

So pl. 128-130oC

1H NMR (DMSO-d6) : to 2.13 (s, 3H), of 2.53 (s, 3H), 2,90 (t, 2H), 3,93 (t, 2H), a 4.86 (s, 2H), 7.18 in-7,34 (sm, 6H), 7,63 (m, 2H), 9,71 (s, 1H), 12,30 (sm, 1H).

Example 76: Synthesis of 5,6-dimethyl-4-(N-methylpentylamino)-2-(1,2,3,4 - tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding N-methylaniline (0.5 ml, 4.2 mmol) to a solution mixture of 5, 6-dimethyl-2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-4-chloropyrimidine (0.6 g, 2.0 m is and 57.

Yield: 37%

So pl. 209-211oC

1H NMR (DMSO-d6) : 1,24 (s, 3H), 2,41 (s, 3H), 2,98 (t, 2H), 3,52 (s, 3H), 4,07 (t, 2H), 5,02 (s, 2H), 7,24 was 7.45 (m, 9H), 12,65 (sm, 1H).

Example 77: Synthesis of 5,6-dimethyl-4-(2-methyl-4-forgenerating)-2- (7-methyl-4, 5, 6, 7-tetrahydrothieno[2,3-C]pyrimidine hydrochloride

Step 1: 5,6-Dimethyl-4-(7-methyl-4,5,6,7-tetrahydrothieno [2,3-C]pyridine-6-yl)-2-hydroxypyrimidine

In accordance with the method of step 2 of example 57, except that as the original substances using 5,6-dimethyl-2-chloro-4-hydroxypyrimidine (6.0 g, 37.8 mmol) obtained in step 2 of example 65, and 7-methyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine (12.2 g, of 79.6 mmol) obtained in the obtaining 1, obtain 6.5 g of the named compound. (Yield: 62.4 per cent)

Stage 2: 5,6-Dimethyl-4-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine-6-yl) -2-chloropyrimidine

In accordance with the method of stage 3 of example 57, except that as the starting material using 5,6-dimethyl-2-(7-methyl - 4,5,6-tetrahydrothieno[2,3-C]pyridine-6-yl)-4-hydroxypyrimidine (6.0 g, to 21.8 mmol) obtained in the above stage 1, obtain 3.5 g of the named compound. (Output: 54,6%)

Stage 3: 5,6-Dimethyl-4-(2-methyl-4-forgenerating)-2-(7-methyl - 4,5,6,7-tetrahydrothieno[2,3-C]pyridine-6-yl)-pyrimidine hydrochloride

Posperity-6-yl)-4 - chloropyrimidine (0.4 g, 1.4 mmol) and dimethylformamide (10 ml), obtain 0.14 g of the above compound in accordance with the method of stage 4 of example 57.

Yield: 24%

So pl. 134-137oC

1H NMR (DMSO-d6): of 1.35 (d, 3H), and 2.14 (s, 3H), of 2.18 (s, 3H), 2,42 (s, 3H), 2,65 (sm, 2H), 3,56 (sm, 1H), 4,54 (m, 1H), 5.56mm (sm, 1H), at 6.84 (d, 1H), 7,15-7,38 (m, 3H), 7,41 (d, 1H), 9,72 (s, 1H), to 12.44 (sm, 1H).

Example 78: Synthesis of 5,6-dimethyl-2-(7-methyl-4,5,6,7-tetrahydrothieno [2,3-C] pyridine-6-yl)-4-(4-forgenerating)pyrimidine hydrochloride

After adding 4-foronline (0.3 ml, 3 mmol) to a solution of a mixture of 5,6-dimethyl-2-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine-6-yl)-4 - chloropyrimidine (0.4 g, 1.4 mmol) and dimethylformamide (10 ml), obtain 0.15 g of the above compound in accordance with the method of stage 4 of example 57.

Output: 26.5 per cent

So pl. 141-145oC

1H NMR (DMSO-d6): of 1.42 (d, 3H), of 2.16 (s, 3H), 2,52 (s, 3H), 2,70 (sm, 2H), 3,38 (m, 1H) and 4.65 (sm, 1H), 5,75 (sm, 1H), at 6.84 (d, 1H), 7,30 (m, 2H), 7,42 (d, 1H), to 7.61 (m, 2H), 9,80 (c, 1H), br12.62 (sm, 1H).

Example 79: Synthesis of 5,6-dimethyl-4-(N-methylpentylamino)-2-(7-methyl - 4,5,6,7-tetrahydrothieno[2,3-C]pyridine-6-yl)pyrimidine hydrochloride

After adding N-methylaniline (0.5 ml, 4 mmol) to a solution of a mixture of 5,6-dimethyl-2-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine-6-yl)-4 - chloropyrimidine (0.64 g, 2 mmol) and dimethylformamide (10 BR> So pl. 117-120oC

1H NMR (CDCl3): of 1.32 (s, 3H), of 1.65 (d, 3H), of 2.72 (s, 3H), 2,78 (sm, 1H), 3,20 (sm, 1H), 3,51 (sm, 1H), of 3.56 (s, 3H), are 5.36 (sm, 1H), 6,03 (sm, 1H), PC 6.82 (d, 1H), to 6.88 (m, 3H), 7,37-of 7.48 (m, 3H), 14,52 (s, 1H).

Example 80: Synthesis of 5-methyl-6-ethyl-4-(2-methyl-4-forgenerating)-2- (1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

Stage 1: 5-methyl-6-ethyl-2-chloro-4-hydroxypyrimidine

In accordance with the methodology stage 1 of example 57, except that as the starting material using 2,4-dichloro-5-methyl-6-ethylpyrimidine (2.7 g, 14.1 mmol), obtained in the obtaining 4, get 1.8 g of the named compound. (Yield: 72%)

Stage 1: 5-Methyl-6-ethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -4-hydroxypyrimidine

In accordance with the method of step 2 of example 57, except that as a starting substance using 5-methyl-6-ethyl-2-chloro-4-hydroxypyrimidine (1.8 g, 10.1 mmol) obtained in the above stage 1, obtain 2.4 g of the named compound. (Yield: 84%)

Stage 3: 5-Methyl-6-ethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2 - yl)-4-chloropyrimidine

In accordance with the method of stage 3 of example 57, except that as a starting substance using 5-methyl-6-ethyl-2-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)-4-hydroxyben the BR> Stage 4: 5-Methyl-6-ethyl-4-(2-methyl-4-forgenerating)-2-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine hydrochloride

After adding 2-methyl-4-foronline (0,42 ml, 3.8 mmol) to a solution mixture of 5-methyl-6-ethyl-2-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)-4-chloropyrimidine (0.6 g, 2.0 mmol) and dimethylformamide (10 ml) to obtain 0.35 g of the above compound in accordance with the method of stage 4 of example 57.

Yield: 41%

So pl. 270-272oC

1H NMR (DMSO-d6): to 1.22 (t, 3H), of 1.35 (d, 3H), of 2.16 (s, 3H), of 2.20 (s, 3H), 2,75-3,00 (m, 4H), of 3.48 (m, 1H), 4,20 (m, 1H), 5,38 (SHS, 1H), 7,00-7,40 (m, 7H).

Example 81: Synthesis of 4-(2-methyl-4-forgenerating)-2-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)cyclopent[d]pyrimidine hydrochloride

Stage 1: 2-Chloro-4-hydroxycyclopent[d]pyrimidine

In accordance with the methodology stage 1 of example 57, except that as the starting material using 2,4-dichlorocyclopentane[d]pyrimidine (2.7 g, of 14.3 mmol), obtained in stage 3 of example 29, obtain 1.7 g of the named compound. (Output: 69,7%)

Stage 2: 2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2 - hydroxycyclopent[d]pyrimidine

In accordance with the method of step 2 of example 57, except that as the starting substance used 2-chloro-4-hydroxycyclopent[d])

Stage 3: 2-(1-Methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-4 - chlorocyclopentane[d]pyrimidine

In accordance with the method of stage 3 of example 57, except that as the initial substance use 2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) -2-hydroxycyclopent[d]pyrimidine (2.2 g, 7.8 mmol) obtained in the above step 2, obtain 1.5 g of the named compound. (Yield: 64%)

Stage 4: 4-(2-Methyl-4-forgenerating)-2-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)cyclopent[d]pyrimidine hydrochloride

After adding 2-methyl-4-foronline ones (0.46 ml, 4.2 mmol) to a solution mixture of 2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-4-chlorocyclopentane[d] pyrimidine (0.6 g, 2.0 mmol) and dimethylformamide (10 ml), obtain 0.10 g of the above compound in accordance with the method of stage 4 of example 57.

Output: 12%

So pl. 165-168oC

3H NMR (CDCl3): of 1.40 (m, 2H), of 1.62 (d, 3H), 2,22 (m, 2H), 2,30 (s, 3H), 2,62-2,98 (sm, 3H), 3,30 (m, 2H), 3,70 (sm, 1H), 4,73 (SHS, 1H), 5,32 (SHS, 1H), 6,98 (m, 2H), 7,20 (m, 5H), 14,02 (sm, 1H).

Example 82: Synthesis of 2-(2-methyl-4-forgenerating)-4-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)-5,6,7,8-tetrahydroquinazolin hydrochloride

Stage 1: 2-Chloro-4-hydroxy-5,6,7,8-tetrahydroquinazolin

In accordance with the methodology stage 1 of example 57, except what Tadei 2 of example 32, gain of 4.2 g of the named compound. (Yield: 72%)

Stage 2: 2-(1-Methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-4-hydroxy - 5,6,7,8-tetrahydroquinazolin

In accordance with the method of step 2 of example 57, except that as starting compounds using 2-chloro-4-hydroxy-5,6,7,8 - tetrahydroquinazolin (2.0 g, a 10.8 mmol) obtained in the above stage 1, and 1-methyl-1,2,3,4-tetrahydroisoquinoline (3.3 grams, of 22.4 mmol), obtain 1.1 g of the named compound. (Output: 34,5%)

Stage 3: 2-(1-Methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-4-chloro - 5,6,7,8-tetrahydroquinazolin

In accordance with the method of stage 3 of example 57, except that as the initial substance use 2-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)-4-hydroxy-5,6,7,8-tetrahydroquinazolin (1.1 g, 3.7 mmol) obtained in the above step 2, obtain 0.7 g of the named compound. (Output: 60,3%)

Stage 4: 4-(2-Methyl-4-forgenerating)-2-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl)-5,6,7,8-tetrahydroisoquinoline hydrochloride

After adding 4-fluoro-2-methylaniline (0.3 ml, 2.7 mmol) to a solution mixture of 2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-4-chloro-5,6,7,8 - tetrahydroquinazoline (0.35 g, 1.1 mmol) and dimethylformamide (5 ml), obtain 0.15 g of the above compound in accordance with the methodology ), 4H), to 2.18 (s, 3H), 2,85 (sm, 4H), 3,40 (sm, 1H), 3,65 (sm, 2H), 4,25 (m,1H), 5.40 to (sm, 1H), 7,05-7,38 (m, 7H), 9,62 (s, 1H), 12,20 (s, 1H).

Example 83: Synthesis of 4-(2-methyl-4-forgenerating)-2-(1,2,3,4 - tetrahydroisoquinoline-2-yl)-5,6,7,8-tetrahydroquinazolin hydrochloride

Stage 1: 2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-4-hydroxy-5,6,7,8 - tetrahydroquinazolin

In accordance with the method of step 2 of example 57, except that as starting compounds using 2-chloro-4-hydroxy-5,6,7,8 - tetrahydroquinazolin (2.0 g, a 10.8 mmol), obtained in stage 1 of example 82, and 1,2,3,4-tetrahydroisoquinoline (2.8 g, of 22.4 mmol), obtain 0.8 g of the named compound. (Output: 26,3%)

Stage 2: 2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-4-chloro-5,6,7,8 - tetrahydroquinazolin

In accordance with the method of stage 3 of example 57, except that as the initial substance use 2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-4-hydroxy-5,6,7,8-tetrahydroquinazolin (0.8 g, 2.8 mmol) obtained in the above stage 1, obtain 0.6 g of the named compound. (Output: 71,5%)

Stage 3: 4-(2-Methyl-4-forgenerating)-2-(1,2,3,4-tetrahydroisoquinoline-2 - yl)-5,6,7,8-tetrahydroquinazolin hydrochloride

After adding 4-fluoro-2-methylaniline (0.3 ml, 2.7 mmol) to a solution mixture of 2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-4-chloro-5,6,7,8 - tetrahydro the stage 4 of example 57.

Yield: 47.1% of

So pl. 150-152oC

1H NMR (DMSO-d6): 1,76 (sm, 4H), of 2.15 (s, 3H), 2,81 (sm, 4H), 3.46 in (sm, 2H), of 3.77 (sm, 2H), 4,74 (s, 1H), 7,02-7,33 (m, 7H), 9,59 (s, 1H), 12,40 (sm, 1H).

Test 1: Inhibition (H+/K+ATP-ASE activity of the proton pump

The source of the enzyme proton pump get in the same way as in experiment 1-1 WO 94/14795. Further, the inhibiting activity of the proton pump is determined in the same way as in experiment 1-2 WO 94/14795.

Namely, the activity of the proton pump, stimulated Mg++use as a negative comparison group, and the activity stimulated Mg++and K+use as a positive comparative group. Comparative compound was omeprazole.

The test tubes are divided into 4 groups: group 1 as a negative comparison group (n=3), group 2 as a positive comparative group (n=3), group 3 (n=52), which was administered the compound of the present invention, and group 4 (n=52), which was appointed as a comparative compound.

The inhibitory activity of groups 3 and 4 on the activity of proton pump determine, using the compound obtained in the examples and omepra">

Each of groups 1, 2, 3 and 4 add 100 μl of a solution obtained by dissolving magnesium chloride (40 mm) in 40 mm Tris-HCl-buffer (pH 6,0), and 100 μl of the source of the enzyme. Then, all groups, except group 1, add 50 ál of a solution of potassium chloride (50 mm) and 50 μl of a solution of ammonium chloride (6 mm) in 40 mm Tris-HCl-buffer (pH 6,0).

Each of the groups 1 and 2 add 10 ál of dimethyl sulfoxide; group 3 add 10 ál of the solution in which the compound obtained in example a dissolved in dimethyl sulfoxide at 5 different concentrations (n=52). Group 4 add 10 μl of a solution obtained by dissolving omeprazole in dimethyl sulfoxide at 5 different concentrations (37,6, 21,4, 12,2, of 7.0 and 4.0 μm) (n= 52). To ensure total volume of 400 ál there is added 40 mm Tris-HCl buffer (pH 6,0).

Then the test tubes of each group are subjected to pre-incubation at 37oC for 30 minutes. Add 100 ál of a solution of ATP (ATP) (6,6 mm), reaching a reaction volume of 500 μl. After the reaction at 37oC for 30 minutes, to stop the enzymatic reaction add 25% cold trichloroacetic acid. The released inorganic phosphate was determined by an automatic analyzer (Express 550, Corning).

Test 2: Inhibition of gastric secretion

Inhibitory effect on gastric secretion is determined in accordance with the method disclosed in the journal /Shay, H., et al., Gastroenteroloqy, 5, 43-61 (1945).

Rat Sprague-Dawley male with a body weight 20010 g, divided into 3 groups (n=5) and kept in the hunger within 24 hours before the experiment with free access to water. Under ether anesthesia dissect the abdomen and are ligated pylorus is preserved. As a comparative group, group 1 enter intraduodenal amount of 0.5 mg/200 g of 30% aqueous solution of polyethylene glycol 400. Groups 2 and 3 intraduodenal enter the compound of example and omeprazole, respectively, each of which is suspended in 30% aqueous solution of polyethylene glycol 400 at a concentration of 20 mg/kg After closing the abdominal cavity of rats was incubated for 5 hours and then slaughtered by cervical shift. The stomach is extracted, obtaining gastric juice.

Gastric juice centrem, the relative concentrations of the acid and the relative outputs acid test compounds are estimated using equations (I), (II) and (III), and these results are presented in table. 2 (see the end of the description).

Test 3: Test the reversibility

Gastric vesicles receive the same manner as in experiment 4-1 WO 94/14795. The mechanism of inhibiting the activity of the proton pump by connection of the present invention have, in accordance with the so-called method of dilution and flushing (Dilution and Washout method) [see, for example, D. J. Keeling, et al., Biochemical Pharmacology, 42(1), 123-130 (1991)].

Namely, the test tubes are divided into 2 groups, group 1 and 2. Each group is divided into four subgroups. To subgroups 1 and 2 of each group add 90 ál of 5 mm Pipes/Tris buffer (pH of 7.4) and 10 μl of DMSO (DMSO). 90 μl of 5 mm Pipes/Tris buffer (pH of 7.4) and 10 μl of the compound obtained in example 43 (50 μm) are added to subgroups 3 and 4 of each group. All two groups add 100 ál liofilizovannyh vesicles at a concentration of 100 μg protein/ml and then pre-cuberoot at 37oC for 15 minutes.

To subgroups 1 and 3 groups 1 add 2 mm MgCl2. The sub-groups 2 and 4 groups 1 add 2 mm MgCl2and 10 mm KCl. 3 mm ATP (ATP) and added to all subgroups of G/SUP>/K+-ATPase (ATPase) activity of the test compound.

After the above preliminary tuberware each subgroup of group 2 was diluted 50-fold volume of 5 mm Pipes/Tris buffer (pH of 7.4) and then centrifuged for 60 minutes using a Beckman centrifuge (Model L8-80). Supernatant discarded and washed with 10 ml of 5 mm Pipes (PIPE - piperazine-N,N-bis-2-econsultancy acid) buffer (pH of 7.4). The precipitate is suspended with 5 mm pipes /Tris buffer (pH 7,4) as long as the volume will not be the same as preincubation volume.

After that, according to treatment group 1, each of the subgroups of a group 2 process 2 mm MgCl210 μl of KCl and 3 mm ATP. And the final volume of each subgroup of group 2 is brought up to 500 μl. After incubation at 37oC for 30 minutes to measure the inhibition of the activity of H+/K+- ATP-ases (ATP-ase).

And then it (the inhibition of activity) are determined according to the same above-described methods, except that the test compound using the compound obtained in example 75. Inhibition of the activity of H+/K+- ATP-ases (ATPase) before and after dilution and leaching are presented in table. 3 (see the end of the description).

Although this invention is described with respect to specific variants of embodiment, it should be borne in mind that various modifications and changes may be made in the invention by specialists in this field, which does not go beyond the scope of the invention defined by the following claims.

1. Derivatives of pyrimidine of the General formula (I - 1) or (I - 2) or their pharmaceutically acceptable salts

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where R4and R5that may be the same or different, independently represent hydrogen or C1- C3is an alkyl group or, taken together, form cyclopentene or tsiklogeksilnogo ring;

A represents a group of formula (II)

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in which R1and R2represent independently from each other hydrogen or C1- C3is an alkyl group, and R3represents hydrogen, C1- C3is an alkyl group or halogen;

B represents a 1-(substituted)-1,2,3,4-tetrahydroisoquinoline R6represents hydrogen or C1- C3is an alkyl group.

2. Connection on p. 1, selected from the group of the following compounds:

hydrochloride of 2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 6-methyl-2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-(4-forgenerating)pyrimidine;

hydrochloride 6-methyl-2-(N-methylpentylamino)-4-(1-methyl-1-2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

the hydrochloride of 6-ethyl-2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

the hydrochloride of 6-ethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

the hydrochloride of 6-ethyl-2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

the hydrochloride of 6-ethyl-2-(2-methylphenylimino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride of 2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-6-propylpyrimidine;

the hydrochloride of 4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-6-propyl-2-(4-forgenerating)-pyrimidine;

hydrochloride of 2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2 and the in-2-yl)pyrimidine;

hydrochloride (R)-5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride (S)-5,6-dimethyl-2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride (R)-5,6-dimethyl-2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride (S)-5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 5,6-dimethyl-2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride (R)-5,6-dimethyl-2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride (S)-5,6-dimethyl-2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 5,6-dimethyl-2-(phenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride (R)-5,6-dimethyl-2-(4-phenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride (S)-5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 5,6-dimethyl-2-(2-methylphenylimino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-Edina;

hydrochloride 5-methyl-6-ethyl-2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 5-methyl-6-ethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 5-methyl-6-ethyl-2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride of 2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)cyclopent [d] pyrimidine;

hydrochloride of 2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)cyclopent [d] pyrimidine;

hydrochloride of 2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)cyclopent [d] pyrimidine;

hydrochloride of 2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-5,6,7,8-tetrahydroquinazoline;

hydrochloride of 2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-5,6,7,8-tetrahydroquinazoline;

hydrochloride 6-methyl-2-(2-methyl-4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 6-methyl-2-(4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 6-methyl-2-(N-methylpentylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

the hydrochloride of 6-ethyl-2-(2-methyl-4-forgenerating)-4-(1,2,3,4-tetrahydroit is;

the hydrochloride of 6-ethyl-2-(N-methylpentylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

the hydrochloride of 6-ethyl-2-(2-methylphenylimino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 5,6-dimethyl-2-(2-methyl-4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 5,6-dimethyl-2-(4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 5,6-dimethyl-2-(N-methylpentylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 5-methyl-6-ethyl-2-(2-methyl-4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 5-methyl-6-ethyl-2-(4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 5-methyl-6-ethyl-2-(N-methylpentylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride of 2-(2-methyl-4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)cyclopent [d]pyrimidine;

hydrochloride of 2-(2-methyl-4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-5,6,7,8-tetrahydroquinazoline;

hydrochloride of 2-(4-forgenerating)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-5,6,7,8-tetrahydroquinazoline;

hydrochloride of 2-(N-methylpentylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-5,6,7,8-tetrahydroquinazoline;

hydrochloride of 2-(2-methylphenylimino)-4-(1,2,3,-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine-6-yl)pyrimidine;

hydrochloride 6-methyl-4-(7-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine-6-yl)-2-(4-forgenerating)pyrimidine;

hydrochloride 6-methyl-2-(N-methylpentylamino)-4-(7-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine-6-yl)pyrimidine;

hydrochloride 5,6-dimethyl-2-(2-methyl-4-forgenerating)-4-(7-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine-6-yl)pyrimidine;

hydrochloride 5-methyl-2-(2-methyl-4-forgenerating)-4-(7-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine-6-yl)-6-ethyl-pyrimidine;

hydrochloride 6-methyl-4-(2-methyl-4-forgenerating)-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 6-methyl-4-(4-forgenerating)-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 6-methyl-4-(2-methyl-4-forgenerating)-2-(7-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine-6-yl)pyrimidine;

hydrochloride 6-methyl-4-(4-forgenerating)-2-(7-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine-6-yl)pyrimidine;

the hydrochloride of 6-ethyl-2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

the hydrochloride of 6-ethyl-4-(2-methyl-4-forgenerating)-2-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

the hydrochloride of 6-ethyl-4-(4-forgenerating)-2-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

the hydrochloride of 6-ethyl-4-(N-methylpentylamino)-2-(1,2,3,4-tetrahydroxy the Jn-2-yl)pyrimidine;

hydrochloride (R)-5,6-dimethyl-4-(2-methyl-4-forgenerating)-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride (S)-5,6-dimethyl-4-(2-methyl-4-forgenerating)-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 5,6-dimethyl-4-(4-forgenerating)-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride (R)-5,6-dimethyl-4-(4-forgenerating)-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride (S)-5,6-dimethyl-4-(4-forgenerating)-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 5,6-dimethyl-4-(N-methylpentylamino)-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride (R)-5,6-dimethyl-4-(N-methylpentylamino)-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride (S)-5,6-dimethyl-4-(N-methylpentylamino)-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 5,6-dimethyl-4-(2-methyl-4-forgenerating)-2-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 5,6-dimethyl-4-(4-forgenerating)-2-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 5,6-dimethyl-4-(N-methylpentylamino)-2-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

hydrochloride 5,6-dimethyl-4-(2-methyl-4-forgenerating)-2-(7-methyl-4,5,6,7-tetrahydrothieno [2,3-c]feast is Ino)pyrimidine;

hydrochloride 5,6-dimethyl-4-(N-methylpentylamino)-2-(7-methyl-4,5,6,7-tetrahydrothieno [2,3-c]pyridine-6-yl)pyrimidine;

hydrochloride 5-methyl-6-ethyl-4-(2-methyl-4-forgenerating)-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;

the hydrochloride of 4-(2-methyl-4-forgenerating)-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)cyclopent [d] pyrimidine;

hydrochloride of 2-(2-methyl-4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-5,6,7,8-tetrahydroquinazoline; and

the hydrochloride of 4-(2-methyl-4-forgenerating)-2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-5,6,7,8-tetrahydroquinazoline.

3. Connection on p. 1, in which the pharmaceutically acceptable salt is a hydrochloride, sulfate, phosphate, nitrate, tartrate, fumarate, citrate, mesilate or acetate derivative of formula (I-1) or (I-2).

4. A method of obtaining a pyrimidine derivative of the formula (I-1), which involves the reaction of the compounds of formula (IV) with the compound of the formula (V-1) or (V-2) obtaining the compounds of formula (VI-1) and the reaction of the compound of formula (VI-1) with the compound of the formula (VII)

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where A, B, R1, R2, R3, R4, R5and R6have the meanings given in paragraph 1.

5. The method according to p. 4, characterized in that the reaction of the compound of the formula is dichloromethane, acetone, acetonitrile and dimethylformamide, and a base selected from the group consisting of triethylamine, N, N-dimethylaniline and pyridine.

6. A method of obtaining a pyrimidine derivative of the formula (I-2), which includes the hydrolysis of compounds of formula (IV) in its 4-position with obtaining the compounds of formula (VIII); the reaction of the compound of formula (VIII) with the compound of the formula (V-1) or (V-2) to obtain the compounds of formula (IX); chlorination of compounds of formula (IX) in its 4-position with obtaining the compounds of formula (VI-2) and then the reaction of the compound of formula (VI-2) with the compound of the formula (VII)

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< / BR>
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< / BR>
< / BR>
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< / BR>
where A, B, R1, R2, R3, R4, R5and R6have the meanings given in paragraph 1.

7. Pharmaceutical composition having protivoraketnoi activity, characterized in that it contains a therapeutically effective amount of a derivative of pyrimidine under item 1 and a pharmaceutically acceptable carrier.

 

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where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

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in which R and m have the above meanings;

Y - group

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where R is the specified value,

mixtures of their isomers or the individual is
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