Derivatives of pyrimidine, pharmaceutical composition, inhibition method and using

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

 

The technical field to which the invention relates.

The present invention relates to new pyrimidine derivative, method of its production, to its containing pharmaceutical preparation and to its use.

Prior art

Adenosine is an important regulatory factor involved in many intracellular processes and metabolism in a living organism, such as regulation of energy levels, levels of cyclic amp (camp), the opening and closing of potassium channels and calcium ions flow into the cells and its interaction with G-protein-coupled adenosine receptors on the cell surface is important for the manifestation of these physiological activities. Adenosine receptors are divided into two subtypes: (A1-a receptor and a2-the receptor, based on the involvement of adenylate cyclase (J. Neurochem., 33, 999-1003, (1979)), and A2the receptor is divided into two subtypes, And2Aand a2Bon the basis of affinity for agonists And2-receptor, NECA and CGS-21680 (Mol. Pharmacol., 29, 331-346, (1986); J. Neurochem., 55, 1763-1771, (1990)). By now identified four subtypes of receptors: A1And2(A2Aand a2Band a3. And1a receptor is a protein associated with the protein family of Gi/o. It serves to inhibition of adenylate cyclase in the binding ligand and red eye reduction is of the most level of camp, and for activation of phospholipase C (PLC), to thereby contribute to the production of Inositol-1,4,5-triphosphate (IP3) and release of intracellular calcium ions. And3the receptor is a receptor that serves as A1-a receptor, to reduce the level of camp and activation of PLC, to thereby promote products IP3and release calcium ions. On the contrary, A2Aand And2Breceptors are receptors that serve to activate adenylate cyclase activity and promotion of the production of camp. There is a message stating that a2B-receptor mates with PLC through Gq/G11protein and promotes products IP3and the flow of calcium ions into cells (Clin. Invest., 96, 1979-1986 (1995)). These subtypes differ from each other in their tissue distribution, namely a1-a receptor in a relatively large number of common, for example, in heart, aorta and bladder, And2A-a receptor in a relatively large number of distributed, for example, in the muscles of the eyeballs and skeletal muscle, And3receptor-for example, in the spleen, uterus, and prostate gland and a2Breceptor-for example, in the proximal colon, as well as in the eyeballs, lung, uterus, and urinary bladder (Br. J. Pharmacol., 118, 1461-1468 (1996)). I believe that these subtypes of adenosine receptors can perform a specific function, is respectively, due to the difference in tissue distribution, and the difference in the level of adenosine in places and the difference between the subtypes in the affinity to the ligand. Adenosine is involved in various physiological functions, such as platelet aggregation, heart rate, smooth muscle tone, inflammation, release of neurotransmitters, neurotransmission, release of hormones, cell differentiation, cell growth, cell death and DNA biosynthesis. Therefore, it is assumed link between adenosine and diseases, such as diseases of the Central nervous system, cardiovascular diseases, inflammatory diseases, respiratory diseases and immune diseases, and it is expected the effective action of agonists and antagonists of adenosine receptors on these diseases. Already described antagonists for adenosine receptors, in particular antagonists to adenosine A2receptors, effective as a means for the treatment or prevention of diabetes, diabetic complications, diabetic retinopathy, obesity or asthma and are expected useful as hypoglycemic agents, tools to facilitate glucose intolerance, a means to increase sensitivity to insulin, antihypertensives, diuretics, antidepressant, with whom estva for the treatment of osteoporosis, for the treatment of Parkinson's disease, for the treatment of Alzheimer's disease, a treatment for inflammatory diseases of the digestive tract or for the treatment of Crohn's disease.

There have been several important messages about the relationship between adenosine A2receptor and intestinal tract. For example, there were several reports that A2the receptor mediates relaxing effect on the longitudinal muscle of the colon (Naunyn-Schmiedeberg''s Arch. Pharmacol., 359, 140-146 (1999)) and a1and And2Breceptors located in the longitudinal muscle, mediate the relaxing effect of adenosine on the contraction of the longitudinal muscles of the distal colon of the Guinea pig (Br. J. Pharmacol., 129, 871-876 (2000)). Have recently found a link between a2Breceptor and constipation and other diseases of the digestive organs, and there is a message about the antagonist And2B-receptor, applicable as a means of urinating, and means for the treatment or prevention of various types of constipation (JP-A 2000-126489). Such antagonists And2B-receptor does not cause diarrhea, have excellent defecation-promoting action and presumably can be used as a tool for treatment and/or prevention of various constipation. It is also expected that they will be useful for the treatment and/or prevention of syndrome is astrazenec colon, constipation, associated with irritable bowel syndrome, organic constipation, constipation accompanying enteroparasites bowel obstruction, and bowel movements during examination of digestive tracts or before or after the operation.

In addition, it was reported that the formation of the clinical condition of Parkinson's disease in addition to dopamine very closely involved adenosine via adenosine A2Athe receptor. For example, it was reported that the effects of improving the symptoms of Parkinson's disease was increased by the use of L-DOPA together with theophylline, which is known as non-selective antagonist of adenosine receptors (J. Pharm. Pharmacol., 46, 515-517 (1994)). It is also known that selective antagonists of adenosine A2A-receptor effective against various types of animal models of Parkinson's disease (JP 1994-A). Parkinson's disease is caused by degradation or destruction of dopaminergic neurons projecting from the thick layer of black substance of the mid-brain in the striatum. Although the disease cannot be prevented, however, symptomatic treatment drugs L-DOPA is the main treatment that compensates for the lack of dopamine. However, prolonged use of drugs L-DOPA reduces efficiency and causes some side effects, such as nepresso the performance communications traffic and mental symptoms. Therefore, the biggest problem is that using drugs L-DOPA, it is impossible to achieve sufficient therapeutic effects. The distribution of adenosine A2Areceptors in the brain is limited to the striatum, nucleus accumbens and olfactory tubercle (Eur. J. Pharmacol., 168, 243-246 (1989)), it is therefore considered that the adenosine A2Areceptors play an important role in the regulation of motor function in the striatum. Furthermore, it is known that the degradation of dopaminergic neurons in the dense layer of black substance midbrain does not affect the ability striped body contact adenosine A2Areceptor, and there is no difference between subjects suffering from Parkinson's disease, and subjects with normal health in relation to the total number of adenosine A2Areceptors (Neuroscience, 42, 697-706, 1991). Recently it has also been reported that selective antagonists of adenosine A2Areceptors harmless and improve motor function of subjects suffering from advanced Parkinson's disease, without amplification dyskinesia as using drugs L-DOPA (Neurology, 58 (6, S) S21. 001 (2002.4)). As can be seen from these found materials, antagonists of adenosine A2Areceptors are useful as therapeutic agents against Parkinson's disease.

Trace the matter of connection is known as a connection having an antagonistic effect on adenosine A2Aand/or And2Breceptors:

(1) Compounds represented by the following formula:

(2) purine Derivative represented by the formula:

(where R1represents (1) formula:

(where X represents a hydrogen atom, hydroxyl group, lower alkyl group which may be substituted, lower alkoxygroup, which may be substituted, and so on, and R5and R6are the same or different from each other and represent each a hydrogen atom, a lower alkyl group which may be substituted, saturated or unsaturated cycloalkyl group having three to eight carbon atoms which may be substituted, etc) or (2) a 5 - or 6-membered aromatic cycle, which may have one or more substituents and heteroatom; W represents the formula-CH2CH2-, -CH=CH - or-C=C-; R2represents an amino group which may be substituted by a lower alkyl group which may be substituted, etc.; R3represents cycloalkyl group having three to eight carbon atoms which may be substituted, arilje the second group, which may be substituted, and so on, and R4represents a lower alkyl group which may be substituted, and so on), its pharmacologically acceptable salt or hydrate (JP-A 11-263789).

(3) purine Derivative represented by the formula:

(where R1represents a hydrogen atom, hydroxyl group, halogen atom, alkyl group having one to eight carbon atoms which may be substituted, etc.; R2represents an amino group which may be substituted by an alkyl group having one to eight carbon atoms, etc.; R3represents alkylamino group having three to eight carbon atoms which may be substituted by halogen atom, hydroxyl group or alkyl group having one to four carbon atoms, etc.; Ar represents an aryl group which may be substituted, a heteroaryl group which may be substituted, etc. Q and W are the same or different from each other and are each N or CH), its pharmacologically acceptable salt or hydrate (JP-A 11-188484).

(4) Antagonists And2Breceptors described in Drug Development Research, 48: 95-103 (1999) and J. Med. Chem., 43: 1165-1172 (2000).

(5) Antagonists And2Breceptors represented by the following formula:

As for the pyrimidine derivatives, there are only messages pertaining to 5-6-aromatic substituted derivatives of pyrimidine, in publications such as WO97/33883, WO98/24782 and WO99/65897. However, the relationship between these compounds and adenosine receptors is not mentioned and is not expected and therefore not yet known.

As described above, compounds exhibiting antagonism to the adenosine receptors, including compounds exhibiting antagonism to the adenosine A2receptors, and, in particular, compounds exhibiting antagonism to the adenosine A2Aand/or And2B-receptors, as expected, can provide an excellent effect as a drug, and there is a great need for the creation of such compounds. However, compounds exhibiting strong antagonism to the adenosine receptors and effective as a drug, still not found. Therefore, the aim of the present invention are finding compounds that serve to inhibition of adenosine receptors (in particular, adenosine A2Aand And2Breceptors and are useful as drugs for the treatment or prevention of diseases which are related adenosine receptors.

The invention

After intensive research, the ri of these circumstances, the creators of this invention succeeded, first, to synthesize the compound represented by the formula:

(in the formula, R1and R2are the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, acyl group having one to six carbon atoms which may be substituted, or alkylsulfonyl group having one to six carbon atoms which may be substituted; R3represents a hydrogen atom, halogen atom, cyano, alkyl group having one to six carbon atoms, which m which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, a nitrogen atom which may be substituted, an oxygen atom which may be substituted or a sulfur atom which may be substituted; R4represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, or a 5 to 14-membered non-aromatic heterocyclic group having at least one or more unsaturated bonds, which may be substituted, and R5represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted), its salt or their MES. It has been unexpectedly found that the compound, its salt or their MES has excellent adenosine antagonism to sub> 2-receptors, in particular to a2Aand/or And2Bthe receptor. As a result, subsequent intensive research it was found that the compound, its salt or their MES significant effects on diseases that are related adenosine receptors, particularly adenosine A2receptors, and more particularly adenosine A2Aand/or And2B-a receptor, and effective in the prevention and/or treatment of various constipation (constipation, irritable bowel syndrome, constipation, associated with irritable bowel syndrome, organic constipation, constipation accompanying enteroparasites ileus, constipation accompanying congenital dysfunction of the digestive tract, or constipation accompanying ileus), and can also be used as a means for the treatment, prevention or relief percolation, for example, diabetes, diabetic complications, diabetic retinopathy, obesity or asthma and as hypoglycemic agents, tools to facilitate glucose intolerance, means for increasing the sensitivity of to insulin, antihypertensives, diuretics, antidepressant, means for treatment of osteoporosis and for the treatment of Parkinson's disease, for the treatment of Alzheimer's disease, is the means for the treatment of inflammatory diseases of the digestive tract or for the treatment of Crohn's disease. On the basis of these discoveries have established the present invention.

Thus, in accordance with the present invention proposed (1) a compound represented by the formula:

(in the formula, R1and R2are the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, acyl group having one to six carbon atoms which may be substituted, or alkylsulfonyl group having one to six carbon atoms which may be substituted; R3is the Wallpaper a hydrogen atom, halogen atom, cyano, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, a nitrogen atom which may be substituted, an oxygen atom which may be substituted or a sulfur atom, which may be substituted; R4represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, or a 5 to 14-membered non-aromatic heterocyclic group having at least one or more unsaturated bonds, which may be substituted, and R5represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted), its salt or their MES; (2) soy is inania, described in (1), its salt or their MES, where R1and R2are the same or different from each other, and each of them represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group, which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, acyl group having one to six carbon atoms which may be substituted, or alkylsulfonyl group having one to six carbon atoms which may be substituted (provided that the excluded group represented by the formula:

(where a represents an aromatic hydrocarbon cyclic group having six to fourteen ug is urodnich atoms, which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted; X1and X2are the same or different from each other, and each of them represents a carbon atom which may be substituted, and X3represents a nitrogen atom which may be substituted, an oxygen atom or a carbon atom which may be substituted)); R3represents cyano and R4represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, or a 5 to 14-membered non-aromatic heterocyclic group having one or more unsaturated bonds, which may be substituted; (3) the compound described in (1), its salt or their MES, where R1and R2are the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group with the ri-eight carbon atoms, which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, acyl group having one to six carbon atoms which may be substituted, or alkylsulfonyl group having one to six carbon atoms which may be substituted (provided that the excluded group, represented formula:

(where a represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted; X1and X2are the same or different from each other and each represents a carbon atom which may be substituted, and X3represents a nitrogen atom which may be substituted, an oxygen atom or a carbon atom which may be substituted)); R3represents a halogen atom, alkyl group, and euwww one to six carbon atoms, which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, an oxygen atom which may be substituted or a sulfur atom which may be substituted, and R4is a 4-pyridyloxy group, 4-pyrimidinyl group, 4-chinazolinei group, 4-pinolillo group or 6-athinodorou group, each of which may have one or two substituent; (4) the compound described in (1), its salt or their MES, where R1and R2are the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon is different atoms, which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, acyl group having one to six carbon atoms which may be substituted, or alkylsulfonyl group having one to six carbon atoms which may be substituted (provided that the excluded group represented by the formula:

(where a represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms, or 5 to 14-membered aromatic heterocyclic group which may be substituted; X1and X2are the same or different from each other and each represents a carbon atom which may be substituted, and X3represents a nitrogen atom which may be substituted, an oxygen atom or a carbon atom which may be substituted)), and R4represents a 5 to 14-membered non-aromatic heterocyclic group having at least one or more unsaturated bonds, which may be substituted (in terms of the AI, what is excluded group, represented shown above formula (II)); (5) the compound described in (1), its salt or their MES, where R1and R2are the same or different from each other, and each of them represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group, which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, acyl group having one to six carbon atoms which may be substituted, or alkylsulfonyl group having one to six carbon atoms which may be substituted (provided that the excluded group represented by the formula:

(where a represents the romantic hydrocarbon cyclic group, having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted; X1and X2are the same or different from each other and each represents a carbon atom which may be substituted, and X3represents a nitrogen atom which may be substituted, an oxygen atom or a carbon atom which may be substituted)), and R4is a 4-pyridyloxy group, 4-pyrimidinyl group, 4-chinazolinei group, 4-pinolillo group or 6-athinodorou group, each of which may have one or two substituent including at least one of ceanography and carbamoyl group represented by the formula:

(where R6and R7are the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl g is the SCP, having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted); (6) the compound described in (2), its salt or their MES, where R4represents a 5 to 14-membered aromatic heterocyclic group which may be substituted, or a 5 to 14-membered non-aromatic heterocyclic group having at least one or more unsaturated bonds, which may be substituted, and R5represents a 5 to 14-membered aromatic heterocyclic group which may be substituted; (7) the compound described in (3), its salt or their MES, where R3represents a halogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, an oxygen atom which may be substituted, or ATO is sulfur, which may be substituted, and R5represents a 5 to 14-membered aromatic heterocyclic group which may be substituted; (8) the compound described in (4), its salt or their MES, where R3represents a hydrogen atom, halogen atom, cyano, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, a nitrogen atom which may be substituted, an oxygen atom which may be substituted or a sulfur atom which may be substituted, and R5represents a 5 to 14-membered aromatic heterocyclic group which may be substituted; (9) the compound described in (5), its salt or their MES, where R3represents a hydrogen atom, halogen atom, cyano, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group is, which may be substituted, an oxygen atom which may be substituted or a sulfur atom which may be substituted, and R5represents a 5 to 14-membered aromatic heterocyclic group which may be substituted; (10) the compound described in any of paragraphs (1)to(9), where R1and/or R2represent a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, or an acyl group having one to sixteen carbon atoms which may be substituted (provided that the excluded group represented by the formula:

(where a represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted; X1and X2are the same or different from each other and each represents a carbon atom which may be substituted, and X3represents a nitrogen atom which may be substituted, an oxygen atom or a carbon atom which may be substituted)), its salt or their MES; (11) the compound described in any of paragraphs (1), (4) and (8), where R4is a group represented by the formula (IV):

(where R8represents a group selected from the following group of substituents, and the ring may be substituted by one to four groups selected from the following group of substituents.

Group a of substituents

Group consisting of hydrogen atom, halogen atom, hydroxyl group, nitro group, ceanography, alkyl groups having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkoxygroup having one to six carbon atoms which may be substituted, alkenylacyl having two to six carbon atoms which may be substituted, alkyloxy having two to six carbon atoms, which may be substituted, ancilliary having one to six carbon atoms which may be substituted, altertekhnogrupp having two to six carbon atoms which may be substituted, alinytjara having two to six carbon atoms which may be substituted, aliphatic acyl group having two to seven carbon atoms, carbamoyl group which may be substituted, Arielle group, heteroallyl group, aminogroup that mo is et to be substituted, alkylsulfonyl group having one to six carbon atoms which may be substituted, alkanesulfonyl group having two to six carbon atoms which may be substituted, alkylsulfonyl group having two to six carbon atoms which may be substituted, alkylsulfonyl group having one to six carbon atoms which may be substituted, alkanesulfonyl group having two to six carbon atoms which may be substituted, alkylsulfonyl group having two to six carbon atoms which may be substituted, formyl group, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, and a 5-14-membered aromatic heterocyclic group which may be substituted), its salt or their MES; (12) the compound described in (11), its salt or their MES, where R3represents a hydrogen atom, halogen atom, cyano, alkyl group having one to six carbon atoms, Kotor which may be substituted, 5-14-membered aromatic heterocyclic group which may be substituted, an amino group or an oxygen atom which may be substituted; (13) the compound described in (11) or (12), where R4is a group represented by the formula:

or the formula:

(in formulas (V) and (VI) R8represents a group selected from the following group of substituents, and the ring may be substituted by one to four groups selected from the following group of substituents.

Group a of substituents

Group consisting of hydrogen atom, halogen atom, hydroxyl group, nitro group, ceanography, alkyl groups having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkoxygroup having one to six carbon atoms which may be substituted, alkenylacyl having two to six carbon atoms which may be substituted, alkyloxy having two to six carbon atoms, which may be substituted, ancilliary having one to six carbon atoms which may be substituted, altertekhnogrupp with DV is six carbon atoms, which may be substituted, alinytjara having two to six carbon atoms which may be substituted, aliphatic acyl group having two to seven carbon atoms, carbamoyl group which may be substituted, Arielle group, heteroallyl group, aminogroup, which may be substituted, alkylsulfonyl group having one to six carbon atoms which may be substituted, alkanesulfonyl group having two to six carbon atoms which may be substituted, alkylsulfonyl group having two to six carbon atoms which may be substituted, alkylsulfonyl group having one to six carbon atoms which may be substituted, alkanesulfonyl group having two to six carbon atoms which may be substituted, alkylsulfonyl group having two to six carbon atoms which may be substituted, formyl group, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms, è5-14-membered aromatic heterocyclic group, which may be substituted), its salt or their MES; (14) the compound described in any of paragraphs (1), (3) and (7), its salt or their MES, where R4is a 4-pyridyloxy group which may have one or two substituent; (15) the compound described in (14), its salt or their MES, where R3represents a halogen atom, a cyano, an alkyl group having one to six carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, or an oxygen atom which may be substituted; (16) the compound described in (14) or (15), where R4is a 4-pyridyloxy group which may have one or two substituent including at least one of ceanography and carbamoyl group represented by the formula (III):

(where R6and R7are the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms, which can the be replaced, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted), its salt or their MES; (17) the compound described in any of paragraphs (1)to(5), its salt or their MES, where R5represents naftalina group or phenyl group, each of which may be substituted; (18) the compound described in any of paragraphs (1)to(16), its salt or their MES, where R5represents pyrrolidino group, pyridyloxy group, pyridazinyl group, pyrimidinyl group, personilnya group, thienyl group, thiazolidine group, follow group, hyalinella group, athinodorou group, talinolol group, naphthyridinone group, indolenine group or isoindolyl group, each of which may be substituted; (19) a pharmaceutical composition comprising the compound described in any of paragraphs (1)to(18), its salt or their MES; (20) the composition described in (19), which is a tool for the treatment or prevention of disease, to which is agains the adenosine receptor; (21) the composition described in (19), which is a tool for the treatment or prevention of disease, which is the ratio of adenosine A2receptor; (22) the composition described in (19), which is a tool for the treatment or prevention of disease, which is the ratio of adenosine A2Areceptor; (23) the composition described in (19), which is a tool for the treatment or prevention of disease, which is the ratio of adenosine A2Breceptor; (24) the composition described in (19), which is an antagonist of adenosine receptor; (25) the composition described in (19), which is an antagonist of adenosine A2receptor; (26) the composition described in (19), which is an antagonist of adenosine A2Areceptor; (27) the composition described in (19), which is an antagonist of adenosine A2Breceptor; (28) the composition described in any of paragraphs(19)-(22), (24)-(26), which is a treatment for Parkinson's disease, or antidepressant; (29) the composition described in any of paragraphs(19)-(21), (23)-(25) and (27), which is the means urinating; (30) the composition described in any of paragraphs(19)-(21), (23)-(25) and (27), which is a tool for the treatment, prevention or improvement of the flow of constipation; (31) the composition described in (30), where constipation assetsfinancial constipation; (32) the composition described in (30), which is a tool for the treatment, prevention or improvement of the flow of irritable bowel syndrome, constipation, associated with irritable bowel syndrome, organic constipation, constipation accompanying enteroparasites ileus, constipation accompanying congenital dysfunction of the digestive tract, or constipation accompanying ileus; (33) the composition described in (19), which is used for emptying the intestinal tracts during examination of digestive tracts or before and after surgery; (34) use of the compound described in any of paragraphs (1)-(18), its salt or their MES for the manufacture of tools, urinating; (35) the composition described in (19), which is a tool for the treatment or prevention of diabetes, diabetic complications, diabetic retinopathy, obesity or asthma; (36) the composition described in (19), which is a hypoglycemic agent, agent for improving glucose intolerance or means for increasing insulin sensitivity; and (37) the composition described in (19), which is an antihypertensive agent, a diuretic, a treatment for osteoporosis treatment for Alzheimer's disease, treatment for inflammatory-related disease is evania digestive tract or treatment for Crohn's disease.

The following describes the meanings of symbols, terms, etc. used in this description, and the present invention is illustrated in more detail.

In this description, the term "antagonist" refers to a tool that has affinitiy to the adenosine receptor, preferably, the adenosine A2-receptor, and more preferably A2Aand/or And2B-receptor and inactivates it.

The expression "disease, which is the ratio of adenosine receptor"used in this description, refers to a disease, which is the ratio of adenosine A1-a receptor, And2A-a receptor, And2B-receptor or a3-the receptor and which includes various fasteners (e.g., functional constipation, irritable bowel syndrome, constipation accompanying irritable bowel syndrome, organic constipation, constipation accompanying enteroparasites ileus, constipation accompanying congenital dysfunction of the digestive tract, or constipation accompanying ileus), diabetes, diabetic complications, diabetic retinopathy, obesity, asthma, and diseases against which effective hypoglycemic agent, agent for improving glucose intolerance, means for increasing insulin sensitivity, hypotens the main tool, diuretic, antidepressant, a remedy for the treatment of osteoporosis, treatment for Parkinson's disease, for the treatment of Alzheimer's disease, a treatment for inflammatory diseases of the digestive tract or treatment for Crohn's disease.

In accordance with the present invention, a method for treatment or prevention of disease, which is the ratio of the adenosine receptor, and a way to facilitate defecation, which include the introduction to the patient a pharmacologically effective dose of the compounds represented by formula (I), its salt or their MES.

In accordance with the present invention also proposed the use of compounds represented by formula (I), its salt or their MES for the manufacture of tools for the treatment or prevention of disease, which is the ratio of the adenosine receptor, or the means urinating.

The compound represented by formula (I), its salt or their MES can also be used as a means of urinating, and used for emptying the intestinal tracts during examination of digestive tracts or before and after the operation.

The term "and/or"used in this description, means and covers both cases: "and" and "or".

In this description for convenience presents the case to the da structural formula represents a specific isomer. But the present invention includes all isomers such as geometrical isomers, optical isomers based on asymmetric carbons, stereoisomers and tautomers, and mixtures of these isomers, and it does not limit the description of the formula shown for convenience. The connection can be any of the isomers or a mixture thereof. Therefore, although in the molecule may contain asymmetric carbon atom and therefore can be optically active and racemic substance substance, the present invention is not limited to and encompasses any of them. In addition, you may be crystalline polymorphism, but again there is no restriction and can be single crystals of any structure or their mixture. The compound (I) or its salt of the present invention can be resoluton or MES, and any of them is included in the scope of the attached claims. In the scope of the claims also includes the metabolite resulting from the decomposition of the compound (I) according to the present inventionin vivoand the prodrug of compound (I) or its salt of the present invention.

The term "halogen atom"used in this description means an atom such as fluorine atom, chlorine atom, bromine atom or iodine atom, and preferred are a fluorine atom, a chlorine atom and a bromine atom.

<> "C1-6alkyl group"used in this description, is an alkyl group having one to six carbon atoms, which comprises an unbranched or branched alkyl groups such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, n-pencilina group, 1,1-dimethylpropylene group, 1,2-dimethylpropylene group, 2,2-dimethylpropylene group, 1-ethylpropyl group, 2-ethylpropyl group, n-exilda group 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-popypropylene group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group or 3-methylpentyl group.

"C2-6Alchemilla group"used in this description, is alkenylphenol group having two to six carbon atoms, and suitable examples of the group include vinyl group, allyl group, 1-protanilla group, 2-protanilla group, Isopropenyl group, 2-methyl-1-protanilla group, 3-methyl-1-protanilla group, 2-methyl-protanilla group, 3-methyl-2-protanilla group, 1-bucinellina group, 2-bucinellina group, 3-bucinellina group, 1-penttila group, 1-examilia group, 1,3-hexadienyl group and 1.6-hexadienyl group.

"C2-6Alchemilla group"used in this description, is alkylamino group having two to six carbon atoms, and suitable examples of the group are etinilnoy group, 1-proponila group, 2-proponila group, 1-Butyrina group, 2-Butyrina group, 3-Butyrina group, 3-methyl-1-proponila group, 1-ethinyl-2-proponila group, 2-methyl-3-proponila group, 1-penicilina group, 1-hexylamine group, 1,3-hexadienyl group and 1.6-hexadienyl group.

"C1-6alkoxygroup"used in this description, is alkoxygroup having one to six carbon atoms, such as methoxy group, ethoxypropan, n-propoxylate, isopropoxide, second-propoxylate, n-butoxypropyl, isobutoxy, second-butoxypropan, tert-butoxypropan, n-pentyloxy, isopentylamine, second-pentyloxy, n-hexachrome, isohexadecane, 1,1-dimethylpropyleneurea, 1,2-DIMETHYLPROPANE, 2,2-dimethylpropylene, 2-ethylpropoxy, 1-methyl-2-ethylpropoxy, 1-ethyl-2-methylpropoxy, 1,1,2-trimethylboroxine, 1,1-di is stilbocarpa, 1,2-dimethylbutyramide, 2,2-dimethylbutyramide, 2,3-dimethylbutyramide, 2-itivuttaka, 1,3-dimethylbutyramide, 2-methylphenoxy, 3-methylphenoxy or hexyloxy.

"C2-6alkenylacyl"used in this description, is alkenylacyl having two to six carbon atoms, and suitable examples of the group are vinyloxy, alliancegroup, 1-propionyloksypo, 2-propionyloksypo, isopropenylacetate, 2-methyl-1-propionyloksypo, 3-methyl-1-propionyloksypo, 2-methyl-2-propionyloksypo, 3-methyl-2-propionyloksypo, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 1-pentyloxy, 1-hexaniacinate, 1,3-hexacyanochromate and 1.6-hexacyanochromate.

"C2-6alkyloxy"used in this description, is alkyloxy having two to six carbon atoms, and suitable examples of the group are atenololviagrawp, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 3-methyl-1-propenyloxy, 1-ethinyl-2-propenyloxy, 2-methyl-3-propenyloxy, 1-pentyloxy, 1-hexyloxy, 1,3-hexadecyloxypropyl and 1.6-hexadecyloxypropyl.

"Allylthiourea having one to six carbon atoms"used in this description, is allylthiourea having one to six carbon atoms, such as methylthiourea, ethylthiourea, n-PropertyGroup, isopropylthio, second-PropertyGroup, n-butylthiourea, isobutylthiazole, second-butylthiourea, tert-butylthiourea, n-intelligroup, isopentype, second-intelligroup, n-vexillographer, isohexanoate, 1,1-dimethylpropyleneurea, 1,2-dimethylpropylene, 2,2-dimethylpropylene, 2-ethylpropylamine, 1-methyl-2-ethylpropylamine, 1-ethyl-2-methylpropionate, 1,1,2-trimethylpropyl, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 2,2-dimethylbutylamino, 2,3-dimethylbutylamino, 1,3-dimethylbutylamino, 2-ethylbutyrate, 2-methylpentylamino or 3-methylpentylamino.

"Alchemistjoshua having two to six carbon atoms"used in this description, is altertekhnogrupp having two to six carbon atoms, and suitable examples of it are visiteurope, allerthorpe, 1-PropertyGroup, 2-PropertyGroup, isopropylthio, 2-methyl-1-PropertyGroup, 3-methyl-1-PropertyGroup, 2-methyl-2-PropertyGroup, 3-methyl-2-PropertyGroup, 1-butylthiourea, 2-butylthiourea, 3-butylthiourea, 1-intertype, 1-hexeditor, 1,3-hexacyanoferrate and 1,6-hexa who animationgroup.

"Alinytjara having two to six carbon atoms"used in this description, is alinytjara having two to six carbon atoms, and suitable examples of it are aministierea, 1-propylthiourea, 2-propylthiourea, 1-butylthiourea, 2-butylthiourea, 3-butylthiourea, 3-methyl-1-propylthiourea, 1-ethinyl-2-propylthiourea, 2-methyl-3-propylthiourea, 1-pertinentia, 1-hexylthiourea, 1,3-examiination and 1.6-examiination.

"Cycloalkyl group having three to eight carbon atoms"used in this description, is cycloalkyl group containing three to eight carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group, cycloheptyl group or cyclooctyl group.

"Cycloalkenyl group having three to eight carbon atoms"used in this description, is cycloalkenyl group containing three to eight carbon atoms, such as cyclopropene-1-ilen, cyclopropene-3-ilen, CYCLOBUTANE-1-ilen, CYCLOBUTANE-3-ilen, 1,3-cyclobutadiene-1-ilen, cyclopenten-1-ilen, cyclopenten-3-ilen, cyclopenten-4-ilen, 1,3-cyclopentadiene-1-ilen, 1,3-cyclopentadiene-2-ilen, 1,3-the cyclopentadiene-5-ilen, cyclohex the n-1-ilen, cyclohexen-3-ilen, cyclohexen-4-ilen, 1,3-cyclohexadiene-1-ilen, 1,3-cyclohexadiene-2-ilen, 1,3-cyclohexadiene-5-ilen, 1,4-cyclohexadiene-3-ilen, 1,4-cyclohexadiene-1-ilen, cyclohepten-1-ilen, cyclohepten-3-ilen, cyclohepten-4-ilen, cyclohepten-5-ilen, 1,3-cyclohepten-2-ilen, 1,3-cyclohepten-1-ilen, 1,3-cycloheptadiene-5-ilen, 1,3-cycloheptadiene-6-ilen, 1,4-cycloheptadiene-3-ilen, 1,4-cycloheptadiene-2-ilen, 1,4-cycloheptadiene-1-ilen, 1,4-cycloheptadiene-6-ilen, 1,3,5-cycloheptatrien-3-ilen, 1,3,5-cycloheptatrien-2-ilen, 1,3,5-cycloheptatrien-1-ilen, 1,3,5-cycloheptatrien-7-ilen, cycloocten-1-ilen, cycloocten-1,3-ilen, cycloocten-4-ilen, cycloocten-5-ilen, 1,3-cyclooctadiene-2-ilen, 1,3-cyclooctadiene-1-ilen, 1,3-cyclooctadiene-5-ilen, 1,3-cyclooctadiene-6-ilen, 1,4-cyclooctadiene-3-ilen, 1,4-cyclooctadiene-2-ilen, 1,4-cyclooctadiene-1-ilen, 1,4-cyclooctadiene-6-ilen, 1,4-cyclooctadiene-7-ilen, 1, 5cyclooctadiene-3-ilen, 1, 5cyclooctadiene-2-ilen, 1,3,5-cyclooctadiene-3-ilen, 1,3,5-cyclooctadiene-2-ilen, 1,3,5-cyclooctadiene-1-ilen, 1,3,5-cyclooctadiene-7-ilen, 1,3,6-cyclooctadiene-2-ilen, 1,3,6-cyclooctadiene-1-ilen, 1,3,6-cyclooctadiene-5-ilen or 1,3,6-cyclooctadiene-6-ilen.

"5 to 14-Membered non-aromatic heterocyclic group"used in this description, refers to monocyclic, bicicletas is Oh or tricyclic 5 to 14-membered non-aromatic heterocyclic group, containing one or more heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom. Specific examples of the group are pyrrolidinyl group, piperidinyl group, piperazinilnom group, piratininga group, morpholinyl group, tetrahydrofuryl group, tetrahydropyranyl group, dihydropyridine group, dihydropyridine group, imidazolinone group and oxazolidinone group. Non-aromatic heterocyclic group includes a group derived from Spiridonovka cycle, and condensed nonaromatic cycle (for example, a group derived from phthalimide cycle or operations of the cycle).

"Aromatic cyclic hydrocarbon group having six to fourteen carbon atoms" and "aryl"used in this description represent an aromatic cyclic hydrocarbon group having six to fourteen carbon atoms, and include monocyclic group, and the condensed groups, such as the bicyclic group and tricyclic groups. Specific examples of the group include phenyl group, indenolol group, 1-naftalina group, 2-naftalina group, azulinebloo group, heptylaniline group, biphenylene group, industriou group, acenaphthylene group, fluorenyl group, f is nelinyeynoy group, phenanthroline group, antarctilyne group, Cyclopentasiloxane group and benzocyclobutene group.

"5 to 14-Membered aromatic heterocyclic group" and "heteroaryl"used in this description represent a monocyclic, bicyclic or tricyclic 5 to 14-membered aromatic heterocyclic group containing one or more heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom. Specific examples of the group include 1) nitrogen-containing aromatic heterocyclic group such as pyrrolidine group, Peregrina group, pyridazinyl group, pyrimidinyl group, piratininga group, thiazolidine group, tetrataenia group, benzotriazolyl group, pyrazolidine group, imidazolidinyl group, benzimidazolyl group, indayla group, isoindolyl group, indolizinyl group, polylina group, indazolinone group, kinolinna group, izochinolina group, hyalinella group, talasila group, naphthyridinone group, khinoksalinona group, chinadaily group, indolenine group, pteridinyl group, imidazolidinyl group, pirazinamida group, accidenily group, phenanthridinone group, carbazolyl group, carbazolyl group, pyrimidinyl the group, phenanthroline group, ventimilia group, imidazopyridine group, imidazolidinyl group, pyrazolopyrimidine group or pyrazolopyrimidine group; 2) sulfur-containing aromatic heterocyclic group such as thienyl group or benzothiazoline group; 3) oxygen-containing aromatic heterocyclic group such as furilla group, Pernilla group, cyclopentadienyl group, benzoperylene group or isobenzofuranone group; and 4) an aromatic heterocyclic group containing two or more different heteroatoms, such as thiazolidine group, isothiazolinone group, benzothiazolyl group, phenothiazinyl group, isoxazolyl group, furazolidine group, phenoxypyridine group, oxazoline group, isoxazolidine group, benzoxazolyl group, oxadiazolyl group, pyrazoloquinoline group, imidazothiazole group, thienopyridine group, properally group or pyridoxamine group.

"Aliphatic acyl group having two to seven carbon atoms"used in this description, is an atomic group derived from aliphatic carboxyl group having two to seven carbon atoms, the removal of the group's IT from its carboxyl group, and suitable examples of which include acetyl group, propylaniline group and motirola group.

"Ariella group"used in this description, a represents a carbonyl group, a substituted aromatic cyclic hydrocarbon group having six to fourteen carbon atoms, and "heteroallyl group" is a carbonyl group, a substituted 5 to 14-membered aromatic heterocyclic group. "Aromatic cyclic hydrocarbon group having six to fourteen carbon atoms", and "5 to 14-membered aromatic heterocyclic group" when used in this specification have the same meanings as defined above.

Suitable examples of "alkylsulfonyl group having one to six carbon atoms", "alkanesulfonyl group having two to six carbon atoms", and "alkylsulfonyl group having two to six carbon atoms"used in this description, include methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylphenyl group, n-butylsulfonyl group, tert-butylsulfonyl group, vinylsulphonyl group, arylsulfonyl group, isopropylacetanilide group, isopentenyladenosine group and etinilestradiolo group. Suitable examples of "alkylsulfonyl group having one to six of plastics technology : turning & is-breaking atoms", "alkanesulfonyl group having two to six carbon atoms" and "alkylsulfonyl group having two to six carbon atoms"used in this description, include methylsulfinyl group, ethylsulfinyl group, n-propylsulfonyl group, isopropylphenyl group, n-butylsulfonyl group, tert-butylsulfonyl group, vinylsulphonyl group, arylsulfenyl group, isopropylacetanilide group, isopentenyladenine group and etinilestradiolo group.

Examples of "substituents" of the "amino group which may be substituted", as used in this description represent one or two groups selected from alkyl groups having one to six carbon atoms, alkenylphenol group having two to six carbon atoms, alkenylphenol group having two to six carbon atoms, alkylsulfonyl group having one to six carbon atoms, alkanesulfonyl group having two to six carbon atoms, alkylsulfonyl group having two to six carbon atoms, alkylcarboxylic group having one to six carbon atoms, alkenylamine group, having two to six carbon atoms, alkylcarboxylic group having two to six carbon atoms, each of which may be substituted. In this regard, should skazat is, the substituents may be combined with the formation of a 3-8-membered nitrogen cycle. Suitable examples of "substituents" alkyl group having one to six carbon atoms, alkenylphenol group having two to six carbon atoms, alkenylphenol group having two to six carbon atoms, alkylsulfonyl group having one to six carbon atoms, alkanesulfonyl group having two to six carbon atoms, alkylsulfonyl group having two to six carbon atoms, With1-6alkylcarboxylic group2-6alkenylamine group and2-6alkylcarboxylic groups include hydroxyl group, halogen atom, nitrile group, alkoxygroup, isopentylamine, neopentylene, n-hexylamine, 1-methylpropylamine, 1,2-dimethylpropylene, 2-ethylpropylamine, 1-methyl-2-ethylpropylamine, 1-ethyl-2-methylpropylamine, 1,1,2-trimethylpropyl, 1-methylbutylamine, 2-methylbutylamine, 1,1-dimethylbutylamino, 2,2-dimethylbutylamino, 2-ethylbutylamine, 1,3-dimethylbutylamino, 2-methylpentylamino, 3-methylpentylamino, N,N-dimethylaminopropyl, N,N-diethylaminopropyl, N,N-di(n-propyl)amino group, N,N-di(isopropyl)amino group, N,N-di(n-butyl)amino group, N,N-di(isobutyl)amino group, N,N-di(tert-is util)amino group, N,N-di(n-pentyl)amino group, N,N-di(isopentyl)amino group, N,N-di(neopentyl)amino group, N,N-di(n-hexyl)amino group, N,N-di(1-methylpropyl)amino group, N,N-di(1,2-dimethylpropyl)amino group, N-methyl-N-ethylamino, N-ethyl-N-(n-propyl)amino group, N-methyl-N-(isopropyl)amino group, Veniaminovna, allylamino, (1-propenyl)amino group, isopropylamino, (1-butene-1-yl)amino group, (1-butene-2-yl)amino group, (1-butene-3-yl)amino group, (2-butene-1-yl)amino group, (2-butene-2-yl)amino group, N,N-diphenylamino, N,N-diallylamine, N,N-di(1-propenyl)amino group, N,N-isopropylamino, N-ethinyl-N-allylamino, itinerating, 1-propanaminium, 2-propylamino, butylamino, pentylamine, hexylamine, N,N-diethylaminopropyl, N,N-(1-PROPYNYL)amino group, N,N-(2-PROPYNYL)amino group, N,N-dibutylamino, N,N-diphenhydramine, N,N-dijksynagogue, hydroxymethylamino, 1-hydroxyethylamino, 2-hydroxyethylamino, 3-hydroxy-n-propylamino, methylsulfonylamino, ethylsulfonylimidazo, n-propylsulfonyl, isopropylaniline, n-butylmethylamine, tert-butylmethylamine, vinylsulfonylacetamido, arylsulfonamides, isopropylacetanilide, isopentenyladenine, is fenilalkilaminov, medicalbilling, ethylcarbodiimide, n-propylnitrosamine, isopropylcarbodiimide, n-BUTYLCARBAMATE, tributylammonium, vinylnorbornene, allylcarbamate, isopropylcarbodiimide, isopentenyladenine and atenololviagrawp.

Examples of "substituents" in the expression "which may be substituted"used in this description, include a halogen atom such as fluorine atom, chlorine atom, bromine atom and iodine atom; a hydroxyl group; a nitro-group; a cyano; alkyl group having one to six carbon atoms, such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, n-pencilina group, 1,1-dimethylpropylene group, 1,2-dimethylpropylene group, 2,2-dimethylpropylene group, 1-ethylpropyl group, 2-ethylpropyl group, n-exilda group or 1-methyl-2-ethylpropyl group; alkenylphenol group having two to six carbon atoms, such as vinyl group, allyl group, 1-protanilla group, 2-protanilla group, Isopropenyl group, 2-methyl-1-protanilla group, 3-methyl-1-protanilla group, 2-methyl-2-protanilla group, 3-methyl-2-protanilla group 1-battilana, 2-bucinellina group, 3-bucinellina group, 1-penttila group, 1-examilia group, 1,3-hexadienyl group or 1,6-hexadienyl group; alkylamino group having two to six carbon atoms, such as etinilnoy group, 1-proponila group, 2-proponila group, 1-Butyrina group, 2-Butyrina group, 3-Butyrina group, 3-methyl-1-proponila group, 1-ethinyl-2-proponila group, 2-methyl-3-proponila group, 1-puntinella group, 1-hexylamine group, 1,3-hexadienyl group or 1,6-hexadienyl group; alkoxygroup having one to six carbon atoms, such as methoxy group, ethoxypropan, n-propoxylate, isopropoxide, second-propoxylate, n-butoxypropyl, isobutoxy, second-butoxypropan, tert-butoxypropan, n-pentyloxy, isopentylamine, second-pentyloxy or n-hexyloxy; alkenylacyl having two to six carbon atoms, such as vinyloxy, alliancegroup, 1-propionyloksypo, 2-propionyloksypo or isopropenylacetate; alkynylamino, having two to six carbon atoms, such as atenololviagrawp, 1-propenyloxy or 2-propenyloxy; allylthiourea having one to six carbon atoms, such as methylthiourea, ethylthiourea, n-PropertyGroup, isopropylthio, second-PropertyGroup is, n-butylthiourea, isobutylthiazole, second-butylthiourea or tert-butylthiourea; altertekhnogrupp having two to six carbon atoms, such as visiteurope, allerthorpe, 1-PropertyGroup or 2-PropertyGroup; alinytjara having two to six carbon atoms, such as aministierea, 1-propylthiourea or 2-propylthiourea; aliphatic acyl group having two to seven carbon atoms, such as acetyl group, propylaniline group or motirola group; karbamoilnuyu group; ariello group; heteroallyl group; an amino group; alkylsulfonyl group having one six carbon atoms, alkanesulfonyl group having two to six carbon atoms, alkylsulfonyl group having two to six carbon atoms, alkylsulfonyl group having one to six carbon atoms, alkanesulfonyl group having two to six carbon atoms, or alkylsulfonyl group having two to six carbon atoms, such as methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylaniline group, n-butylsulfonyl group, tert-butylsulfonyl group, vinylsulphonyl group, arylsulfonyl group, isopropylacetanilide group, isopentenyladenosine group, ethinyl alfonsina group, methylsulfinyl group, ethylsulfinyl group, n-propylsulfonyl group, isopropylaniline group, n-butylsulfonyl group, tert-butylsulfonyl group, vinylsulphonyl group, arylsulfenyl group, isopropylacetanilide group, isopentenyladenine group or ethinically group; formyl group; cycloalkyl group having three to eight carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group, cycloheptyl group or cyclooctyl group; cycloalkenyl group having three to eight carbon atoms, such as cyclopropylamine, cyclobutylamine, cyclopentadiene or cyclohexadiene group; 5 to 14-membered non-aromatic heterocyclic group, such as pyrrolidinyl group, pyrrolidine group, piperidinyl group, piperazinilnom group, imidazolidinyl group, pyrazolidine group, imidazolidinyl group, morpholinyl group, tetrahydrofuryl group, tetrahydropyranyl group, pyrrolidinone group, dihydropyridine group, dihydropyridine group, imidazolidine group, oxazolidine group, a group derived from Spiridonovka cycle, and a group derived from phthalimide cycle or operations cycle; aromaticas the cyclic hydrocarbon group, having six to fourteen carbon atoms, such as phenyl group, angenlina group, 1-naftalina group, 2-naftalina group, biphenylene group or Indianola group; 5 to 14-membered aromatic heterocyclic group, such as pyrrolidine group, Peregrina group, pyridazinyl group, pyrimidinyl group, piratininga group, thiazolidine group, tetrataenia group, benzotriazolyl group, pyrazolidine group, imidazolidinyl group, benzimidazolyl group, indayla group, isoindolyl group, indolizinyl group, polylina group, indazolinone group, kinolinna group, izochinolina group, hyalinella group, phthalazinone group, naphthyridinone group, khinoksalinona group, chinadaily group, indolenine group, pteridinyl group, imidazolidinyl group, pirazinamida group, accidenily group, phenanthridinone group, carbazolyl group, carbazolyl group, pyrimidinyl group, phenanthroline group, ventimilia group, imidazopyridine group, imidazolidinyl group, pyrazolopyrimidine group, pyrazolopyrimidine group, thienyl group, benzothiazoline group, furilla group, Pernilla group, cyclopentadienyl group, benzofuranyl the group, isobenzofuranyl group, thiazolidine group, isothiazolinone group, benzothiazolyl group, benzothiadiazole group, phenothiazinyl group, isoxazolyl group, furazolidine group, phenoxypyridine group, oxazoline group, isoxazolyl group, benzoxazolyl group, oxadiazolyl group, pyrazoloquinoline group, imidazothiazole group, thienopyridine group, properally group or pyridoxamine group. Each of these substituents may also be substituted.

In the formula (I) suitable examples of "substituents" in the "carbamoyl group which may be substituted", are groups selected from alkyl groups having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, and a 5-14-membered aromatic heterocyclic group, to the which may be substituted. The nitrogen atom carbamoyl group may be substituted by one or two groups selected from the above group of substituents. The substituents may be combined with education 3-14-membered nitrogen cycle, such as pyrrolidine group, pyrrolidinone group, piperideine group, piperazinilnom group, imidazolidinyl group, pyrazolidine group, imidazolidinyl group, morpholinyl group, tetrahydropyranyl group, aziridinyl group, oxiranyl group, occasioanlly group, telemedicine group, Succinimidyl group, pyrrolidine group, Peregrina group, pyridazinyl group, pyrimidinyl group, piratininga group or pyrazolidine group. In addition, the nitrogen cycle can be overridden.

In the formula (I) is preferred group in R1and/or R2not particularly limited, but preferable groups are a hydrogen atom, an alkyl group having one to six carbon atoms, and aliphatic acyl group having two to seven carbon atoms, each of which may be substituted, and particularly preferred is a hydrogen atom.

In the formula (I) is preferred group in R3not particularly limited, but preferable groups are a hydrogen atom, amino group, cyano, alkiline the group, having one to six carbon atoms, alkoxygroup having one to six carbon atoms, phenyl group, naftalina group, Peregrina group, pyridazine group, piramidalnaya group, perazella group, thienyl group, furilla group, imidazolidinyl group and so on, each of which may be substituted, and particularly preferred is a hydrogen atom.

In the formula (I) R4represents an aromatic cyclic hydrocarbon group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group having one or more unsaturated bonds, or a 5-14-membered aromatic heterocyclic group which may be substituted, and suitable examples are aromatic cyclic hydrocarbon group having six to fourteen carbon atoms, such as phenyl group or naftalina group; 5 to 14-membered non-aromatic heterocyclic group, such as pyrrolidinyl group, pyrrolidinone group, piperidinyl group, piperazinilnom group, imidazolidine group, pyrazolidinone group, imidazolidinyl group, morpholinyl group, tetrahydropyranyl group, aziridinyl group, oxiranyl group, occasioanlly group, 6-oxo-1,6-dihydropyri ininna group, in which the nitrogen atom may be substituted, or 2-oxo-1,2-digidropiridina group in which the nitrogen atom may be substituted; or a 5 to 14-membered aromatic heterocyclic group, such as pyrrolidine group, Peregrina group, pyridazinyl group, pyrimidinyl group, piratininga group, pyrazolidine group, imidazolidinyl group, indayla group, isoindolyl group, indolizinyl group, kinolinna group, izochinolina group, hyalinella group, phthalazinone group, naphthyridine group, khinoksalinona group, chinadaily group, imidazolidinyl group, pirazinamida group, thienyl group, benzothiazoline group, furilla group, Pernilla group, cyclopentadienyl group, benzoperylene group, isobenzofuranyl group, thiazolidine group, isothiazolinone group, benzothiazolyl group, benzothiadiazole group, fenotiazinas group, isoxazolyl group, pyrazoloquinoline group, imidazothiazole group, thienopyridine group, properally group or pyridoxamine group. Each of these groups can be optionally substituted. More preferred examples of R4include groups represented by the formulas:

each of which which may be substituted. When 6-oxo-1,6-dihydropyridine group or 2-oxo-1,2-dihydropyridine group has a Deputy, he can also be combined with the nitrogen atom.

In the formula (I) R5represents an aromatic cyclic hydrocarbon group having six to fourteen carbon atoms, or 5 to 14-membered aromatic heterocyclic group, each of which may be substituted, and suitable examples include aromatic cyclic hydrocarbon group having six to fourteen carbon atoms, such as phenyl group or naftalina group, or a 5-14-membered aromatic heterocyclic group, such as pyrrolidine group, Peregrina group, pyridazinyl group, pyrimidinyl group, piratininga group, pyrazolidine group, imidazolidinyl group, indayla group, isoindolyl group, indolizinyl group, kinolinna group, izochinolina group, hyalinella group, phthalazinone group, naphthyridine group, khinoksalinona group, chinadaily group, imidazolidinyl group, pirazinamida group, thienyl group, benzothiazoline group, furilla group, Pernilla group, cyclopentadienyl group, benzoperylene group, isobenzofuranyl group, thiazolidine group, isothiazolinone group, benzothiazolyl the group, benzothiadiazole group, fenotiazinas group, isoxazolyl group, pyrazoloquinoline group, imidazothiazole group, thienopyridine group, properally group or pyridoxamine group. Each of these groups may be substituted. More preferred examples of R5include groups represented by the formulas:

each of which may be substituted.

In the "substituents" in the "aromatic cyclic hydrocarbon group having six to fourteen carbon atoms which may be substituted", and "5 to 14-membered aromatic heterocyclic group which may be substituted", in R3, R4and R5(1) preferred examples include one or more groups selected from hydroxyl group, halogen atom, ceanography, nitro, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkoxygroup having one to six carbon atoms which may be substituted, alkenylacyl having two to six carbon atoms which may be substituted, ancilliary with about the in-six carbon atoms, which may be substituted, altertekhnogrupp having two to six carbon atoms which may be substituted, alinytjara having two to six carbon atoms which may be substituted, a substituted carbonyl group, amino group which may be substituted, alkylsulfonyl group having one to six carbon atoms which may be substituted, alkanesulfonyl group having two to six carbon atoms which may be substituted, alkylsulfonyl group having two to six carbon atoms which may be substituted, alkylsulfonyl group having one to six carbon atoms, which may be substituted, alkanesulfonyl group having two to six carbon atoms which may be substituted, alkylsulfonyl group having two to six carbon atoms which may be substituted, formyl group, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic cyclic hydrocarbon group having six to fourteen carbon atoms which may be substituted, 5-14 membered aroma is achieved heterocyclic group, which may be substituted; (2) more preferably one or more groups selected from (1) hydroxyl group, (2) halogen atom, (3) ceanography, (4) nitro group, (5) an alkyl group having one to six carbon atoms, alkenylphenol group having two to six carbon atoms, or alkenylphenol group having two to six carbon atoms, each of which may be substituted by one or more groups selected from (i) hydroxyl group, (ii) ceanography, (iii) of halogen atom, (iv) alkylamino having one to six carbon atoms, (v) di(C1-6alkyl)amino group, (vi)2-6alkynylamino, (vii) di(C2-6alkenyl)amino group, (viii) alkynylamino having two to six carbon atoms, (ix) di(C2-6quinil)amino group, (x) N1-6alkyl-N-C2-6alkynylamino, (xi) N-C1-6alkyl-N-C2-6alkynylamino, (xii) N-C2-6alkenyl-N-C2-6alkynylamino, (xiii) aralkylated, (xiv) of tert-butyldimethylsilyloxy (TBDMS(TBDMS)-oxy)group, (xv)1-6alkylsulfonamides, (xvi)1-6alkylcarboxylic, (xvii)2-6alkenylboronic, (xviii)2-6alkylcarboxylic, (xix) N-C1-6alkylcarboxylic group, (xx) N-C2-6alkenylamine group and (xxi) N-C2-6alkylcarboxylic group, (6) alkoxygroup, is within one to six carbon atoms, alkenylacyl having two to six carbon atoms, alkyloxy having two to six carbon atoms, each of which may be substituted by one or more groups selected from (i) alkylamino having one to six carbon atoms, (ii) aralkylated and (iii) hydroxyl groups, (7) ancilliary having one to six carbon atoms, altertekhnogrupp having two to six carbon atoms, alinytjara having two to six carbon atoms, each of which may be substituted by one or more groups selected from (i) hydroxyl group, (ii) nitrile group, (iii) halogen atom, (iv) alkylamino having one to six carbon atoms, (v) aralkylated, (vi) TBDMS-oxypropyl, (vii)1-6alkylsulfonamides, (viii)1-6alkylcarboxylic and (ix)1-6alkylcarboxylic group, (8) a carbonyl group substituted by a group selected from (i) alkoxygroup having one to six carbon atoms, (ii) amino, (iii) alkylamino having one to six carbon atoms, (iv) di(C1-6alkyl)amino group, (v) alkynylamino having two to six carbon atoms, (vi) di(C2-6alkenyl)amino, (vii) alkynylamino having two to six carbon atoms, (viii) di(C2-6quinil)amino group, (ix) N-C1-6alkyl-N-C2-6Ala is ylamino group, (x) N-C1-6alkyl-N-C2-6alkynylamino and (xi) N-C2-6alkenyl-N-C2-6alkynylamino, (9) amino group which may be substituted by one or two groups selected from (i) alkyl groups having one to six carbon atoms, (ii) alkenylphenol group having two to six carbon atoms, (iii) alkenylphenol group having two to six carbon atoms, (iv) alkylsulfonyl group having one to six carbon atoms, (v) alkanesulfonyl group having two to six carbon atoms, (vi) alkylsulfonyl group having two to six carbon atoms, (vii) 1-6alkylcarboxylic group, (viii)2-6alkenylamine group and (ix)2-6alkylcarboxylic group, (10) alkylsulfonyl group having one to six carbon atoms, (11) alkanesulfonyl group having two to six carbon atoms, (12) alkylsulfonyl group having two to six carbon atoms, (13) alkylsulfonyl group having one to six carbon atoms, (14) alkanesulfonyl group having two to six carbon atoms, (15) alkylsulfonyl group having two to six carbon atoms, (16) formyl group, (17) cycloalkyl group having three to eight carbon atoms, or cycloalkenyl group having three to eight carbon atoms, each of which can be Zam is placed one or more groups, selected from (i) hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) alkyl groups having one to six carbon atoms, (v) alkoxygroup having one to six carbon atoms, (vi)1-6alkoxy-C1-6alkyl group and (vii) Uralkaliy group, (18) 5-14-membered non-aromatic heterocyclic group which may be substituted by one or more groups selected from (i) hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) alkyl groups having one to six carbon atoms, (v) alkoxygroup having one to six carbon atoms, (vi)1-6alkoxy-C1-6alkyl group and (vii) Uralkaliy group, (19) an aromatic cyclic hydrocarbon group having six to fourteen carbon atoms which may be substituted by one or more groups selected from (i) hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) alkyl groups having one to six carbon atoms, (v) alkoxygroup having one to six carbon atoms, (vi)1-6alkoxy-C1-6alkyl group and (vii) Uralkaliy group, and (20) 5-14-membered aromatic heterocyclic group which may be substituted by one or more groups selected from (i) hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) alkyl groups, and eUSA one to six carbon atoms, (v) alkoxygroup having one to six carbon atoms, (vi)1-6alkoxy-C1-6alkyl group and (vii) Uralkaliy group; and (3) most preferably one or more groups selected from hydroxyl group, halogen atom (e.g. fluorine atom, chlorine atom, bromine atom or iodine atom), ceanography, nitro, alkyl group having one to six carbon atoms (e.g. methyl group, ethyl group, n-sawn group, isopropyl group, n-butilkoi group, isobutylene group, tert-butilkoi group, n-Pintilei group, isopentyl group, neopentyl group or n-hexylene group), alkenylphenol group having two to six carbon atoms (for example, vinyl group, allyl group, 1-propenyloxy group or Isopropenyl group), alkenylphenol group having two to six carbon atoms (for example, etinilnoy group, 1-propanolol group, 2-propanolol group, botinelli group, pentesilea group or hexenlini group), alkoxygroup having one to six carbon atoms (for example, metoxygroup, ethoxypropan, n-propoxylate, isopropoxy or n-butoxypropyl) and alkenylacyl having two to six carbon atoms (for example, vinyloxy, alliancegroup, 1-propenyloxy or isopropenylacetate).

Preferred variancecovariance, represented by formula (I)according to the present invention, its salts or their MES not particularly limited, but preferred options are compounds in which R4it is a 6-oxo-1,6-digidropiridinovykh group or 2-oxo-1,2-digidropiridinovykh group represented by the formula:

or the formula:

(where R8represents a group selected from the groups described above as the substituents, and the ring is a nitrogen-containing 6-membered cycle which may be substituted by one to four groups selected from the groups described above as the substituents), or 4-pyridyloxy group which may have one or two substituent, or a salt or solvate of them. Preferred options R8are those indicated above.

The term "salt"used in this description, means a salt formed from a compound of the present invention, is preferably a pharmacologically acceptable salt. Preferred examples of it are Sol halogenation acid, such as hydroptere, hydrochloride, hydrobromide or hydroiodide salt of an inorganic acid, such as sulfate, nitrate, perchlorate, phosphate, carbonate or bicarbonate; salt of organic carboxylic KIS is the notes, such as acetate, triptorelin, oxalate, maleate, tartrate, fumarate or citrate salt of organic sulfonic acid, such as methanesulfonate, triftorbyenzola, aconsultant, bansilalpet, toluensulfonate or camphorsulfonate; salt with amino acid such as aspartate or glutamate; salt, Quaternary amine salt of an alkali metal such as sodium salt or potassium salt; alkali earth metal salt such as magnesium salt or calcium salt. More preferred examples of the pharmacologically acceptable salts are the hydrochloride and oxalate.

"MES"used in this description, means the MES compounds of the present invention or salts thereof and are not particularly limited. Preferably MES is a hydrate, MES with alcohol, such as methanol, ethanol, propanol or isopropanol, MES with complex ester such as ethyl acetate, MES with simple ether such as methyl ether, ethyl ether or THF (tetrahydrofuran), or MES with DMF (dimethylformamide), and more preferred is a hydrate or MES with alcohol, such as methanol or ethanol. The solvent for the formation of MES is preferably a pharmacologically acceptable solvent.

The way to obtain

The following describes typical methods of producing compounds, pre is raised by the formula (I), according to the present invention. "Room temperature" as used in this description further indicates a temperature of from about 0°With up to about 40°C.

(Method And receipt)

In the above formulas, Ar1Arepresents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, Xandrepresents an alkyl group having one to six carbon atoms, and R1Arepresents a 5 to 14-membered aromatic heterocyclic group having a nitrogen atom in position 4, which may be substituted (such as 4-Peregrina group, 4-pyrimidinyl group or 4-pyridazinyl group). The compound (A3), which serves as starting material for obtaining compounds of the present invention, presents shown above formula (I)can be obtained through dealcoholization-condensation of the implementation of the interaction of aromatic carboxylate (A1) with 4-methyl aromatic heterocyclic compound (A2)represented by the formula, R1A-CH3in a solvent in the presence of a base. Used base vary depending on starting materials, the COI is lisemore solvent, and so forth. Preferred bases include metal salt of a secondary amine such as bis(trimethylsilyl)amide lithium and diisopropylamide lithium, but not particularly limited to, until the slow reaction. Solvent used is changed depending on, for example, from the source materials and the used reagents. Preferred solvents include ethers, such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and diethylene glycol, but not particularly limited to, yet not slow down the reaction and dissolve to some extent the original materials. The reaction temperature is usually in the range from -78°C to room temperature, and preferably about 0°C.

(How To obtain)

In the above formulas, Ar1band R1bare the same or different from each other and each represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, and Xbrepresents a halogen atom, alkylsulfonate or arylsulfonate. The compound (B3), which serves as starting material for obtaining the compounds of the present invention presented above is armoloy (I), can be obtained by this method, instead of the way And get. That is, the compound (B3) is obtained by condensation between aromatic trialkylaluminium derived from aromatic aldehyde (B1)and the compound (B2)represented by the formula, R1b-CH2Xbin the presence of a base and subsequent implementation of the interaction with the fluoride connection for de(trialkylsilyl)cyanidation. As a reagent for obtaining aromatic trialkylsilanes from compound (B1) is preferably used trialkylsilyl, such as trimethylsilane. It is also preferred to use a salt of a metal, such as iodide of zinc(II) as a catalyst, providing a quick reaction. Used base vary depending on starting materials, solvent used, and so forth. Preferred bases include metal salt of a secondary amine such as bis(trimethylsilyl)amide lithium and diisopropylamide lithium, but not particularly limited to, until the slow reaction. Used fluoride compound vary depending on the source materials used solvents and so on. The preferred fluoride compounds include hydrofluoric acid and hydrofloric amine, more preferably tetrabutylammonium torid, but not particularly limited to, until the slow reaction. Solvent used vary depending on starting materials, reagents, and so forth. Preferred examples of solvents include ethers, such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane or diethylene glycol, but not particularly limited to, until dissolved to some extent the original materials. The reaction temperature preferably is in the range from -78°C to room temperature.

(How To obtain)

In the above formulas, Ar1Cand R1Care the same or different from each other and each represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted. 3-(Dimethylamino)-2-propen-1-it (C2) is the starting material for the production of compound (I) of the present invention. The compound (C2) can be obtained by the action of dimethylacetal N,N-dimethylformamide in an active methylene compounds (C1)obtained in method a or b is received. Most preferred is the implementation of this reaction without any solvent. But the preferred result can so is e to be obtained even at a dilution of compounds (C1) a solvent (such as N,N-dimethylformamide, tetrahydrofuran, dioxane, N-organic, benzene or toluene), dissolving starting materials to some extent without slowing down the reaction. The reaction temperature is usually in the range from room temperature to 120°C, preferably about 100°C.

(Method D receipt)

In the above formulas, Ar1dand R1dare the same or different from each other and each represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, and R2dand R3dare the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic gets riikliku group, which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted. The compound (D3) according to the present invention can be obtained by conducting derivative (D2) guanidine with 3-(dimethylamino)-2-propen-1-one (D1)obtained by the method, in the presence of a base. Used derivative (D2) guanidine may form a salt with an acid, such as chloromethane acid, Hydrobromic acid, sulfuric acid or acetic acid. Used base vary depending on starting materials, solvent used, and so forth. Preferred examples of the base include carbonates of alkali metal such as potassium carbonate or sodium carbonate, or alkali metal alkoxide such as sodium methoxide, ethoxide or sodium tert-piperonyl potassium, but not particularly limited to, until the slow reaction. Solvent used vary depending on starting materials, reagents, and so forth. Preferred examples of the solvent include N,N-dimethylformamide, N-organic, dimethylsulfoxide, and ethanol, but not particularly limited to, yet not slow down the reaction and dissolve to some degree IP is adnie materials and substrate. The reaction temperature is preferably in the range from room temperature to 120°C, more preferably about 70°C.

(Method E receipt)

In the above formulas, Ar1, R1and R4thare the same or different from each other and each represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, and R2Eand R3Eare the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen coal is adnych atoms, which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted. The compound (E4) according to the present invention can be obtained by the interaction of the aldehyde (E2) and derived (E3) with guanidine compound (E1)obtained as described above, or in the presence of base followed by aromatization of the oxidant. Used derivative (E3) guanidine may form a salt with an acid, such as chloromethane acid, Hydrobromic acid, sulfuric acid or acetic acid. Used base vary depending on starting materials, solvent used, and so forth. Preferred to be used may be an alkali metal alkoxide such as sodium methoxide, ethoxide or sodium tert-piperonyl potash, or carbonate of an alkali metal such as potassium carbonate or sodium carbonate, but it is not particularly limited, until slows down the reaction. Examples of the oxidant include manganese compounds, such as active manganese dioxide, quinones such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and sulfur. The used solvent is not particularly limited, if it does not slow down the reaction and dissolves to some extent, raw materials and intermediate compounds. Examples of solvents may include the substance of the ethanol, methanol, tetrahydrofuran, dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide, N-organic, dimethylsulfoxide and mixtures thereof. The reaction temperature is preferably in the range of 0°to 120°C.

(Method F receipt)

In the above formulas, Ar1fand R1fare the same or different from each other and each represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, and R2fand R3fare the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic coal is hydrogen cyclic group, having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted. Connection (F5) of the present invention and the compound (F6), which serves as starting material for the production of compound (I) of the present invention, can be obtained by the implementation stages of the F-1 and F-2 in method F receipt.

Stage F-1: At this stage get a connection (F3) by dehydration and condensation of the compound (F1) and aldehyde (F2) in the presence of a base. Preferred examples used in the reaction bases include alkoxides of alkali metals such as sodium methoxide, ethoxide or sodium tert-piperonyl potassium. Or can be used carbonates of alkali metals such as potassium carbonate or sodium carbonate. The reaction is carried out in a solvent, which is not particularly limited, until it slows down the reaction and dissolves to some extent, raw materials and intermediate compounds.

Examples of the solvent may include ethanol, methanol, tetrahydrofuran, dichloromethane, chloroform, N,N-dimethylformamide, N-organic, dimethylsulfoxide and mixtures thereof. The reaction is carried out at a temperature from 0°to 120°C.

Stage F-2: At this stage receive derivative (F5) pyrimidine by vzaimodeistviyami (F3), obtained in stage F-1, derived from (F4) guanidine in the presence of base followed by aromatization of the oxidant. Used derivative (F4) guanidine may form a salt with an acid, such as chloromethane acid, Hydrobromic acid, sulfuric acid or acetic acid. Preferred examples used in the reaction bases include alkoxides of alkali metals such as sodium methoxide, ethoxide or sodium tert-piperonyl potassium. Or can be used carbonates of alkali metals such as potassium carbonate or sodium carbonate. The examples used in the reaction of the oxidant include manganese compounds, such as active manganese dioxide, quinones such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and sulfur. The reaction is carried out in a solvent, which is not particularly limited, until it slows down the reaction and dissolves to some extent, raw materials and intermediate compounds. The solvent may include ethanol, methanol, tetrahydrofuran, dichloromethane, chloroform, N,N-dimethylformamide, N-organic, dimethylsulfoxide and mixtures thereof. The reaction temperature is from 0°to 120°C.

In accordance with another option at the stage F-1 derivative (F5) pyrimidine can be obtained even without isolating the compound (F3)if to ensure the availability of derivative (F4) guanidine in the region of the promotional mix from the beginning of the reaction and then spend the aromatization oxidant. In addition, at the stage F-2 in the implementation of the interaction between the compound (F3) and derived (F4) guanidine in the presence of base, the reaction (when heated) conducted a long time, within two to seven days, in wet conditions, followed by oxidation gave the derivative (F6) pyrimidinone.

(Method G receipt)

In the above formulas, Ar1gand R1gare the same or different from each other and each represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, and Xgrepresents a halogen atom, alkylsulfonate or arylsulfonate. This method is an alternative synthesis of the compound (F3) in method F described above. That is, the method includes a step of communicating complex diapir cyanomethylphosphonate acid with compound (G1)in the presence of base and palladium catalyst and then dephosphorylation and condensation with the aldehyde represented by the formula Ar1g-CHO, obtaining compound (G2). Used in the reaction, a base is preferably sodium hydride, and the palladium catalyst are the two which is preferably tetrakis(triphenylphosphine)palladium (O). Preferred solvents include ethers, such as dimethoxyethane, diethyl ether or tetrahydrofuran. The reaction is carried out at a temperature of from 0°to 120°C.

(Method N receipt)

In the above formulas, Ar1hand R1hare the same or different from each other and each represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R2hand R3hare the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having the Yu six to fourteen carbon atoms, which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, and Xhrepresents an alkyl group having one to six carbon atoms. This method of production is another method of synthesis of compound (F6) in method F receipt.

Stage N-1: At this stage get a connection (N3) implementation of dehydration and condensation between the compound (H1) and the compound (H2) using a carboxylic anhydride in the presence of a base. The examples used in the reaction of the base include amines such as triethylamine, pyrrolidine, piperidine or diisopropylethylamine. The carboxylic anhydride is preferably acetic anhydride. The reaction is carried out at a temperature from room temperature to 120°C.

Stage N-2: At this stage receive derivative (F5) pyrimidinone as starting material for obtaining compounds of the present invention, presents shown above formula (I), the interaction of the compound (H3)obtained at stage N-1, derived from (H4) guanidine in the presence of base followed by aromatization of the oxidant. Used derivative (N4) guanidine may form a salt with an acid, such as chloromethane acid, Hydrobromic acid, sulfuric acid sludge is acetic acid. Preferred examples used in the reaction bases include alkoxides of alkali metals such as sodium methoxide, ethoxide or sodium tert-piperonyl potassium. Or can be used carbonates of alkali metals such as potassium carbonate or sodium carbonate. The examples used in the reaction of the oxidant include manganese compounds, such as active manganese dioxide, quinones such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and sulfur. The reaction is carried out in a solvent that does not slow down the reaction and dissolves to some extent, raw materials and intermediate compounds. Examples of solvents include ethanol, methanol, tetrahydrofuran, dichloromethane, chloroform, N,N-dimethylformamide, N-organic, dimethylsulfoxide and mixtures thereof. The reaction is carried out at a temperature of from 0°to 120°C.

(The way I get)

In the above formulas, Ar1iand R1iare the same or different from each other and each represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, and R2iand R3iare the same or different from each other and each of them represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms, which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R4irepresents an oxygen atom which may be substituted, and Xirepresents a halogen atom. The way I get can be obtained compound (I2) and (I3) of the present invention.

Stage I-1: At this stage receive derivative (I2) 4-halogenpyrimidines of the present invention derived from (I1) of pyrimidinone obtained by method F or H by the transformation of the carbonyl group derived (I1) of pyrimidinone to the halogen atom. The reaction is carried out in the absence of solvent or in suspension with a solvent, such as acetonitrile, DIAC is an or tetrahydrofuran, using a halogenation agent such as phosphorous oxychloride or phosphorous oxybromide, at a temperature of from 70°to 120°C. the Reaction can be accelerated by adding a tertiary amine such as dimethylaniline, diisopropylethylamine or Tripropylamine, salt, Quaternary amine, such as tetraethylammonium, or N,N-dimethylformamide.

Stage I-2: At this stage receive derivative (I3) 4-alkoxyimino of the present invention derived from (I2) 4-halogenopyrimidines obtained in the above stage I-1, the action of the alkoxide of the alkali metal derivative of 4-chloropyrimidine with conversion of the halogen atom in position 4 in alkoxygroup. The alkoxide of the alkali metal can be obtained by the action of a base or an alkali metal on the alcohol in the solvent or in the absence of solvent. Used alkali metal is preferably sodium or potassium. Used in the reaction base change depending on the source materials used solvents and so on. Preferred bases include alkali metal hydride such as sodium hydride and so on, but especially their limit, only they would not have slowed down the reaction. In accordance with an alternative option can also be used alkoxides of alkali metals such as sodium methoxide, toxic or sodium tert-piperonyl potassium. Solvent used vary depending on starting materials, reagents, and so forth. Although solvents are not particularly limited, if only they didn't slow down the reaction and dissolved to a certain extent the source material and substrate, examples of the solvents preferably include N,N-dimethylformamide, N-organic, dimethyl sulfoxide, alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran or 1,4-dioxane, and mixtures thereof. The reaction temperature ranges from room temperature to 120°C.

(Method J receipt)

In the above formulas, Ar1jand R1jare the same or different from each other and each represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R2jand R3jare the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group, having the Yu two to six carbon atoms, which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, and X4jrepresents an alkyl group which may be substituted. Way J obtain can be obtained connection (J4) according to the present invention.

Stage J-1: At this stage get a connection (J2) by reacting the Grignard reagent with compound (J1), obtained at the stage N-1 of the above-described method N receipt. The reaction is carried out in a solvent that does not slow down the reaction and to a certain extent dissolves the starting materials and intermediate compounds. Solvents may include ethers such as tetrahydrofuran, diethyl ether or dimethoxyethane. The reaction is carried out at a temperature from -78°C to room temperature.

Stage J-2: At this stage receive derivative (J4) pyrimidine according to the present invention by vzaimode istia connection (J2), received at stage J-1, derived from (J3) guanidine in the presence of base followed by aromatization of the oxidant. Used derivative (J3) guanidine may form a salt with an acid, such as chloromethane acid, Hydrobromic acid, sulfuric acid or acetic acid. Preferred examples used in the reaction bases include alkoxides of alkali metals such as sodium methoxide, ethoxide or sodium tert-piperonyl potassium. Or can be used a carbonate of an alkali metal such as potassium carbonate or sodium carbonate. The examples used in the reaction of the oxidant include manganese compounds, such as active manganese dioxide, quinones such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and sulfur. The reaction is carried out in a solvent that does not slow down the reaction and dissolves to a certain extent, raw materials and intermediate compounds. Examples of solvents include ethanol, methanol, tetrahydrofuran, dichloromethane, chloroform, N,N-dimethylformamide, N-organic, dimethylsulfoxide and mixtures thereof. The reaction is carried out at a temperature of from 0°to 120°C.

(Method K receipt)

In the above formulas, Ar1krepresents an aromatic hydrocarbon cyclic group having six to fourteen carbon the atoms, which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R2kand R3kare the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R4krepresents a hydrogen atom, a cyano, an alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which can be the replacement of the military, aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, a nitrogen atom which may be substituted, an oxygen atom which may be substituted or a sulfur atom which may be substituted, ring Andkrepresents pyridyloxy group, pyrimidinyl group, personilnya group or pyridazinyl group, the ring A'krepresents dihydroactinidiolide group, dihydroactinidiolide group, dihydroartemisinin group or dihydroactinidiolide group and Xkrepresents a halogen atom. At this stage receive 5-(α-oxo nitrogen-containing heterocyclyl)pyrimidine (K2) according to the present invention by conversion of the halogen atom (Xk) 5-(α-halogen containing heteroaryl)pyrimidine (K1) 4-methoxybenzyloxy, and the halogen atom (Xk) 5-(α-halogen containing heteroaryl)pyrimidine (K1) replace 4-methoxybenzyloxy followed by treatment with an acid. 4-Methoxybenzyloxy obtained using an alkali metal such as sodium or potassium, or a base such as sodium hydride, in the absence of a solvent or by dilution with a solvent, such as N,N-dimethylformamide or dimethylsulfoxide, at a temperature ranging from room temperature to 120°C. Used in the reaction of the acid may be triperoxonane acid, chloromethane acid, polnovata acid or the like. The reaction is carried out in the absence of solvent or by dilution with a solvent, such as dichloromethane, dichloroethane or tetrahydrofuran, at a temperature ranging from room temperature to 150°C.

(Method L receipt)

In the above formulas, Ar1lrepresents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R2land R3lare the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms, which may be samewe is Noah, 5-14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R4lrepresents a hydrogen atom, a cyano, an alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, a nitrogen atom which may be substituted, an oxygen atom which may be substituted or a sulfur atom which may be substituted, R5lrepresents an alkyl group having one to six carbon atoms which may be substituted, ring Andlrepresents pyridyloxy group, pyrimidinyl group, personilnya group or pyridazinyl group, and ring A'lrepresents dihydroactinidiolide group, dihydroartemisinin niloy group, dihydroartemisinin group or dihydroactinidiolide group. At this stage receive 5-(α-oxo nitrogen-containing heterocyclyl)pyrimidine (L2) of the present invention by hydrolysis of the alkyl groups of 5-(α-alkoxy nitrogen containing heteroaryl)pyrimidine (L1). The reaction is carried out in an aqueous solution of mineral acid, such as chloromethane acid, Hydrobromic acid or sulfuric acid, or in a mixed solvent of water and acetic acid or the like at a temperature ranging from room temperature to 120°C.

(Method M receipt)

In the above formulas, Ar1mrepresents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R2mand R3mare the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having Proc. of the eight carbon atoms, which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R4mrepresents a hydrogen atom, a cyano, an alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, a nitrogen atom which may be substituted, an oxygen atom which may be substituted or a sulfur atom which may be substituted, R5mrepresents an alkyl group which may be substituted, alkenylphenol group which may be substituted, or alkylamino group which may be substituted, and ring Andmrepresents the t dihydroactinidiolide group, dihydroactinidiolide group, dihydroartemisinin group or dihydroactinidiolide group. At this stage receive connection (M3) of the present invention joining the substituent to the nitrogen atom in the ring Andm5-(α-oxo nitrogen-containing heterocyclyl)pyrimidine (M1). The reaction is carried out through interaction with a halogenated alkyl compound or the like in a solvent in the presence of a base. The base include sodium methoxide, ethoxide sodium tert-piperonyl potassium, sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate and potassium carbonate. The solvents include alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, N,N-dimethylformamide, dimethylsulfoxide, N-organic and mixtures thereof. The reaction is carried out at a temperature from 0°to 100°C.

(Method N receipt)

In the above formulas, Rnrepresents an alkyl group having one to six carbon atoms which may be substituted, ring Andnrepresents pyridyloxy group, pyrimidinyl group, personilnya group or pyridazinyl group and X1nand X2nare the same or different is Rog from each other and each represents a halogen atom. At this stage, get α-alkoxy nitrogen-containing heteroaryl compound (N2) as a starting material for obtaining compounds of the present invention, represented by formula (I), the implementation of the interaction of alkali metal alkoxide with α-halogen nitrogen-containing heteroaryl compound (N1) in the solvent. The alkali metal alkoxide is obtained by engagement of the alkali metal or the base of the alcohol in the solvent or in the absence of solvent. Used alkaline metal is preferably, for example, sodium or potassium. Used in the reaction base change depending on the source materials used solvents and so on. Preferred bases include alkali metal hydride such as sodium hydride, but especially their limit, only they would not have slowed down the reaction. In accordance with an alternative option can also be used alkoxides of alkali metals such as sodium methoxide, ethoxide or sodium tert-piperonyl potassium. Solvent used vary depending on starting materials, reagents, and so forth. Although solvents are not particularly limited, if only they didn't slow down the reaction and dissolved to a certain extent, raw materials and bases, solvents preferably include N,N-dimethy is formamid, N-organic, dimethyl sulfoxide, alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran or 1,4-dioxane, and mixtures thereof. The reaction temperature preferably ranges from room temperature to 120°C.

(Manner Of receipt)

In the above formulas, R5orepresents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, Xaboutrepresents a halogen atom and Yorepresents an alkyl group having one to six carbon atoms. Tin-containing reactant (O2) as a starting material for obtaining compounds of the present invention, shown previously presented formula (I)can be obtained by litrownik connection (O1) with the subsequent implementation of the interaction galahitiyawa with litrownik connection. In response litrovaya is preferred to use alkylate, such as n-utility, second-utility or tert-utility. Used halogenalkyls vary depending on the source materials used solvents and so on. Preferably you can offer tribute olowokere, trimethylolpropane, triethylborane or the like, although special restrictions no, only there was no slowing of the reaction. Used in the reaction solvent vary depending on starting materials, reagents, and so forth. Preferred solvents include ethers, such as tetrahydrofuran and diethyl ether, or hydrocarbons such as hexane and heptane, and mixtures of these solvents, although solvents are not limited to, until they slow down the reaction and dissolve to a certain extent the source material. The reaction temperature is preferably in the range from -100°C to room temperature.

(Method R receipt)

In the above formulas, Ar1represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted. Derived (P2) 3-(dimethylamino)-2-propen-1-it as source material for obtaining compounds of the present invention, represented by formula (I)can be obtained by engagement of dimethylacetal N,N-dimethylformamide with compound (P1). Most preferred is the implementation of the reaction of no is e solvent. But the preferred result can be obtained by dilution with a solvent that dissolves starting materials to some extent without slowing response (e.g., such as N,N-dimethylformamide, tetrahydrofuran, dioxane, N-organic, benzene or toluene). The reaction temperature is usually in the range from room temperature to 120°C, preferably about 100°C.

(Method Q receipt)

In the above formulas, Ar1qrepresents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, and R2qand R3qare the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, 5-14-CL is nnow non-aromatic heterocyclic group, which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted. At this stage receive derivative (Q3) pyrimidine as starting material for obtaining compounds of the present invention, presents shown above formula (I), the implementation of synergies derived (Q2) guanidine with 3-(dimethylamino)-2-propen-1-one (Q1), obtained by the process P described above. Used derivative (Q2) guanidine may form a salt with an acid, such as chloromethane acid, Hydrobromic acid, sulfuric acid or acetic acid. Used base vary depending on starting materials, solvent used, and so forth. Preferably the base is a carbonate of an alkali metal such as potassium carbonate or sodium carbonate, or alkali metal alkoxide such as sodium methoxide, ethoxide or sodium tert-piperonyl potassium, but not particularly limited to, but would not slow the reaction. Solvent used vary depending on starting materials, reagents, and so forth. Preferred examples of the solvent include N,N-dimethylformamide, N-organic, on methylsulfoxide and ethanol, but not particularly limited to, yet not slow down the reaction and dissolve to a certain extent the source material and substrate. The reaction temperature is preferably in the range from room temperature to 120°C, more preferably about 100°C.

(Method R receipt)

In the above formulas, Ar1rand R4rare the same or different from each other and each represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, and R2rand R3rare the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group, to the area may be substituted, aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted. Connection (R4) as a starting material for obtaining compounds of the present invention, presents shown above formula (I)can be obtained by the interaction of the aldehyde (R2) and derived (R3) with guanidine compound (R1) in the presence of base followed by aromatization of the oxidant. Used derivative (R3) guanidine may form a salt with an acid, such as chloromethane acid, Hydrobromic acid, sulfuric acid or acetic acid. Used base vary depending on starting materials, solvent used, and so forth. Preferred to be used may be an alkali metal alkoxide such as sodium methoxide, ethoxide or sodium tert-piperonyl potash, or carbonate of an alkali metal such as potassium carbonate or sodium carbonate, but it is not particularly limited, until slows down the reaction. Examples of the oxidant include manganese compounds, such as active manganese dioxide, quinones such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and sulfur. The used solvent is not particularly limited is icipat, until it slows down the reaction and dissolves to a certain extent, raw materials and intermediate compounds. Examples of solvents include ethanol, methanol, tetrahydrofuran, dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide, N-organic, dimethylsulfoxide and mixtures thereof. The reaction temperature is preferably in the range of 0°to 120°C.

(How's receipt)

In the above formulas, Ar1sand R1sare the same or different from each other and each represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R2sand R3sare the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight in narodnih atoms, which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R4srepresents a hydrogen atom, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, and Xsrepresents a halogen atom. Way S receipt can be obtained compound (S3) according to the present invention.

Stage S-1: At this stage receive derivative (S2) 5-halogenopyrimidines halogenoalkanes in position 5 of the pyrimidine cycle derived (S1) pyrimidine is obtained as described above Q or R, using a halogenation agent in the solvent. Used halogenation agent is preferably N-bromosuccinimide, bromine or the like. Solvent used vary depending on starting materials, reagents, and so forth. Preferred solvents include alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran, dioxa is, dimethoxyethane or dimethyl ether of diethylene glycol, N,N-dimethylformamide and N-methylpyrrolidinone, but not particularly limited to, yet not slow down the reaction and dissolve to a certain extent the original materials. The reaction temperature is usually in the range from -20°C to room temperature.

Stage S-2: At this stage receive derivative (S3) pyrimidine by reacting tin-containing reagent or the like, such as the compound (A2)obtained by way Of, with derivative (S2) 5-halogenopyrimidines obtained at stage S-1 receiving, in a solvent in the presence of palladium catalyst. Used palladium catalyst vary depending on the source materials used solvents and so on. Preferably, the palladium catalysts include dichlorobis(triphenylphosphine)palladium(II), palladium(II)acetate, tetrakis(triphenylphosphine)palladium(0) and Tris(dibenzylideneacetone)dipalladium(0), but not particularly limited to, until the slow reaction. Solvent used vary depending on starting materials, reagents, and so forth. Preferred solvents include alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, toluene, xylene, N,N-dimethylformamide and N-methylpyrrolidone is, but not particularly limited to, yet not slow down the reaction and dissolve to a certain extent the original materials. The reaction temperature is usually in the range from room temperature to 150°C, preferably about 100°C.

(How T get)

In the above formulas, Ar1trepresents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R2tand R3tare the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen ug is urodnich atoms, which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, acyl group having one to six carbon atoms which may be substituted, or alkylsulfonyl group having one to six carbon atoms which may be substituted, R4trepresents a hydrogen atom, halogen atom, cyano, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, a nitrogen atom which may be substituted, an oxygen atom which may be substituted, or a sulfur atom which may be substituted, R5trepresents alkenylphenol group having two to six carbon atoms which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms, or 5 to 14-membered aromatic heterocyclic group which may be substituted, and ring Andtbefore the hat is dihydroactinidiolide group, dihydroactinidiolide group, dihydroartemisinin group or dihydroactinidiolide group. Connection (T2) according to the present invention can be obtained by the engagement between the connection (T1) and boron reagent in a solvent in the presence of a base and a copper catalyst. Used in the reaction base vary depending on starting materials, solvent used, and so forth. Preferred bases include tertiary amines, such as pyridine, diisopropylethylamine or triethylamine, but not particularly limited to, until the slow reaction. Used copper catalyst vary depending on starting materials, solvent used, and so forth. Copper catalysts are not particularly limited, while not slow down the reaction, but preferably include compounds of divalent copper, such as copper acetate, copper bromide or copper sulfate, and more preferred is copper acetate. Solvent used vary depending on starting materials, reagents, and so forth. The solvents are not particularly limited as they do not inhibit the reaction and dissolves to a certain extent the source material, but preferably include N,N-dimethylformamide, tetrahydrofuran, ethyl acetate, dichloromethane and dioxane. The reaction temperature finds the I is preferably in the range from room temperature to 120° C.

(The way U get)

In the above formulas, Ar1urepresents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R2uand R3uare the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, acyl group having one to six carbon atoms which may be substituted, or alkyls Lionello group, having one to six carbon atoms which may be substituted, R4urepresents a hydrogen atom, a cyano, an alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, a nitrogen atom which may be substituted, or an oxygen atom which may be substituted, R5urepresents a nitrogen atom which may be substituted, an oxygen atom which may be substituted or a sulfur atom which may be substituted, ring Andurepresents pyridyloxy group, pyrimidinyl group, personilnya group or pyridazinyl group and Xurepresents a halogen atom, alkylsulfonate or arylsulfonate. Connection (U2) according to the present invention can be obtained by the engagement between the connection (U1) and the nucleophilic reagent in a solvent or in no solvent. Used in the reaction of the nucleus is safe reagent is a primary or secondary amine or alkoxide of an alkali metal. The alkali metal alkoxide is obtained by engagement of the alkali metal or the base of the alcohol in the solvent or in the absence of solvent. The alkali metal used for obtaining the alkali metal alkoxide is sodium or potassium. The basis used to obtain alkoxide of an alkali metal, vary depending on starting materials, solvent used, and so forth. The base is not particularly limited, until slows down the reaction, but preferably represents an alkali metal hydride such as sodium hydride, or an alkali metal alkoxide such as sodium methoxide, ethoxide or sodium tert-piperonyl potassium. Solvent used vary depending on starting materials, reagents, and so forth. The solvents are not particularly limited as they do not inhibit the reaction and dissolves to a certain extent the original materials and reagents, but preferably include N,N-dimethylformamide, N-organic, dimethyl sulfoxide, alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane, water and their mixtures. The reaction temperature is preferably in the range from room temperature to 200°C.

(Method V receipt)

In the above formulas, Arv represents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R2vand R3vare the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, acyl group having one to six carbon atoms which may be substituted, or alkylsulfonyl group having one to six carbon atoms which may be substituted, R4vpre whom represents a hydrogen atom, halogen atom, cyano, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, a nitrogen atom which may be substituted, an oxygen atom which may be substituted or a sulfur atom, which may be substituted, R5vrepresents an alkyl group having one to six carbon atoms, the ring Andvrepresents pyridyloxy group, pyrimidinyl group, personilnya group, pyridazinyl group, dihydroactinidiolide group, dihydroactinidiolide group, dihydroartemisinin group or dihydroactinidiolide group andvrepresents an alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl gr the PPU, having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted. Connection (V2) of the present invention can be obtained by engagement of the base with the compound (V1) in the solvent. The base used in the reaction, vary depending on starting materials, solvent used, and so forth. The base is not particularly limited, until slows down the reaction, but preferably represents an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. Solvent used vary depending on starting materials, reagents, and so forth. The solvents are not particularly limited as they do not inhibit the reaction and dissolves to a certain extent the source material, but preferably include methanol, tetrahydrofuran, dichloromethane, 1,2-dimethoxyethane, 1,4-dioxane, water and their mixtures. The reaction temperature is preferably in the range of 0°to 120&x000B0; C.

(Way W receipt)

In the above formulas, Ar1wrepresents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R2vand R3vare the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R4wrepresents a hydrogen atom, halogen atom, cyano, alkyl group, the ima is the relevant one to six carbon atoms, which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, a nitrogen atom which may be substituted, an oxygen atom which may be substituted or a sulfur atom which may be substituted, ring Andwrepresents pyridyloxy group, pyrimidinyl group, personilnya group or pyridazinyl group, the ring A'wrepresents dihydroactinidiolide group, dihydroactinidiolide group, dihydroartemisinin group or dihydroactinidiolide group and Xwrepresents a halogen atom. The compound (W2) of the present invention can be obtained, for example, this way of W. That is, the compound (W2) can be obtained by hydrolysis of the compound (W1) as a starting material in acidic conditions. Used acid vary depending on starting materials, reagents, solvents, and so forth. Acid is not particularly limited, until slows down the reaction, but preferably of t is made by chloroethanol acid, Hydrobromic acid, sulfuric acid or the like. This reaction is carried out in water or in a mixed solvent consisting of water and acetic acid or alcohols, such as ethanol, for example. In addition, the reaction temperature is usually in the range from room temperature to about 120°C, preferably 80°S-100°C.

(Method X receipt)

In the above formulas, Ar1xrepresents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R2and R3are the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic gr the PPU, which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, acyl group having one to six carbon atoms which may be substituted, or alkylsulfonyl group having one to six carbon atoms which may be substituted, R4represents a hydrogen atom, halogen atom, cyano, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, a nitrogen atom which may be substituted, an oxygen atom which may be substituted, or a sulfur atom which may be substituted, Rand R10xare the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms, which can the be replaced, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, ring Andxrepresents pyridyloxy group, pyrimidinyl group, personilnya group, pyridazinyl group, dihydroactinidiolide group, dihydroactinidiolide group, dihydroartemisinin group or dihydroactinidiolide group andxrepresents an alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted. Connection (x2) of the present invention can be obtained by dehydration with condensation derivative (X1) carboxylic acid with amine in the presence of a condensing agent in a solvent. Used condensing agent is preferably 3-(3'-dimethylaminopropyl)-1-ethylcarbodiimide. The reaction can be accelerated by the addition of 1-hydroxybenzotriazole or the like. In addition, Amin, condensed with the carboxylic acid forms a salt with hydrogen chloride or the like, add appropriate amount of a tertiary amine such as triethylamine. Preferred examples of the solvent include ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane or diethyleneglycol, N,N-dimethylformamide and 1-methylpyrrolidinone. The reaction temperature is usually in the range of 0°C to 50°C, preferably about room temperature.

(Method Y receipt)

In the above formulas, R1yrepresents an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R2yrepresents a hydrogen atom or alkyl group having one to six carbon atoms, R3yrepresents an alkyl group having one to six carbon atoms which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, and Xyrepresents a halogen atom. In this way the Y can be obtained compound (Y4) as a starting material for obtaining compounds of the present invention, represented by formula (I).

Stage Y-1: At this stage get a connection (Y2) by reacting the reducing agent with the compound (Y1) in the solvent for the conversion of the ester or carboxyl group of the compound (Y1) in hydroxymethylene group. Used solvent is preferably tetrahydroborate sodium, sociallyengaged, balancerationality complex or the like that is. Solvent used vary depending on starting materials, reagents, and so forth. The solvents are not particularly limited as they do not inhibit the reaction and dissolves to a certain extent the original materials, but preferably the solvents include alcohols, such as ethanol, and ethers, such as diethyl ether, tetrahydrofuran and 1,4-dioxane. The reaction temperature is preferably in the range from -20°C to room temperature.

Stage Y-2: At this stage receive derivative (Y4) of ester sulfonic acid by reacting the compound (Y2) with derivative (Y3) sulphonylchloride in a solvent in the presence of a base. Used in the reaction, a base is preferably a tertiary amine such as triethylamine. Solvent used vary depending on starting materials, reagents, and so forth. The solvents are not particularly limited as they do not inhibit the reaction and dissolves to a certain extent the original materials, but preferably the solvent include dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran and 1,4-dioxane. The reaction temperature is preferably in the range from -20°C to room temperature.

(Method Z receipt)

In the above formulas, Ar1znot only is em an aromatic hydrocarbon cyclic group, having six to fourteen carbon atoms which may be substituted, or a 5 to 14-membered aromatic heterocyclic group which may be substituted, R2zand R3zare the same or different from each other and each represents a hydrogen atom, alkyl group having one to six carbon atoms which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, cycloalkyl group having three to eight carbon atoms which may be substituted, cycloalkenyl group having three to eight carbon atoms which may be substituted, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, acyl group having one to six carbon atoms which may be substituted, or alkylsulfonyl group having one to six carbon atoms which may be substituted, R4zrepresents a hydrogen atom, cyano, alkyl group, with the Dean to six carbon atoms, which may be substituted, alkenylphenol group having two to six carbon atoms which may be substituted, alkylamino group having two to six carbon atoms which may be substituted, an aromatic hydrocarbon cyclic group having six to fourteen carbon atoms which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, a nitrogen atom which may be substituted, an oxygen atom which may be substituted or a sulfur atom which may be substituted, ring Andzrepresents pyridyloxy group, pyrimidinyl group, personilnya group or pyridazinyl group and Xzrepresents a halogen atom. Connection (Z2) according to the present invention can be obtained by implementing the interaction between the compound (Z1) and the alkali metal cyanide in a solvent. Cyanide of an alkali metal used in the reaction, is preferably sodium cyanide or potassium cyanide. Solvent used vary depending on starting materials, reagents, and so forth. The solvents are not particularly limited as they do not inhibit the reaction and dissolves to a certain extent the original materials, but preferably the solvents include dimethylsulfoxide, N,N-dimethylformamide and N-methyl shall irreligion. The reaction temperature is preferably from 100°to 200°C.

We have described above are typical examples of methods for producing compounds (I) of the present invention. The compounds used as starting materials for preparing compounds of the present invention can form a salt and/or solvate and is not particularly limited, as long as they do not impact adversely on the reaction. When the compound (I) of the present invention is manufactured in the form of free connection, you can convert them to possible salts of the above compounds (I) traditional method. Received as compounds (I) according to the present invention, various isomers such as geometric isomers, optical isomers based on asymmetric carbon atom, the rotary isomers, stereoisomers and tautomers, can be cleaned and selected traditional partitioning methods. Such methods include, for example, recrystallization, the method of the diastereomeric salts, enzymatic separation and various chromatography methods such as thin layer chromatography, chromatography on a column and gas chromatography.

Compounds of the present invention, represented by formula (I), their salts or solvate those and others can be made in the form of pharmaceutical preparations by themselves or in a mixture, for example, known is the major pharmacologically acceptable carrier to the traditional method. Preferred dosage forms are tablets, powders, fine granules, granules, coated tablets, capsules, syrups, lozenges, pharmaceutical forms for inhalation, suppositories, injections, ointments, eye ointments, eye drops, nose drops, ear drops, poultices and lotions. In the manufacture of drugs can be used if necessary, commonly used excipients, binders, disintegrating agents, lubricants, dyes and corrigentov, as well as stabilizers, emulsifiers, binders, surface-active substances, substances for regulating the pH, antiseptics and antioxidants. The preparations can be manufactured by the traditional method using components commonly used as raw materials for pharmaceutical preparations. Examples of such components include (1) liquid animal fats and vegetable oils, such as soybean oil, beef tallow and synthetic glycerides; (2) hydrocarbons such as liquid paraffin, squalane and solid paraffin; (3) essential oils, such as octyldodecanol and isopropylmyristate; (4) higher alcohols, such as cetosteatil alcohol and beganovic alcohol; (5) a silicone resin; and (6) silicone oil; (7) surface-active substances, such as polyoxyethylene esters of fatty acids, esters sorbitane fatty acids, glitzer the new esters of fatty acids, polyoxyethylenesorbitan esters of fatty acids, polyoxyethylene hydrogenated castor oil and block copolymers of polyoxyethylene and polyoxypropylene; (8) water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymers, polyethylene glycol, polyvinylpyrrolidone and methylcellulose; (9) lower alcohols, such as ethanol and isopropanol; (10) polyhydric alcohols, such as glycerin, propylene glycol, dipropyleneglycol and sorbitol; (11) sugars such as glucose and sucrose; (12) inorganic powders such as silicic anhydride, aluminum silicate of magnesium and aluminum silicate; and (13) distilled water. 1) Fillers include, for example, lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide; 2) binders include, for example, polyvinyl alcohol, simple, polyvinyl ether, methylcellulose, ethylcellulose, Arabian gum, tragacanth gum, gelatin, shellac, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, block-polymers of polypropylenglycol and polyoxyethylene, meglumine, calcium citrate, dextrin and pectin; 3) leavening agents include, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, actin and calcium carboxymethylcellulose; 4) lubricants include, for example, manganese stearate, talc, polyethylene glycol, silica and hardened vegetable oil; 5) the dye may be any coloring substances approved for addition to pharmaceuticals; (6) corrigentov include, for example, cocoa powder, menthol, aromatic powder (mpasm), peppermint oil, campal (borneol and cinnamon powder; and (7) antioxidants can be any antioxidants approved for addition to pharmaceuticals, such as ascorbic acid and α-tocopherol.

1) Oral drugs are made by mixing the compounds of the present invention or its salt with a filler and, if necessary, a binder, baking powder, lubricant, dye, Corrigendum and other components and the transformation mixture on traditional technology, for example, powder, fine granules, granules, tablets, coated tablets or capsules. 2) Tablets and granules may be appropriately covered, for example, sugar or gelatin. 3) Liquid medicines, such as syrups, preparations for injeti or eye drops can be made according to the traditional technology by adding substances that regulate pH, a solubilizer and isotherwise substances and, if necessary, the means, the method is adequate solubilization, stabilizer, buffer, suspending substances, antioxidants, and other components. Liquid preparations can also be made in the form liofilizovannyh products. Injections can be administered intravenously, subcutaneously and/or intramuscularly. Preferred examples suspendida substances are methylcellulose, Polysorbate 80, hydroxyethylcellulose, Arabian gum, powdered tragakant, sodium carboxymethylcellulose and polyoxyethylenesorbitan; preferred examples of solubilization are polyoxyethylene hydrogenated castor oil, Polysorbate 80, nicotinamide and polyoxyethylenesorbitan; preferred examples of stabilizers include sodium sulfite, metasulfite sodium and ether; preferred examples of preservatives are methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol. 4) External preparations can be manufactured by conventional technology without special restrictions. The materials for the base in this case can be any source materials that are commonly used, for example, in pharmaceutical preparations, quasilogarithmic and cosmetics. Such starting materials include, for example, liquid animal fats and vegetable oils, mineral oils, difficult is Fernie oil, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals and distilled water. If necessary, can be added to any of the pH regulators, antioxidants, chelating agents, antiseptics and anti musty substances, dyes corrigentov and other substances. In addition, can be added on demand components with inducing differentiation effect, accelerators blood flow, bactericides, anti-inflammatory agents, cell activators, vitamins, amino acids, wetting agents, keratolytic agents, and other components.

The dose of the pharmaceutical preparation of the present invention varies depending on the degree of symptom, age, sex, body weight, route of administration, type of salt, the difference in sensitivity to the medication, specific types of the disease and other factors. Usually pharmaceutical drug can be introduced to the adult one or several separate doses with a daily dose of from about 30 μg to about 10 g, preferably from 100 μg to 5 g, and more preferably from 100 μg to 100 mg, by oral administration, or from about 30 μg to about 1 g, preferably 100 μg to 500 mg and more preferably from 100 μg to 30 mg p and the introduction by way of injection.

In accordance with the present invention is offered a new derivative of pyrimidine. Compounds of the present invention and their salts or solvate both have excellent antagonism of adenosine receptors (adenosine A1-And2A-And2Bor As3-receptor) and is particularly effective as antagonists to adenosine A2-receptors, particularly adenosine A2Aand/or And2Bthe receptor. They are useful as a means for the treatment or prevention of disease, which is the ratio of adenosine receptor (adenosine A1-And2A-And2Bor As3-receptor), and diseases against which effective receptor antagonist. They are applicable as a means for the treatment, prevention or improvement of the flow of various constipation (functional constipation, irritable bowel syndrome, constipation, associated with irritable bowel syndrome, organic constipation, constipation accompanying enteroparasites ileus, constipation accompanying congenital dysfunction of the digestive tract, constipation accompanying ileus), and also as a means for treating, preventing or improving the course of diabetes, diabetic complications, diabetic retinopathy, obesity, or as is TMI and as, for example, hypoglycemic agents, agents for improving glucose intolerance, a means to increase sensitivity to insulin, antihypertensives, diuretics, antidepressant, means for treatment of osteoporosis and for the treatment of Parkinson's disease, for the treatment of Alzheimer's disease, a treatment for inflammatory diseases of the digestive tract or for the treatment of Crohn's disease.

Examples

The following reference examples, examples and sample tests are illustrative and do not under any circumstances do not limit the present invention. Specialists in this field can change not only the following examples, but the invention in accordance with this description, to use the fullness of the present invention, and such changes and additions are also included in the scope of the attached claims related to this description.

Reference example 1 Ethyl (E)-3-(3-forfinal)-2-(4-pyridyl)-2-propenoate

A solution of ethyl 4-pyridylacetate (25,0 g, 0,151 mol) and 3-forventelige (20.7 g, 0,167 mol) in a mixture of acetic anhydride (100 ml) and triethylamine (20 ml) was boiled under reflux for 5.5 hours. Allowing to stand for cooling, the reaction mixture koncentrirovalisb was diluted with ethyl acetate and saturated aqueous sodium bicarbonate and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous solution of sodium bicarbonate twice and a saturated salt solution, dried over anhydrous sodium sulfate and then concentrated. The residue was subjected to chromatography on a column of silica gel (eluent: hexane to hexane:ethyl acetate = 9:1) to obtain specified in the connection header (25,5 g, 62%) as a red-orange oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 1.28 (3H, t, J=7.2 Hz), 4,27 (2H, q, J=7,2 Hz), 6,70 to 6.75 (1H, m), 6,80-6,84 (1H, m), 6,91-6,97 (1H, m), 7,12-to 7.18 (1H, m), 7,16 (2H, DD, J=1,6, 4,4 Hz), the 7.85 (1H, s), to 8.62 (2H, DD, J=1,6, 4,4 Hz).

Reference example 2: Ethyl (E)-3-(2-furyl)-2-(4-pyridyl)-2-propenoate

Specified in the title compound was synthesized by the method of reference example 1 using 2-furaldehyde.

1H NMR (400 MHz, CDCl3) δ ppm; of 1.20 (3H, t, J=7.2 Hz), 4,18 (2H, q, J=7.2 Hz), 6,51 (1H, d, J=3.6 Hz), is 6.54 (1H, DD, J=1,6, 3.6 Hz), 7,29 (2H, DD, J=1,6, 4,4 Hz), 7,66 (1H, s), of 7.69 (1H, d, J=1.6 Hz), to 8.62 (2H, DD, J=1,6, 4,4 Hz).

Reference example 3: (E)-4-(2-Furyl)-3-(4-pyridyl)-3-butene-2-he

In nitrogen atmosphere, 3.0 M solution methylacrylamide in diethyl ether (3,7 ml, 11.1 mmol) was added dropwise over 5 minutes to a 1 M solution of bis(trimethylsilyl)amide lithium in tetrahydrofuran (22 ml, 22 mmol) at -50°With (bath with dry ice and acetone), followed by stirring the mixture in the form ka is Oh she was within 1 hour. Then to the mixture was added dropwise over 5 minutes a solution of ethyl (E)-3-(2-furyl)-2-(4-pyridyl)-2-propenoate (2.4 g, 9,87 mmol) in tetrahydrofuran (20 ml). The reaction mixture was stirred for 30 minutes while raising the temperature to room and then the reaction was stopped by adding chloroethanol acid. After dilution with saturated aqueous solution of ammonium chloride, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 1:1-4:1) to obtain the specified title compound (0.52 g, 23%).

1H NMR (400 MHz, CDCl3) δ ppm; a 2.36 (3H, s), 6,07 (1H, d, J=3.2 Hz), 6,34 (1H, DD, J=1,6, and 3.2 Hz), 7,16 (2H, DD, J=1,8, 4,4 Hz), 7,38 (1H, d, J=1.6 Hz), 7,55 (1H, s), to 8.70 (2H, DD, J=1,8, 4,4 Hz).

Reference example 4: (E)-3-(3-Forfinal)-2-(4-pyridyl)-2-propenenitrile

Sodium (3.0 g, 130 mmol) was dissolved in ethanol (150 ml), to the solution was added 4-pyridylacetonitrile (10 g, 65 mmol) and the mixture was stirred at room temperature. After 10 minutes, was added to a mixture of 3-forbindelse (8 g, 65 mmol), followed by stirring the mixture as it was within 30 minutes. The obtained precipitates were collected by filtration and washed not the largest portion of water with obtaining specified in the title compound (8.2 g, 56%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 7,40-7,46 (1H, m), to 7.61-to 7.68 (1H, m), of 7.75 (2H, DD, J=1,6, 4,4 Hz), to 7.77-7,86 (2H, m), of 8.37 (1H, s), 8,73 (2H, DD, J=1,6, 4,4 Hz).

Reference example 5: 1-(2-Furyl)-2-(4-pyridyl)-1-alanon

To a solution of 4-picoline (4.6 g, 49.4 mmol) and ethyl 2-furancarboxylic (7.7 g, 54,9 mmol) in tetrahydrofuran (40 ml) was added dropwise bis(trimethylsilyl)amide lithium (100 ml, 100 mmol) for 1 hour at 0°C in an atmosphere of nitrogen gas, followed by stirring the mixture as it was, within 2 hours. Was added to the reaction mixture hexane (140 ml) and the resulting crystals were collected by filtration. The obtained crystals were dissolved in ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride twice and a saturated salt solution, dried over anhydrous sodium sulfate and concentrated. To the residue was added hexane and the resulting precipitates were collected by filtration and washed with hexane to obtain specified in the title compound (6.5 g, 70%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 4.26 deaths (2H, s), 6,77 (1H, DD, J=2,0, 3.6 Hz), 7,31 (2H, DD, J=1,6, 4,4 Hz), the 7.65 (1H, DD, J=0,8, 3.6 Hz), with 8.05 (1H, DD, J=0,8, 2.0 Hz), 8,51 (2H, DD, J=1,6, 4,4 Hz).

Reference example 6: 3-(Dimethylamino)-1-(2-furyl)-2-(4-pyridyl)-2-ol is pen-1-he

Dimethylacetal N,N-dimethylformamide (5 ml) was added to 1-(2-Furyl)-2-(4-pyridyl)-1-ethanone (2.0 g, is 10.7 mmol) and the mixture was stirred at 100°C for 2 hours. Allowing the reaction mixture to cool, it was diluted with ethyl acetate and saturated aqueous ammonium chloride. The aqueous solution was extracted with ethyl acetate (6 times). The combined organic layers were dried over anhydrous sodium sulfate and then concentrated to obtain specified in the title compound (2.5 g, 97%) as a reddish brown oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,80 (6H, CL), 6,53 (1H, sh), 6,60 (1H, sh), 7,10 (2H, d, J=4.0 Hz), the 7.65 (1H, sh), of 7.75 (1H, s), 8,44 (2H, d, J=4.0 Hz).

Reference example 7: (6-Chloro-3-pyridyl)methanol

To a solution of ethyl 6-chloronicotinate (25,8 g, 0,139 mol) in ethanol was added borohydride sodium (10.5 g, 0,278 mol), followed by stirring in an atmosphere of nitrogen gas at room temperature. After 41 hours, the reaction mixture was concentrated and then the residue was diluted with saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to chromatography on a column of silica gel (eluting solvent: hexane, hexane:ethyl acetate = :1, 2:1 and 3:2) to obtain the specified title compound (11.7 g, 58%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 4.54 (2H, d, J=5.6 Hz), 5,43 (1H, t, J=5.6 Hz), of 7.48 (1H, d, J=8,4 Hz), 7,80 (1H, DD, J=2,4, and 8.4 Hz), 8,35 (1H, d, J=2,4 Hz).

Referential example 8: (6-Chloro-3-pyridyl)methylmethanesulfonate

To a solution of (6-chloro-3-pyridyl)methanol (4.5 g, 31,3 mmol) and triethylamine (13,2 ml, 94.7 mmol) in dichloromethane (90 ml) was added dropwise methanesulfonanilide (3.6 ml, 46.5 mmol) for 45 minutes at temperature from -9°to 4°C in an atmosphere of nitrogen gas, followed by stirring the mixture as it was. After 1 hour, the temperature of the reaction mixture was raised to room temperature. The reaction mixture was washed with aqueous saturated sodium bicarbonate solution and saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and concentrated to obtain specified in the connection header (6,14 g, 88%) as a pale brown solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 3,30 (3H, s), of 5.34 (2H, s), to 7.61 (1H, DD, J=0,6, 8.0 Hz), of 7.97 (1H, DD, J=2,4, 8.0 Hz), 8,53 (1H, DD, J=0,6, 2,4 Hz).

Referential example 9: 2-(6-Chloro-3-pyridyl)-1-(2-furyl)-1-alanon

To a mixture of 2-furaldehyde (7.9 g, and 82.2 mmol) and zinc iodide(II) (110 mg, 0,345 mmol) was added dropwise, trimetric Elland (11,0 ml, of 82.5 mmol) for 10 minutes at 0°C in an atmosphere of nitrogen gas, followed by stirring the mixture as it was. After 30 minutes the reaction mixture was diluted with tetrahydrofuran (200 ml) and then cooled to -78°C. To the mixture was added dropwise within 1 hour 1.0 M solution of bis(trimethylsilyl)amide lithium in tetrahydrofuran (86 ml, 86 mmol) and then was added dropwise over 1.5 hours a solution of (6-chloro-3-pyridyl)methylmethanesulfonate (18,1 g of 81.7 mmol) in tetrahydrofuran (50 ml), followed by stirring while gradually raising the temperature to room temperature. After 12.5 hours to the reaction mixture was added a 1.0 M solution of tetrabutylammonium in tetrahydrofuran (86 ml, 86 mmol) followed by stirring the mixture as it was. After another 30 minutes the reaction mixture was diluted with saturated aqueous ammonium chloride and ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of ammonium chloride twice, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to chromatography on a column of silica gel (eluting solvent: hexane, hexane:ethyl acetate= 1:1, 4:1, 3:1 2:1) and then suspended in hexane. The resulting precipitates were collected by filtration to obtain specified in the title compound (11.9 g, 54%) as a pale brown solid matter what.

1H NMR (400 MHz, DMSO-d6) δ ppm; or 4.31 (2H, s), is 6.78 (1H, DD, J=1,8, 3,4 Hz)to 7.50 (1H, d, J=8,4 Hz), to 7.64 (1H, d, J=3,4 Hz), to 7.77 (1H, DD, J=2,4, and 8.4 Hz), of 8.06 (1H, d, J=1,8 Hz), with 8.33 (1H, d, J=2,4 Hz).

Reference example 10: 2-(6-Chloro-3-pyridyl)-3-(dimethylamino)-1-(2-furyl)-2-propen-1-he

Specified in the title compound was synthesized by the method of reference example 6 using 2-(6-chloro-3-pyridyl)-1-(2-furyl)-1-ethanone.

1H NMR (400 MHz, DMSO-d6) δ ppm; and 2.79 (6H, CL), 6,55 (1H, DD, J=2.0 a, 3,4 Hz), 6,62 (1H, d, J=3,4 Hz), was 7.45 (1H, d, J=8.0 Hz), to 7.59 (1H, DD, J=2,4, 8.0 Hz), to 7.77 (2H, d, J=2.0 Hz), 8,14 (1H, d, J=2,4 Hz).

Referential example 11: (E)-3-(3-Forfinal)-2-(6-methoxy-3-pyridyl)-2-propenenitrile

To a suspension of sodium hydride (8.8 g, 0,220 mol) in 1,2-dimethoxyethane (300 ml) was added gradually dieticiansupervised (19.7 g, 0,122 mol) at room temperature in an atmosphere of nitrogen gas. After permisiunea for 15 minutes, to the mixture were added successively 5-bromo-2-methoxypyridine (20,0 g, 0,106 mol) and tetrakis(triphenylphosphine)-palladium(0) (2.0 g, at 1.73 mmol) followed by heating to 90°and stirring for 6 hours. Allowing the reaction mixture to cool, it was additionally cooled with ice. Was added thereto dropwise 3-forbindelse (13,7 g, 0,110 mol) for 1.5 hours at 4°C in an atmosphere of nitrogen gas, followed by stirring is for another 2.5 hours while gradually raising the temperature to room temperature. The reaction mixture was diluted with saturated aqueous ammonium chloride and ethyl acetate and then the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous solution of ammonium chloride twice, dried over anhydrous sodium sulfate and then concentrated. The residue is suspended in methanol and then the obtained solid substance was collected by filtration and washed with diethyl ether and hexane to obtain specified in the connection header (7,80 g, 29%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 3.92 (3H, s), 7,00 (1H, d, J=8,8 Hz), 7,34-7,40 (1H, m), EUR 7.57-to 7.64 (1H, m), 7,69 for 7.78 (2H, m), 8,03 (1H, s), 8,11 (1H, DD, J=2,6, 8,8 Hz), 8,53 (1H, d, J=2,6 Hz).

Reference example 12: 2-Amino-6-(3-forfinal)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone

(Method 1)

Sodium (3.2 g, 139 mmol) was dissolved in ethanol (200 ml) and then to the resulting solution was added sequentially 4-pyridylacetonitrile (10.0 g, or 64.7 mmol), 3-forbindelse (7.3 ml, of 68.8 mmol) and guanidine hydrochloride (7.0 g, 73,3 mmol), after which the mixture was boiled under reflux for 2 days. Was filtered, the insoluble materials and the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel (eluting solvent: dichloromethane, dichloromethane:methanol= 20:1, 10:1, 5:1) obtaining 5,6-d the hydro product (13,6 g) specified in the title compound as crude product. To the product were added sulfur (26,4 g that 82.3 mmol in the form of S) followed by heating at 185°C for 2.5 hours. Allowing the reaction mixture to cool, it is suspended in methanol, and insoluble materials were filtered off and washed 2 N. was carried out. The methanol in the filtrate was concentrated and the residue was washed with ethyl acetate two times. The aqueous layer was brought to pH 11 by adding 5 N. aqueous sodium hydroxide solution, washed with ethyl acetate two times, and then neutralized 2 N. was carried out. The obtained crystals were collected by filtration and washed with water and ethyl acetate to obtain specified in the title compound (6.2 g, 34%) as a colourless solid. In addition, this method is listed in the title compound was also obtained by selection (E)-3-(3-forfinal)-2-(4-pyridyl)-2-propenenitrile and then placing it cyclization with guanidine by method of reference example 4.

(Method 2)

Sodium (3.4 g, 147 mmol) was dissolved in ethanol (500 ml) and then to the resulting solution was added ethyl (E)-3-(3-forfinal)-2-(4-pyridyl)-2-propenoate (33 g, 121 mmol) and guanidine hydrochloride (13,9 g, 146 mmol), after which the mixture was boiled under reflux for 13 hours. Allowing the mixture to cool, the solvent was removed. To the residue was added tetrahydrofuran (500 ml)was filtered, the insoluble materials and the filtrate was concentrated. To a solution of the residue of smesi tetrahydrofuran (1500 ml)-methanol (100 ml) was added active manganese dioxide (250 g), after which the mixture was boiled under reflux. After 2 hours was added to it additional active manganese dioxide (100 g), after which the mixture was boiled under reflux for another 1 hour and 15 minutes. Allowing the mixture to cool, manganese dioxide was filtered through Celite and washed with tetrahydrofuran and methanol. The collected filtrate was concentrated and to the residue was added acetonitrile. The obtained precipitates were collected by filtration to obtain specified in the title compound (15 g, 44%) as a yellow powder.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,86 (2H, CL), of 6.96 (1H, d, J=7,6 Hz), 7,00-7,07 (3H, m), 7,00-to 7.15 (1H, m), 7,20-7,28 (1H, m), a 8.34 (2H, d, J=3.2 Hz); MS m/e (ESI) 283 (MN+).

Reference example 13: 2-Amino-6-(2-furyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone

Specified in the title compound was synthesized by method 1 of reference example 12 using 2-furaldehyde.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,48 (1H, DD, J=1,6, 3.6 Hz), is 6.54 (1H, DD, J=0,8, 3.6 Hz), 6,91 (2H, CL), 7,21 (2H, DD, J=1,6, 4.6 Hz), 7,54 (1H, DD, J=0,8 and 1,6 Hz), charged 8.52 (2H, DD, J=1,6, 4.6 Hz); MS m/e (ESI) 255 (MN+).

Reference example 14: 3-(Dimethylamino)-1-(2-furyl)-2-propen-1-he

A mixture of 2-acetylfuran (25,0 g, 0,227 mmol) and dimethylacetal N,N-dimethylformamide (40 mm) was stirred at 100°C for 9 hours. Allowing the reaction mixture to cool, it concentri is ovale. To the residue was added diethyl ether and hexane. The obtained solid substance was collected by filtration and washed with hexane to obtain specified in the title compound (36.5 g, 97%) as a brown solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,88 (3H, CL), 3,14 (3H, CL), the 5.65 (1H, d, J=12,6 Hz), 6,60 (1H, DD, J=2.0 a, 3,4 Hz), 7,10 (1H, DD, J=0,8, 3,4 Hz), to 7.68 (1H, d, J=12,6 Hz), 7,79 (1H, DD, J=0,8, 2.0 Hz).

Reference example 15: 4-(2-Furyl)-2-pyrimidinamine

A suspension of 3-(dimethylamino)-1-(2-furyl)-2-propen-1-she (5.0 g, 30.3 mmol), guanidine hydrochloride (5.8 g, 60,7 mmol) and potassium carbonate (8,4 g, 60,9 mmol) in N,N-dimethylformamide (50 ml) was stirred at 100°C for 21 hours. Allowing the reaction mixture to cool, diluted with ice water (250 ml). The obtained solid substance was collected by filtration and washed with water to obtain specified in the connection header (4,19 g, 86%) as a pale brown solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,66 (2H, CL), of 6.68 (1H, DD, J=2.0 a, and 3.2 Hz), to 6.88 (1H, d, J=5,2 Hz), 7,17 (1H, DD, J=0,8, a 3.2 Hz), 7,88 (1H, DD, J=0,8, 2.0 Hz), of 8.28 (1H, d, J=5,2 Hz); MS m/e (ESI) 162 (MN+).

Reference example 16: 5-Bromo-4-(2-furyl)-2-pyrimidinamine

To a solution of 4-(2-furyl)-2-pyrimidinamine (4,10 g, and 25.4 mmol) in N,N-dimethylformamide (40 ml) was added N-bromosuccinimide (4,53 g, 25.5 mmol) in 2°With subsequent p is remesiana mixture, what she was. After 6 hours the reaction mixture was diluted with aqueous saturated sodium bicarbonate solution (240 ml). The mixture was cooled with ice and then the crystals were collected by filtration and washed with water to obtain specified in the title compound (5.10 g, 84%) as a pale brown solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; was 6.73 (1H, DD, J=1,6, 3.6 Hz), of 6.96 (2H, CL), to 7.50 (1H, DD, J=0,8, 3.6 Hz), of 7.97 (1H, DD, J=0,8 and 1,6 Hz), to 8.41 (1H, s).

Reference example 17: 2-(Benzyloxy)-5-bromopyridin

To a solution of benzyl alcohol (11.4 g, 0,105 mol) in N,N-dimethylformamide (250 ml) was added 70% oily sodium hydride (4,2 g, 0,123 mol) at 0°C, followed by stirring the mixture as it was, for 1.5 hours. Then was added to a mixture of 2,5-dibromopyridine (25 g, 0,106 mol), and then mixed it with 70°C for 2 hours. Allowing the reaction mixture to cool, it was diluted with saturated aqueous ammonium chloride and was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of ammonium chloride twice, dried over anhydrous magnesium sulfate and concentrated to obtain the crude specified in the title compound (29.5 g) as pale yellow liquid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 5,33 (2H, s), make 6.90 (1H, d, J=9.0 Hz), 7,30-7,41 (3H, m), 7,41-7,46 (2H, m), 7,92 (1H, DD, J=2,8, 9.0 Hz), 8,30 (1H,d, J=2,8 Hz).

Reference example 18: 2-(Benzyloxy)-5-(1,1,1-tributylstannyl)pyridine

To the suspension obtained above crude 2-(benzyloxy)-5-bromopyridine (29.5 g) in diethyl ether (300 ml) was added dropwise to 2.66 M solution of n-utility in hexane (40 ml, 0,106 mol) over 30 minutes at a temperature of -76°to -72°C in an atmosphere of nitrogen gas. Then to the mixture was added dropwise a tetrahydrofuran (170 ml), after which the mixture was stirred as it was. After 1.5 hours was added thereto dropwise over 1.5 hours a solution of tributyltinchloride (35 g, 0,114 mol) in tetrahydrofuran (50 ml). Then the reaction mixture was stirred as it was, with a gradual increase in the temperature to room. After 6 hours the reaction mixture was diluted with saturated aqueous ammonium chloride and ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of ammonium chloride twice, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to chromatography on a column of silica gel (eluting solvent: hexane, hexane:ethyl acetate = 20:1) to obtain specified in the connection header (47,0 g, 94%) as a colourless oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 0.85 (9H, t, J=7,Hz), 0,97-of 1.15 (6H, m)of 1.29 (6H, sextet, J=7,6 Hz), 1,46-of 1.55 (6H, m), 5,33 (2H, s), 6,85-of 6.90 (1H, m), 7,29-7,41 (3H, what), 7,41-7,47 (2H, m), 7,66 for 7.78 (1H, m), 8,08-of 8.15 (1H, m).

Reference example 19: 2-(2-Fluoro-4-pyridyl)-1-(2-furyl)-1-alanon

Specified in the title compound was synthesized by the method of reference example 5 using 2-fluoro-4-methylpyridine.

1H NMR (400 MHz, DMSO-d6) δ ppm; 4,36 (2H, s)6,76 (1H, DD, J=1,6, 3.6 Hz), 7,11 (1H, s), 7.24 to 7,29 (1H, m), 7,63 (1H, DD, J=0,4, 3.6 Hz), with 8.05 (1H, DD, J=0,8 and 1,6 Hz), 8,17 (1H, d, J=4,8 Hz).

Reference example 20: 2-(2-Bromo-4-pyridyl)-1-(2-furyl)-1-alanon

Specified in the title compound was synthesized by the method of reference example 5 using 2-bromo-4-methylpyridine.

1H NMR (400 MHz, DMSO-d6) δ ppm; or 4.31 (2H, s), 6,77 (1H, DD, J=1,6, 3.6 Hz), was 7.36 (1H, DD, J=1,6, 5,2 Hz), 7,60 (1H, DD, J=0,4, and 1.6 Hz), a 7.62 (1H, DD, J=0,8, 3.6 Hz), with 8.05 (1H, DD, J=0,8 and 1,6 Hz), 8,32 (1H, DD, J=0,4, 5,2 Hz).

Reference example 21: 4,6-Di(2-furyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of reference example 12 using 2-acetylfuran, instead of 1-(2-furyl)-2-(4-pyridyl)-1-ethanone.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,69 (2H, DD, J=1,6, 3.6 Hz), 6,76 (2H, CL), 7,21 (1H, s), 7,21 (2H, DD, J=0,8, 3.6 Hz), of 7.90 (2H, DD, J=0,8 and 1,6 Hz).

Reference example 22: 5-Bromo-4,6-di(2-furyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method sulochna the example 16 using 4,6-di(2-furyl)-2-pyrimidinamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,72 (2H, DD, J=1,6, 3.6 Hz), 7,01 (2H, CL), 7,47 (2H, DD, J=0,8, 3.6 Hz), 7,95 (2H, DD, J=0,8 and 1,6 Hz).

Reference example 23 (the synthesis method, an alternative method of reference example 9): 2-(6-Chloro-3-pyridyl)-1-(2-furyl)-1-alanon

Specified in the title compound was synthesized by the method of reference example 9 using 2-chloro-5-(chloromethyl)-pyridine, instead of (6-chloro-3-pyridyl)methylmethanesulfonate.

Reference example 24: 2-(6-Chloro-3-pyridyl)-1-(2-thienyl)-1-alanon

Specified in the title compound was synthesized by the method of reference example 9 using 2-tiefenanzeige.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 4.46 (2H, s), 7,31 (1H, DD, J=4,0, 4,8 Hz)to 7.50 (1H, d, J=8,2 Hz), 7,78 (1H, DD, J=2,4, and 8.2 Hz), 8,07 (1H, DD, J=1,2, 4,8 Hz), 8,16 (1H, DD, J=1,2, 4.0 Hz), 8,35 (1H, d, J=2,4 Hz).

Reference example 25: 2-(6-Chloro-3-pyridyl)-3-(dimethylamino)-1-(2-thienyl)-2-propen-1-he

Specified in the title compound was synthesized by the method of reference example 6 using 2-(6-chloro-3-pyridyl)-1-(2-thienyl)-1-ethanone.

1H NMR (400 MHz, DMSO-d6) δ ppm; and 2.79 (6H, CL), 7,06 (1H, DD, J=3,8, 5.0 Hz), 7,13 (1H, DD, J=1,0, and 3.8 Hz), 7,47 (1H, d, J=8.0 Hz), a 7.62 (1H, DD, J=2,4, 8.0 Hz), 7,69 (1H, s), 7,73 (1H, DD, J=1,0, 5.0 Hz), 8,16 (1H, d, J=2.4 Hz).

Reference example 26: 2-(6-Chloro-3-pyridyl)-1-phenyl-1-alanon

Specified in the title compound was synthesized by the method of reference example 9 using benzaldehyde.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 4.54 (2H, s)to 7.50 (1H, d, J=8.0 Hz), 7,55-to 7.61 (2H, m), 7,66-7,72 (1H, m), 7,76 (1H, DD, J=2,4, 8.0 Hz), 8,04-of 8.09 (2H, m), 8,32 (1H, d, J=2,4 Hz).

Reference example 27: 2-(6-Chloro-3-pyridyl)-3-(dimethylamino)-1-phenyl-2-propen-1-he

Specified in the title compound was synthesized by the method of reference example 6 using 2-(6-chloro-3-pyridyl)-1-phenyl-1-ethanone.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,73 (6H, CL), 7,29 (1H, s), of 7.36 was 7.45 (6H, m), 7,60 (1H, DD, J=2,2, 8.0 Hz), 8,14 (1H, d, J=2.2 Hz).

Reference example 28: 2-(6-Chloro-3-pyridyl)-1-(3-forfinal)-1-alanon

Specified in the title compound was synthesized by the method of reference example 9 using benzaldehyde.

1H NMR (400 MHz, DMSO-d6) δ ppm; 4,55 (2H, s), 7,51 (1H, d, J=8,2 Hz), 7,52-to 7.59 (1H, m), to 7.61-to 7.68 (1H, m), 7,60 (1H, DD, J=2,4, and 8.2 Hz), 7,82-7,87 (1H, m), of 7.90-of 7.95 (1H, m), 8,31 (1H, d, J=2,4 Hz).

Reference example 29: 2-(6-Chloro-3-pyridyl)-3-(dimethylamino)-1-(3-forfinal)-2-propen-1-he

Specified in the title compound was synthesized by the method of reference example 6 using 2-(6-chloro-3-pyridyl)-1-(3-forfinal)-1-ethanone.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,74 (6H, CL), 7,17-7,29 (3H, m), 7,31 (1H, is), 7,39-7,47 (2H, m), to 7.61 (1H, DD, J=2,2, 8.0 Hz), 8,15 (1H, d, J=2.2 Hz).

Example 1: 4-Chloro-6-(3-forfinal)-5-(4-pyridyl)-2-pyrimidinamine

A suspension of 2-amino-6-(3-forfinal)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone (1.0 g, 3.54 mmol) in phosphorus oxychloride (15 ml) was stirred at 100°C for 30 minutes in an atmosphere of nitrogen gas. Allowing the reaction mixture to cool, it was concentrated and the residue was dissolved in ethyl acetate and 2 N. the sodium hydroxide. The organic layer is washed with aqueous saturated sodium bicarbonate solution twice and with a saturated salt solution, dried over anhydrous sodium sulfate and concentrated. To the residue was added diethyl ether and the resulting precipitates were collected by filtration and washed with diethyl ether to obtain specified in the title compound (513 mg, 48%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 7,00-7,03 (1H, m), 7,05-7,10 (1H, m), 7,12-to 7.18 (1H, m), 7.24 to 7,31 (1H, m), 7,25 (2H, DD, J=1,6, 4,4 Hz), 8,51 (2H, DD, J=1,6, and 4.4 Hz); MS m/e (ESI) 301 (MN+).

Example 2: 4-Chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 1 using 2-amino-6-(2-furyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,27 (1H, d, J=3.6 Hz), 6.48 in (1H, DD, J=2,0, 3.6 Hz), 7,34 (2H, DD, J=1,6, 4,4 Hz), and 7.5 (2H, SHS), to 7.67 (1H, DD, J=0,8, 2.0 Hz), 8,66 (2H, DD, J=1,6, and 4.4 Hz); MS m/e (ESI) 273 (MN+).

Example 3: 4-(3-Forfinal)-6-methoxy-5-(4-pyridyl)-2-pyrimidinamine

After dissolution of the sodium (20 mg, 0,870 mmol) in methanol (3 ml) to the resulting solution was added 4-chloro-6-(3-forfinal)-5-(4-pyridyl)-2-pyrimidinamine (50 mg, 0,166 mmol) and the mixture was stirred in an atmosphere of gaseous nitrogen at 60-65°C for 30 minutes. Allowing the reaction mixture to cool, it was diluted with ethyl acetate. The mixture is then washed with a saturated aqueous solution of ammonium chloride three times and with saturated salt solution, dried over anhydrous sodium sulfate and concentrated. To the residue was added diethyl ether and the resulting precipitates were collected by filtration and washed with diethyl ether to obtain specified in the title compound (16 mg, 32%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; a 3.83 (3H, s), 6.90 to-7,16 (7H, m), 7,22-7,29 (1H, m), 8,40 (2H, d, J=4,8 Hz); MS m/e (ESI) 297 (MN+).

Example 4: 4-Ethoxy-6-(3-forfinal)-5-(4-pyridyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 3 using ethanol.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.23 (3H, t, J=7,2Hz), to 4.33 (2H, q, J=7.2 Hz), 6,92 (2H, CL), 6,94-7,16 (5H, m), 7,22-7,29 (1H, m), 8,39 (2H, d, J=6.0 Hz); MS m/e (ESI) 311 (MN+).

Example 5: -(3-Forfinal)-6-propoxy-5-(4-pyridyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 3 using 1-propanol.

1H NMR (400 MHz, DMSO-d6) δ ppm; 0,86 (3H, t, J=7.2 Hz), of 1.62 (2H, sextet, J=7.2 Hz), 4,22 (2H, t, J=7.2 Hz), 6,92 (2H, CL), of 6.96-7,00 (1H, m), 7,02-7,16 (2H, m), was 7.08 (2H, DD, J=1,6, 4,4 Hz), 7.23 percent-7,29 (1H, m), 8,40 (2H, DD, J=1,6, 4,4 Hz); MS m/e (ESI) 325 (MN+).

Example 6: 4-(3-Forfinal)-6-isopropoxy-5-(4-pyridyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 3 using 2-propanol.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.23 (6H, d, J=6.0 Hz), 5,32 (1H, m), 6.89 in (2H, CL), 6,92-7,16 (5H, m), 7,21-7,28 (1H, m), scored 8.38 (2H, sh); MS m/e (ESI) 325 (MN+).

Example 7: 4-Ethoxy-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 3 using 4-chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinamine and ethanol.

1H NMR (400 MHz, DMSO-d6) δ ppm; at 1.17 (3H, t, J=6,8gts), 4,28 (2H, q, J=6.8 Hz), 6,36 (1H, DD, J=0,8, 3.6 Hz), 6,45 (1H, DD, J=1,6, 3.6 Hz), for 6.81 (2H, CL), 7,19 (2H, d, J=4.4 Hz), EUR 7.57 (1H, DD, J=0,8 and 1,6 Hz), 8,54 (2H, d, J=4.4 Hz); MS m/e (ESI) 283 (MN+).

Example 8: 4-(2-Furyl)-6-propoxy-5-(4-pyridyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 3 using 4-chloro-6-(2-FSD is l)-5-(4-pyridyl)-2-pyrimidinamine and 1-propanol.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 0.80 (3H, t, J=7,2 Hz), and 1.56 (2H, sextet, J=7.2 Hz), 4,17 (2H, t, J=7.2 Hz), 6,38 (1H, DD, J=0,8, 3.6 Hz), 6,45 (1H, DD, J=1,6, 3.6 Hz), to 6.80 (2H, CL), 7,19 (2H, DD, J=1,6, 4,4 Hz), EUR 7.57 (1H, DD, J=of 0.8, and 1.6 Hz), 8,54 (2H, DD, J=1,6, and 4.4 Hz); MS m/e (ESI) 297 (MN+).

Example 9: 4-(2-Furyl)-6-isopropoxy-5-(4-pyridyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 3 using 4-chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinamine and 2-propanol.

1H NMR (400 MHz, DMSO-d6) δ ppm; at 1.17 (6H, d, J=6.4 Hz), 5,28 (1H, septet, J=6.4 Hz), 6.35mm (1H, DD, J=0,8, 3.6 Hz), 6,45 (1H, DD, J=1,6, 3.6 Hz), 6,78 (2H, CL), 7,17 (2H, DD, J=1,6, 4,4 Hz), 7,56 (1H, DD, J=0,8 and 1,6 Hz), 8,53 (2H, DD, J=1,6, and 4.4 Hz); MS m/e (ESI) 297 (MN+).

Example 10: 4-(Allyloxy)-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 3 using 4-chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinamine and allyl alcohol.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 4.77 (2H, dt, J=1,6, 5,2 Hz), 5,12 (1H, DQC, J=1,6, 10.4 Hz), 5,14 (1H, DQC, J=1,6, and 17.2 Hz), to 5.93 (1H, DDT, J=5,2, 10,4, and 17.2 Hz), 6,38 (1H, DD, J=0,8, 3,4 Hz), 6,46 (1H, DD, J=1,6, 3,4 Hz), at 6.84 (2H, CL), 7,21 (2H, DD, J=1,6, 4,4 Hz), EUR 7.57 (1H, DD, J=0,8 and 1,6 Hz), 8,55 (2H, DD, J=1,6, and 4.4 Hz); MS m/e (FAB) 295 (MN+).

Example 11: 4-(2-Furyl)-6-methyl-5-(4-pyridyl)-2-pyrimidinecarbonitrile

Pointed to by the e in the title compound was synthesized by method 2 of reference example 10 using (S)-4-(2-furyl)-3-(4-pyridyl)-3-butene-2-it.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 2.09 (3H, s), 6,53 (1H, DD, J=1,6, 3.6 Hz), of 6.66 (1H, d, J=0,8, 3.6 Hz), 7,63 (1H, DD, J=0,8, 1, 6 Hz), a 7.85 (2H, DD, J=1,2, 5,2 Hz), of 8.90 (2H, DD, J=1,2, 5,2 Hz).

Example 12: 4,6-Di(2-furyl)-5-(4-pyridyl)-2-pyrimidinamine

After dissolution of the sodium (540 mg, 23.5 mmol) in anhydrous ethanol (200 ml) to the resulting solution was sequentially added 1-(2-furyl)-2-(4-pyridyl)-1-Etalon (2.00 g, is 10.7 mmol) and 2-furaldehyde (0,97 ml, 11.7 mmol) and the mixture was stirred at room temperature. 1.5 hours to the mixture was added guanidine hydrochloride (7.0 g, 73,3 mmol), after which the mixture was boiled under reflux for 14 hours. Allowing the reaction mixture to cool, it was concentrated and the residue suspended in tetrahydrofuran. Then insoluble materials were filtered off and washed with tetrahydrofuran and the filtrate evaporated solvent. To the residue was added tetrahydrofuran (80 ml) and active manganese dioxide (30.0 g), after which the mixture was boiled under reflux for 2 hours. Allowing the mixture to cool, manganese dioxide was filtered through celite and washed with tetrahydrofuran. The combined filtrates were concentrated and to the residue was added methanol. The obtained precipitates were collected by filtration and washed with methanol to obtain specified in the connection header (1,32 g, 41%) as a pale brown solid substances is STV.

1H NMR (400 MHz, DMSO-d6) δ ppm; the 6.06 (2H, DD, J=0,8, 3,4 Hz), 6,44 (2H, DD, J=1,8, 3,4 Hz), of 6.96 (2H, CL), 7,33 (2H, DD, J=1,6, 4,4 Hz), the 7.65 (2H, DD, J=0,8, 1.8 Hz), 8,66 (2H, DD, J=1,6, 4,4 Hz).

Example 13: 4-(2-Furyl)-6-phenyl-5-(4-pyridyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 12 using benzaldehyde.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 6.19 (1H, DD, J=0,8, 3.6 Hz), 6,46 (1H, DD, J=1,6, 3.6 Hz), 6,99 (2H, CL), 7,14 (2H, DD, J=1,6, 4,4 Hz), 7,17-7,27 (5H, m), of 7.64 (1H, DD, J=0,8 and 1,6 Hz), 8,43 (2H, DD, J=1,6, 4,4 Hz).

Example 14: 5-(6-Chloro-3-pyridyl)-4-(2-furyl)-2-pyrimidinamine

A suspension of 2-(6-Chloro-3-pyridyl)-3-(dimethylamino)-1-(2-furyl)-2-propen-1-it (7,49 g, 27,1 mmol), guanidine hydrochloride (7.7 g, 81.0 mmol) and potassium carbonate (22,4 g, 162 mmol) in N,N-dimethylformamide (105 ml) was stirred at 70°C for 21 hours. Allowing the reaction mixture to cool, it was diluted with water. The obtained crystals were collected by filtration and washed with water to obtain specified in the connection header (5,48 g, 74%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,56 (1H, DD, J=1,6, 3.6 Hz), of 6.71 (1H, DD, J=0,8, 3.6 Hz), of 6.96 (2H, CL), 7,55 (1H, DD, J=0,6, 8, 4 Hz), 7,69 (1H, DD, J=0,8 and 1,6 Hz), to 7.77 (1H, DD, J=2,8, and 8.4 Hz), by 8.22 (1H, s), 8,31 (1H, DD, J=0,6 and 2.8 Hz).

Example 15: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

After dissolution of the sodium (455 mg, and 19.8 mmol) in 4-methoxybenzylamine alcohol (15 ml) at 90°C in an atmosphere of nitrogen gas to the resulting solution was added 5-(6-chloro-3-pyridyl)-4-(2-furyl)-2-pyrimidinamine (1.80 g, 6,60 mmol) and the mixture was stirred as it was. After 1.5 hours the reaction mixture was cooled to room temperature and then diluted with saturated aqueous ammonium chloride and ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous sodium sulfate and concentrated. To the residue was added triperoxonane acid (40 ml) followed by stirring at 65°C. After 18 hours the reaction mixture was allowed to cool and diluted it with water and dichloromethane 5 N. was carried out. The resulting aqueous layer was washed with ethyl acetate and brought to pH 6 by adding 5 n sodium hydroxide. The obtained crystals were collected by filtration and washed with water to obtain crude crystals specified in the connection header. The crude crystals suspended in ethyl acetate, collected by filtration and washed with ethyl acetate to obtain specified in the title compound (820 mg, 49%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,33 (1H, d, J=9,2 Hz), to 6.58 (1H, DD, J=1,8, 3.6 Hz), 6,69 (1H, DD, J=0,8, 3.6 Hz), 6,79 (2H, CL), from 7.24 (1H, is d, J=2,8, 9,2 Hz), 7,34 (1H, d, J=2,8 Hz), to 7.77 (1H, DD, J=0,8, 1.8 Hz), to 8.12 (1H, s); MS m/e (ESI) 255 (MN+).

Example 16: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone

To a suspension of 5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone (2.2 g, 8,65 mmol) in methanol (44 ml) was added sodium methoxide (940 mg, of 17.4 mmol) at room temperature in an atmosphere of nitrogen gas, followed by stirring. After 15 minutes, to the mixture was added itmean (1.6 ml, of 25.7 mmol) followed by stirring the mixture as it was, for 22 hours. After concentration of the reaction mixture, to the residue was added water. Then the precipitation was collected by filtration and washed with water to obtain crude crystals indicated in the title compound (1.98 g). The crude crystals suspended in ethanol and then the precipitation was collected by filtration and washed with ethanol to obtain specified in the title compound (1.54 g, 66%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 3.46 (3H, s)6,38 (1H, d, J=9,2 Hz), to 6.58 (1H, DD, J=1,6, 3.6 Hz), was 6.73 (1H, DD, J=0,8, 3.6 Hz), for 6.81 (2H, CL), 7,21 (1H, DD, J=2,6, 9,2 Hz), of 7.75 (1H, d, J=2.6 Hz), to 7.77 (1H, DD, J=0,8 and 1,6 Hz), to 8.14 (1H, s); MS m/e (ESI) 269 (MN+).

Example 17: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-ethyl-1,2-dihydro-2-pyridinone

Specified in the header of the connection sintesio the Ali method of example 16 using ethyliodide.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.24 (3H, t, J=7.2 Hz), 3,93 (2H, q, J=7.2 Hz), 6,38 (1H, d, J=9,2 Hz), to 6.58 (1H, DD, J=1,6, and 3.2 Hz), of 6.71 (1H, d, J=3.2 Hz), PC 6.82 (2H, CL), of 7.23 (1H, DD, J=2,8, 9,2 Hz), 7,73 (1H, d, J=2,8 Hz), 7,78 (1H, d, J=1.6 Hz), 8,17 (1H, s); MS m/e (ESI) 283 (MN+).

Example 18: 1-Allyl-5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 16 using allylbromide.

1H NMR (400 MHz, DMSO-d6) δ ppm; a 4.53 (2H, d, J=5,2 Hz), 5,10 (1H, DD, J=1,6, and 17.2 Hz), 5,19 (1H, DD, J=1,6, 10.4 Hz), 5,97 (1H, DDT, J=5,2, 10,4, and 17.2 Hz), 6.42 per (1H, d, J=9,2 Hz), to 6.58 (1H, DD, J=1,8, 3.6 Hz), was 6.73 (1H, DD, J=0,8, 3,6 Hz), PC 6.82 (2H, CL), 7,27 (1H, DD, J=2,2, 9,2 Hz), to 7.64 (1H, d, J=2.2 Hz), 7,76 (1H, DD, J=0,8, 1.8 Hz), 8,14 (1H, s).

Example 19: 5-[2-Amino-4-(2-thienyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 15 using 5-(6-chloro-3-pyridyl)-4-(2-thienyl)-2-pyrimidinamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,36 (1H, d, J=9,2 Hz), 6,77 (2H, CL), 7,05 (1H, DD, J=3,6, and 4.8 Hz), 7,13 (1H, DD, J=1,2, 3,6 Hz), 7,26 (1H, DD, J=2,4, 9,2 Hz), 7,39 (1H, d, J=2.4 Hz), to 7.68 (1H, DD, J=1,2, 4,8 Hz), 8,10 (1H, s).

Example 20: 5-[2-Amino-4-(2-thienyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 16 using 5-[2-amino-4-(2-thienyl)-5-pyrim dinyl]-1,2-dihydro-2-pyridinone.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 3.46 (3H, s)6,41 (1H, d, J=9,2 Hz), to 6.80 (2H, CL), 7,05 (1H, DD, J=3,8, 5,2 Hz), 7,16 (1H, DD, J=1,0, and 3.8 Hz), 7,24 (1H, DD, J=2,8, 9,2 Hz), to 7.68 (1H, DD, J=1,0, 5,2 Hz), 7,80 (1H, d, J=2,8 Hz), to 8.12 (1H, s).

Example 21: 5-[2-Amino-4-(3-forfinal)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 15 using 5-(6-chloro-3-pyridyl)-4-(3-forfinal)-2-pyrimidinamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 6.19 (1H, d, J=9.6 Hz), 6,86 (2H, CL), 7,00 (1H, DD, J=2,8, 9.6 Hz), 7,15-7,30 (4H, m), of 7.36-7,46 (1H, m), compared to 8.26 (1H, s), 11,68 (1H, CL); MS m/e (ESI) 283 (MN+).

Example 22: 5-[2-Amino-4-(3-forfinal)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 16 using 5-[2-amino-4-(3-forfinal)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 3.42 (3H, s), 6,21 (1H, d, J=9.6 Hz), 6.87 in (1H, DD, J=2,8, 9.6 Hz), 6.89 in (2H, CL), 7,20-7,29 (3H, m), 7,37-7,44 (1H, m), of 7.75 (1H, d, J=2,8 Hz), of 8.28 (1H, s).

Example 23: 5-[2-Amino-4-phenyl-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 15 using 5-(6-chloro-3-pyridyl)-4-phenyl-2-pyrimidinamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,16 (1H, d, J=9.6 Hz), to 6.80 (2H, CL), of 6.96 (1H, DD, J=2,6, 9.6 Hz) of 7.23 (1H, d, J=2.6 Hz), 7,34-7,44 (5H, m), 8,23 (1H, s).

Example 24: 5-(2-Amino-4-phenyl-5-pyrimidinyl)-1-methyl-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 16 using 5-(2-amino-4-phenyl-5-pyrimidinyl)-1,2-dihydro-2-pyridinone.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 3.42 (3H, s), 6,18 (1H, d, J=9,2 Hz), PC 6.82 (1H, DD, J=2,4, 9,2 Hz), 6,83 (2H, CL), 7,32-7,47 (5H, m), 7,74 (1H, d, J=2.4 Hz), of 8.25 (1H, s).

Example 25: 5-(6-Chloro-3-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 12 using 2-(6-Chloro-3-pyridyl)-1-(2-furyl)-1-ethanone.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,21 (2H, DD, J=0,6, 3,4 Hz), of 6.49 (2H, DD, J=1,8, 3,4 Hz), 6,97 (2H, CL), a 7.62 (1H, d, J=8,4 Hz), to 7.67 (2H, DD, J=0,6, 1.8 Hz), 7,80 (1H, DD, J=2,4, and 8.4 Hz), of 8.28 (1H, d, J=2,4 Hz).

Example 26: 5-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 15 using 5-(6-chloro-3-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,36 (2H, DD, J=0,8, 3.6 Hz), 6,46 (1H, d, J=9,2 Hz), 6,55 (2H, DD, J=1,6, 3.6 Hz), to 6.67 (2H, CL), from 7.24 (1H, d, J=2.2 Hz), 7,31 (1H, DD, J=2,2, 9,2 Hz), 7,78 (2H, DD, J=0,8 and 1,6 Hz), 11,76 (1H, s); MS m/e (ESI) 321 (MN+).

Example 27: 5-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridi what he

Specified in the title compound was synthesized by the method of example 16 using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 3.43 (3H, s), to 6.39 (2H, DD, J=0,8, 3.6 Hz), of 6.52 (1H, d, J=9,2 Hz), is 6.54 (2H, DD, J=1,8, 3.6 Hz), to 6.88 (2H, CL), 7,32 (1H, DD, J=2,6, 9,2 Hz), to 7.64 (1H, d, J=2.6 Hz), to 7.77 (2H, DD, J=0,8, 1.8 Hz); MS m/e (ESI) 335 (MN+).

Example 28: 6-(3-Forfinal)-5-(6-methoxy-3-pyridyl)-2,4-pyrimidinediamine

Specified in the title compound was synthesized by method 2 of reference example 12, using (S)-3-(3-forfinal)-2-(6-methoxy-3-pyridyl)-2-propenenitrile.

1H NMR (400 MHz, DMSO-d6) δ ppm; 3,81 (3H, s), 5,96 (2H, CL), 6,12 (2H, CL), 6,74 (1H, d, J=8.6 Hz), 6,92-7,06 (3H, m), 7.18 in-7,24 (1H, m), 7,41 (1H, DD, J=2,4, 8.6 Hz), 7,80 (1H, d, J=2,4 Hz).

Example 29: 5-[2,4-Diamino-6-(3-forfinal)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

A solution of 6-(3-forfinal)-5-(6-methoxy-3-pyridyl)-2,4-pyrimidinediamine (5,00 g, 16,1 mmol) in a mixture of acetic acid (30 ml)/concentrated Hydrobromic acid (50 ml) was stirred at 100°C for 1.5 hours. Allowing the reaction mixture to cool, it was brought to pH 12-13 by adding 5 n sodium hydroxide and washed with ethyl acetate. The aqueous layer was neutralized with 5 N. chloroethanol acid. The obtained solid substance was collected filter is a W with obtaining specified in the connection header (3,36 g, 70%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; the 6.06 (2H, CL), 6,07 (2H, CL), 6,21 (1H, d, J=9,2 Hz), 6,97 (1H, d, J=2.4 Hz), 7,01-to 7.09 (4H, m), 7.23 percent-7,30 (1H, m); MS m/e (ESI) 298 (MN+).

Example 30: 5-[2,4-Diamino-6-(3-forfinal)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 16 using 5-[2,4-diamino-6-(3-forfinal)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 3.32 (3H, s), 6,07 (2H, CL), 6,17 (2H, CL), 6,23 (1H, d, J=9.4 Hz), 6,94 (1H, DD, J=2,6, and 9.4 Hz), 7,02 for 7.12 (3H, m), 7.23 percent-7,30 (1H, m), 7,46 (1H, d, J=2.6 Hz); MS m/e (ESI) 312 (MN+).

Example 31: 5-[6-(Benzyloxy)-3-pyridyl]-4-(2-furyl)-2-pyrimidinamine

A solution of 5-bromo-4-(2-furyl)-2-pyrimidinamine (10,5 g and 43.9 mmol), 2-(benzyloxy)-5-(1,1,1-tributylstannyl)pyridine (41.7 g, 87.9 mmol) and dichlorobis(triphenylphosphine)palladium(II) (1.6 g, 2.28 mmol) in N,N-dimethylformamide (100 ml) was stirred at 100°C for 25 hours in an atmosphere of nitrogen gas. Allowing the reaction mixture to cool, it was diluted with ethyl acetate and saturated aqueous ammonium chloride. Was filtered, the insoluble materials, and then the organic layer in the filtrate was washed with a saturated aqueous solution of ammonium chloride twice, dried over anhydrous magnesium sulfate and concentrated. OST the current suspended in hexane and then the solid was collected by filtration and washed with hexane. The obtained solid is suspended in ethyl acetate, and then collected by filtration and washed with ethyl acetate to obtain specified in the connection header (8,35 g, 55%) as a pale orange solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; are 5.36 (2H, s), 6,50 (1H, DD, J=0,8, 3,4 Hz), of 6.52 (1H, DD, J=1,8, 3,4 Hz), PC 6.82 (2H, CL), of 6.90 (1H, DD, J=0,6, 8, 4 Hz), 7,30-to 7.35 (1H, m), of 7.36-7,41 (2H, m), 7,44-7,49 (2H, m), to 7.59 (1H, DD, J=2,6, and 8.4 Hz), of 6.68 (1H, DD, J=0,8, 1.8 Hz), of 8.06 (1H, DD, J=0,6, and 2.6 Hz), 8,14 (1H, s).

Example 32 (the synthesis method, alternative to the method of example 15): 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

A suspension of 5-[6-(benzyloxy)-3-pyridyl]-4-(2-furyl)-2-pyrimidinamine (8,35 g, and 24.2 mmol) in a mixture of concentrated chloromethane acid (40 ml)-water (40 ml) was stirred at 80°C for 1 hour. Allowing the reaction mixture to cool, it was washed with ethyl acetate twice. The aqueous layer was neutralized with 5 N. aqueous sodium hydroxide solution. The obtained solid substance was collected by filtration, washed with water and dried at 50°C for 14 hours to obtain specified in the connection header (5,54 g, 90%) as a pale brown solid.

Example 33: 5-[6-(Benzyloxy)-3-pyridyl]-4,6-di(2-furyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 31, using 5-bromo-4,6-di(2-furyl)-2-pyrimidine is on.

1H NMR (400 MHz, DMSO-d6) δ ppm; 5,42 (2H, s), to 5.93 (2H, DD, J=0,4, 3.6 Hz), 6,44 (2H, DD, J=1,6, 3.6 Hz), to 6.88 (2H, CL), 7,01 (1H, DD, J=0,4, 8,8 Hz), 7,30-7,51 (5H, m), a 7.62 (1H, DD, J=2,4, 8,8 Hz), to 7.67 (2H, DD, J=0,4, and 1.6 Hz), of 7.97 (1H, d, J=2,4 Hz).

Example 34: 5-(2-Fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 12 using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,33 (2H, DD, J=0,8, 3.6 Hz), 6.48 in (2H, DD, J=1,6, 3.6 Hz), 6,99 (2H, CL), 7,21 (1H, sh), 7,28-to 7.32 (1H, m), the 7.65 (2H, DD, J=0,8 and 1,6 Hz), 8,31 (1H, d, J=5,2 Hz).

Example 35: 5-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-(3-furyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 12 using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and 3-furaldehyde.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 6.31 (1H, DD, J=0,8, 2.0 Hz), 6,37 (1H, DD, J=0,8, 3.6 Hz), 6,47 (1H, DD, J=1,6, 3.6 Hz), 6,91 (2H, CL), 7,17-to 7.18 (2H, m), 7,26-7,30 (1H, m), 7,58 (1H, DD, J=1,6, 2.0 Hz), a 7.62 (1H, DD, J=0,8 and 1,6 Hz), 8,30 (1H, d, J=4,8 Hz).

Example 36: 5-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-(2-thienyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 12 using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and 2-thiophenecarboxaldehyde.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,35 (1H, d, J=3.6 Hz), 6.42 per (1H, DD, J=,8, 3.6 Hz), 6.48 in (1H, DD, J=1,6, 3.6 Hz), 6,91 (1H, DD, J=3,6, 5,2 Hz), to 6.95 (2H, CL), 7,27 (1H, sh), 7,34-7,38 (1H, m), to 7.61-7,66 (2H, m), a 8.34 (1H, d, J=4,8 Hz).

Example 37: 5-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-(3-thienyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 12 using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and 3-thiophenecarboxaldehyde.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 6.39 (1H, DD, J=0,8, 3.6 Hz), 6.48 in (1H, DD, J=1,6, 3.6 Hz), 6,94-6,97 (3H, m), 7,07 (1H, sh), 7,18-7,20 (1H, m), 7,27 (1H, DD, J=1,2, 2,8 Hz), 7,40 (1H, DD, J=2,8, 5,2 Hz), a 7.62 (1H, DD, J=0,8 and 1,6 Hz), to 8.20 (1H, d, J=5,2 Hz).

Example 38: 5-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-(2-pyridyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 12 using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and 2-pyridinecarboxamide.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 6.43 (1H, DD, J=0,8, 3.6 Hz), 6,50 (1H, DD, J=2,0, 3.6 Hz), 6.89 in (1H, sh), 7,02? 7.04 baby mortality (1H, m), to 7.09 (2H, CL), 7,27 (1H, DDD, J=1,2, 4,8 and 7.6 Hz), 7,60 (1H, DDD, J=0,8, of 1.2 and 7.6 Hz), the 7.65 (1H, DD, J=0.8, the 2.0 Hz), 7,79 (1H, DDD, J=1,6, of 7.6 and 7.6 Hz), 8,03 (1H, d, J=5,2 Hz), of 8.27 (1H, DDD, J=0,8, of 1.6, 4.8 Hz).

Example 39: 5-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-(3-pyridyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 12 using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and 3-pyridinecarboxamide.

1H NMR(400 MHz, DMSO-d6) δ ppm; 6,48 (1H, d, J=3.6 Hz), 6,51 (1H, DD, J=1,6, 3.6 Hz), 7,05 (1H, sh), 7,12 (2H, CL), 7,14-to 7.18 (1H, m), 7,28 (1H, DD, J=5,2, 8.0 Hz), 7,60 (1H, DDD, J=1,6, of 2.0, 8.0 Hz), the 7.65 (1H, DD, J=0,8 and 1,6 Hz), 8,10 (1H, d, J=4,8 Hz), 8,39 (1H, d, J=2.0 Hz), to 8.45 (1H, DD, J=1,6, 5,2 Hz).

Example 40: 5-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-(4-pyridyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 12 using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and 4-pyridinecarboxamide.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,48 (1H, d, J=3.6 Hz), 6,51 (1H, DD, J=2,0, 3.6 Hz), 7,05 (1H, s), 7,12-to 7.18 (1H, m), to 7.15 (2H, CL), 7,19 (2H, DD, J=1,6, 4,4 Hz), 7,63-to 7.67 (1H, m), 8,10 (1H, d, J=5.6 Hz), 8,46 (2H, DD, J=1,6, 4,4 Hz).

Example 41: 5-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-phenyl-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 12 using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and benzaldehyde.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,44 (1H, d, J=3.2 Hz), of 6.49 (1H, DD, J=1,6, and 3.2 Hz), 6,97 (1H, sh), 7,02 (2H, CL), 7,07 for 7.12 (1H, m), 7,16-7,29 (5H, m), 7,60-to 7.64 (1H, m), 8,07 (1H, d, J=5,2 Hz).

Example 42: 5-(2-Bromo-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 12 using 2-(2-bromo-4-pyridyl)-1-(2-furyl)-1-ethanone.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,33 (2H, DD, J=0,8, 3.6 Hz), of 6.49 (2H, DD, J=,6, 3.6 Hz), 6,97 (2H, CL), 7,40 (1H, DD, J=1,6, 4,8 Hz), 7,63 (1H, DD, J=0,8 and 1,6 Hz), to 7.64 (2H, DD, J=0,8 and 1,6 Hz), 8,44 (1H, DD, J=0,8, 4,8 Hz).

Example 43: 5-[2-(Dimethylamino)-4-pyridyl]-4,6-di(2-furyl)-2-pyrimidinamine

In the autoclave suspended 5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine (200 mg, 0,621 mmol) in 1,2-dimethoxyethane (10 ml) and then to the suspension was added 50% aqueous solution (5 ml) of dimethylamine, followed by stirring the mixture at 70°C. After 11 hours, the reaction mixture was extracted with ethyl acetate and the extract was washed with water and saturated salt solution, dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated. The obtained solid is suspended in ethanol, collected by filtration and washed with ethanol to obtain specified in the title compound (92 mg, 43%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,99 (6H, s), of 6.02 (2H, d, J=3.2 Hz), 6,44 (2H, DD, J=1,6, and 3.2 Hz), of 6.49 (1H, DD, J=1,2, 4,8 Hz), is 6.54 (1H, s)6,86 (2H, CL), of 7.70 (2H, d, J=1.6 Hz), 8,17 (1H, d, J=4,8 Hz).

Example 44: 4,6-Di(2-furyl)-5-[2-(methylamino)-4-pyridyl]-2-pyridylamine

Specified in the title compound was synthesized by the method of example 43 at 70-80°using 40% aqueous solution of methylamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,78 (3H, d, J=5,2 Hz), 6,07 (2H, d, J=3.6 Hz), 6,30 (1H, s), 641 (1H, DD, J=1,2, 5,2 Hz), 6,46 (2H, DD, J=2,0, 3.6 Hz), 6,51 (1H, q, J=5,2 Hz)6,86 (2H, CL), 7,71 (2H, d, J=2.0 Hz), 8,08 (1H, d, J=5,2 Hz).

Example 45: 5-[2-(Ethylamino)-4-pyridyl]-4,6-di(2-furyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 43 at 80°With 70% aqueous solution of ethylamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.12 (3H, t, J=7.2 Hz), 3,23-3,30 (2H, m), 6,07 (2H, DD, J=0,8, a 3.2 Hz), 6,30 (1H, DD, J=0,8, 1.2 Hz), 6,41 (1H, DD, J=1,2, 4,8 Hz), 6,46 (2H, DD, J=1,6, and 3.2 Hz), 6,47 (1H, t, J=3.2 Hz), 6,86 (2H, SHS), 7,72 (2H, DD, J=0,8 and 1,6 Hz), 8,07 (1H, DD, J=0,8, 4,8 Hz).

Example 46: 4,6-Di(2-furyl)-5-[2-(propylamino)-4-pyridyl]-2-pyrimidinamine

In the reaction vessel were mixed with each other 5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine (200 mg, 0,621 mmol) and n-Propylamine (5 ml) and the mixture was stirred at 120°C. After 18 hours the reaction mixture was extracted with ethyl acetate and the extract was washed with water and saturated salt solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The obtained solid is suspended in ethanol, collected by filtration and washed with ethanol to obtain specified in the connection header (64%, 72 mg) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 0.89 (3H, t, J=7.2 Hz), 1,47-of 1.57 (2H, m), 3,18 is 3.23 (2H, m), 6,07 (2H, DD, J=0,8, a 3.2 Hz), of 6.31-6,32 (1H, m), to 6.39 (1H, DD, J=1,2, 5,2 Hz),6,46 (2H, DD, J=1,6, and 3.2 Hz), 6,51 (1H, t, J=5.6 Hz), 6,86 (2H, CL), 7,72 (2H, DD, J=0,8 and 1,6 Hz), of 8.06 (1H, DD, J=0,8, 5,2 Hz).

Example 47: 5-[2-(Butylamino)-4-pyridyl]-4,6-di(2-furyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 46 at 80-120°using n-butylamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 0.89 (3H, t, J=7.2 Hz), of 1.28 to 1.37 (2H, m), 1,45-of 1.53 (2H, m), 3,21-3,26 (2H, m), 6,07 (2H, DD, J=0,8, 3.6 Hz), 6,29-6,30 (1H, m), to 6.39 (1H, DD, J=1,2, 5,2 Hz), 6,46 (2H, DD, J=1,6, 3.6 Hz), 6.48 in (1H, t, J=5,2 Hz)6,86 (2H, CL), 7,71 (2H, DD, J=0,8 and 1,6 Hz), of 8.06 (1H, DD, J=0,8, 5,2 Hz).

Example 48: 4,6-Di(2-furyl)-5-[2-(isopropylamino)-4-pyridyl]-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 46 at 120-200°using Isopropylamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.13 (6H, d, J=6.8 Hz), 3,97-of 4.05 (1H, m), 6,07 (2H, DD, J=0,8, a 3.2 Hz), 6,28 (1H, s), of 6.31 (1H, d, J=7,2 Hz), to 6.39 (1H, DD, J=1,2, 5,2 Hz), 6,46 (2H, DD, J=1,6, and 3.2 Hz), 6,86 (2H, CL), 7,72 (2H, DD, J=0,8 and 1,6 Hz), 8,07 (1H, d, J=5,2 Hz).

Example 49: 5-(2-Amino-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 43 with 80-120°using 25% aqueous ammonia.

1H NMR (400 MHz, DMSO-d6) δ ppm; 5,98 (2H, CL), between 6.08 (2H, d, J=3.2 Hz), of 6.29 (1H, s), 6.42 per (1H, d, J=5,2 Hz), 6,46 (2H, DD, J=1,6, and 3.2 Hz), 6,86 (2H, CL), 7,72 (2H, s), 8,01 (1H, d, J=5,2 Hz).

Por the measures 50: 2-(4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridylamino)-1-ethanol

Specified in the title compound was synthesized by the method of example 46 at 120°using ethanolamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; only 3.57 (2H, TD, J=4,4, 5,2 Hz), a-3.84 (2H, t, J=4.4 Hz), 4,88 (1H, t, J=5,2 Hz), 5,28 (2H, CL), between 6.08 (2H, DD, J=0,4, 3.6 Hz), 6,33 (2H, DD, J=1,6, 3.6 Hz), 6,38 (1H, sh), 6,59 (1H, DD, J=1,2, 5,2 Hz), of 7.48 (2H, d, J=1.6 Hz), 8,18 (1H, d, J=5,2 Hz).

Example 51: 5-[2-(Benzylamino)-4-pyridyl]-4,6-di(2-furyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 46 at 120°using benzylamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 4.52 (2H, d, J=6.0 Hz), equal to 6.05 (2H, DD, J=0,8, 3.6 Hz), to 6.39 (1H, sh), to 6.43 (1H, DD, J=1,6, 5,2 Hz), 6,46 (2H, DD, J=1,6, 3.6 Hz), 6,86 (2H, CL), 7,07 (1H, t, J=6.0 Hz), 7,17-7,21 (1H, m), 7,26-7,31 (4H, m), 7,71 (2H, DD, J=0,8 and 1,6 Hz), of 8.06 (1H, DD, J=0,8, 5,2 Hz).

Example 52: 1-{4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-4-piperidinol

Specified in the title compound was synthesized by the method of example 46 at 120°using 4-hydroxypiperidine 1-methyl-2-pyrrolidinone.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.25 and 1.33 (2H, m), 1,69-1,72 (2H, m), 3,03-to 3.09 (2H, m)to 3.67 (1H, sh), 3,96-3,99 (2H, m), of 4.67 (1H, sm, J=3.2 Hz), 6,03 (2H, DD, J=0,8, a 3.2 Hz), 6,44 (2H, DD, J=1,6, and 3.2 Hz), 6,51 (1H, DD, J=1,2, 5,2 Hz), 6,76 (1H, sh), 6,86 (2H, CL), of 7.70 (2H, DD, J=0,8 and 1,6 Hz), 8,18 (1H, d, J=5,2 Hz).

Example 53 Ethyl 1-{4-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]2-pyridyl}-4-piperidinecarboxylate

Specified in the title compound was synthesized by the method of example 46 at 120°using ethyl isonipecotate.

1H NMR (400 MHz, DMSO-d6) δ ppm; at 1.17 (3H, t, J=7.2 Hz), 1,44-of 1.53 (2H, m), of 1.78 and 1.80 (2H, m), 2,56-2,62 (1H, m), 2,90-2,96 (2H, m)4,06 (2H, t, J=7.2 Hz), 4,16-4,19 (2H, m), 6,04 (2H, d, J=3.2 Hz), to 6.43 (2H, DD, J=1,2, 3,2 Hz), is 6.54 (1H, DD, J=0,8, 4,8 Hz), 6,78 (1H, s), 6.87 in (2H, CL), of 7.69 (2H, d, J=1.2 Hz), 8,19 (1H, d, J=4,8 Hz).

Example 54: N1-{4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-1,2-amandemen

Specified in the title compound was synthesized by the method of example 46 using Ethylenediamine while boiling under reflux.

1H NMR (400 MHz, CDCl3) δ ppm; at 2.93 (2H, t, J=5.6 Hz), to 3.36 (2H, dt, J=5,6, and 5.6 Hz), 4,96 (1H, NJ, J=5.6 Hz), and 5.30 (2H, CL), the 6.06 (2H, DD, J=0,8, 3.6 Hz), of 6.31 (2H, DD, J=2,0, 3.6 Hz), 6,34 to 6.35 (1H, m), 6,55 (1H, DD, J= 1,6, 5,2 Hz), 7,49 (2H, DD, J=0,8, 2.0 Hz), by 8.22 (1H, DD, J=0,8, 5,2 Hz).

Example 55: N1-{4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-1,3-propandiamine

Specified in the title compound was synthesized by the method of example 46 at 120°using 1,3-diaminopropane.

1H NMR (400 MHz, CDCl3) δ ppm; total 1.74 (2H, TT, J=6,8, 6,8 Hz), and 2.83 (2H, t, J=6.8 Hz), 3,37 (2H, dt, J=5,2, 6,8 Hz), to 5.08 (1H, NJ, J=5,2 Hz), 5,28 (2H, CL), the 6.06 (2H, DD, J=0,8, 3.6 Hz), 6.30-in-6,32 (1H, m), of 6.31 (2H, DD, J=1,6, 3,6 Hz), 6,53 (1H, DD, J=1,6, 5,2 Hz), 7,49 (2H, DD, J=0,8 and 1,6 Hz), 8,21 (1H, DD, J=0,8, 5,2 Hz).

Specified in the title compound was synthesized by the method of example 46 at 120°using 1,4-diaminobutane.

1H NMR (400 MHz, CDCl3) δ ppm; 1,49 by 1.68 (4H, m), a 2.71 (2H, t, J=6.8 Hz), with 3.27 (2H, t, J=6.4 Hz), of 4.77 (1H, sh), from 5.29 (2H, CL), the 6.06 (2H, DD, J=0,8, 3.6 Hz), 6.30-in-6,32 (1H, m), of 6.31 (2H, DD, J=1,6, 3.6 Hz), is 6.54 (1H, DD, J=1,2, 5,2 Hz), 7,49 (2H, DD, J=0,8 and 1,6 Hz), 8,21 (1H, DD, J=0,8, 5,2 Hz).

Example 57: 5-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-(3-furyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 43 at 80°using 5-(2-fluoro-4-pyridyl]-4-(2-furyl)-6-(3-furyl)-2-pyrimidinamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,99 (6H, s), 6,07 (1H, d, J=3.6 Hz), 6,44-6,46 (2H, m), 6.48 in (1H, DD, J=1,2, 4,8 Hz), 6,53 (1H, s)6,76 (2H, CL), 7,14 (1H, s), 7,58 (1H, DD, J=1,2, 1.2 Hz), of 7.70 (1H, d, J=1.6 Hz), 8,17 (1H, d, J=5,2 Hz).

Example 58: 5-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-(2-thienyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 43 at 80°using 5-(2-fluoro-4-pyridyl]-4-(2-furyl)-6-(2-thienyl)-2-pyrimidinamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; 3,00 (6H, s), of 6.02 (1H, DD, J=0,8, 3.6 Hz), 6,45 (1H, DD, J=2,0, 3.6 Hz), of 6.52 (1H, DD, J=1,2, 5,2 Hz), 6,59 (1H, s), 6,62 (1H, DD, J=1,2, 4.0 Hz), for 6.81 (2H, CL), 6,91 (1H, DD, J=4,0, 5,2 Hz), to 7.59 (1H, DD, J=1,2, 5,2 Hz), 7,71 (1H, DD, J=0,8, 2.0 Hz), to 8.20 (1H, DD, J=0,8, 5,2 Hz).

Example 59: 5-[2-(dime is ylamino)-4-pyridyl]-4-(2-furyl)-6-(3-thienyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 43 at 80°using 5-(2-fluoro-4-pyridyl]-4-(2-furyl)-6-(3-thienyl)-2-pyrimidinamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 2.94 (6H, s),the 6.06 (1H, d, J=3.2 Hz), 6,39-6,46 (3H, m), 6,78 (2H, CL), 7,05 (1H, DD, J=1,2, 4,8 Hz), 7,34-7,39 (2H, m), 7,68 (1H, d, J=1.2 Hz), 8,07 (1H, d, J=4,8 Hz).

Example 60: 5-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-(2-pyridyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 43 at 80°using 5-(2-fluoro-4-pyridyl]-4-(2-furyl)-6-(2-pyridyl)-2-pyrimidinamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,84 (6H, s), to 6.19 (1H, DD, J=0,8, a 3.2 Hz), of 6.26 (1H, sh), 6,28 (1H, DD, J=1,2, 5,2 Hz), 6,46 (1H, DD, J=1,6, and 3.2 Hz), to 6.95 (2H, CL),of 7.25 (1H, DDD, J=1,2, 4,8 and 7.6 Hz), 7,38-7,40 (1H, m), 7.68 per-7,73 (2H, m), 7,87 (1H, DD, J=0,4, 5,2 Hz), at 8.36 is 8.38 (1H, m).

Example 61: 5-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-(3-pyridyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 43 at 80°using 5-(2-fluoro-4-pyridyl]-4-(2-furyl)-6-(3-pyridyl)-2-pyrimidinamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,87 (6H, s), 6,17 (1H, DD, J=0,8, 3.6 Hz), 6,36 (1H, DD, J=1,2, 5,2 Hz), to 6.39 (1H, sh), 6,46 (1H, DD, J=1,6, 3.6 Hz), of 6.96 (2H, CL), 7,27 (1H, DDD, J=0,8, 5,2, 8.0 Hz), to 7.67 (1H, dt, J=2,0, 8.0 Hz), of 7.70 (1H, DD, J=0,8 and 1,6 Hz), 17,94 (1H, d, J=5,2 Hz), to 8.41-to 8.45 (2H, m).

Example 62: 5-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-(4-pyridyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 43 at 80°using 5-(2-fluoro-4-pyridyl]-4-(2-furyl)-6-(4-pyridyl)-2-pyrimidinamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; is 2.88 (6H, s), 6,17 (1H, d, J=3.6 Hz), 6,36 (1H, d, J=5,2 Hz), to 6.39 (1H, s), 6,47 (1H, DD, J=1,6, 3.6 Hz), 7,01 (2H, CL), from 7.24 (2H, d, J=5.6 Hz), 7,72 (1H, s), 7,95 (1H, d, J=5,2 Hz), 8,44 (2H,, d, J=5.6 Hz).

Example 63: 5-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-phenyl-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 43 at 80°using 5-(2-fluoro-4-pyridyl]-4-(2-furyl)-6-phenyl-2-pyrimidinamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,84 (6H, s), 6,12 (1H, d, J=3.2 Hz), of 6.31 (1H, sh), 6,32 (1H, sh), 6,44 (1H, DD, J=1,6, and 3.2 Hz), 6,85 (2H, CL), 7,19-7,26 (5H, m), to 7.67-to 7.68 (1H, m), to $ 7.91 (1H, d, J=5.6 Hz).

Example 64: 5-(2-Butoxy-4-pyridyl]-4,6-di(2-furyl)-2-pyrimidinamine

In the reaction vessel was dissolved sodium (21 mg, 0,931 mmol) in n-butanol (4 ml), and then to the resulting solution was added 5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine (100 mg, 0,310 mmol) followed by stirring while boiling under reflux for 5 hours in an atmosphere of nitrogen gas. The reaction was stopped by addition of water in the reaction mixture. Then the reaction mixture was extracted with ethyl acetate, the extract washed with the water and a saturated salt solution, was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The obtained solid is suspended in ethanol, collected by filtration and washed with ethanol to obtain specified in the title compound (63 mg, 54 %) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 0, 92 (3H, t, J=7.2 Hz), 1,36-to 1.45 (2H, m), 1,66-of 1.73 (2H, m), the 4.29 (2H, t, J=6.8 Hz), 6,09 (2H, DD, J=0,8, 3.6 Hz), 6,45 (2H, DD, J=1.6,the3.6 Hz), 6,69 (1H, DD, J=0,8 and 1,6 Hz), make 6.90 (1H, DD, J=1,6, 5,2 Hz)6,91 (2H, CL), 7,66 (2H, DD, J=0,8 and 1,6 Hz), by 8.22 (1H, DD, J=0,8, 5,2 Hz).

Example 65: 2-({4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}oxy)-1-ethanol

In the reaction vessel suspended sodium hydride (15 mg, 0,372 mmol) in N,N-dimethylformamide (4 ml) and the resulting suspension was added ethylene glycol (23 g, 0,372 mmol), followed by stirring at 80°C for 30 minutes in an atmosphere of nitrogen gas. Then added 5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine (100 mg, 0,310 mmol) followed by stirring for 14 hours in the same conditions. Then the reaction was stopped by addition of water in the reaction mixture. The reaction mixture was extracted with ethyl acetate, washed with water and saturated salt solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The crude product was purified of chromatogra what s on a column of silica gel with obtaining specified in the title compound (41 mg, 36%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 3,71 (2H, TD, J=5,2, 5,2 Hz), 4,30 (2H, t, J=5,2 Hz), 4,84 (1H, t, J=5,2 Hz)6,09 (2H, d, J=3.2 Hz), 6,45 (2H, DD, J=1,6, and 3.2 Hz), of 6.71 (1H, sh), 6,91-6,92 (3H, m), 7,66 (2H, d, J=1.6 Hz), by 8.22 (1H, d, J=5,2 Hz).

Example 66: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-propyl-1,2-dihydro-2-pyridinone

In the reaction vessel suspended 5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridine (100 mg, 0,393 mmol) and potassium carbonate (109 mg, 0,787 mmol) in methanol (2 ml). Then add propyliodide (134 mg, 0,787 mmol) followed by stirring at 50°C for 17 hours. After the reaction mixture was concentrated and suspended in dimethyl sulfoxide. Was removed by filtration of insoluble materials and the filtrate was purified by HPLC to obtain specified in the title compound (48 mg, 41%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 0,86 (3H, t, J=7,2 Hz), 1,67 (2H, TCEs, J=7,2, 7,2 Hz), 3,85 (2H, t, J=7.2 Hz), 6,37 (1H, DD, J=0,4, and 9.6 Hz), to 6.57 (1H, DD, J=1,6, and 3.2 Hz), of 6.68 (1H, DD, J=0,8, a 3.2 Hz), 6,79 (2H, CL), 7,22 (1H, DD, J=2,4, and 9.6 Hz), to 7.68 (1H, DD, J=0,4, 2.4 Hz), of 7.75 (1H, DD, J=0,8 and 1,6 Hz), 8,13 (1H, s).

Example 67: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-butyl-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using butylated.

1H I Is R (400 MHz, DMSO-d6) δ ppm; to 0.89 (3H, t, J=7,2 Hz), 1.28 (in 2H, TCEs, J=7,2, 7,2 Hz), and 1.63 (2H, dt, J=7,2, 7,2 Hz), 3,88 (2H, t, J=7.2 Hz), 6,37 (1H, d, J=9,2 Hz), to 6.57 (1H, DD, J=1,6, 3.6 Hz), of 6.68 (1H, d, J=3.6 Hz), 6,79 (2H, CL), 7,22 (1H, DD, J=2,4, 9,2 Hz), to 7.68 (1H, d, J=2.4 Hz), 7,73 to 7.75 (1H, m), 8,13 (1H, s).

Example 68: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-foradil)-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using 1-iodine-2-floridana.

1H NMR (400 MHz, DMSO-d6) δ ppm; 4,24 (2H, dt, J=4,8, 26,0 Hz), 4,70 (2H, dt, J=4,8, or 47.2 Hz), 6.42 per (1H, d, J=9,2 Hz), to 6.57 (1H, DD, J=1,6, 3.6 Hz), 6,70 (1H, DD, J=0,8, 3.6 Hz), for 6.81 (2H, CL), 7,27 (1H, DD, J=2,8, 9,2 Hz), 7,68 (1H, d, J=2,8 Hz), 7,74-7,76 (1H, m), 8,11 (1H, s).

Example 69: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(8-hydroxyacyl)-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using 8-bromo-1-octanol.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.20 to 1.31 (8H, m), 1,37-to 1.45 (2H, m), 1,62-1,71 (2H, m), 3,42 (2H, t, J=6,8 Hz)to 3.92 (2H, t, J=7.2 Hz), 6.42 per (1H, DD, J=2,0, 3.6 Hz), 6,46 (1H, d, J=9,2 Hz), to 6.75 (1H, d, J=3.6 Hz), 7,27 (1H, DD, J=2,4, 9,2 Hz), 7,46-of 7.48 (1H, m), 7,53 (1H, d, J=2.4 Hz), 8,03 (1H, s).

Example 70: Methyl 4-{5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}of butanoate

Specified in the title compound was synthesized by the method of example 66, using ethyl 4-bromobutyrate.

1H the Mr (400 MHz, CDCl3) δ ppm; 2,12 (2H, TT, J=7,2, 7,2 Hz), is 2.41 (2H, t, J=7.2 Hz), to 3.67 (3H, s), Android 4.04 (2H, t, J=7.2 Hz), the 5.45 (2H, CL), 6,44 (1H, DD, J=1,6, 3.6 Hz), 6,60 (1H, d, J=9,2 Hz), of 6.71 (1H, d, J=3.6 Hz), 7,20 (1H, DD, J=2,8, 9,2 Hz), 7,24 (1H, d, J=2,8 Hz), 7,49 (1H, DD, J=0,8 and 1,6 Hz)to 8.14 (1H, s).

Example 71: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-PROPYNYL)-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using propylbromide.

1H NMR (400 MHz, CDCl3) δ ppm; 2,49 (1H, t, J=2,8 Hz), 4,82 (2H, d, J=2,8 Hz), 5,31 (2H, CL), of 6.45 (1H, DD, J=3.6 Hz), is 6.61 (1H, DD, J=0,4, 9,2 Hz), 6,74 (1H, DD, J=1,6, 3.6 Hz), 7.23 percent (1H, DD, J=2,4, 9,2 Hz), 7,49 (1H, DD, J=of 0.8, and 1.6 Hz), to 7.59 (1H, DD, J=0,4, 2.4 Hz), 8,16 (1H, s).

Example 72: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-isobutyl-1,2-dihydropyridine

Specified in the title compound was synthesized by the method of example 66, using 1-iodine-2-methylpropane.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.96 (6H, t, J=7.2 Hz), 2,16-of 2.27 (1H, m), of 3.78 (2H, d, J=7,6 Hz), 5,26 (2H, CL), to 6.43 (1H, DD, J=1,6, 3.6 Hz), is 6.61 (1H, d, J=9.6 Hz), of 6.68 (1H, DD, J=0,8, 3.6 Hz), 7,14 (1H, DD, J=0,4, 2,4 Hz), 7,19 (1H, DD, J=2,4, and 9.6 Hz), of 7.48 (1H, DD, J=0,8 and 1,6 Hz)to 8.12 (1H, s).

Example 73: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-butenyl)-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using 1-bromo-2-butyne.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.80 (3H, s), of 4.67 (2H, d, J=2.0 Hz), 6,41 (1H, d, J=9,2 Hz), 6,56-6,59 (1H, m), 6,74 (1H, d, J=3.2 Hz), to 6.80 (2H, CL), 7,26 (1H, DD, J=2.0 a, 9,2 Hz), 7,72 (1H, d, J=2.0 Hz), 7,74 (1H, sh), 8,13 (1H, s).

Example 74: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-benzyl-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using benzylchloride.

1H NMR (400 MHz, CDCl3) δ ppm; 5,14 (2H, s), is 5.18 (2H, s), to 6.39 (1H, DD, J=1,6, 3.6 Hz), 6,64 of 6.68 (2H, m), 7.18 in-of 7.23 (2H, m), 7,27 and 7.36 (5H, m), 7,41 (1H, DD, J= 0,8 and 1,6 Hz), 8,07 (1H, s).

Example 75: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-isopentyl-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using 1-iodine-3-methylbutane.

1H NMR (400 MHz, MeOH-d6) δ ppm; 0, 98 (6H, d, J=6.0 Hz), 1,60-1,70 (3H, m), of 4.05 (2H, t, J=7.2 Hz), 6,53 (1H, DD, J=1,6, 3.6 Hz), to 6.57 (1H, d, J=9,2 Hz), 6,86 (1H, DD, J=0,4, 3.6 Hz), 7,38 (1H, DD, J=2,8, 9,2 Hz), 7,58 (1H, DD, J=0,4, and 1.6 Hz), the 7.65 (1H, d, J=2,8 Hz), 8,14 (1H, s).

Example 76: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-methylbutyl)-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using 1-iodine-2-methylbutane.

1H NMR (400 MHz, MeOH-d6) δ ppm; of 0.91 (3H, d, J=6,8 Hz)to 0.96 (3H, t, J=7,6 Hz), 1,17 of 1.28 (1H, m), 1,38 of 1.50 (1H, m), 1.93 and-2,04 (1H, m), with 3.79 (1H, DD, J=8,4, to 12.8 Hz), 3,99 (1H, DD, J=6,8, to 12.8 Hz), 6,53 (1H, DD, J=1,6, 3.6 Hz), to 6.58 (1H, d, J=9,2 Hz) 6,87 (1H, d, J=3.6 Hz), 7,39 (1H, DD, J=2,4, 9,2 Hz), EUR 7.57 (1H, sh), 7,60 (1H, d, J=2.4 Hz), to 8.12 (1H, s).

Example 77: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-octyl-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using activated.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.87 (3H, t, J=7.2 Hz), 1.18 to 1,42 (10H, m), 1,72-of 1.81 (2H, m), 3,95 (2H, d, J=7,6 Hz)to 5.17 (2H, CL), to 6.43 (1H, DD, J=1,6, 3.6 Hz), 6,60 (1H, d, J=10.4 Hz), of 6.66 (1H, DD, J=0,8, 3.6 Hz), 7,16-7,22 (2H, m), of 7.48-7,51 (1H, m), 8,13 (1H, s).

Example 78: 2-{5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}achilleid

Specified in the title compound was synthesized by the method of example 66, using 3-bromopropionitrile.

1H NMR (400 MHz, CDCl3) δ ppm; 2,99 (2H, t, J=6.0 Hz), 4,20 (2H, t, J=6.0 Hz), 5,18 (2H, CL), of 6.45 (1H, DD, J=1,6, 3.6 Hz), 6,62 (1H, d, J=9.6 Hz), 6,78 (1H, d, J=3.6 Hz), 7,22-7,33 (2H, m), of 7.48-7,51 (1H, m), 8,16 (1H, s).

Example 79: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-forproper)-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using 1-bromo-3-febraban.

1H NMR (400 MHz, CDCl3) δ ppm; of 2.21 (2H, DTT, J=6,0, 6,8, 27,2 Hz), of 4.12 (2H, t, J= 6.8 Hz), 4,51 (2H, dt, J=6,0 and 46.8 Hz), 5,42 (2H, CL), 6,46 (1H, DD, J=1,6, 3.6 Hz), 6,60 (1H, DD, J=0,8, 9,2 Hz), to 6.75 (1H, d, J=3.6 Hz), 7,20-7,26 (2H, m), of 7.48-7,52 (1H, m), 8,11 (1H, s).

Example 80: 5-[2-Amino-4-(2-furyl)-5-p is rimidine]-1-(2-hydroxyethyl)-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using 2-idechannel.

MS m/e (ESI) 299 (MN+).

Example 81: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-hydroxypropyl)-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using 3-iodopropane.

1H NMR (400 MHz, MeOH-d6) δ ppm; up to 1.98 (2H, dt, J=6,4, 6.4 Hz), of 3.60 (2H, t, J=6.4 Hz), 4,14 (2H, t, J=6.4 Hz), is 6.54 (1H, DD, J=2,0, 3.6 Hz), to 6.58 (1H, d, J=9,2 Hz), 6.89 in (1H, d, J=3.6 Hz), 7,39 (1H, DD, J=2,4, 9,2 Hz), 7,58-7,60 (1H, m), 7,66 (1H, d, J=2.4 Hz), 8,15 (1H, s).

Example 82: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-methoxyethyl)-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using 2-pomatoleios ether.

1H NMR (400 MHz, CDCl3) δ ppm; 3,30 (3H, s), 3,70 (2H, t, J=4,8 Hz)to 4.16 (2H, t, J=4,8 Hz), 5,23 (2H, CL), 6,40-6,46 (1H, m), 6,60 (1H, d, J=9,2 Hz), of 6.65 (1H, d, J=3.2 Hz), 7,20 (1H, DD, J=2,4, 9,2 Hz), 7,31 (1H, d, J=1,6 Hz)to 7.50 (1H, sh), 8,14 (1H, s).

Example 83: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-[2-(1H-1-pyrrolyl)ethyl]-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using 1-(2-bromacil)pyrrole.

1H NMR (400 MHz, CDCl3) δ ppm; is 4.21-4.26 deaths (2H, m), 4,28-to 4.33 (2H, m), 5,12 (2H, the) 6,12 (2H, DD, J=2,0, 2,0 Hz), 6,37 (1H, d, J=2.4 Hz), to 6.43 (1H, DD, J=1,6, 3.6 Hz), of 6.52 (2H, DD, J=2,0, 2,0 Hz), to 6.57 (1H, d, J=9.6 Hz), of 6.66 (1H, DD, J=0,8, 3.6 Hz), to 7.15 (1H, DD, J=2,4, and 9.6 Hz), 7,47 (1H, DD, J=0,8 and 1,6 Hz), to 7.84 (1H, s).

Example 84: 2-{5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}ndimethylacetamide

Specified in the title compound was synthesized by the method of example 66, using 2-bromoacetamide.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 4.52 (2H, s)6,38 (1H, d, J=9,2 Hz), 6,56 (1H, DD, J=1,6, 3.6 Hz), was 6.73 (1H, d, J=3.6 Hz), to 6.80 (2H, CL), 7,19 (1H, CL), from 7.24 (1H, DD, J=2,4, 9,2 Hz), a 7.62 (1H, CL), 7,63 (1H, d, J=2.4 Hz), to 7.77 (1H, sh), 8,10 (1H, s).

Example 85: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(cyclopropylmethyl)-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using cyclopropanemethylamine.

1H NMR (400 MHz, CDCl3) δ ppm; 0,36-0,41 (2H, m), is 0.58-0.65 (2H, m), 1,22-of 1.33 (1H, m), a-3.84 (2H, d, J=7,2 Hz), 5,16 (2H, CL), 6,44 (1H, DD, J=1,6, 3.6 Hz), 6,62 (1H, d, J=9,2 Hz), of 6.68 (1H, d, J=3.6 Hz), 7,21 (1H, DD, J=2,4, 9,2 Hz), 7,32 (1H, d, J=2.4 Hz), of 7.48-7,52 (1H, m), 8,15 (1H, s).

Example 86: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-[2-(2-methoxyethoxy)ethyl]-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using 1-bromo-2-(2-methoxyethoxy)ethane.

1H NMR (400 MHz, CDCl3) δ ppm; with 3.27 (3H, s), 3,39-of 3.46 (2H, m), 3,3-3,61 (2H, m)3,81 (2H, t, J=4,8 Hz), 4,19 (2H, t, J=4,8 Hz), 5,50 (2H, CL), to 6.43 (1H, DD, J=1,6, and 3.2 Hz), 6,59 (1H, d, J=9,2 Hz), of 6.66 (1H, d, J=3.2 Hz), 7,19 (1H, DD, J=2,4, 9,2 Hz), 7,41 (1H, d, J=2.4 Hz), 7,50 (1H, d, J=1.6 Hz), 8,15 (1H, s).

Example 87: 5-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-ethyl-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone and ethyliodide.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 1.15 (3H, t, J=7,2 Hz), the 3.89 (2H, q, J=7.2 Hz), 6,37 (2H, DD, J=0,8, 3.6 Hz), 6.48 in (1H, DD, J=0,4, 9,2 Hz), 6,53 (2H, DD, J=1,6, 3.6 Hz), 6.87 in (2H, CL), 7,27 (1H, DD, J=2,4, 9,2 Hz), to 7.61 (1H, d, J=2.4 Hz), of 7.75 (2H, DD, J=0,8 and 1,6 Hz).

Example 88: 5-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-allyl-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone and allylbromide.

1H NMR (400 MHz, DMSO-d6) δ ppm; 4,50 (2H, d, J=5,2Hz), of 4.95 (1H, DD, J=1,2, and 17.2 Hz), to 5.08 (1H, DD, J=1,2, 10,0 Hz), 5,88 (1H, DDT, J=5,2, 10,0, and 17.2 Hz), to 6.43 (2H, DD, J=0,8, 3.6 Hz), of 6.52 (1H, DD, J=0,8, 9,2 Hz), 6,53 (2H, DD, J=of 1.6, 3.6 Hz), 6,86 (2H, CL), 7,32 (1H, DD, J=2,4, 9,2 Hz), to 7.50 (1H, DD, J=0,8, 2.4 Hz), 7,74 (2H, DD, J=0,8 and 1,6 Hz).

Example 89: 5-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-propyl-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized ways the ohms of example 66, using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone and propyliodide.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.90 (3H, t, J=7.2 Hz), of 1.76 (2H, TCEs, J=7,2, 7,2 Hz), 3,93 (2H, t, J=7.2 Hz), 6,12 (2H, CL), 6,44 (2H, DD, J=1,6, 3.6 Hz), to 6.57 (2H, d, J=3.6 Hz), 6,78 (1H, d, J=9,2 Hz), 7,11 (1H, d, J=2,4 Hz), from 7.24 (1H, DD, J=2,4, 9,2 Hz), 7,53 (2H, DD, J=0,8 and 1,6 Hz).

Example 90: 5-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-butyl-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone and mutiliated.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.90 (3H, t, J=7.2 Hz), of 1.23 to 1.34 (2H, m), 1,65-of 1.74 (2H, m), 3,98 (2H, t, J=7.2 Hz), 6,50 (2H, DD, J=1,6 3,6 Hz), to 6.75 (2H, d, J=3.6 Hz), for 6.81 (1H, d, J=9,2 Hz),? 7.04 baby mortality (2H, CL), 7,14 (1H, d, J=2,4 Hz), 7,22-7,30 (1H, m), 7,56 (2H, d, J=1.6 Hz).

Example 91: 5-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-(2-butenyl)-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone and 1-bromo-2-butyne.

1H NMR (400 MHz, DMSO-d6) δ ppm; total 1.74 (3H, t, J=2,4 Hz)and 4.65 (2H, q, J=2,4 Hz), 6,41 (2H, DD, J=0,8 3,6 Hz), of 6.52 (1H, DD, J=0,4 9,2 Hz), is 6.54 (2H, DD, J=2.0 to 3.6 GHz), to 6.88 (2H, CL), 7,30 (1H, DD, J=2,4 9,2 Hz), a 7.62 (1H, DD, J=0,4 2,4 Hz), of 7.75 (2H, DD, J=0,8 2,0 Hz).

Example 92: 5-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-(2-foradil)-1,2-dihydro-2-pyridinone

Specified in the header connect the tion was synthesized by the method of example 66, using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone and 1-iodine-2-floridana.

1H NMR (400 MHz, DMSO-d6) δ ppm; 4,22 (2H, dt, J=4,8, 26,0 Hz), with 4.64 (2H, dt, J=4,8, or 47.6 Hz), 6,38 (2H, DD, J=0,8, 3.6 Hz), of 6.52 (2H, DD, J=1,6, 3.6 Hz), of 6.52 (1H, d, J=9,2 Hz), 6.87 in (2H, CL), 7,30 (1H, DD, J=2,8, 9,2 Hz), to 7.59 (1H, d, J=2,8 Hz), 7,74 (2H, DD, J=0,8 and 1,6 Hz).

Example 93: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-thienyl)-1,2-dihydro-2-pyridinone

In the reaction vessel suspended 5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridine (50 mg, 0,197 mmol), thiophene-3-Bronevoy acid (50 mg, 0,393 mmol) and copper acetate (4 mg, 0,0197 mmol) in N,N-dimethylformamide (3 ml). Then was added pyridine (31 mg, 0,393 mmol) followed by stirring at room temperature for a period of 14.5 hours in the air. After the reaction mixture was concentrated and suspended in dimethyl sulfoxide. Was removed by filtration of insoluble materials and the obtained filtrate was purified by HPLC to obtain specified in the title compound (34 mg, 51%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,47 (1H, DD, J=0,8 and 9.6 Hz), 6,59 (1H, DD, J=1,6, and 3.2 Hz), 6,78 (2H, CL), PC 6.82 (1H, DD, J=0,8, a 3.2 Hz), 7,28 (1H, DD, J=2,4, and 9.6 Hz), 7,35 (1H, DD, J=1,6, 5,2 Hz), to 7.61 (1H, DD, J=3.2, and 5.2 Hz), 7,71 (1H, DD, J=0,8, 2.4 Hz), 7,78-7,81 (2H, m), 8,23 (1H, s).

Example 94: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-phenyl-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 93 and with the use of phenylboronic acid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,47 (1H, DD, J=0,8, 9,2 Hz), 6,60 (1H, DD, J=1,6, 3.6 Hz), 6,77 (2H, CL), PC 6.82 (1H, DD, J=0,8, 3.6 Hz), 7,32 (1H, DD, J=2,4, 9,2 Hz), 7,40-7,52 (5H, m), a 7.62 (1H, d, J=2.4 Hz), 7,81 (1H, DD, J=0,8 at 1.6 Hz), 8,21 (1H, s).

Example 95: 5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-[(E)-2-phenyl-1-ethynyl]-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 93 using E-feniletinilpireny acid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,48 (1H, d, J=9,2 Hz), 6,59 (1H, DD, J=1,6, and 3.2 Hz), 6,79-6,84 (3H, m), to 7.15 (1H, d, J=15.2 Hz), 7,27 (1H, DD, J=2,4, and 9.6 Hz), 7,29 (1H, d, J=7,6 Hz), 7,37 (2H, t, J=7,6 Hz), 7,51 (2H, d, J=7,6 Hz), 7,78 (1H, DD, J=0,8 and 1,6 Hz), to 7.93 (1H, d, J=15.2 Hz), of 8.06 (1H, d, J=2.4 Hz), of 8.25 (1H, s).

Example 96: 1-{4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-4-piperidinecarbonitrile acid

In the reaction vessel suspended ethyl-1-{4-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-4-piperidinecarboxylate (59 mg, 0,128 mmol) in methanol (0.8 ml). To the resulting suspension were added 5 N. aqueous sodium hydroxide solution (0.2 ml) followed by stirring at room temperature for 15 hours. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate, washed with water and saturated salt solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to obtain specified in sagola the ke of the compound (20 mg, 36%) as a white solid.

1H NMR (400 MHz, MeOH-d4) δ ppm; 1,60-of 1.73 (2H, m), 1,88 is 1.96 (2H, m), 2,50-2,60 (1H, m), 2,96 was 3.05 (2H, m), 4,17-of 4.25 (2H, m), and 6.25 (2H, DD, J=0,8, 3.6 Hz), 6,40 (2H, DD, J=2,0, 3.6 Hz), to 6.58 (1H, DD, J=1,2, 5,2 Hz), 6,78 (1H, sh), at 7.55 (2H, DD, J=0,8, 2.0 Hz), to 8.20 (1H, DD, J=0,8, 5,2 Hz).

Example 97: 4-{5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}butyric acid

Specified in the title compound was synthesized by the method of example 96 using 4-{5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}butanoate.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,89 (2H, TT, J=7,2, 7,2 Hz), of 2.21 (2H, t, J=7.2 Hz), 3,91 (2H, t, J=7.2 Hz), 6,37 (1H, d, J=9,2 Hz), 6,56 (1H, DD, J=1,6, 3.6 Hz), 6,70 (1H, d, J=3.6 Hz), 6,79 (2H, CL), 7,22 (1H, DD, J=2,4, 9,2 Hz), the 7.65 (1H, d, J=2.4 Hz), 7,74-7,76 (1H, m), 8,15 (1H, s).

Example 98: 5-(2-Fluoro-4-pyridyl)-4-(2-furyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of reference example 6 and example 14 using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,59 (1H, DD, J=1,8, 3.6 Hz), for 6.81 (1H, DD, J=0,8, 3.6 Hz), 7,06 (2H, CL, 2H), 7,13 (1H, s), 7.18 in-7,22 (1H, m), of 7.70 (1H, DD, J=0,8, 1.8 Hz), 8,21 (1H, d, J=5,2 Hz), of 8.27 (1H, s).

Example 99: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

A suspension of 5-(2-fluoro-4-pyridyl)-4-(2-furyl)-2-pyrimidinamine (3.00 g, 11,70 mmol who) in a mixture of concentrated chloromethane acid (15 ml)-water (15 ml) was stirred at 100° C for 2 hours. Allowing the reaction mixture to cool, neutralized her 5 N. aqueous sodium hydroxide solution. The obtained solid substance was collected by filtration, washed with water and dried at 60°C for 22 hours to obtain specified in the connection header (2,19 g, 70%) as a pale brown solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 5.93 (1H, DD, J=1,8, 6,8 Hz), of 6.26 (1H, d, J=1,8 Hz), 6,59 (1H, DD, J=1,8, 3,4 Hz), PC 6.82 (1H, DD, J=0,8, 3,4 Hz), of 6.96 (2H, CL), 7,31 (1H, d, J=6.8 Hz), 7,78 (1H, DD, J=0,8, 1.8 Hz), 8,19 (1H, s).

The following compounds of examples 100-142 synthesized by the method(s) example(s) 16, 66 and/or 96 using 4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone.

Example 100: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-benzyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 345 (MN+).

Example 101: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-phenethyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 359 (MN+).

Example 102: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-phenylpropyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 373 (MN+).

Example 103: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-terbisil)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 363 (MN+).

Example 104: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-terbisil)-1,2-dihydro-2-pyridinone

<>

MS m/e (ESI) 363 (MN+).

Example 105: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(4-terbisil)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 363 (MN+).

Example 106: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2,4-diferensial)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 381 (MN+).

Example 107: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2,5-diferensial)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 381 (MN+).

Example 108: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-trifloromethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 413 (MN+).

Example 109: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(4-trifloromethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 413 (MN+).

Example 110: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 269 (MN+).

Example 111: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-ethyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 283 (MN+).

Example 112: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-propyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 297 (MN+).

Example 113: 1-Allyl-4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

MS m/e (ESI) 295 (MN+).

Example 114: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-butenyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 309 (MN+).

Example 115: 7-{4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}heptanenitrile

MS m/e (ESI) 364 (MN+).

Example 116: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-cyclobutylmethyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 323 (MN+).

Example 117: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-forproper)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 315 (MN+).

Example 118: 4-{4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}butyronitrile

MS m/e (ESI) 322 (MN+).

Example 119: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(6-chloro-3-pyridylmethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 380 (MN+).

Example 120: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-pyridylmethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 346 (MN+).

Example 121: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-pyridylmethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 346 (MN+).

Example 122: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(4-pyridylmethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 346 (MN+).

Example 123: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-butenyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 307 (MN+).

Example 124: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(4,4,4-trifloromethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 365 (MN+).

Example 125: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-methoxyethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 313 (MN+).

Example 126: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-pentenyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 321 (MN+).

Example 127: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-methylallyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 309 (MN+).

Example 128: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-isobutyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 311 (MN+).

Example 129: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-pentenyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 323 (MN+).

Example 130: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-methyl-2-butenyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 323 (MN+).

Example 131: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-methylbutyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 325 (MN+).

Example 132: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(4-methyl-3-pentenyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 337 (MN+).

Example 133: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-PROPYNYL)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 293 (MN+).

Example 134: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-diethylaminoethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 354 (MN+).

Example 135: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2,2,2-triptorelin)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 337 (MN+).

Example 136: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-foradil)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 301 (MN+).

Example 137: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(1,2,2,2-tetraborate)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 355 (MN+).

Example 138: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2,2-dottorati)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 319 (MN+).

Example 139: 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-ethoxyethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 327 (MN+).

Example 140: Methyl {4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}acetate

MS m/e (ESI) 327 (MN+).

Example 141: {4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}acetic acid

MS m/e (ESI) 313 (MN+).

Example 142: 4-{4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}butyric acid

MS m/e (ESI) 341 (MN+).

Example 143: N1,N1-Diethyl-2-{4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}ndimethylacetamide

A suspension of {4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}acetic acid (10 mg, 32 μmol), 1-hydroxybenzotriazole (15 mg, 98 μmol), 3-(3'-dimethylaminopropyl)-1-ethylcarbodiimide (15 mg, 96 μmol), diethylaminopropylamine (18 mg, 164 μmol) and triethylamine (22 μl, 160 μmol) in N,N-dimethylformamide (1.0 in ml) was stirred at room temperature for 17 hours. The reaction mixture was diluted with water and then was extracted with ethyl acetate. The organic layer was concentrated and then purified by HPLC to obtain specified in the title compound (0.73 mg, 6%).

MS m/e (ESI) 368 (MN+).

Example 144: N1-Phenyl-2-{4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}ndimethylacetamide

Specified in the title compound was synthesized by the method of example 143 using aniline.

MS m/e (ESI) 388 (MN+).

Example 145: 4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 99 using 5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,13 (1H, DD, J=1,6, 6,8 Hz), to 6.19 (1H, d, J=1.6 Hz), 6,51-6,56 (4H, m)6,91 (2H, shwith), of 7.48 (1H, d, J=6.8 Hz), 7,74 for 7.78 (2H, m).

The following compounds of examples 146-148 synthesized by the method of example 16 or 66 using 4-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone.

Example 146: 4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 335 (MN+).

Example 147: 4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-ethyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 349 (MN+).

Example 148: 4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-propyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 363 (MN+).

Example 149: 5-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-(3-hydroxypropyl)-1,2-dihydro-2-pyridinone

Specified in the title compound was synthesized by the method of example 66, using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone and 3-iodopropane.

MS m/e (ESI) 379 (MN+).

Example 150: 4-[2-Amino-4-(2-furyl)-5-rimidine]-2-pyridinecarboxamide

A suspension of 5-(2-fluoro-4-pyridyl)-4-(2-furyl)-2-pyrimidinamine (300 mg, at 1.17 mmol) and sodium cyanide in dimethyl sulfoxide (3 ml) was stirred at 150°C for 46 hours. Allowing the reaction mixture to cool, it was diluted with ethyl acetate and washed with saturated aqueous solution of ammonium chloride twice. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was subjected to chromatography using plates coated with silica gel (manifesting solvent: dichloromethane:methanol = 10:1), and then washed with diethyl ether to obtain specified in the title compound (10 mg, 3%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,40 (1H, DD, J=1,2, 5,2 Hz), 6,51 (1H, d, J=1.2 Hz), is 6.54 (1H, DD, J=1,6, 3,4 Hz), 6, 60 (1H, DD, J=0,8, 3,4 Hz), 6.89 in (2H, CL), 7,72 (1H, DD, J=0,8 and 1,6 Hz), of 8.04 (1H, d, J=5,2 Hz), 8,18 (1H, C).

Example 151: 5-(2-Methoxy-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 64 using methanol.

1H NMR (400 MHz, DMSO-d6) δ ppm; 3,88 (3H, s), between 6.08 (2H, d, J=3.6 Hz), 6,44 (2H, DD, J=1,6, 3.6 Hz), was 6.73 (1H, s), 6.87 in-6,94 (3H, m), the 7.65 (2H, d, J=1.6 Hz), 8,23 (1H, d, J=5,2 Hz).

Example 152: 5-(2-Ethoxy-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine

Specified in the header with the Association synthesized by the method of example 64 using ethanol.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.32 (3H, t, J=7,2 Hz), 4,34 (2H, q, J=7.2 Hz), 6,09 (2H, DD, J=0,8, 3.6 Hz), 6,45 (2H, DD, J=1,6, 3.6 Hz), 6,70 (1H, DD, J=0,8, 1.2 Hz), 6,88-6,94 (3H, m), to 7.67 (2H, DD, J=0,8 and 1,6 Hz), by 8.22 (1H, DD, J=0,8, 5,2 Hz).

Example 153: 5-(2-Propoxy-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine

Specified in the title compound was synthesized by the method of example 64 using n-propanol.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 0.95 (3H, t, J=7,2 Hz), 1,72 (2H, TCEs, J=7,2, 7,2 Hz), 4,25 (2H, t, J=7.2 Hz), 6,09 (2H, DD, J=0,8, 3.6 Hz), 6,45 (2H, DD, J=1,6, 3.6 Hz), 6,70 (1H, DD, J=0,8, 1.2 Hz), 6.89 in-6,94 (3H, m), to 7.67 (2H,, DD, J=0,8 and 1,6 Hz), by 8.22 (1H, DD, J=0,8, 5,2 Hz).

Example 154: 5-(6-Chloro-3-pyridyl)-4-(2-thienyl)-2-pyrimidinamine

Specified in the title compound was obtained by the method of example 14 using 2-(6-chloro-3-pyridyl)-3-(dimethylamino)-1-(2-thienyl)-2-propen-1-it.

1H NMR (400 MHz, DMSO-d6) δ ppm; was 6.73 (1H, DD, J=1,2, 4.0 Hz), 6,94 (2H, CL), 6,98 (1H, DD, J=4,0, 5,0 Hz), to 7.59 (1H, DD, J=0,8, 8,2 Hz), to 7.67 (1H, DD, J=1,2, 5.0 Hz), 7,83 (1H, DD, J=2,4, and 8.2 Hz), 8,17 (1H, s), at 8.36 (1H, DD, J=0,8, 2,4).

Example 155: 5-(6-Chloro-3-pyridyl)-4-phenyl-2-pyrimidinamine

Specified in the title compound was obtained by the method of example 14 using 2-(6-chloro-3-pyridyl)-3-(dimethylamino)-1-phenyl-2-propen-1-it.

1H NMR (400 MHz, DMSO-d6) δ ppm; 7,01 (2H, CL), 7,27-7,40 (5H, m), 7,42 (1H, DD, J=0,8, 8,2 Hz),7,55 (1H, DD, J=2,8, 8,2 Hz), 8,14 (1H, DD, J=0.8, the 2,8 Hz), 8,35 (1H, s).

Example 156: 5-(6-Chloro-3-pyridyl)-4-(3-forfinal)-2-pyrimidinamine

Specified in the title compound was obtained by the method of example 14 using 2-(6-chloro-3-pyridyl)-3-(dimethylamino)-1-(3-forfinal)-2-propen-1-it.

1H NMR (400 MHz, DMSO-d6) δ ppm; 7,00-7,06 (1H, m), 7,07 (2H, CL),7,15-of 7.25 (2H, m), 7,33-7,39 (1H, m), 7,44 (1H, DD, J=0,6, 8,2 Hz), 7,58 (1H, DD, J=2,6, 8,2 Hz), 8,18 (1H, DD, J=0,6, and 2.6 Hz), scored 8.38 (1H, s).

Compounds of the present invention, presents shown above formula (I)useful as antagonists at adenosine receptor (A1-And2A-And2Bor As3-receptor) and particularly as antagonists And2B-receptor. Below are examples of tests demonstrating the effectiveness of the compounds of the present invention as a medicine.

Example 1 test: determination of the ability of binding to adenosine A1receptor

Human adenosine A1the receptor cDNA expressed in abundance in cells SNACK, and the resulting membrane sample is suspended at a protein concentration of 66.7 mg/ml in 20 mm HEPES buffer, pH 7.4 (10 mm MgCl2, 100 mm NaCl). To 0.45 ml of the resulting suspension membrane sample was added to 0.025 ml of 60 nm of tritium-labeled chlorocyclopentane (3N-SSRA from NEN Ltd.) and 0.025 ml of the tested soybean is inane. The resulting mixture was kept at 30°C for 120 minutes, rapidly filtered with suction through a glass fiber filter (GF/B Whatman) and immediately washed twice with 5 ml of 50 mm water-cooled Tris-HCl buffer. Then fiberglass filter was transferred into a vial was added the scintillator and measured the radioactivity on the filter using a liquid scintillation counter. Inhibition of binding3N-SSRA with a1receptor test compound was determined using the following formula, and the value of inhibition was calculated concentration of 50%inhibition (IC50) (the following equation). Inhibition (%)=[1-{binding in the presence of the test compound-nonspecific binding)/(total binding-nonspecific binding)}]X100.

In the above formula full linking means3H-CPA-bound radioactivity in the absence of the test compound; the nonspecific binding means3N-SSRA-associated radioactivity in the presence of 100 μm RPIA ([R]-[1-methyl-2-phenylethyl]adenosine) and binding in the presence of the test compound indicates3N-SSRA-associated radioactivity in the presence of the test compound at a given concentration. The inhibition constant (Ki value) in the table was determined by the formula of Cheng-Prusoff (Cheng-Prusoff).

p> Example 2 test: determination of the ability of binding to adenosine A2Areceptor

Experiment on inhibition of the binding of adenosine A2Areceptor was performed using a membrane sample (Receptor Biology Inc.), where adenosine A2Athe receptor cDNA was expressed in excess. This membrane sample is suspended at a protein concentration of 22.2 μg/ml in 20 mm HEPES buffer, pH 7.4 (10 mm MgCl2and 100 mm NaCl). To 0.45 ml of the resulting suspension membrane sample was added to 0.025 ml of 500 nm tritium-labeled 2-p-[2-carboxyethyl]phenethylamine-5'-N-ethylcarbodiimide (3N-GS21680, from NEN) and 0.025 ml of test compounds. The resulting mixture was kept at 25°C for 90 minutes, rapidly filtered with suction through a glass fiber filter (GF/B Whatman) and immediately washed twice with 5 ml of 50 mm cooled ice Tris-HCl buffer. Then fiberglass filter was transferred into a vial was added the scintillator and measured the radioactivity on the filter using a liquid scintillation counter. Inhibition of binding3N-GS21680 with a2Areceptor test compound was determined using the following formula, and the value of inhibition was calculated concentration of 50%inhibition (IC50).

Inhibition (%)=[1-{[(binding in the presence of the test is about connection)-(nonspecific binding)]/[(total binding)-(nonspecific binding)}]X100.

In the above formula full linking means3N--bound radioactivity in the absence of the test compound; the nonspecific binding means3N-GS21680-associated radioactivity in the presence of 100 μm RPIA and binding in the presence of the test compound indicates3N--associated radioactivity in the presence of the test compound at a given concentration. The inhibition constant (Ki value) in the table was determined by the formula of Cheng-Prusoff.

Example 3 tests: Experiment on inhibition of NECA-stimulated production camp in cells expressing the adenosine A2Breceptor

Cells SNACK, where the human adenosine A2Bthe receptor was expressed in excess, were sown on 24-cell Petri dish at a density of 1,5x105cells/cell were cultured overnight and used in the experiment. The degree of inhibitory effect of the test compound on the amount of camp received by the stimulation of 30 nm 5'-N-ethylcarbodiimide (NECA from Sigma), were evaluated for affinity to a2Bthe receptor. That is, fused cells were washed twice with 2 ml of cell buffer solution of Krebs-ringer (containing 0.1% BSA; pH 7.4) and pre-incubated for 30 minutes in a volume of 0.5 ml/cell. Then was added a mixed solution containing NECA and the tested soybean is inania, in a volume of 0.1 ml/cell in the presence of the phosphodiesterase inhibitor Ro-20-1724 (product RBI). After pre-incubation for 15 minutes, the reaction was stopped by addition of 0.1 n HCl in a volume of 300 μl/cell. Measurement of intracellular camp was performed using the kit for immunoassay on camp production Amersham. Inhibition of NECA-stimulated production of camp the test compound was determined using the following equation: inhibition %=[1-{(the amount of camp in the joint presence of NECA and the test compound-amount of camp in a buffer solution of Krebs-ringer only)/(number of camp upon stimulation by only NECA-the amount of camp in a buffer solution of Krebs-ringer only)}]X100.

The ability of the compounds of the present invention to contact adenosine receptor or the ability to resist him can be seen below (see table 1).

Table 1
Test connectionKi(nm)1Ki(nm)2AIC50 (nm)
Example 16175629
Example 17289325
Example 18114226

Connect the of the present invention, their salt or solvate both have excellent inhibitory effect on adenosine receptors.

Example 4 testing: Evaluation of actions, urinating

Defecation-promoting action of compounds that inhibits adenosine A2B-the receptor that was identified by determining its binding ability and inhibitory capacity towards adenosine receptor in examples 1-3 trials, its salts, their MES or pharmaceutical composition containing any of them, may be estimated in the following way. Rats SD IGS (age 6 weeks, F. Charles River) were placed in cages (3 animals/cage) and first gave them food and water at will and was reared in 1 week. Then under each cage was placed calibrated water-absorbing sheet, and animals continued to feed, but gave them water on request throughout the experiment. From every cell of 1.5 hours was collected fecal balls, watching this deviation from the norm prior to the experiment. The compound suspended or dissolved in 0.5% (wt./about.) methylcellulose (MC), is administered orally in an amount of 5 ml/kg Control group was administered orally with only a 0.5% (wt./about.) MC. After entering the connection rats were returned to the cage, with the new water-absorbing sheet, and 90 minutes after injection were collected from the each cell fecal balls on the water-absorbing sheet and looked at their appearance, and then counted and weighed. To determine the number of fecal balls on each cell (see table 2).

Table 2
Test connectionDoseThe number of fecal pellets.

Average±S.E. (mean square error)
Control-1,25±0,63
Example 163 mg/kg12,50±0,96
Example 173 mg/kg15,50±3,18
Example 183 mg/kg14,50±1,26

Compounds of the present invention, their salts or solvate both have excellent defecation-promoting action.

Example 5 tests: Assessment of effects caused by haloperidol catalepsy

Parkinson's disease is a disease caused by the degeneration or death of nigrostriatal dopaminergic neurons. The introduction of haloperidol (a dopamine antagonist D1/D2receptors) blocks postsynaptic D2receptors, causing catalepsy. Haloperidol-induced catalepsy is known as a classic simulating Parkinson's disease model, obtained by administration of a medicinal product (Eur. J. Pharmacol., 182, 327-334 (1990)).

Connection-antagonists adenosine A2 is receptors identified by determining their ability to bind with receptors in examples 1-3 trials, and their salts, solvate and those of other or containing pharmaceutical composition was evaluated by the effect on haloperidol-induced catalepsy in the manner described below. The experiment was conducted in mice male ICR (supplier f. Charles River) by 5 weeks of age, eight mice per group. Haloperidol (manufacturer Sigma Co., Ltd.) dissolved 6.1% solution of tartaric acid and the resulting solution at a dose of 1 mg/kg) was then injected into mice intraperitoneally. The test compound used in the form of a 0.5% suspension in MC. 1.5 hours after intraperitoneal administration of haloperidol mice orally was administered (0.1 ml per 10 g of body weight of a mouse) as a suspension with the test compound and the suspension without the test compound (control). Within 1 hour after administration of the test compounds was measured by the degree of catalepsy in each of the mice by putting only a couple of the forelimbs and only a couple of hind legs alternately on a stand with a height of 4.5 cm and a width of 10 cm Oral was administered 0.1 mg/kg and 0.3 mg/kg of each of the tested compounds. Points and signs of catalepsy were as follows.

PointsThe duration of catalepsy
0:When a couple only p is radnich limbs and only a couple of hind legs independently placed on the stand, the duration of this state of each pair is less than 5 seconds.
1:The duration of the posture in which the forelimbs were left on the stand, was 5 seconds or more, but less than 10 seconds, and the duration of such provisions of the hind limbs was less than 5 seconds.
2:The duration of the posture in which the forelimbs were left on the stand was 10 or more seconds, and the duration of such provisions pair of hind limbs was less than 5 seconds.
3:The duration of the posture in which the front and hind legs remained on the stand, was 5 seconds or more, but less than 10 seconds, the duration of the posture in which the forelimbs were left on the stand, was less than 5 seconds, and the duration of such provisions of the hind limbs was 5 or more seconds.
4:The duration of the posture in which the forelimbs were left on the stand was 10 or more seconds, and the duration of such provisions of the hind limbs was 5 seconds or more, but less than 10 seconds; or the duration of the posture in which the forelimbs were left on the stand, was less than 5 seconds or more, but less than 10 seconds, and the duration of such provisions of the hind limbs was 10 or more seconds.
5:The duration of the posture in which the front and hind legs remained on the stand was 10 or more seconds.

The effects of the compounds were determined by comparison between the scores of the control group and the scores of the group for the test, which was administered the test compound. Significant differences were analyzed by the test of Dunnet. The results are shown in table 3.

1. The compound represented by formula (I)or its pharmacologically acceptable salt:

where R1and R2each represents a hydrogen atom;

R3represents a hydrogen atom, halogen atom, amino group, cyano, an alkyl group having one to six carbon atoms, alkoxygroup having one to six carbon atoms, alkenylacyl having two to six carbon atoms, phenyl group which may be substituted by a halogen atom, pyridyloxy group, follow group or thienyl group;

R4represents pyridyl which may be substituted by the Deputy selected from the group comprising a hydrogen atom, halogen atom, amino, mono - or dialkylamino, aminoethylamino, each of which has an alkyl residue of from one to six carbon atoms; an alkyl group having from one to six carbon atoms which may be substituted by halogen atom, hydroxy-group, amino, mono - or dialkylamino, alkoxycarbonyl, each of which has an alkyl residue of from one to six carbon atoms; hydroxycarbonyl; alkoxygroup having in the alkyl residue of from one to six carbon atoms and appropriately substituted phenyl or pyridium; hydroxyl is xygraph, having in the alkyl residue of from one to six carbon atoms; hydroxycarbonyl; alkoxycarbonyl having from one to six carbon atoms in the alkyl residue; alkenylphenol group having from two to six carbon atoms; alkylamino group having from two to six carbon atoms; piperidinyl group which may be substituted by a hydroxyl group; or represents a group of formula IV

where R8represents (I) hydrogen, II) alkyl group, having from one to six carbon atoms which may be substituted by the Deputy selected from the following group (b), (III) alkenylphenol group having from two to six carbon atoms which may be substituted by phenyl group;

IV) alkylamino group having from two to six carbon atoms;

V) thienyl group, or (VI) phenyl group;

the group of substituents (C) consists of a halogen, a hydroxyl group, ceanography, carboxyl group, carbamoyl group which may be substituted by an alkyl group having one to six carbon atoms, or phenyl group, alkoxygroup having one to six carbon atoms which may be substituted by alkoxygroup having one to six carbon atoms, alkoxycarbonyl group is within one to six carbon atoms in the alkyl part, cycloalkyl group having from three to eight carbon atoms, peredelnoj group which may be substituted by a halogen atom, pyrrolidino group or phenyl which may be substituted by a halogen atom or alkyl group having from one to six carbon atoms which may be substituted with halogen;

R5represents phenyl which may be substituted by a halogen atom, pyridyloxy group, thienyl or follow group;

provided that the compounds in which R3represents a hydrogen atom, R4represents a 4-pyridyl and R5is a 4-forfinal excluded.

2. The compound according to claim 1, where R4represents a group of formula (V) or (VI)

where R8defined in claim 1,

or its pharmacologically acceptable salt.

3. The compound according to claim 2, where R4represents a group of formula (V)or its pharmacologically acceptable salt.

4. The compound according to any one of claims 1 to 3, where R3represents a hydrogen atom or alkyl group having one to six carbon atoms, or its pharmacologically acceptable salt.

5. The compound according to any one of claims 1 to 4, where R5represents phenyl which may be substituted by a halogen atom, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl,3-thienyl, 2-furyl or 3-furyl, or its pharmacologically acceptable salt.

6. The compound according to any one of claims 1 to 5, where R8represents II) an alkyl group having from one to six carbon atoms which may be substituted by the Deputy selected from the following group (b), (III) alkenylphenol group having from two to six carbon atoms which may be substituted by phenyl, (IV) alkylamino group having from two to six carbon atoms;

the group of substituents (b) consists of a halogen, a hydroxyl group, ceanography, carboxyl group, carbamoyl group which may be substituted by an alkyl group having one to six carbon atoms or phenyl group, alkoxygroup having one to six carbon atoms which may be substituted by alkoxygroup having one to six carbon atoms, alkoxycarbonyl group, cycloalkyl group having from three to eight carbon atoms, peredelnoj group which may be substituted by a halogen atom or phenyl which may be substituted by a halogen atom or alkyl group having from one to six carbon atoms which may be substituted with halogen; or its pharmacologically acceptable salt.

7. The compound according to any one of claims 1 to 6, where R8is (II) an alkyl group having one to six carbon atoms which kind which may be substituted by a halogen atom or alkoxygroup having one to six carbon atoms, or alkenylphenol group having two to six carbon atoms which may be substituted by phenyl, or its pharmacologically acceptable salt.

8. The compound according to claim 1, selected from the group including:

(1) 5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone;

(2) 5-[2-amino-4-(2-furyl)-5-pyrimidinyl]- 1-ethyl-1,2-dihydro-2-pyridinone;

(3) 1-allyl-5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone;

(4) 5-[2-amino-4-(2-thienyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone;

(5) 5-[2-amino-4-(3-forfinal)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone;

(6) 5-{2-amino-4-phenyl-5-pyrimidinyl)-1-ethyl-1,2-dihydro-2-pyridinone;

(7) 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone and

(8) 5-[2,4-diamino-6-(3-forfinal)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone, or its salt.

9. Pharmaceutical composition having the properties of antagonists to adenosine receptor And2containing the compound according to any one of claims 1 to 8, or its pharmacologically acceptable salt.

10. The pharmaceutical composition according to claim 9 for preparing a medicinal product for the treatment or prevention of diseases, which has the relation of a2the receptor.

11. Pharmaceutical to the position according to claim 9, which is a tool for the treatment or prevention of disease, which is the ratio of adenosine A2Athe receptor.

12. The pharmaceutical composition according to claim 9, which is a tool for the treatment or prevention of disease, which is the ratio of adenosine A2Bthe receptor.

13. Method of inhibiting the binding of adenosine receptors, which includes an introduction to the patient a pharmacologically effective amount of a compound according to claim 1 or its pharmacologically acceptable salt.

14. The method according to item 13, where the said inhibition is used to facilitate defecation.

15. The use of compounds according to claim 1, its pharmacologically acceptable salts for the preparation of drugs for treatment or prevention of disease, which is the ratio of the adenosine receptor.

16. The application indicated in paragraph 15, where the drug is intended to facilitate defecation.



 

Same patents:

FIELD: organic chemistry, chemical technology, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of heteroaryl-substituted aminocyclohexane of the formula (I) and their pharmaceutically acceptable salts possessing the inhibitory effect on activity of 2,3-oxydosqualene-lanosterolcyclase (OSC). In the formula (I) V means a simple bond, oxygen atom (O), -CH=CH-CH2- or -C≡C-; m and n = 0-7 independently of one another and m+n = 0-7 under condition that m is not 0 if V means O; o = 0-2; A1 means hydrogen atom, lower alkyl, hydroxy-lower alkyl or lower alkenyl; A2 means lower alkyl, or A1 and A2 are bound and form 5-6-membered cycle, and -A1-A2- means (C4-C5)-alkylene; A3 and A4 mean hydrogen atom independently of one another; A5 means hydrogen atom, lower alkyl; A6 means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl optionally substituted with one substitute chosen independently from the group including halogen atom, lower alkyl, lower alkoxy-group and 5-6-membered heteroaryl comprising nitrogen or sulfur atom as a heteroatom, Also, invention relates to a pharmaceutical composition and using proposed compound for preparing medicinal agents. Proposed compounds can be used in treatment of such diseases as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycosis, parasitic infections, cholelithiasis, tumors and/or hyperproliferative disorders, and/or in disordered tolerance to glucose and diabetes mellitus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

24 cl, 7 sch, 28 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

11 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes new derivatives of triazole of the general formula (I): wherein X represents group of the general formula (II): wherein R' means halogen atom; R4 means (C1-C6)-alkyl; L means group of the formula: -La-Lb wherein La means a simple bond, oxygen atom, phenyl group that can be optionally substituted with halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group or (C1-C6)-alkyl substituted with a single group -O-P(=O)(OH)2, naphthyl group, 5-membered heteroaryl group comprising as a heteroatom oxygen (O) or sulfur (S) atom, or (C3-C7)-cycloalkyl group that is substituted with carboxyl group; and Lb means (C1-C5)-alkylene group that can be optionally substituted with (C1-C6)-alkyl, carboxyl group or di-[(C1-C6)-alkyl]-amino-(C1-C6)-alkyl group; R means hydrogen atom, (C1-C6)-alkanoyl that can be optionally substituted with group: -Q-NR2'R3' wherein Q means a simple bond or carbonyl group, and R2' and R3' in common with nitrogen atom with that they are bound form piperazinyl ring substituted with (C1-C6)-alkyl and/or carboxyl group, or group: -O-P(=O)(OH)2; or their pharmacologically acceptable salts, pharmaceutical composition based on thereof, and a method for treatment of fungal infections.

EFFECT: valuable medicinal properties of compounds and composition, improved method for treatment of infections.

24 cl, 14 tbl, 1 dwg, 45 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

FIELD: organic chemistry, medicinal biochemistry, pharmacy.

SUBSTANCE: invention relates to substituted benzimidazoles of the formula (I): and/or their stereoisomeric forms, and/or their physiologically acceptable salts wherein one of substitutes R1, R2, R3 and R4 means a residue of the formula (II): wherein D means -C(O)-; R8 means hydrogen atom or (C1-C4)-alkyl; R9 means: 1. (C1-C6)-alkyl wherein alkyl is linear or branched and can be free of substituted by one-, bi- or tri-fold; Z means: 1. a residue of 5-14-membered aromatic system that comprises from 1 to 4 heteroatoms as members of the cycle that represent nitrogen and oxygen atoms wherein aromatic system is free or substituted; 1.1 a heterocycle taken among the group of oxadiazole or oxadiazolone that can be unsubstituted or substituted; 2. (C1-C6)-alkyl wherein alkyl is a linear or branched and monosubstituted with phenyl or group -OH; or 3. -C(O)-R10 wherein R10 means -O-R11, -N(R11)2 or morpholinyl; or R8 and R9 in common with nitrogen atom and carbon atom with that they are bound, respectively, form heterocycle of the formula (IIa): wherein D, Z and R10 have values given in the formula (II); A means a residue -CH2-; B means a residue -CH-; Y is absent or means a residue -CH2-; or X and Y in common form phenyl. The cyclic system formed by N, A, X, Y, B and carbon atom is unsubstituted or monosubstituted with (C1-C8)-alkyl wherein alkyl is monosubstituted with phenyl, and other substitutes R1, R2, R3 and R4 mean independently of one another hydrogen atom, respectively; R5 means hydrogen atom; R6 means the heteroaromatic cyclic system with 5-14 members in cycle that comprises 1 or 2 nitrogen atoms and can be unsubstituted or substituted. Also, invention relates to a medicinal agent for inhibition of activity of IkB kinase based on these compounds and to a method for preparing the indicated agent. Invention provides preparing new compounds and medicinal agents based on thereof for aims for prophylaxis and treatment of diseases associated with the enhanced activity of NFkB.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 7 tbl, 224 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new 4-piperazinyl-(8-quinolinyl)-methyl)-benzamides of general formula I

1, wherein R1 is phenyl, pyridinyl, thiophenyl, furanyl, and inidazolyl, and each phenyl or heteroaromatic ring is optionally and independently substituted with 1, 2 or 3 substituents, selected from linear or branched C1-C6-alkyl, NO2, CF3, C1-C6-alkoxy, halogen, or pharmaceutically acceptable salts thereof. Compounds of present invention are useful in therapy, in particular for pain alleviation. Also disclosed are pharmaceutical composition based on compounds of formula I and method for pain treatment.

EFFECT: new compounds and compositions for pain treatment.

12 ck, 19 ex, 3 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of aminoquinoline and aminopyridine. Invention describes compounds of the general formula (I): wherein R1 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R2 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R3 means hydrogen atom or direct or branched (C1-C4)-alkyl group or phenyl group, thienyl group or furyl group optionally substituted with one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group or halogen atom; R4 and R5 form in common 1,3-butadienyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group or halogen atom; R6 means hydrogen atom or cyano-group; R7 means hydrogen atom or direct or branched (C1-C4)-alkyl group, phenyl group, benzyl group, thienyl group, or furyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group, trifluoromethyl group, cyano-group or halogen atom; X means -NH-group, -NR8-group or sulfur atom, or oxygen atom, or sulfo-group, or sulfoxy-group wherein R8 means direct or branched (C1-C4)-alkyl group or (C3-C6)-cycloalkyl group; n = 0, 1 or 2, and their salts. Also, invention describes a method for preparing compounds of the formula (I). a pharmaceutical composition based on thereof, using compounds of the formula (I) as antagonists of A3 receptors for preparing a pharmaceutical composition used in treatment of different diseases (variants), compounds of the formula (IA), (II), (III) and (IV) given in the invention description. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

15 cl, 6 tbl, 6 dwg, 172 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of N-heterocyclic compounds of the formula: , wherein n and m mean independently a whole number from 1 to 4; A means -C(O)OR1 or -C(O)N(R1)R2; W means -CH; R1 means hydrogen atom or (C1-C8)-alkyl; R means hydrogen atom, (C1-C8)-alkyl, heterocyclyl-(C1-C4)-alkyl chosen from the group comprising benzodioxolyl-, benzodioxanyl- or dihydrobenzofuranylalkyl or phenyl-(C1-C4)-alkyl substituted possibly with alkoxy-group; R4 means cyano-group or heterocyclyl chosen from the group comprising pyridinyl, morpholinyl, benzodioxolyl or benzodioxanyl-radical if m = 1; if m means from 2 to 4 then R4 can mean additionally hydroxy-group, -NR1R2 wherein R1 and R2 mean independently hydrogen atom, (C1-C8)-alkyl or benzyl-radical, -N(R1)-C(O)-R1, -N(R1)-C(O)-OR1, -N(R1)-S(O)t-R1 wherein R1 means hydrogen atom or (C1-C8)-alkyl, -N(R1)-C(O)-N(R1)2 wherein R1 means hydrogen atom; R5 means (C1-C8)-alkyl; t = 2, and their stereoisomers and pharmaceutically acceptable salts, pharmaceutical composition based on thereof and a method for treatment of diseases, in particular, rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds and composition.

12 cl

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

11 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes new derivatives of triazole of the general formula (I): wherein X represents group of the general formula (II): wherein R' means halogen atom; R4 means (C1-C6)-alkyl; L means group of the formula: -La-Lb wherein La means a simple bond, oxygen atom, phenyl group that can be optionally substituted with halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group or (C1-C6)-alkyl substituted with a single group -O-P(=O)(OH)2, naphthyl group, 5-membered heteroaryl group comprising as a heteroatom oxygen (O) or sulfur (S) atom, or (C3-C7)-cycloalkyl group that is substituted with carboxyl group; and Lb means (C1-C5)-alkylene group that can be optionally substituted with (C1-C6)-alkyl, carboxyl group or di-[(C1-C6)-alkyl]-amino-(C1-C6)-alkyl group; R means hydrogen atom, (C1-C6)-alkanoyl that can be optionally substituted with group: -Q-NR2'R3' wherein Q means a simple bond or carbonyl group, and R2' and R3' in common with nitrogen atom with that they are bound form piperazinyl ring substituted with (C1-C6)-alkyl and/or carboxyl group, or group: -O-P(=O)(OH)2; or their pharmacologically acceptable salts, pharmaceutical composition based on thereof, and a method for treatment of fungal infections.

EFFECT: valuable medicinal properties of compounds and composition, improved method for treatment of infections.

24 cl, 14 tbl, 1 dwg, 45 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to quinazoline derivatives of the formula (I) or their pharmaceutically acceptable salts wherein m = 0 or 1; each group R1 can be similar or different and represents halogen atom, hydroxy- and (C1-C6)-alkoxy-group, or group of the formula Q3-X1 wherein X1 represents oxygen atom (O); Q3 represents phenyl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl, and wherein heteroaryl group represents aromatic 5- or 6-membered monocyclic rings with one or two nitrogen heteroatoms, and any heterocyclyl group defined as the group R1 represents non-aromatic saturated or partially saturated 3-6-membered monocyclic ring with one or two heteroatoms chosen from oxygen and nitrogen atoms, and wherein adjacent carbon atoms in any (C2-C6)-alkylene chain in the substitute R1 are separated optionally by incorporation of oxygen atom (O) in the chain, and wherein any group CH2 or CH3 in the substitute R1 comprises optionally in each of indicated groups CH2 or CH3 one or some halogen substitutes or a substitute chosen from hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkylsulfonyl or pyridyloxy-group, and wherein any heteroaryl or heterocyclyl group in the substitute R1 comprises optionally 1, 2 or 3 substitutes that can be similar or different and chosen from hydroxy-group, carbamoyl, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]-carbamoyl, (C1-C6)-alkoxy-(C1-C6)-alkyl and cyano-(C1-C6)-alkyl, or among group of the formula -X5-Q6 wherein X5 represents a direct bond or -CO, and Q6 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that comprises optionally (C1-C6)-alkyl as a substitute wherein heterocyclyl group represents non-aromatic, fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from nitrogen and oxygen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; Z represents a direct bond or oxygen atom; Q1 represents phenyl, (C3-C7)-cycloalkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl wherein heteroaryl group represents 5- or 6-membered aromatic monocyclic ring with I, 2 or 3 heteroatoms of nitrogen, and any heterocyclyl group represents non-aromatic fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from oxygen, nitrogen or sulfur atom, or when Z represents oxygen atom (O) then Q1 can represent (C1-C6)-alkyl or (C1-C6)-alkoxy-(C1-C6)-alkyl and wherein any heterocyclyl group in the group -Q1-Z- comprises substitutes chosen from (C1-C6)-alkyl, (C1-C)-alkoxycarbonyl and pyridylmethyl, and wherein any heterocyclyl group in the group -Q1-Z- comprises optionally 1 or 2 oxo-substitutes; Q2 represents aryl group of the formula (Ia): wherein G1 represents halogen atom, trifluoromethyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C2-C6)-alkanoyl, pyrrolyl, pyrrolidinyl, piperidinyl and morpholinomethyl, and each G2, G3, G4 and G5 that can be similar or different represents hydrogen, halogen atom, cyano-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group, or G1 and G2 form in common group of formulae -CH=CH-CH=CH-, -CH=CH-O- or -O-CH=CH- being each group carries optionally halogen atom as a substitute, or G1 and G2 form in common group of formulae -O-CH2-O- or -O-CH2-CH2-O-, or -O-CH2-CH2-O-, and each among G3 and G4 represents hydrogen atom, and G5 is chosen from hydrogen and halogen atom. Proposed compounds possess anti-tumor activity and designated for preparing a medicine preparation for its using as an anti-tumor agent for suppression and/or treatment of solid tumors. Also, invention relates to a pharmaceutical composition based on abovementioned compounds.

EFFECT: valuable medicinal properties of compounds.

20 cl, 7 tbl, 57 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention relates to a novel heterocyclic compound, in particular, 3-(5-nitrofuryl)-7-(5-nitrofurfurylidene-3,3a,4,5,6,7-hexahydro-2H-indazole of the formula (1): that elicits an antibacterial activity with respect to bacterium of genus Staphylococcus and can be used in medicine. The compound of the formula 91) is prepared by reaction of 2,6-di-(5-nitrofurfurylidene)-cyclohexanone with hydrazine hydrate in propanol-2 medium. The yield is 80%, m. p. at 193-195°C, empirical formula is C16H14N4O6, LD50 value at intraperitoneal administration is 500 mg/kg. This compound exceeds activity of furacilinum and furazolidone by 16 and 2-31 times, respectively. Invention provides preparing compound possessing the higher and selective antibacterial activity and low toxicity.

EFFECT: valuable properties of compound.

1 cl, 3 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new derivatives of quinazoline of the formula (I):

wherein m = 0, 1, 2 or 3; each group R1 that can be similar or different is taken among halogen atom, trifluoromethyl, hydroxy-, amino-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-, (C2-C6)-alkynyloxy-, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino- and (C2-C6)-alkanoylamino-group, or among the group of the formula: Q1-X1- wherein X1 represents oxygen atom (O); Q1 represents aryl-(C1-C6)-alkyl, heteroaryl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl and wherein neighboring carbon atoms in any (C2-C6)-alkylene chain in substitute at R1 are separated optionally by insertion to the chain the group taken among oxygen atom (O) and N(R5) wherein R5 represents hydrogen atom or (C1-C6)-alkyl, or when the inserted group represents N(R5); R5 can represent also (C2-C6)-alkanoyl and wherein any group -CH2 or -CH3 in substitute R1 carries one or more substitutes in each indicated group -CH2 or -CH3 and wherein these substitutes are taken among halogen atom or (C1-C6)-alkyl, or substitute taken among hydroxy-, amino-group, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino-, (C2-C6)-alkanoyloxy, (C2-C6)-alkanoylamino- and N-(C1-C6)-alktyl-(C2-C6)-alkanoylamino-group, or among the group of the formula: -X3-Q3wherein X3 represents oxygen atom (O) and Q3 represents heteroaryl, and wherein any aryl, heteroaryl or heterocyclyl group in substitute at R1 carries optionally 1, 2 or 3 substitutes that can be similar or different and taken among halogen atom, trifluoromethyl, cyano-, hydroxy-, amino-group, carbamoyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy, (C2-C6)-alkynyloxy,(C1-C6)-alkylthio-group, (C1-C)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino-group, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]carbamoyl, (C2-C6)-alkanoyl, (C2-C6)-alkanoyloxy-, (C2-C)-alkanoylamino- and N-(C1-C6)-alkyl-(C2-C6)-alkanoylamino-group, or among the group of the formula: -X4-R8 wherein X4 represents a simple bond and R8 represents hydroxy-(C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, cyano-(C1-C6)-alkyl, amino-(C1-C6)-alkyl, (C1-C6)-alkylamino-(C1-C6)-alkyl or di-[(C1-C6)-alkyl]amino-(C1-C6)-alkyl, or among the group of the formula: -X5-Q4 wherein X5 represents a simple bond or -CO, and Q4 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that carries optionally 1 or 2 substitutes that can be similar or different and taken among halogen atom, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group and wherein any heterocyclyl group in substitute at R1 carries optionally 1 or 2 oxo-substitutes, and wherein any aryl group in the group R1 represents phenyl; any heteroaryl group in the group R1 is taken among pyrrolyl, imidazolyl, triazolyl and pyridyl, and any heterocyclyl group in the group R1 is taken among oxyranyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, 1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl; R2 represents hydrogen atom; n = 0, 1, 2 or 3; R3 represents halogen atom, trifluoromethyl, cyano-, hydroxy-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or (C1-C6)-alkoxy-group, or its pharmaceutically acceptable salt. Also, invention relates to methods for preparing compounds of the formula (1) and to pharmaceutical composition based on thereof for using as an anti-tumor agent. Invention provides preparing new derivatives of quinazoline possessing an anti-tumor activity.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 7 tbl, 7 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a novel triazole derivative of the general formula (I): wherein R1 represents phenyl group optionally substituted with one or two groups chosen from (C1-C6)-alkyl group, (C1-C6)-halogenalkyl group, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkoxy-group, halogen atom, nitro-group or cyano-group, styrenyl group, (C1-C6)-alkoxystyrenyl-group or pyridyl group; R2 represents methyl or amino-group; A and B are carbon atoms; C and D represent independently carbon or nitrogen atom, and its nontoxic salt and pharmaceutical composition based on thereof. Also, invention relates to methods for synthesis of novel compounds, novel intermediate substances of the formula: wherein R2, A, B, C and D have above given values; n means a whole number from 0 to 2, and to a method for their synthesis. Compounds of the formula (I) possess anti-inflammatory activity and can be used potentially in treatment of fever, pain and inflammation.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 2 tbl, 50 ex

Up!
Table 3
Group namePut some contentThe dose of the test compoundPoints catalepsy

Average±S.E.
ControlHaloperidol5,00±0,00
Example 16Haloperidol+test connection0.1 mg/kg4,63±0,38
Example 16Haloperidol+test connection1.0 mg/kg0,88±0,64**
Example 17Haloperidol+test connection0.1 mg/kg3,38±0,53**
Example 17Haloperidol+test connection1.0 mg/kg1,13±0,67**
** p < 0,01 (comparison with control group)