1-n-alkyl-n-arylpyrimidines, the method of treatment of diseases, the pharmaceutical composition

 

(57) Abstract:

The invention relates to new biologically active compounds, methods of treating diseases with their use and pharmaceutical compositions based on these compounds. 1-N-Alkyl-N-arylpyrimidines correspond to the General formula I

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The values of the radicals indicated in the claims. The proposed pharmaceutical composition comprising the compounds of formula I in an effective quantity, further comprises a carrier and active on the CRF receptors. The method of treatment of diseases caused by the activity of CRF receptors in affective disorders, anxiety States, and the other is the introduction of the active compounds of the formula I to a mammal in a therapeutically effective amount. 5 s and 5 C.p. f-crystals, 23 PL.

The invention relates to new compounds, compositions and pharmaceutical compositions based on them, as well as methods of their use for the treatment of psychiatric disorders and neurological diseases including extensive depression, anxiety, posttraumatic stress, paralysis, abnormal increase in appetite, symptoms of irritability of the intestines, the weakening of the immune Sinzig, addiction to the excessive use of drugs, inflammatory processes, problems of fertility.

Releasing factor corticotropin (labeled ACTH), a peptide consisting of 41 amino acids, is the primary physiological regulator selection propiomelanocortin (ROMA) from the anterior pituitary gland (J. River, et al., Proc. Nat. Acad. Sci. (USA) 80: 4851 (1983); W. Vale et al., Science 213:1394 (1981)). In addition to the endocrine functions of ACTH in the activity of the pituitary immunochemical localization of ACTH suggests that this hormone is characterized by a wide distribution in the Central nervous system outside of the hypothalamus and produces many Autonomous electro-physical and behavioral effects associated with neurotransmission and neuromodulatory processes in the brain (W. Vale et al., Rec.Prog.Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5: 3189 (1985)). There is also evidence suggesting that ACTH may also play a significant role in the response of the immune system on the physiological, psychological and immunological stress factors (J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)).

Clinical data show that ACTH may be relevant to psychiatric Russ is

It is also suggested that ACTH plays a role in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive paralysis and side amiotroficheskogo sclerosis (Lou Gehrig's disease), because they are associated with dysfunction of the ACTH-neurons in the Central nervous system, an overview is given in E. B. De Souza, Hosp. Practice 23:59 (1988).

In affective disorders or depressive disorder, the concentration of ACTH in the cerebrospinal fluid (CSF) is not taking medications individuals increases significantly (C. B. Nemero et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28: 86 (1988); M. Arato et al., Biol. Psychiatry 25:355 (1989)). In addition, the density of ACTH receptors in the anterior part of the cerebral cortex of suicide is significantly reduced, which is combined with hypersecretion of ACTH (C. B. Nemero et al., Arch. Gen. Psychiatry, 45:577 (1988)). In addition to this report reactions adrenocorticotropin (ACTH) ACTH observed in patients with depression (P. W. Gold et al., Am. J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al. New Eng. J. Med. 314:1129 (1986)). Preclinical studies in rats and nonhuman primates additionally confirm the hypothesis that the hypersecretion of ACTH may be associated with symptoms is about tricyclic antidepressants can change the level of ACTH and thus to modulate the amount of ACTH receptors in the brain (Grigoriadis et al., Neuropsychopharmacology. 2:53 (1989)).

It is also suggested that ACTH plays a role in the etiology of disorders with anxiety. Preclinical studies of behavioral reactions using the supposed antagonist ACTH-receptor and-spiral sheep ACTH (9-41) show that the antagonist produces like effects caused by the action of a tranquilizer similar to the action of benzodiazepines (C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)).

Neurochemical and endocrine research, as well as improving the process of binding the receptor to witness the interaction between ACTH and benzodiazepine tranquilizers, confirming the relationship ACTH with neurochemical and endocrine disorders. Chlordiazepoxid softens "antitransglutaminase" the effect of ACTH when conducting experiments on rats, as in testing for conflicts (K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al. , Psychopharmacology 94:306 (1988)), and acoustic tests on terror (N. R. Swerdlow et al., Psychopharmacology 88: 147 (1986)). Antagonist of benzodiazepine receptors (R015-1788), which in itself does not affect the behavior of rats in the test for conflicts, reduces the activity of ACTH depending on Ispat. Brillon et al., Psychopharmacology 94:306 (1988)).

The mechanism of action and areas of the structure responsible for therapeutic effect inherent in the action of conventional tranquilizers and antidepressants, remain unclear. However, I believe that between them there is a link in these diseases. Of particular interest are the preliminary study of the influence of antagonists of the ACTH receptor (spiral ACTH9-41) on behavioral responses, suggesting that antagonist ACTH causes effects similar to the effects of tranquilizers, qualitatively similar to the action of benzodiazepines, an overview is given in G. F. Koob and K. T. Britton. In: Contricotropin-Releasing Facor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p. 221 (1990)).

To study these specific proteins, surface receptors of cells must be selected compounds that interact with ACTH receptors in a special way, correlated with the pharmacological characteristics of this receptor. In conclusion, it should be noted that there is evidence that the connections are antagonists ACTH and compositions of the present invention, which softens the physiological reaction caused by the stress of the disease, will be useful for the treatment of depression and Saba structural formula (A)

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It is reported about the possibility of using these compounds for the treatment of asthma, allergic diseases, inflammation and diabetes in mammals.

In the PCT application WO 89/01938 described the synthesis and application of compounds of the formula (B)

< / BR>
These compounds may be useful for treatment of neurological diseases, giving the effect of renewal and restoration of nerve cells, improving and restoring the capacity for learning and memory.

In U.S. patent N 4783459 describes the application and synthesis of compounds with the following structural formula (C)

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These compounds have fungicidal activity, especially against fungal diseases of plants.

In U.S. patent N 4992438 described the application and synthesis of compounds with the following structural formula:

< / BR>
These compounds applicable as a fungicide with a broad spectrum of activity against pathogenic fungal diseases of plants.

In the patent application CIS countries 0013143 A2 describes the use and synthesis of compounds with the following structural formula:

< / BR>
These compounds are pre - and post-harvest herbicides.

In U.S. patent N 5063245 the claimed method of producing ACTH-antagonistic compounds of General formula

1-C4-alkyl, and R3can represent substituted phenyl; these compounds are useful for inhibiting the secretion of acid in the stomach.

In the EPO application EP 0588762 A1 of the claimed compounds of General formula

< / BR>
where R4can be C1-C3-alkyl, these compounds are useful as inhibitors of protein kinase C and antitumor agents. Also stated the use of these compounds for the treatment of AIDS, atherosclerosis, diseases of the cardiovascular and Central nervous system.

In the EPO application EP 336494 A2 of the claimed compounds of General formula

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where X represents NR4and R4may be a substituted or unsubstituted alkyl, these compounds are useful as herbicides.

In U.S. patent N 3988338 the claimed compounds of General formula

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where R" means phenyl, possibly substituted, these compounds have anticytokines activity.

In the EPO application EP 0563001 A1 of the claimed compounds of General formula

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These compounds are stated as applicable for the treatment of psychosis, depression and seizures.

In the EPO application EP 0155911 A1 of the claimed compounds of General formula

< / BR>
where R3means samewe the compounds of General formula

< / BR>
where R2means substituted phenyl group: these compounds are useful as antiulcer agents.

In the work of Eswaran et al., Org. Prep. Proced. Int. 24 (1): 71-3, (1992) describes the use of derivatives of 5,7-desandro as synthetic intermediates. In the work of El-Bayouki et al., J. Heterocycl. Chem., 22(3): 853-6, 1985 reported using derivatives of 5,7-desandro as synthetic intermediates.

Compounds and methods of the present invention make it possible to develop a methodology for obtaining compounds having specific affinity and is able to inhibit the action of ACTH on protein - ACTH receptors in the brain. These compounds may be useful for the treatment of various neurodegenerative, neuropsychiatric and related stress disorders such as irritability of the intestines, immune suppression, Alzheimer's disease, gastrointestinal disorders, anorexia, drug and alcohol abstinence, addiction to the excessive use of drugs, inflammatory processes, problems of fertility. Other advantages of the present invention will be clear to experts from the following description.

This is adnych. These compounds interact and have antagonistic activity towards ACTH receptors and, thus, may have a therapeutic effect in relation to psychiatric disorders and neurological diseases, including extensive depression, anxiety, posttraumatic stress and disturbance of appetite, paralysis, symptoms of irritability of the intestines, immune suppression, Alzheimer's disease, gastrointestinal disorders, drug and alcohol abstinence, addiction to the excessive use of drugs, inflammatory processes, problems of fertility.

The new compounds of the present invention comprise the compounds of formula I

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in which J represents CX1where X1represents H, halogen, C1-C6alkyl, CHO, HE or OC1-C4alkyl;

K, L are N or CX1where X1represents H, halogen or OC1-C4alkyl;

M is CR5and R5represents a C1-C6alkyl, halogen, -OC1-C4alkyl, optionally substituted by 1-3 Halogens, CN; C1-C4halogenated, C3-C6recloak/BR>-C1-C4-alkyl-OR1where R1represents H or C1-C4alkyl,

NR14R15where each R14, R15represent H or C1-C4alkyl, or

-C(=O)NR14R15where each R14, R15represents a C1-C14alkyl;

V is N;

Y is N, CH, CCN, or CR29where R29together with R4forms a 5-membered ring and a is-C(R30)= or-N=, and R30represents H or CN;

Z is N, CH or CCH3;

R4together with R29forms a 5-membered ring and a is-CH= or-N=, or represents a group selected from C1-C4of alkyl, OC1-C4-alkyl, propargyl, allyl, -CH2C3-C6cycloalkyl, -(CH2)nN(R1)2where R1is C1-C4the alkyl, and n is 1-3;

X represents halogen, halogenmethyl, -OC1-C4alkyl, CN or S(O)nC1-C4alkyl where n is 0, 1 or 2;

R1represents a C1-C4alkyl, C1-C4-alkoxy, halogen;

R3represents halogen, aryl (C1-C2haloalkyl, CHO, C1-C4alkyl, neobyazatelR8where R8is C1-C4-alkyl, C1-C4-alkoxy, optionally substituted C1-C4alkoxy; morpholinyl; thienyl; pyrrolyl; picolyl; imidazolines; phenyl, substituted C1-C4-alkyl or C1-C4-alkoxy; OR8; NR6R7; -C(= O)R9; -C(O)R25; C(OH)R25R25a; - C(=O)NR6R7; (CH2)kOR8; (CHR16R25; (CHR16)NR6R7; -CH(CO2R16)2where R16is C1-C4the alkyl, or-C(CN)(R25)(R16), where R16is H;

each of R6, R7independently represents hydrogen, with at least one of R6and R7different from H when R29and R4together denote-CH= or-N=, C3-C6cycloalkyl; -(CH2)kR13; -(CHR16)pOR8where R8represents H, C1-C4alkyl or (CH2)kR25where R25is phenyl, imidazolyl, fullam; or R6and R7together denote -(CH2)qA(CH2)r-;

R8represents a C1-C6alkyl; pyrimidinyl; pyridyl; furyl; phenyl, optionally substituted by 1-3 CH3or OCH3; (CHSUB>3; (CH2)tR22or (CH2)kR25;

R9represents a C1-C4alkoxy;

R13represents CN, C3-C6cycloalkyl or or19where R19is C1-C6by alkyl;

R16represents H or C1-C4alkyl;

R22represents C(O)R25, SR24, S(O)nR31, NR23R24or or24; each of R23and R24represents H or C1-C4alkyl;

R31represents a C1-C4alkyl;

R25is morpholinyl; tetrahydrofuryl; tetrahydroquinoline; phenyl, optionally substituted C1-C4the alkyl or alkoxy; indolyl; pyridyl; pyrazolyl; furyl; pyrimidyl; pyrazinyl; piperidinyl; pyrrolidinyl, optionally substituted C1-C4by alkyl; or piperazinil, optionally substituted C1-C4by alkyl;

R25arepresents H or R25;

A represents O; NC(=O)R17with R17being H or C1-C4by alkyl; S(O)n; C(H)(OR20) with R20which is H; CH2or NR25;

k is 1-4;

t is 1-3;

p and n are each equal 0-2;< the compounds are N-alkyl-N - arylpyrimidines General formula I

< / BR>
where Y represents CH, CCN, or N, a R1, R3, R4, X, Z, V, J, K, L, M have the meanings specified in paragraph 1 of the formula or its pharmaceutically acceptable salt.

In particular these include compounds where

R3means C1-C4-alkyl, phenyl, halogen, C1-C2-haloalkyl, NR6R7, OR8C(=O)R9C(O)NR6R7, (CH2)kOR8, NR10CH(R11)CO2R12, -(CHR16)pOR8- C(OH)(R25)(R25a), -C(CN)(R25)(R16), provided that if R25doesn't mean NH-containing ring, -C(= O)R25, -CH(CO2R16)2, NR10C(=O)CH(R11)NR10R12C1-C4-alkyl, substituted C1-C4alkoxy, C3-C6-cycloalkyl, C1-C4phenyl, substituted C1-C4-alkoxy, phenyl substituted C1-C4-alkyl, imidazolyl, 2-thienyl, 3-thienyl, morpholinyl, pyrrolidyl, J, K, L is independently chosen in each case from CX',

M means CR5,

R1, R2and R30independently chosen in each case from the series comprising hydrogen or cyano, or R1means C1-C4-alkyl;

X represents halogen, aryl, S(O)2C1-C4Alki is,

X1means hydrogen, halogen, -OC1-C4alkyl, HE, C1-C4alkyl,

R5means halo, -C(=NOR16)-C1-C4-alkyl, C1-C4-alkyl, C1-C3-haloalkyl, C1-C4-alkoxy, optionally substituted with 1-3 halogen, S(O)nC1-C6alkyl, n = 0-2, C3-C6cycloalkyl, cyano, C1-C4alkyl-OR1where R1- H or C1-C4-alkyl, C(O)C1-C4alkyl,

R6and R7independently chosen in each case from the group comprising hydrogen, C3-C6-cycloalkyl, (CHR16)pOR8,

or R6, R7together form a group -(CH2)qA(CH2)r,

R8independently chosen in each case from the series comprising hydrogen, C1-C6-alkyl, pyrimidinyl, pyridyl, furyl, (CH2)tR22, phenyl, optionally substituted by 1-3 CH3or OCH3,

-NR16(CH2)nNR6R7, -(CH2)kR25, (CH2)4-heteroaryl or (CH2)4-aryl, where heteroaryl or each aryl may be substituted for CH3,

R13independently chosen in each case from a range that includes OR19and C3is the genus, C1-C6-alkyl,

R17independently chosen in each case from the series comprising hydrogen, C1-C4-alkyl,

R19independently chosen in each case from the series, including C1-C6-alkyl,

R22independently chosen in each case from the series, including cyano, OR24, SR24, NR23R24, -S(O)nR31and C(=O)R25,

R25chosen in each case from the series comprising phenyl, optionally substituted C1-C4the alkyl or alkoxy, pyrazolyl, furyl; pyrazinyl, morpholinyl, piperazinil, optionally substituted C1-C4the alkyl, piperidinyl, pyridyl, pyrimidyl, pyrrolidinyl, optionally substituted C1-C4the alkyl,

R25a, which is independently chosen in each case from the series comprising phenyl, optionally substituted C1-C4the alkyl, pyrazolyl, furyl, pyrazinyl, piperazinil, optionally substituted C1-C4the alkyl, piperidinyl, pteridinyl, purinol, pyranyl, pyrazolidine, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, optionally substituted C1-C4the alkyl,

independently chosen in each case from 1-3.

Especially the connection UB>4alkoxy,

R3independently chosen in each case from the group comprising C1-C4-alkyl, C1-C2-haloalkyl, NR6R7, OR8C(=O)R9C(=O)NR6R7, (CH2)kOR8, - C(CN)(R25)(R16), provided that if R25does not mean NH-containing ring, C(OH)(R25)(R25a), -C(= O)R25CH(CO2R16)22-thienyl, 3-thienyl, imidazolyl, morpholinyl, pyrrolidyl,

R1a, R2and R3aindependently chosen in each case from the series comprising hydrogen, methyl,

X denotes Cl, Br, I, OC1-C6alkyl,

X1denotes hydrogen, Cl, Br, I, OC1-C6alkyl,

R5represents halo, C1-C6-alkyl, C1-C3-haloalkyl, C1-C6-alkoxy,

R6and R7independently chosen in each case from the series, including C1-C6-alkyl, (CHR16)pOR8C1-C6-alkoxy, -(CH2)kR13or R6and R7taken together form the group -(CH2)qA(CH2)r,

A stands for O, S(O)nN(C(=O)R17), C(H)(OR20), NR25,

R8independently chosen in each case from a range that includes-C1-C<4-alkyl,

R14, R15independently chosen in each case from the series comprising hydrogen, C1-C2-alkyl, R16means hydrogen;

R19means C1-C3-alkyl,

R22independently chosen in each case from a range that includes OR24, - C(= O)R25,

R23, R24independently chosen in each case from the series comprising hydrogen, C1-C2-alkyl,

R25independently chosen in each case from the series comprising phenyl, optionally substituted C1-C4the alkyl or alkoxy, pyrazolyl, furyl, 4-pyrazinyl, indolyl, morpholinyl, piperazinil, optionally substituted C1-C4the alkyl, piperidinyl, pyridyl, pyrrolidinyl, tetrahydrofuranyl, 1-tetrahydroquinoline,

R25aindependently chosen in each case from the series comprising hydrogen, phenyl, possibly substituted C1-C4the alkyl or alkoxy, pyrazolyl, furanyl, 4-pyrazinyl, indolyl, morpholinyl, piperazinil, possibly substituted C1-C4the alkyl, pyridinyl, pyrimidinyl, pyrrolidinyl, possibly substituted C1-C4the alkyl, tetrahydrofuranyl, 1-tetrahydroquinoline, and

k denotes 1-3,

p is 0-2,

q denotes 1, 2,
< / BR>
where Y represents CR29where R29together with R4form a 5-membered ring and a is-C(R30)= or-N=, a R30represents hydrogen or CN; R1, R3, Z, V, K, L, M, and X have the meanings specified in paragraph 1 of the formula

or their pharmaceutically acceptable salts.

In particular compounds, where

Z denotes CH,

R1means C1-C2-alkyl,

R3represents a C1-C4-alkyl, phenyl, halogen, NR6R7, OR8C(=O)R9C(= O) NR6R7, (CH2)kOR8, -C(OH)(R25)(R25a), -C(=O)R25, -CH(CO2R16)2substituted C1-C4-alkyl, C3-C6-cycloalkyl, phenyl-(substituted C1-C4)-alkyl, phenyl-(substituted C1-C4)-alkoxy, substituted C3-C6-cycloalkyl,

J, K, L is independently chosen in each case from a range that includes CX1,

M means CR5,

R4forms together with R29five-membered cycle and represents-CH=,

X represents Br, I, S(O)nC1-C4-alkyl, OC1-C4-alkyl,

X1represents hydrogen, Br, I, HE,

R5independently chosen in each case from a number, vklucil, C(=O)C1-C4alkyl, C(=O)NR8R15,

R6and R7independently chosen in each case from the series comprising hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, -(CH2)kR13, -(C1-C4-alkyl) phenyl, -(C1-C4-alkyl)-imidazolyl or furyl or

R6and R7together form a group -(CH2)qA(CH2)r,

A represents O, NR25or S(O)n,

R8independently chosen in each case from the series, including C1-C6-alkyl, (CH2)tR22, phenyl, optionally substituted by 1-3 CH3, OCH3, -(CH2)kR25and (CH2-heteroaryl or (CH2)t-phenyl, each of which may be substituted CH3group.

R14and R15independently chosen in each case from the series comprising hydrogen, C1-C2-alkyl,

R16independently chosen in each case from the series comprising hydrogen, C1-C2-alkyl,

R17independently chosen in each case from the series comprising hydrogen, C1-C2-alkyl,

R22independently chosen in each case from a range that includes OR24, SR24, NR23R241-C2-alkyl,

R25, which is independently chosen in each case from the series comprising phenyl, optionally substituted C1-C4is alkyl or alkoxy, pyrazolyl, 4-pyrazinyl, morpholinyl, piperazinil, optionally substituted C1-C4the alkyl, piperidinyl, pteridinyl, purinol, pyranyl, pyrazolidine, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, optionally substituted C1-C4the alkyl, tetrahydrofuranyl, tetrahydropyranyl,

R25aindependently chosen in each case from the group comprising H and C1-C4-alkyl,

R29together with R4form a 5-membered cycle and mean C(R30)=,

R30means hydrogen, cyano,

k is 1-3,

p is 0-2,

q and r is 2,

t is chosen from 1-2.

Especially among them should be allocated to the connection, where

R1denotes methyl,

R3represents C1-C2-alkyl, NR6R7, OR8C1-C2-alkyl or phenyl, substituted C1-C4by alkyl, halogen or imidazolines,

X denotes Br, I, S(O)nC1-C4alkyl, NR14R15OC1-C4alkyl,

X1represents hydrogen, Br, I, HE,
6
, R7independently chosen in each case from the group comprising hydrogen, C1-C2alkyl,

R8independently chosen in each case from the series, including C1-C2-alkyl or phenyl, possibly substituted by 1-2 groups selected from a range, including CH3, OCH3,

R14, R15independently chosen in each case from the series comprising hydrogen, C1-C2-alkyl;

R30denotes hydrogen or cyano.

A specific preferred compound is a compound selected from the group:

N-(2,4-acid)-N-methyl-4,6-dimethyl-2-pyrimidinamine:

N-(2-bromophenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-were)-N-methyl-4-morpholino-6-methyl-2-pyrimidinamine;

N-(2,4-acid)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,4-dibromophenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-ethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-tert-butylphenyl)-N-ethyl-4,6-dimethyl-2-pyridylamine;

N-(2-bromo-4-tert-butylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-trifter the mines;

N-(2,4,6-trimethoxyphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,4,6-trimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl-N-ethyl-4-morpholino-6-methyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-allyl-4-morpholino-6-methyl-2 - pyrimidinamine;

N-(2-bromo-4-n-butylphenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-n-butylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-n-butylphenyl)-N-propyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-cyclohexylphenol)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-diethyl-2-pyrimidinamine;

N-(2-bromo-4-n-butylphenyl)-N-ethyl-4,6-diethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-formylpiperazine)-6-methyl - 2-pyrimidinamine,

N-(2-bromo-4-(1-methylethyl)phenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-iodide-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-trifluoromethyl-2 - pyrimidinamine;

N-(2-bromo-4-methoxyethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-iodide-4-(1-methylethyl)phenyl)-N-ethyl-morpholino-6-methyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-m
N-(2-bromo-4-(1-methylethyl)phenyl)-N-cyclopropylmethyl-4,6-dimethyl-2 - pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-propargyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-iodide-4-(1-methylethyl)phenyl)-N-ethyl-4-thiomorpholine-6-methyl-2-pyrimidinamine,

N-(2-iodide-4-methoxyacetyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-iodide-4-methoxymethyl)-N-ethyl - 4,6-dimethyl-2-pyrimidinamine;

N-(2-iodide-4-methoxyacetyl)-N-ethyl-4-morpholino-6-methyl-2-pyrimidinamine;

N-(2-iodide-4-methoxymethyl)-N-ethyl-4-morpholino-6-methyl-2 - pyrimidinamine;

N-(2-methylthio-4-methoxymethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-dimethylamino-4-methoxymethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-methylthio-4-methoxymethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-dimethylamino-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,4-dimethylthiophenol)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-methylthio-4-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,6-dibromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,6-dibromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-thiomorpholine-2 - pyrimidinamine;

N-(2,4-diiodophenyl)-N-ethyl-4,6-dimethyl-2-PI)-N-ethyl-4-methyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(N-methyl-2 - hydroxyethylamino)-2-pyrimidinamine;

N-(2,6-dimethoxy-4-were)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

4,6-dimethyl-2-(N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethylamino)pyrimidine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-2,4-dimethoxy-6-pyrimidinamine;

2,6-dimethyl-4-(N-(2-bromo-4-(1-methylethyl)phenyl)amino)pyridine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(4-morpholinylcarbonyl) -2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(morpholinylmethyl)-2 - pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(1-piperidinylcarbonyl)- 2-pyrimidinamine;

Methyl-2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-6-methyl-4 - pyrimidinecarboxylic;

2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-N-cyclohexyl-6-methyl-4 - pyrimidinecarboxylic;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(4-methyl-1 - piperazinylcarbonyl)-2-pyrimidinamine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4,6-dimethyl-1,3,5-triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-methyl-6-(4-morpholinyl)-1,3,5 - triazine-2-amine;

N-ethyl-N-[2-iodide-4-(1-methylethyl)phenyl] -4-methyl-6-(4-timerline)-1,3,5 - triazine-2-amine;

N-ethyl-N-[2-iodide-4-(1-methylethyl)phenyl] -4-methyl-6-(4-morpholinyl)-1,3,5 - triazine-2-amine the Nile)-4,6-dimethyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-3-cyano-4-phenyl-6-methyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-4-phenyl-6-methyl-7-azaindole;

1-(2-bromo-4,6-acid)-3-cyano-4,6-dimethyl-7-azaindole;

1-(2-bromo-4,6-acid) of 4,6-dimethyl-7-azaindole;

N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-4-N,N-diethylamino-6-methyl-1,3,5 - triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4,6-sodium dichloro-1,3,5-triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4,6-dimethoxy-1,3,5-triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-imidazoline-6-methyl-1,3,5 - triazine-2-amine;

N-[2-bromo-4,6-acid)-N-ethyl-4-morpholino-6-methyl-1,3,5-triazine - 2-amine;

N-(2-bromo-4,6-acid)-N-ethyl-4-N, N-dimethylamino-6-methyl-1,3,5 - triazine-2-amine;

N-(2,4,6-trimethoxyphenyl)-N-ethyl-4-morpholino-6-methyl-1,3,5-triazine - 2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-N, N-dimethylamino-6-methyl - 1,3,5-triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-thiazolidine-6-methyl - 1,3,5-triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-benzyloxy-6-methyl-1,3,5 - triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-phenyloxy-6-methyl-1,3,5 - triazine-2-amine;

N-(2-bromo-4,6-acid)-N-ethyl-4-[4-(ATIP ethyl-1,3,5-triazine-2-amine:

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-[3-(Malone-2-yl-diethyl ether)]-6-methyl-1,3,5-triazine-2-amine;

N-(2-bromo-4,6-acid)-N-ethyl-4-(1-cyano-1-phenylmethyl)-6 - methyl-1,3,5-triazine-2-amine;

N-(2-bromo-4,6-acid) N-1-methylethyl-4-morpholino-6-methyl-1,3,5 - triazine-2-amine;

N-(2-iodide-4-dimethylhydroxylamine)-N-ethyl-4,6-sodium dichloro-1,3,5 - triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-methyl-6-(Dometic)-2 - pyrimidinamine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-methyl-6-(methylsulfinyl) -2-pyrimidinamine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-methyl-6-(methylsulphonyl)-2 - pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-methyl-6-benzyloxy-1,3,5 - triazine-2-amine;

N-(2-iodide-4-dimethylhydroxylamine)-N-ethyl-4,6-sodium dichloro-1,3,5-triazine - 2-amine;

N-[2-iodide-4-(1-methylethyl)phenyl] -N-allyl-4-morpholino-6-methyl-2 - pyrimidinamine;

N-[2-iodide-4-(1-methylethyl)phenyl]-N-ethyl-4-chloro-6-methyl-2-pyrimidinamine;

N-[2-methylthio-4-(1-methylethyl)phenyl] -N-ethyl-4-(S)-(N-methyl-2'- pyrrolidinyloxy)-6-methyl-2-pyrimidinamine;

N-[2,6-dibromo-4-(1-methylethyl)phenyl] -4-thiomorpholine-6-methyl-2 - pyrimidinamine;

N-[2-methylthio-4-(1-methylethyl)phenyl]-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-[2-methylthio-4-(1-methylethyl)phenyl]-N-ethyl-4,6-dimethyl-2-pyrimidinamine] -N-ethyl-4-thiazolidine-6-methyl-2-pyrimidinamine;

N-(2-iodide-4-methoxymethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4,6-dimethyl-2-pyrimidinamine)-2,3,4,5-tetrahydro-4-(1-methylethyl)- 1,5-benzothiazepin;

N-[2-methylsulphonyl-4-(1-methylethyl)phenyl] -N-ethyl-4,6-dimethyl-2 - pyrimidinamine;

N-[2-ethylthio-4-(1-methylethyl)phenyl]-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-ethylthio-4-methoxyaminomethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine,

N-(2-methylthio-4-methoxyaminomethyl)-N-ethyl-4,6-dimethyl-2 - pyrimidinamine;

N-(2-methylsulphonyl-4-methoxyaminomethyl)-N-ethyl-4,6-dimethyl-2 - pyrimidinamine;

N-(4-bromo-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-ethyl-2-methylthiophenyl)-N-(1-methylethyl)-4,6-dimethyl-2-pyrimidinamine;

N-(4-ethyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-[2-methylthio-4-(N-acetyl-N-methylamino)phenyl] -N-ethyl-4,6-dimethyl-2 - pyrimidinamine;

N-(4-carboethoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-methoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-cyano-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-acetyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-propionyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-[4-(1-methoxyethyl)-2-methylthiophenyl] -N-ethyl-4,6-dimethyl-2-PI is)-2-methylthiophenyl] -N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-4-formyl-6-methyl-2-pyridylamine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-hydroxy-ethoxymethyl-6-methyl-2 - pyrimidinamine;

N-(2-bromo-6-hydroxy-4-methoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(3-bromo-4,6-acid)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,3-dibromo-4,6-acid)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,6-dibromo-4-(ethoxy)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-4,6-dimethyl-7-azaindole:

1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-4-phenyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-6-methyl-4-phenyl-7-azaindole:

1-(2-bromo-4,6-acid)-3-cyano-4,6-dimethyl-7-azaindole;

1-(2-bromo-4,6-acid) of 4,6-dimethyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-6-chloro-3-cyano-4-methyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-6-chloro-4-methyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-4-chloro-3-cyano-6-methyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-4-chloro-6-methyl-7-azaindole;

N-(2-bromo-6-methoxypyridine-3-yl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(3-bromo-5-methylpyridin-2-yl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(6-methoxypyridine-3-yl)-N-ethyl-4,6-dimethano-4-(1-methylethyl)phenyl]-N-ethyl-4-[N-(2-furylmethyl-N-methylamino] carbonyl-6-methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-[(4,4-ethylenedioxythiophene) carbonyl]-6-methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-(4-oxopiperidine)carbonyl-6 - methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-(4-oxopiperidine)methyl-6 - methylpyrimidine hydrochloride;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-(imidazol-1-yl)methyl-6 - materialization;

N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-4-[3-(methoxyphenyl)methoxymethyl] -6 - methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-(2-thiazolyl)carbonyl-6 - methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-(2-imidazolyl)carbonyl-6 - methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-(5-indolocarbazole)-6 - methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-(4-forefeel)carbonyl-6 - materialization;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-carboxy-6 - methylpyrimidine:

N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-4-acetyl-6-methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-(hydroxy-3-pyridylmethyl)-6 - methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-[4-(methoxyphenyl)-3 - pyridylcarboxylic]-6-methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-(3-pyrazole is in;

N-[2-[bromo-4-(1-methylethyl)phenyl]-N-ethyl-4-[2-(4-tetrazolyl)-1 - methylethyl]-6-methylpyrimidine;

2-(N-[2-bromo-4-(2-propyl)phenyl]amino-4-carbomethoxy-6-methylpyrimidin;

2-(N-[2-bromo-4-(2-propyl)phenyl]-N-ethylamino)-4-carbomethoxy-6 - methylpyrimidin;

2-(N-[2-bromo-4-(2-propyl)phenyl]-N-ethylamino)-6-methylpyrimidin-4 - morpholinoethyl;

9[2-bromo-4-(2-propyl)phenyl]-2-methyl-6-morpholinopropan;

9[2-bromo-4-(2-propyl)phenyl]-2-methyl-6-morpholino-8-agapurin;

1[2-bromo-4-(2-propyl) phenyl]-6-methyl-4-morpholino-5,7-diakanda;

2-N-[2-bromo-4-(2-propyl)phenyl)-N-ethylamino-4-(morpholinomethyl)-6 - methylpyrimidin.

The object of the present invention are also pharmaceutical compositions containing a pharmaceutically acceptable carrier and a therapeutically effective amount of one of the above compounds.

Connection, which allows you to get the present invention (especially, labeled compounds of the present invention can also find application as standards and reagents for determining the ability of a potential pharmaceutical to contact ACTH receptors. These compounds can be used in commercial kits comprising the compounds claimed in the present and shall be used as antagonists releasing factor corticotropin and for the treatment of various disorders, state of excitement, anxiety or depression.

This invention relates also to methods of treatment of anxiety or depression by introducing into the body an effective amount of the compounds of formula (I) above. Under a therapeutically effective amount of understand the amount of compounds of the present invention, effective to counteract abnormal level of ACTH or to treat symptoms of agitation, anxiety or depression, inherent in the body.

All of the compounds described herein may have centers of asymmetry. The present invention includes all chiral, diastereomeric and racemic forms. The compounds described herein can be characterized by a geometric isomerism olefinic double bond, the C=N double bond and others, and all such stable isomers are the subject of the present invention. It should be noted that some compounds contain asimmetricheskii substituted carbon atom and can be isolated in optically active or racemic form. Specialists are well aware of how to obtain optically active forms as the separation of the racemate, or by synthesis using optically active starting compound. It is also clear that CIS - and transitkniga isomer. The invention includes all chiral, diastereomeric and racemic forms, as well as geometric isomers, unless the specific stereochemistry or isomeric form is not specified.

In the case when a variable value (for example, R1-R10, m, n, A, w, Z and so on ) is specified more than once in the designation of the Deputy or the formula (I), or any other given here to the formula, the definition of the variable in each case depends on its definition in any other case. So for example,- NR8R9each of the substituents may be independently selected from a specific list of possible substituents R8and R9. Combinations of substituents and/or variables are permissible only if such combinations provide for a stable connection.

The term "alkyl" refers here both branched and linear chain aliphatic hydrocarbon groups having the specified number of carbon atoms. Specifying "quinil" means a hydrocarbon group, branched or linear configuration, which may have one or more hydrocarbon bond, which can be in any stable position along the chain, such as ethinyl, propinyl, etc. to Ocealssweetle one or more triple carbon bond, which can be in any stable position along the chain, such as ethynyl, PROPYNYL, and so on, the Indication "haloalkyl" means both branched and linear saturated aliphatic hydrocarbon group containing a certain number of carbon atoms, substituted by one or more halogen; "alkoxy" corresponds to the alkyl group with a specific number of carbon atoms attached through an oxygen bridge, "cycloalkyl" means a saturated ring groups, including mono-, bi - or polycyclic ring system, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. "Halo" or "halogen" when used here refers to the fluorescent, chloro, bromo and iodide.

Specifying "aryl" or "aromatic residue" means phenyl, biphenyl and naphthyl.

The term "heteroaryl" means unsubstituted, monosubstituted or disubstituted 5-, 6-, or 10-membered mono - or bicyclic aromatic ring, which may possibly contain 1 to 3 heteroatoms selected from the group consisting of O, N and S and is assumed to be active.

Heteroaryl in accordance with this definition include, but are not limited to, the following: 2-, 3 - or 4-pyridil, 2 - or 3-furyl; 2 - and 4-ethenolysis; 2 - or 3-pyrrolyl; 1 or 2 - or 3-indolyl or 4 - or 5-oxazolyl, 2-benzoxazolyl; 2 - or 4 - or 5-imidazolyl; 1 - or 2-benzimidazolyl; 2 - or 4 - or 5-isothiazolin; 3 - or 4-pyridazinyl; 2 - or 4-or 5-pyrimidinyl; 2-pyrazinyl; 2-triazinyl; 3 - or 4-cinnoline; 1-phthalazine; 2 - or 4-hintline or 2-oxasolinone cycle. Especially preferred are 2-, 3 - or 4-pyridyl; 2 - or 3-furyl; 2 - or 3-thiophenyl; 2-, 3 - or 4-chinoline; or 1-, 3 - or 4-ethenolysis.

Specifying "carbocycle" or "carbocyclic residue" means any stable 3-7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic or tricyclic, or up to 26-membered polycyclic carbon ring system, each of which may be saturated, partially unsaturated or aromatic. Examples of such carbocycles include (but are not limited to) such carbocycle as cyclopropyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, substituted or tetrahydronaphthyl (tetralin).

The term "heterocycle" means a stable 5 to 7-membered monocyclic or bicyclic 7-10-membered bicyclic heterocyclic ring system which is saturated or ninasimone and which contains carbon atoms and from 1 to 4 heteroatoms, n nitrogen, may be Quaternary, including any bicyclic group, such that any of the above heterocyclic ring system attached to benzene ring. The heterocyclic ring can be attached through its Deputy to any heteroatom or carbon atom with the formation of a stable structure. Heterocyclic ring systems described herein may be substituted at the carbon atom or nitrogen, if the resulting compound is stable. Examples of such compounds include (but are not limited to, the following: pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophene, indolyl, indolinyl, chinoline, ethenolysis or benzimidazolyl, piperidinyl, 4-piperidinyl, pyridinyl, 2 - pyrrolidin-4-piperidinyl, pyrrolidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroisoquinoline, decahydroquinoline or octahydronaphthalene, azocines, triazinyl, 6H-1,2,5-thiadiazine, 2H, 6H-1,5,2-detainer, thiophenyl, thianthrene, furanyl, pyranyl, isobenzofuranyl, chromanol, xantener, 2H-pyrrolyl, pyrrole, imidazole, pyrazolyl, isothiazolin, isoxazol, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, ISO is l, honokalani, cinnoline, pteridine, 4aH-carbazolyl, carbazolyl, beta-carbolines, phenanthridines, acridines, pyrimidinyl, phenanthrolines, phenazines, phenothiazines, furutani, phenoxazines, isopropanol, bromanil, pyrrolidinyl, pyrrolyl, imidazolidinyl, imidazolyl, pyrazolidine, pyrazoline, piperidine, piperazinil, indolinyl, isoindolyl, hinokitiol, morpholinyl or oxazolidinyl.

Among the heterocycles are also substituted rings and spiraeoideae containing, for example, the above cycles.

The term "substituted" when used here means that one or more hydrogen atoms of these fragments substituted with a choice of a specific group, provided that you do not exceed the normal valency of the atom and that the substitution leads to the formation of stable compounds. If the Deputy is keto (namely, = O), then replaced by two hydrogen atoms attached to the atom specified section.

By "stable compound" or "stable structure" understand the connection that is stable enough to be isolated with the necessary degree of purity from the reaction mixture and can be used in effective therapeutic genericism synthesis to protect the amino - or carboxyl groups. Protective group AMINOPHENYL includes the groups listed in the book Green and Wuts, "Protective Groups in Organic Synthesis" John Wiley & Sons, New York (1991) and "The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), which is given here as a reference. Can be used any known protection of amino groups. Examples of protective groups AMINOPHENYL includes (but is not limited to, the following: 1) acyl protective groups such as formyl, TRIFLUOROACETYL, phthalyl and n-toluensulfonyl, 2) aromatic protective group of the urethane type, such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyl 1-(p-biphenyl)-1-methylethanolamine and 9 - fluorenylmethoxycarbonyl (Fmoc), 3) aliphatic protective group of the urethane type, such as tert-butyloxycarbonyl (Vos), etoxycarbonyl, diisopropylperoxydicarbonate and allyloxycarbonyl; 4) cycloalkyl protective group of the urethane type, such as cyclopentanecarbonyl and adamantanecarbonyl; 5) protective group of the alkyl type, such as triphenylmethyl and benzyl: trialkylsilyl, such as trimethylsilyl; 7) tiradera, including phenylthiocarbamyl and datasection.

The term "amino acid" here means an organic compound containing as a basic amino group, and Kylie amino acids, and amino acids that occur in nature in free or bound form, but not part of the protein. The term includes modified and rare amino acids, such as for example, described in Roberts and Vellaccio (1983) The Peptides. 5:342 - 429, listed as references. Modified and rare amino acids, which are used in accordance with this invention, include, but are not limited to) the following: D-amino acids, hydroxylysine, 4-hydroxyproline, N-Cbz-substituted amino acids, ornithine, 2,4-diaminopentane acid, homoarginine, norleucine, N-methylaminomethyl acid, nafcillin, phenylglycine-phenylpropan, tert-leucine, 4-aminocyclohexanol, N-methyl-norleucine, 3,4-dihydropyran, N,N-dimethylaminomethyl, N-methylaminophenol, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, TRANS-4-(aminomethyl)-cyclohexanecarbonyl acid, 2,3 - and 4-(aminomethyl) benzoic acid, 1-aminocyclopentane acid, 1-aminocyclopropane acid and 2-benzyl-5-aminopentanoic acid.

The term "amino acid residue" as used here means a portion of amino acids (as defined here), which is present in the peptide.

The term "peptide" means here with the pmin "peptide" also includes peptide, and ones components, such as pseudopeptide or mimicries peptide residues or other diaminotoluene components. Such compounds containing both peptide and ones components can be referred to as "peptide analogue".

The term "peptide bond" means a covalent amide fragment formed by the interaction of the carboxyl group of the amino acid and amino group, secondary amino acids with elimination of a molecule of water.

Specifying "pharmaceutically acceptable salt" refers here to the derived declared here compounds in which the compound of formula (I) is modified by the action of acid or alkali with the formation of salts of the compound (1). Examples farmatsevticheskii acceptable salts include, but are not limited to, mineral or organic salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids, etc.

"Prodrug", as discussed here, are any covalently bound carriers that release the active source drug of formula (I) in vivo when administered to a mammal. Prodrugs of compounds of formula (I) are prepared by modifying funkadelala with the formation of the starting compound (1) or under normal handling, or in vivo. Prodrugs include compounds of formula (I), in which hydroxy, amino or sulfide group is associated with any group in such a way that when administered to a mammal fission occurs with the formation of free hydroxyl, amino or sulfhydryl group, respectively. Examples of prodrugs include (but are not limited to) acetate, formatted, benzoate derivatives of alcohol and amine functional groups of the compounds of formula (I) and similar.

Pharmaceutically acceptable salts of the compounds of the present invention can be obtained by the interaction of the free acid or basic forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or mixtures thereof, in General, the preferred non-aqueous environment, such as ether, ethyl acetate, ethanol, isopropanol, list of suitable salts can be found in Remington''s Pharmaceutical Science, 17th ed. Mack Publishing Company, Easton, PA (1985), p. 1418 listed as references.

Synthesis of

New substituted-2-pyridylamine, substituted triazine, substituted pyridine and substituted anilines of the present invention can be obtained in accordance with the General schemes provided in order to be received, as shown in figure 1. 2-Hydroxy-4,6-dialkylamides translated into the corresponding derivative (III) with a suitable tsepliaeva group in 2-position, such as Cl, Br, SO2CH3, OSO2CH3or OSO2C6H4-CH3or OSO2C6H4-CH3or SCH3or by treatment with phosphorus oxychloride (POCl3), oxybromide phosphorus (POBr3), methanesulfonamide (MSCl), n-toluensulfonate (TSCl) or thiamethoxam sodium, possibly with subsequent oxidation with hydrogen peroxide, gaseous chlorine or organic percolate, such as m-chloroperbenzoic acid, respectively. It is derived interacts with the appropriate 2,4-substituted aniline (IV) high-boiling solvent, such as for example, ethylene glycol, methoxyethoxymethyl and others, or an aprotic solvent such as tetrahydrofuran, dioxane, toluene, xylene, N,N-dimethylformamide, it is possible (optional) to accelerate in the presence of a base, preferably such as sodium hydride (NaH), diisopropylamide lithium (LDA).

The addition products (V) is then treated with base, such as NaOH or LDA in an aprotic solvent such as tetrahydrofuran (THF) or N,N - dime is ω R4L1such as alkylated, mesilate or tosylate to obtain the corresponding alkylated product of formula (I).

The compound of formula (I), where V and Y is N, a Z, J, K and L are all equal CH, can be obtained as shown in scheme 2. Substituted aniline (VI) is transformed into the corresponding guanidine salt (VII) the processing of an appropriate reagent, such as cyanamide.

Guanidine salt (VII) interacts with the diketone (VII) in the presence of a base such as potassium carbonate (K2CO3) in N,N-dimethylformamide (DMF) or in an alcohol solvent in the presence of the corresponding alkoxide to obtain the corresponding pyrimidine (IX). This compound is then alkylate and get (X), the compound of formula (I), where X1- hydrogen, under conditions identical to the conditions shown in scheme 1.

The compounds of formula (I), where V and Y represent N, a Z, J, K and L are all equal to CH and R3- NR6R7can be obtained as shown in scheme 3.

Treatment of 2,4-d sodium dichloro-6-alkylpyridine (XI) primary or secondary amine in the presence of nucleophilic base, such as trialkylamine, allows you to selectively obtain the corresponding 4-substituted amino-adduct, which, in its oulanem corresponding pyrimidinamine (XIII). This compound is then alkylate in the conditions shown in schemes 1 and 2.

The compound of formula (I), where J, R, and L represents CH and Z is CR2and V and Y is N, can be obtained using the method shown in scheme 4. Salt guanidine (XII) interacts with Betaferon (XV) in the presence of a base such as alkoxide in the corresponding alcohol solvent with the formation of the adduct (XVI).

Processing hydroxyl groups of the adduct (XVI) or POCl3, POBr3, metaalgorithm, n-toluensulfonate or anhydride of tricresylphosphate network (XVII), where L represents tsepliaeva group and is accordingly Cl, Br, J, OMs, OTs or Otf. Tsepliaeva group L of the compound (XVII) is removed with the help of a nucleophile, such as NR6R7, OR6, SR6CN or organic compound of lithium, magnesium, sodium, potassium, alkyl-cuprate or, in General, the ORGANOMETALLIC reagent with the formation of the corresponding adduct (IX), which is then alkylate under standard conditions and receive (XVIII).

The compounds of formula (I) which are substituted in the second position of the phenyl ring, can be obtained as shown in scheme 5.

The compound of formula (I), where X is not is, the de X is bromine or hydrogen, with metallorum agent, such as H-BuLi or tert-BuLi in an aprotic solvent, mainly ether or tetrahydrofuran, leads to the formation of the corresponding 2-lithium derivative (X= Li, do not emit), which then reacts with an electrophile, such as chloride, iodine or trimethylolpropane with the formation of the corresponding 2-substituted product (XIX). These derivatives can also join catalyzed by palladium reaction accession, well known in the art, synthesizing compounds of the present invention.

The compounds of formula (I), where Z, K, L are all equal to CH and R4- ethyl, can be obtained as shown in scheme 6. The subsequent addition/re-oxidation alkyllithium 2-chloropyrimidine can lead to the intermediate product (XXII), where R1and R3can be independent from each other. The substitution of chlorine suitable nitrogen-containing nucleophile, such as aniline, in conditions similar to those shown in scheme 1, with subsequent attachment of the group R4the alkylation according to the method similar to those shown in schemes 1 and 2 may lead to the formation of compounds of the present invention.

The compounds of formula (I), where Z presin (XXIII), the synthesis of which is described in J. Amer. Chem Soc. 77:2447 (1956) can interact with substituted aniline (IV), in the same way as shown in scheme 1. Similarly, 2,4-d sodium dichloro-6-mailtrain, which can be obtained according to the method specified in U.S. patent 3947374, can connect with substituted aniline (IV) education (XXIV), where R3- chlorine. Nucleophilic attach a proton or an aprotic solvent provides for a number of substituents in this position (XXV).

Alkylation of the secondary amine, as described previously, leads to a triazine derivative of the formula (I).

Compounds in which the radical R3is carboxypropanoyl, synthesized according to scheme 8. Pyrimidine ether of the formula (XXVI), which is produced well-known from the literature method Budesinsky and Roubinek., Collection. Chech. Chem. Comm. 26: 2871-2885 (1961) is reacted with an amine of formula (IV) in the presence of an inert solvent with the formation of intermediate compounds of formula (XXVII). The group of inert solvents include lower alkalemia alcohols containing from 1 to 6 carbon atoms, dialkyl ethers containing from 4 to 10 carbon atoms, cyclic ethers containing from 4 to 10 carbon atoms (mainly dioxane), dialkylated amides (mainly N-organic, diallylsulfide (mainly dimethyl sulfoxide), hydrocarbons containing from 5 to 10 carbon atoms, and aromatic hydrocarbons containing from 6 to 10 carbon atoms.

The compounds of formula (XXVII) is treated with base and a compound of formula R4X, where X is halogen (mainly chlorine, bromine or iodine) in an inert solvent. Such bases include tertiary amines, hydrides of alkali metals, preferably sodium hydride, aromatic amines (predominantly pyridine) or carbonates or alkoxides of the alkali metal. The choice of inert solvent should be based on the choice of the basis (J. March, Advanced Organic Chemistry (New York: J. Wiley and Sons., 1985, pp. 364-366, 412; H. O. House. Modern Synthetic Reactions (New York: W. A. Benjamin Inc., 1972, pp. 510-536). The group of solvents include lower alkalemia alcohols containing from 1 to 6 carbon atoms, lower alkanolamine (mainly acetonitrile), dialkyl ethers containing from 4 to 10 carbon atoms, cyclic ethers containing from 4 to 10 carbon atoms (mainly tetrahydrofuran or dioxane), dialkylamide (mainly N,N-dimethylformamide), cyclic amides (mainly N-organic, diallylsulfide (mainly dimethyl sulfoxide), uglevodoroy formula (XXVIII) can be transformed into an acid of formula (XXIX) acid or basic hydrolysis. (J. March, Advanced Organic Chemistry, J. Wiley and Sons, New York (1985), pp. 334-338), or processing salt of an alkali metal (mainly LiI or NaCN) in the presence of an inert solvent at temperatures of from 50 to 200oC (mostly from 100 to 180oC) as described in (Mc Murray, J. E. Organic Reactions, Dauben, W. G. et al. eds. J. Wiley and Sons, New York (1976), vol. 24, pp. 187-224). Inert solvents include dialkylamide (mainly N,N-dimethylformamide), dialkylacrylamide (mainly N,N-dimethylacetamide), cyclic amides (mainly N-organic and diallylsulfide (mainly dimethyl-sulfoxide) or aromatic amines (predominantly pyridine). Acid of the formula (XXIX) can be processed with a halogenation agent to obtain a halide, which can be selected or unselected, and subsequent interaction with the amine of the formula HNR6R7in the presence or absence of an inert solvent, with or without the use of reason, as is known from the literature (J. March, Advanced Organic Chemistry (New York: J. Wiley and Sons, 1985, pp. 370-373, 389) to give amides of formula (XXX). Halogenation agents include SOCl2, (COCl)2, PCl3, PCl5, POCl3. Inert solvents include lower hydrocarbons containing from 1 to 6 carbon atoms and carbon (mainly dioxane) or aromatic hydrocarbons, containing from 6 to 10 carbon atoms. Includes trialkylamine or aromatic amines (predominantly pyridine). Or esters of the formula (XXVIII) can interact with amines of the formula HNR6R7in the presence or absence of an inert solvent, with or without the use of reason, as is known from the literature (J. March. Advanced Organic Chemistry (New York: Wiley and Sons, 1985, pp. 370-373, 389) to give amides of formula (XXX). Solvents include lower alkalemia alcohols containing from 1 to 6 carbon atoms, lower alkanolamine (mainly acetonitrile), dialkyl ethers containing from 4 to 10 carbon atoms, cyclic ethers containing from 4 to 10 carbon atoms (mainly tetrahydrofuran or dioxane), dialkylamide (mainly N,N-dimethylformamide), dialkylacrylamide (mainly N, N-dimethylacetamide), cyclic amides (mainly N-organic, diallylsulfide (mainly dimethyl sulfoxide), hydrocarbons containing from 5 to 10 carbon atoms, and aromatic hydrocarbons, containing from 6 to 10 carbon atoms. Suitable bases include tertiary amines, hydrides of alkali metals (mainly sodium hydride), aromatic amines, (becoming allivaudi agent in an inert solvent to obtain an amine of formula (XXXI). Suitable reducing agents include, but are not limited to) aluminiumhydride alkali metals, mainly alumoweld lithium, borhydride alkali metals, especially lithium borohydride, tralkoxydim alkali metals (such as tri-tert-butoxyaniline lithium), dialkylaminoalkyl (such as diisobutylaluminium), boron, dealivery (such as digitalriver), trialkylborane alkali metals (such as triethylborohydride lithium). Suitable inert solvents include lower alkalemia alcohols containing from 1 to 6 carbon atoms, ether solvents such as diethyl ether or tetrahydrofuran), aromatic and not aromatic hydrocarbons containing from 6 to 10 carbon atoms. The reaction temperature recovery lies in the range of from -78 to 200oC, mostly from 50 to 120oC. the Choice of a suitable reducing agent and solvent are well understood specialists and shown in the above-cited work of March (pp. 1093-1110).

Figure 9 shows the chemical reactions leading to the formation of compounds of formula (XXXIII). Esters of formula (XXVIII) or acid of the formula (XXIX) can be treated regenerating agent in entranceways this) alumoweld alkali metals, mainly alumoweld lithium, borhydride alkali metals (mainly lithium borohydride), trielaxhillshire alkali metals (such as tri-tert-butoxyaniline), borhydride alkali metals (mainly lithium borohydride), trielaxhillshire (such as, three-tertbutoxycarbonyl), dialkylaminoalkyl (such as diisobutylaluminium hydride), boron, dealivery (such as vitaminbody), trialkylborane alkali metals (such as triethyl-lithium borohydride).

Inert solvents include lower alkalemia alcohols containing from 1 to 6 carbon atoms, ether solvents such as diethyl ether or tetrahydrofuran), aromatic and non-aromatic hydrocarbons containing from 6 to 10 carbon atoms. The temperature may lie in the range of from about -78 to 200oC, mostly from 50 to 120oC. the Choice of reducing agent and solvent known to the expert and described in the previously cited work, March (pp. 1093-1110).

Alcohols of formula (XXXII) can be converted into esters of formula (XXXIII) by treatment with a base and a compound of formula R8X, where X is halogen. The Foundation, which can be used for e is arbonate alkali metals, mainly potassium carbonate, dialkylamide alkali metals, mainly diisopropylamide lithium bis- (trialkylsilyl) amides, predominantly bis-(trimethylsilyl)-amide, alkali alkali metals (such as utility), alkoxides of alkali metals (such as ethoxide sodium), halide of Akilov alkaline-earth metals, such as methylmagnesium, trialkylamine (such as triethylamine or di-isopropylaniline), polycyclic diamines such as 1,4-diaza-bicyclo [2,2,2] octane or 1,8-diazabicyclo-[5,4,0, ] undecan or Quaternary ammonium salt (such as Triton). The choice of inert solvent should be consistent with the choice of the basis (J. March. Advanced Organic Chemistry (New York: J. Wiley and Sons, 1985) p. p. 255-446; H. O. House, Vjdern Synthetic Reactions (New York: W. A. Benjamin Inc., 1972, p.p. 546-553).

Suitable solvents include lower alkalemia alcohols containing from 1 to 6 carbon atoms, dialkyl ethers containing from 4 to 10 carbon atoms, cyclic ethers containing from 4 to 10 carbon atoms, preferably tetrahydrofuran or dioxane, dialkylamide, mainly N, N-dimethylformamide, dialkylacrylamide, mainly N, N-dematiaceae, cyclic amides, mainly N-organic, hydrocarbons containing from 5 on the side the compounds of formula XXII can be converted into compounds of formula (XXIV), where Y is halide, arylsulfonate (mainly n-toluensulfonate), alkylsulfonate (such as methanesulfonate), halosulfuron (mainly trifluoromethyl-sulfonyloxy) by reaction with a halogenation agent, or sulfonium agent. Suitable halogenation agents include (but are not limited to) SOCl2, PCl3, PCl5, POCl3Ph3P-CCl4Ph3P-CBr4Ph3P-CBr2Ph3P-I2, PBr3, PBr3. The choice of halogenation agent and reaction conditions well known in the art, the above link to work March,..., pages 382-384.

Sulfonylurea agents include (but are not limited to) (lower alkyl) sulphonylchloride, mainly methanesulfonyl-chloride (lowest haloalkyl). The anhydride of sulfonic acids, mainly anhydride of triftoratsetata, phenyl or alkyl substituted phenylsulfonylacetate, mainly n-toluensulfonate.

For sulfonylurea or halogenation may be needed basis, as is known from the literature (the above link to March,..., page 1172, 382-384). Such grounds include t the NGOs pyridine), or carbonates or alkoxides of alkali metals. Solvents for carrying out the halogenation or sulfating should be inert in the reaction conditions, as is known from the literature. Such solvents include lower kalogeraki (mainly dichloroethane) or esters (mainly tetrahydrofuran or dioxane). Intermediates of formula (XXIV) can then be converted into compounds of formula (XXIII) by treatment with a compound of the formula R8OH in the presence of a base or without a base in an inert solvent (reference work March,..., pages 342-343). Such grounds include hydrides of alkali metals, preferably sodium hydride, carbonates of alkali metals, especially potassium carbonate, dialkylamide alkali metals, mainly diisopropylamide lithium bis-(trialkylsilyl) amides of alkali metals, predominantly bis-(trialkylsilyl) amide sodium, alkali alkali metals (such as n-utility), alkoxides of alkali metals (such as ethoxide sodium), halide of Akilov alkaline-earth metals, such as methyl magnesium bromide, trialkylamine (such as triethylamine or diisopropylethylamine), polycyclic diamines such as 1,4 diazabicyclo [2,2,2] octane or 1,8-giacobini the e alcohols, containing from 1 to 6 carbon atoms, dialkyl ethers containing from 4 to 10 carbon atoms, cyclic ethers containing from 4 to 10 carbon atoms, preferably tetrahydrofuran or dioxane, dialkylamide, mainly N,N-dimethyformamide, dialkylacrylamide, mainly N, N-dimethylacetamide), cyclic amides, mainly N-organic, hydrocarbons containing from 5 to 10 carbon atoms or aromatic hydrocarbons containing from 6 to 10 carbon atoms. Intermediate compounds of formula (XXXIII) can be obtained from intermediates of formula (XXXII) by reaction with triarylphosphines (mainly triphenylphosphine), di-(lower alkyl) azodicarboxylate and the compound of the formula R8OH in the presence of an inert solvent, as described previously (Mitsunobo Oh, Synthesis, 1:1-28 (1981)).

The compounds of formula (XXXI) can be obtained by treating compounds of formula (XXXIV) with a compound of the formula HNR6R7in the presence or in the absence of a base in an inert solvent (scheme 9). Suitable base and an inert solvent can be the same as used for the conversion of compound (XXVIII) in the compound (XXX) in accordance with scheme 8.

The compounds of formula (I), which is hydrated pyrimidine (XXXV), the synthesis of which is described in an Ear. J. Med. Chem. 23: 60 (1988), can interact with substituted aniline (IV) similarly, as shown in figure 1. Treatment of the hydroxy groups of compound (XXXVI) as POCl3, POBr3n-toluensulfonate and anhydride of triftoratsetata network (XXXVII), where L is tsepliaeva group. Alkylation under standard conditions leads to (XXXVIII). Group L of the compound (XXXVIII) is substituted by a nucleophile, such as NR6R7, OR6, SR6CN or ORGANOMETALLIC reagent with the formation of the corresponding adduct (XXXIX).

The compounds of formula (I), where X1- allylmercaptan or modified allylmercaptan can be obtained under the conditions presented in figure 11.

Processing of the corresponding ortho-functional aniline XXXIX substituted 2-mercaptopyrimidine XL in the presence of a base such as potassium carbonate, sodium carbonate, alkali metal alkoxide, potassium hydride, sodium or lithium, dialkylamide lithium, sodium or potassium or an alkaline metal in the presence of copper powder or copper salts, leads to the corresponding allsolid XLI, which is subjected to the rearrangement of Smiles treatment in a strong acid, such as HCl, HBr, HI, sulfuric, fosforylation reductant, such as borohydride sodium, and alkylate the sulfur atom with a suitable alkylating agent, such as alkylhalides, toilet or mesilate. Regrouping XLI can be carried out using a strong base such as lithium hydride, sodium or potassium, dialkylamide lithium, sodium or potassium or lithium metal, sodium or potassium hydroxide, in a suitable solvent, such as decahydronaphthalene, xylene, high boiling alcohols, dimethylformamide, dimethylsulfoxide, dematiaceae, N-organic. The product of the rearrangement can be selectively alkylated on the sulfur atom using a base such as potassium carbonate, sodium or lithium, potassium alkoxide, sodium or lithium, or trialkylamine, and a suitable alkylating agent, such as described above. Alkylsulfate may be further alkylated on the nitrogen atom in conditions similar to those described above to obtain compound XLV.

The compounds of formula (I), where R3represents (CH2)kOR8and R8-(CH2)tC(= O) OR24, (CH2)tC(=O) NR6R7or (CH2)tNR6R7can be obtained according to scheme 12.

Connection XLVII, XLVIII and XLIX get using the quality of the produce product, described in example 26, 16, 17, respectively.

New 7-azaindole of the present invention receive in accordance with the following scheme 13. Potassium salt of formulaction treated with the appropriate substituted aniline L and get the LI. This compound undergoes base catalyzed cyclization and turns into a 1-aryl-2-amino-4-cyanoprop LII. Reaction with a suitable 1,3-dicarbonyl compound leads to the target 7-azaindole LIII.

Nitrile Deputy connection LIII, 3-position can be easily removed by heating under reflux for 3-cyanocobalamine with 65% sulfuric acid. At the 3-position then enter another Deputy halogenoalkanes or nitration. The restoration of the nitro group gives 3-aminosubstituted.

Or nitrile group can be converted into the required L-groups according to the method described in Comprehensive Organic Transformation, by Richard C. R. Lavock, VCH Publishers, Inc. New York. New York 1989. For example, the nitrile group can be restored diisobutylaluminium hydride to form a 3-aldehyde. 3-Aldehyde can be recovered through hydrazone under the reaction conditions of the wolf-Kishner (CON hot diethylene glycol) with the formation of compounds, where L = methyl. Then aldegonda and tert-butoxide sodium in tetrahydrofuran (Wittig reaction). Recovery etinilnoy groups gives L=CH2CH3and can be done by hydroabrasive-protoanalysis (J. Am.Chem.Soc. 81:4108 (1959)).

In accordance with the circuit 13 receives the mixture of isomers, which can then be separated. In some cases, the preferred isomer get with a lower output. In these cases, to obtain the preferred isomer can be used in scheme 14. Intermediate compound LII treated with a suitable acyl - or aroyl-acetophenon or when heated or in conditions of acid catalysis with the formation of 6-hydroxycodone LV. Connection LV transferred to 6-chloromethylene LVI and decibelios with the formation of compound LVII. When necessary, the substituents R1other than chloro, chloropropyl can be substituted by other substituents. For example, treatment of compound LVII alkyl Grignard reagent gives compound LVIII, where R1= alkyl. Heating with a primary or secondary amine can lead to the formation of compound LVIII, where R1= amino.

Scheme 15 illustrates another approach to obtaining the compounds of the present invention. Intermediate compound LII can be treated with a suitable allaalalallalalaallala in ustvennye. Connection LXa can be oxidized m-chloroperoxybenzoic acid with the formation of N-oxide LXI. Heating of compound LXI with POCl3leads to the formation of compound XIIa, which can be decamillionaire in connection LXIII.

Compound LXIV, where R3- aminosalicylic, can be synthesized by heating LXIII with the appropriate amine; where R3= alkoxide, by heating metalloid in the presence LXIII, where R3means aryl - by treating compound LXIII airborne acid in the presence of tetrakis (triphenylphosphine) palladium (TTR) and sodium carbonate, and where R3= alkyl, alkenyl, aralkyl and cycloalkyl, compound LXIII can interact with a suitable ORGANOTIN reagent, in the presence of TTR.

Compound LXIV, where R3= the nitro-group, can be obtained by nitration LXI, decamillionaires and restoring N-oxide compound of trivalent phosphorus, such as triethylphosphite.

Connection LXb may be substituted in position 6 by using the methods described for replacement of LXa.

New azobenzenes of the present invention can be obtained, as shown in figure 16, where R29means nitrogen. Connection L and LXV can vzaimodeystviya of the nitro group with tin chloride may lead to the formation LXVII, which can be translated in LXVIII.

Purines present invention can be obtained, as shown in schemes 17 and 18.

Connections L and LXIX (J. Heterocyclic Chem. 28: 465 (1991)) can be heated in the presence of a base such as sodium hydride, with the formation of compound LXX. Heating of the LXX with the appropriate carboxylic acid in the presence of a catalyst is a mineral acid can lead to the formation LXXI, where R28is hydrogen, alkyl, alkenyl, quinil. Horsemaster can then be replaced by R3getting connection LXXII, using one of the methods described above for the introduction of R3when the connection is LXIV.

Circuit 18 may be used to produce purines, in which R22means halogen or alkoxide. Connection LXX can be heated with dialkylammonium, such as diethylcarbamoyl with the formation of carbonyl compounds LXXXIII, if the conversion is not large enough, instead of diethylmalonate you can use the more reactive compounds such as trichloromethylcarbonate or carbonyldiimidazole. Horsemaster can then be transferred to R3with the formation of LXXXIV, using one of the methods described above for the introduction RA is 2-chloropurine, LXXV. To obtain 2-alkoxyamino, LXXXV, compound LXXV can be heated in the presence of a metal salt of the alcohol R31OH, namely sodium or potassium salts, where R31represents a C1-C4-alkyl.

Method for the synthesis of 7-azaindole of the present invention is shown in scheme 19.

A series of compounds of General structural formula LXXVIII with R1and R2groups described in W. Pandler and T. K. Chen., J. Heterocyclic Chem., 7:767 (1970).

These compounds can be oxidized percolate such as m-chloroperoxybenzoic acid, sulfon LXXIX. Sulfon LXXIX can be heated in the presence of aniline and a suitable base, for example sodium hydride, to form diarylamino LXXX. Alkylarene LXXX suitable substituted or unsubstituted or 4-substituted 3-butenolide (or 3-butylmethylether) can lead to the formation of LXXXI. LXXXI can undergo intramolecular reaction of the Diels-alder reaction with the formation LXXXII.

In some cases, required 4-substituted 3-butenolide is not easily accessible or unstable. In this case, to obtain a compound LXXXII, where R3=H, unsubstituted use 3-butenolide.

Synthesis of 5,7-desandro this izobreteniya with the formation of pyrimidine LXXXV. The reflux LXXXV in the presence of POCl3gives dichloropyrimidine LXXXVI.

Compound X can be translated into a carbonyl compound LXXXVII treatment with one equivalent of ozone at - 78oC with the formation of ozonide, which upon treatment with sodium iodide and acetic acid gives the necessary carbonyl compound. Getting LXXXVII (R1=H, R28=CH3, R1=R28= CH3different ways described E. Basagni et al., Bull. Soc. Chim. Fr., 4338 (1969).

Before the addition reactions of carbonyl compound LXXXVII protect processing 2,2-dimethoxypropane in the presence of catalytic amount of acid with the formation of compound LXXXVIII. Connection LXXXVIII then interacts with the appropriate aniline L when heated in the presence of a base such as sodium hydride, with the formation of compound LXXXIX. Compound LXXXIX may be subjected to cyclization, forming 5,7-diakanda XC, the target compound, where R3= Cl. Connection XC is also useful as an intermediate compound to obtain a compound XCI with other groups of R3. Heat chlorosilane with the appropriate amine gives the desired alkoxysilane. The process of joining XC (R3= Cl) with R

Compounds where R5represents dimethylhydroxylamine, X1- iodine, R1and R3- chlorine, can be obtained according to scheme 21. Ethyl-4-aminobenzoate audiruetsya in a mixture of methylene chloride/water (50:50) in the presence of sodium bicarbonate to obtain compounds (XCII). This product interacts with chloride cyanuric acid, then the secondary amine alkylate in accordance with the fact, as shown in figure 1, and get XCIII. Connection XCIII treated with 5 equivalents of MeMgBr and get the desired product of formula (XCIV).

Figure 22 illustrates the synthesis of compounds of formula (I), where Y=N, Z=CR2, R3= COR25CH(OH)R25or C(OH)R25R25a. The ester of formula (XCVI) can be transformed into an amide of formula (C) by treatment of an amine of formula NH(ORaRbwhere Raand Rbmean lowest alkali, mainly Me, in the presence of reagent - trialkylamine (mainly, Me3Al) in an inert solvent, mainly aromatic hydrocarbon (e.g. benzene or ether solvent (e.g. tetrahydrofuran) as known from the prior art (J. I. Levin, E. Tuvos, S. M. Weinreib, Synthetic Communications, 12:989-993 (1982)).

Amides of the formula (C) can be converted into ketones of the formula (CI) is the I in an inert solvent, mainly, ether solvent (e.g. diethyl ether or tetrahydrofuran), as is known from the prior art (S. Nahm and S. M. Weinreb, Tetrahed von Letters, 22: 3815-3818 (1981)) or ketones of the formula (CL) can be obtained from the acids of formula (XCV) processing organolithium reagent R25Li in the presence of inorganic salts (mostly halide of the transition metal, for example CeCl3in ethereal solvent, for example tetrahydrofuran, as known from the prior art (Y. Ahn and J. Cohen. Tetrahed von Letters, 35: 203-206 (1994)). Or esters of the formula XCVI can be directly converted into ketones of the formula XCVIII by reaction with organolithium reagent R25aL; or organomagnesium R25aMgX, where X = Cl, Br or I, in an inert solvent (mainly, in the ether solvent such as diethyl ether or tetrahydrofuran) in the temperature range from -100 to 150oC, mainly -78 - 80o(J. March, Advance Organic Chemistry (New York: J. Wiley and Sons, 1985), pp. 433-434). Ketones of the formula (XCVIII) can be converted to alcohols of the formula (XCIX) by reaction with an organolithium reagent R25aLi or organohalide R25aMgX, where X = Cl, Br or I, in an inert solvent, mainly ethereal solvent such as diethyl ether or tetrahydro-435). Or esters of the formula (XCVI) can be converted to alcohols of the formula (XCIX) by reaction with an organolithium reagent R25aLi or organomagnesium R25aMgX, where X = Cl, Br, I, in an inert solvent (mainly ether solvent such as diethyl ether or tetrahydrofuran) in the temperature range from - 100 to 150oC (mainly -78 - 100oC) mainly using excess organolithium reagent (above link March, pp. 434-435). In this last example, R25= R25a. Ketones of the formula XCVIII can be converted to alcohols of the formula (C) by treatment with a reducing agent in an inert solvent.

Suitable reducing agents include, but are not limited to) alumoweld alkali metals, mainly alumoweld lithium, borohydride alkali metals (mainly, borohydride sodium), trielaxhillshire alkali metals (such as diisobutylaluminium), boron, dealivery (such as vitaminbody), trialkylborane alkali metals (such as triethylborohydride lithium). Inert solvents include lower alkalemia alcohols containing from 1 to 6 carbon atoms, ether solvents such as diethyl ether or tetrahydrofuran is becoming lies in the range of from -78 to 200oC, mainly from 0 to 120oC. the Choice of reducing agent and solvent known in the art and described in the above link to work March, Advanced Organic Chemistry, pp. 1093-1110.

The compounds of formula (I) can also be obtained according to the method shown in scheme 23. The compound of the formula (CI) (formula I, where Z = CR2Y = N, R3= (CHR11)pCN) can interact with sodium azide and ammonium chloride in a polar solvent at high temperature (mainly 70-150oC) with the formation of tetrazole formula (CII), as described previously (R. N. Butler, Tetrazoles, in Comprehencive Heterocyclic Chemistry: A. R. Katritzky, C. W. Rces, Eds.; New York: Pergamon Press, 1984, pp. 828-832).

These polar solvents may include dialkylamide (mainly N,N-dimethylformamide), dialkylacrylamide (mainly N, N - dimethylacetamide), cyclic amides (mainly N-organic, diallylsulfide (mainly dimethylsulfoxide and dioxane. The compound of formula (III) (formula I, where Y = N, Z = CR2, R3= COCH3can be processed halogenation agent in an inert solvent with the formation of halogeton formula (CIV). Such halogenation agents include bromine, chlorine, iodine, N-glowczewski, for example N-bromo perbromide of tetraethylammonium) (the above link March, Advanced Organic Chemistry, pp. 539-531; S. Kajigaeshi, T. Kakinami, T. Okamoto, S. Fujusaki. Bull. Chem. Soc. Japan, 60: 1159-1160 (1987) and T. Okamoto, S. Fujisaki, Bull. Chem. Soc. Japan 60:1159-1160 (1987)) and in the references. Inert solvents include lower hydrocarbons containing from 1 to 6 carbon atoms and 1 to 6 halogen atoms (mainly dichloromethane and dichloroethane), dialkyl ethers containing from 4 to 10 carbon atoms, cyclic ethers containing from 4 to 10 carbon atoms (mainly dioxane) and aromatic hydrocarbons containing from 6 to 10 carbon atoms. Haloketones formula (CIV) can be translated in the imidazoles of formula (VII) by treatment with formamide with or without an inert solvent, as described previously (N. Brederick, G. Theilig, Chem. Ber. 86-88-108 (1953)). On the other hand, the ketones of the formula (S) can be converted into amides-minilogue (CV) by reaction with N,N-di(lower alkyl)-formamide di-(lower alkyl)acetals (for example, N,N-dimethylformamidine) or gold reagent (dimethylaminomethylene - dimethylammoniumchloride) in an inert solvent or without using a base, as described previously (J. T. Gupton, S. S. Anrew, C. Colon, Synthetic Communications, 12: 35-41 (1982); R. F. Abdulla, K. H. Fuhr, J. Organic Chem. 43: 4248-4250 (1978)).

Suitable inert solvents include the 1 to 6 carbon atoms, dialkyl ethers containing from 4 to 10 carbon atoms and cyclic ethers containing from 4 to 10 carbon atoms (mainly dioxane). Suitable bases include tertiary amines, hydrides of alkali metals (mainly sodium hydride), aromatic amines (mainly pyridine) or carbonates or alkoxides of alkali metals. Vynalogica amides (CVI) can enter into a condensation with hydrazine in an inert solvent with the formation of pyrazoles of the formula (CV), as described previously (G. Savodnick, Chemische Zeitung, 101:161, 1977; J. V. Greenhill, Chem. Soc. Reviews' 6: 277, 1977). Suitable inert solvents include aromatic hydrocarbons containing from 6 to 10 carbon atoms, lower alkalemia alcohols containing from 1 to 6 carbon atoms, dialkyl ethers containing from 4 to 10 carbon atoms or cyclic ethers containing from 4 to 6 carbon atoms (mainly dioxane).

Purines and 8-Aza-purines of the present invention can be easily obtained by using the methods shown in schemes 24 and 25. Purines (XI) are obtained from the corresponding substituted pyrimidines (VIII). Tizanidine hydroxypyrimidine nitrous under standard conditions with fuming nitric acid. Subsequent transformations of gidroksosoedinenii in x is the slot and methanol lead to aminopyrimidine (CIX). Connection (CIX) communicates with the appropriate substituted aniline in the presence of a basic catalyst with the formation of aminopyrimidine (CX), which is then transferred to the target purine (XI) by reaction with triethylorthoformate in acetic anhydride. Using as starting compound CX, target 8-Aza-purine can be obtained by reaction with sodium nitrate in acetic acid.

If R3purine is a chloro group, this group can then be converted into another substituent R3as shown in scheme 25. Connection (CXII), where R3is Cl, interacts with the nucleophile in an inert solvent or without it at a temperature of from 20 to 200oC with the formation of 8-sapurina (CXIII). Similarly, the group R3the corresponding substituted purine (XI) can be converted into another functional group with the formation of purine (CXIV), containing the appropriate Deputy. Similarly, if R1is a group of chloro, it can be converted into another functional group by reaction with a suitable nucleophile. Suitable nucleophiles include amino, hydroxy and mercaptoethane and their salts.

The compounds of formula (I), where J, K and/or L is N, such as the th, corresponding to the formula I, is shown in scheme 26. 2,4-Dihydro-5 - nitropyrimidin (CXV) first turn in dichloroethane (CXVI) processing POCl3. Connection (CXVI) then transferred to a symmetrical bis-substituted pyrimidines (CXVII) and (CXVIII) by reacting with suitable MR5and MX containing group MR5and MX, respectively, where M is the metal atom. It is clear that the compounds of formula I, where R5and X have the same definition, related to the subject matter of the present invention. Method of obtaining asymmetric bis-substituted compounds (CXIX) and (CXX) consists in processing (CXVI) equimolar quantities MR5and X and obtaining the statistical mixture of products (CXVII), (CXVIII), (CXIX), (XX), which can be purified by known techniques, such as recrystallization or chromatography.

Compounds of the present invention (N-pyrimidine-N-alkyl) aminopyrimidine receive in accordance with the scheme 27. Suitable substituted 2-hydroxypyrimidine (CXXI) turn 2-chloropyrimidine (CXXII) processing POCl3. Intermediate (N-pyrimidine) aminopyrimidine, (CXXIII), (CXXIV), (CXXV) and (CXXVI) is produced by processing (CXXII) an appropriate 5-aminopyrimidine, (CXVII), (CXVIII), (CXIX), (XX), respectively, in the presence of a base, such as NaOH. Ppivodit to the formation of the target (N-pyrimidine N-alkyl) aminopyrimidines, (CXXVII), (CXXVIII), (CXXIX), (CXXX).

(N-heterocycle-N-alkyl) aminopyrimidine and (N-heterocycle-N - alkyl) aminotriazines of the present invention receive in accordance with the scheme 28. Industrial available substituted heterocycles (CXXXI) can be bromirovanii with the use of Tetra-substituted umanitaria, mainly benzyltrimethylammonium (BTMABr3), to form the corresponding o-bromoquinoline (CXXXII). Such reactions take place in an inert solvent such as lower alcohols or halogenated containing from 1 to 4 carbon atoms and 1 to 4 atoms of halogen in the presence of bases, such as carbonates of alkaline or alkaline-earth metals. Connection (CXXXII) then interact with substituted pyrimidine or triazine (CXXXIII), forming (N-heterocycle) aminopyrimidine (CXXXIVa) or (N-heterocycle) aminotriazol (CXXXIVb), (CXXXIVa or b), then alkylate in the presence of a base and get target (N-heterocycle-N-alkyl) aminopyrimidine (CXXVa) or (N-heterocycle-N-alkyl) aminotriazol (CXXXVb), respectively.

Below the connection of the present invention and their synthesis are illustrated by examples. In all cases the temperature is given in degrees Celsius.

Example 1

N- (2-Bromo-4-m is effected in an ice bath, slowly add POCl3(60 ml), the mixture was stirred at 0oC for 15 minutes and heated under reflux for 23 hours. The mixture is allowed to cool to room temperature, slowly poured on ice and extracted with diethyl ether (CH ml). The combined ether layers are dried over magnesium sulfate and concentrated in vacuo, get whitish crystal solid (19,77 g). The remaining product is subjected to extraction using diethyl ether, in the course of 19.5 h for additional quantities of whitish crystalline substance (3,53 g) after concentration. The total yield of 2-chloro-4,6-dimethylpyrimidine is 23,31 g (55%).

Part C. To a solution of the product, the receipt of which is described in part a (2.0 g) in ethylene glycol (80 ml) is added 2-bromo-4-methylaniline (2.6 g, 1 EQ) and heat the mixture under reflux for 4.5 hours After cooling to room temperature, the mixture was separated between water (200 ml) and ethyl acetate (3 x 100 ml). Connect an ethyl acetate layers are washed with brine, dried over magnesium sulfate, concentrated in vacuo and get a solid brown substance (4,92 g). This product is then purified on a column of silica gel-60 using a UV is dynamin (3,29 g) are obtained in the form of light reddish-brown crystals (yield 80%).

Part C. To the product, the receipt of which is described in part b (1.0 g) in dry tetrahydrofuran (40 ml) is added tert - piperonyl potassium 2-methyl-2-propanol (1.0 M, 6.8 ml) and iodomethane (1.0 ml, 5 EQ). The mixture is stirred for 72 hours at room temperature. After partitioning between water (50 ml) and ethyl acetate (HTL), an ethyl acetate layers are combined and washed with brine, dried over magnesium sulfate and after concentration in vacuo receives a yellow liquid (1.06 g). The resulting product was then purified on a column of silica gel-60 using as eluent 15% solution of ethyl acetate in hexane. Specified in the title compound, in the form of the free base is obtained in the form of a thick yellow liquid (0,89 g, 85% yield). Elemental analysis: calculated for C14H16Br N3In %: C 54,92, P, 5,27, N 13,72, Br 26,09. Found, %: C 54,61, H A 5.25, N 13,55, Br 26,32.

The hydrochloride is obtained by the action of anhydrous hydrogen chloride in diethyl ether, so pl. 120-121oC.

Example 2

N-(2-Bromo-4-(1-methyl-ethyl)phenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine.

Part A. a Mixture of the product described in example 1, part a (2,01 g, 14,01 mmol), 2-bromo-4-(1-methylethyl) aniline (3 g, 14,10 mmol) in ethylene glycol (20 ml) is heated under reflux with astora of sodium hydroxide (1 M, 50 ml) the organic layer is washed with brine and concentrated in vacuo. The obtained residue chromatographic on silica gel using 5% solution of ethyl acetate in hexane and get 2-N-(2-bromo-4-(1-methylethyl)phenyl)-4,6 - dimethylpyrimidine (3.28 g).

Part C. the Product obtained in part a (1.64 g, 5,12 mmol), treated with sodium hydride (60% in oil, 0,41 g of 10.25 mmol) in tetrahydrofuran (10 ml) at 25oC for 15 min and add iodomethane (of 0.82 ml, 13 mmol). The mixture is stirred at 25oC for 90 hours and is divided between ethyl acetate (100 ml) and water (30 ml). The aqueous layer was extracted with additional ethyl acetate (60 ml) and the combined organic extracts washed with brine, dried and concentrated in vacuo. The remainder chromatographic on silica gel, using an 8% solution of ethyl acetate in hexane, and get mentioned in the title compound (1.4 g) in the form of free base.

The free base was dissolved in ether (10 ml) and treated with a solution of anhydrous hydrogen chloride in ether (1 M, 6 ml). The precipitation is collected and dried in vacuum (so pl. 163-164oC).

Example 3

N-(2-Bromo-4-ethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine.

Part A. 2-8 ml, 17.5 mmol). The mixture is heated and stirred without cooling for 4 hours. Then the reaction mixture is alkalinized conc. NH4OH and NaHCO3and extracted with EtOAc (chml). The organic extracts are combined, washed with brine, dried and concentrated in vacuo. Clean residue > 90%, and it is directly used in the next stage.

Part B. Using the product obtained in part A, and the procedure described in example 1, is obtained in a good yield of the target compound.

Example 4

N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-morpholino-6-methyl-2-pyrimidinamine.

Part A. a Mixture of 2,4-d sodium dichloro-6-methylpyrimidine (4 g, and 25.4 mmol), research (2.14 g, 24,54 mmol) and N,N-diisopropylethylamine (4.52 ml) in ethanol (60 ml) was stirred at 0oC for 3 hours, at 25oC for 24 hours followed by heating under reflux for 1 hour.

After vacuum concentration, the residue is divided between ethyl acetate (200 ml) and aqueous solution of sodium hydroxide (1 M, 50 ml). The organic layer is washed with water and with brine and dried, concentrated in vacuo. The residue is recrystallized from a mixture of ethyl acetate/hexane and get 2-chloro-4-morpholino-6 methylpyrimidine (1 g, of 4.67 mmol) is heated under reflux in ethylene glycol (6 ml) for 1.5 hours. After cooling, the mixture fractionary between ethyl acetate (100 ml) and aqueous solution of sodium hydroxide (1 M, 200 ml). The organic layer is washed with water and with brine, dried and concentrated on a rotary evaporator. The remainder chromatographic on silica gel using 25% ethyl acetate in hexane and get 2-N-(2-bromo-4(-1-methylethyl)phenyl)-4 - morpholino-6-methylpyrimidine (1.5 g).

Part C. the Product, the receipt of which is described in part B (1.0 g 2.56 mmol), treated with sodium hydride (60% in oil, 0.15 g, 3.75 mmol) in tetrahydrofuran (10 ml) at 25oC for 20 minutes, then add Iodate (of 0.32 ml, 4 mmol). The mixture is stirred at 25oC for 24 hours and heated under reflux for 5 hours. After partitioning between ethyl acetate (100 ml) and water (20 ml) the organic layer is washed with brine, dried and concentrated in vacuo. The remainder chromatographic on silica gel using 12% ethyl acetate in hexane, and get mentioned in the title compound (0,94 g) in the form of free base.

Salt is a hydrochloride of the above compound get, dissolving the isolated product in ether (10 ml) and the IU (so pl. 219-222oC).

Example 5

N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,-6-dimethyl-2-pyrimidinamine.

Part A. To a solution of 2-bromo-4-(1-methylethyl) aniline (6 g, of 28.2 mmol) and cyanamide (4.7 g, 112,08 mmol), dissolved in ethyl acetate (100 ml) and ethanol (13 ml) add a solution of hydrogen chloride in ether (1 M, 38 ml, 38 mmol) and the mixture stirred at 25oC for 1 hour. The volume of solution is reduced by distillation to 75 ml of the Residue is heated under reflux for 3 hours and after cooling, add ether (120 ml). The precipitate, 2-bromo-4-(1-methylethyl)phenylquinoline hydrochloride is collected and dried (10.4 g) and then used in further reactions without additional purification.

Part B. the product Mixture, the receipt of which is described in part A (5.0 g; 13,47 mmol), potassium carbonate (1.86 g; 13,47 mmol) and 2,4-pentanedione (2.8 ml, 27,28 mmol) in N,N-dimethylformamide (35 ml) is heated under reflux for 24 hours. After cooling, the reaction mixture was separated between ethyl acetate (120 ml) and aqueous solution of sodium hydroxide. The aqueous layer was extracted with additional ethyl acetate (120 ml) and the combined organic extracts washed with water, salt solution, dried and concentri-4-(1-methylethyl)phenyl)-4,6 - dimethylpyrimidine (3,37 g).

Part C. the Product selected in part B (3.0 g, 9,37 mmol), alkylate sodium hydride and iodoethanol in tetrahydrofuran by the procedure similar to that described in example 4, part C. Specified in the title compound is isolated in the form of the free base (2,88 g).

Salt is a hydrochloride get by the method similar to the method described in example 4, using hydrogen chloride in ether, with the formation of the solid product (melting point of 151-153oC).

Example 6

N-Ethyl-N-(2-bromo-4-(2-methoxyethyl)phenyl)-4-morpholino-6-methyl-2 - pyrimidinamine.

Part A. 4-hydroxyethylamino, 16,55 g (0.12 mol) in a mixture of pyridine (0,23 ml, 0.29 mol) and CH2Cl2(100 ml), cooled to 0oC added dropwise acetylchloride (18.8 ml, 0.26 mol). The mixture was stirred at 0oC for 2 hours and at 25oC for 48 hours and then added to the saturated solution of NaHCO3(100 ml). CH2Cl2separated, washed with brine, dried and concentrated in vacuo. The remainder chromatographic on silica gel, using 26% and 1:1 EtOAc/hexane, and obtain the target product (24 g, yield 90%).

Part B. 4-Acetoxyacetyl bromilow according to the method described in Org. Synth. Coll. Vol.1,11, according to which analizator stirred at 25oC 60 hours, then add sodium sulfite (20 ml), water (200 ml) and precipitated bromide precipitate is separated by filtration. The filtrate is then diluted with water (300 ml) and cooled to produce additional quantities of bromide. Selected bromide is then heated under reflux (6 M, 100 ml) for 2 hours, the mixture is neutralized solid NaHCO3and extracted with EtOAc (g ml). United EtOA extracts washed with brine, dried and concentrated in vacuo. The remainder chromatographic on silica gel using a mixture of 1:1 EtOAc/hexane to obtain the desired product (2.8 g) with 20% yield, based on two stages.

Part C. 2-Bromo-4-hydroxyacetanilide (1.6 g, 7,3 mmol) and 2-chloro-4,6-dimethylpyrimidin (1.1 g, 7,3 mmol) is subjected to interaction with ethylene glycol (6 ml) at reflux for 1.5 hours. After cooling, the mixture was separated between EtOAc (100 ml) and NaOH solution (0.5 M, 25 ml). The aqueous layer was extracted with additional EtOAc (50 ml) and the combined organic extracts washed with brine, dried and concentrated in vacuo. The remainder chromatographic on silica gel using a mixture of EtOAc/hexane and get the desired product (1.3 g) with a yield of 64%.

and add 3,4-dihydro-2H-Piran (1.65 ml, 11,98 mmol), then controlando sulfuric acid (conc. H2SO40.2 ml). The mixture is stirred at 25oC for 60 hours and add K2CO3(1 g), then a saturated solution of NaHCO3(50 ml). The mixture was separated between EtOAc (120 ml) and a solution of NaHCO3(20 ml). EtOAc extract was washed with brine, dried and concentrated in vacuo. The dried crude product is dissolved in dry THF (15 ml) and treated with sodium hydride (60% in oil, 380 mg) at 25oC for 15 minutes, and then add Iodate (1 ml of 9.45 mmol). The mixture is stirred at 25oC for 12 hours and heated under reflux for 4 hours. Then carry out the separation between EtOAc (120 ml) and water (20 ml). EtOAc extract was washed with brine and concentrated in vacuo. The remainder chromatographic on silica gel using 15% EtOAc/hexane, and get the desired product (1.6 g) in 78% yield, calculated in two stages.

Part E. the Product, the receipt of which is described in part D, was dissolved in MeOH (20 ml) and added dropwise concentrated sulfuric acid (0.4 ml), then hydrochloric acid in ether (1 M, 1.5 ml). The mixture is stirred at 25oC for 2 hours, quenched with solid K2CO3(1 g) and separated between EtOAc (100 ml) and a solution of NaHCO

Part F. the Product, the receipt of which is described in part E (720 mg; of 2.06 mmol), treated with NaOH (60% in oil, 120 mg, 3 mmol) in THF (10 ml) at 0oC for 5 minutes and at 25oC for 15 minutes. Add iodomethane (0.25 ml, 4 mmol) and the resulting mixture was stirred at 25oC for 20 hours. The reaction mixture was separated between EtOAc (100 ml) and water (25 ml). EtOAc layer washed with brine, dried and concentrated in vacuo. The remainder chromatographic on silica gel using 20% EtOAc/hexane, and obtain the required product (680 mg, 91% yield, which is then transferred into the hydrochloride by treatment with a mixture of 1 M HCl and ether, so pl. 117-118,5oC.

Example 7

N-Ethyl-N-(2-iodide-4-(1-methylethyl)phenyl-4-morpholinyl-6-methyl-2 - pyrimidinamine.

The solution of the free base, the receipt of which is described in example 4 (1.4 g; to 3.34 mmol) in tetrahydrofuran (15 ml) at -78oC is treated with n-butyllithium (1.6 M in hexane, 3.3 ml, 3.7 mmol). After stirring for 15 minutes, added dropwise a solution of iodine (1.0 g, 4 mmol) in tetrahydrofuran (5 ml) and additional parameterization (100 ml) and a solution of sodium bisulfite (saturated, 20 ml). An ethyl acetate layer washed with water, with brine and concentrated in vacuo. The remainder chromatographic on silica gel, using as eluent: 15% ethyl acetate in hexane and get listed in the title compound (0.9 g) as a solid, melting point 96-98oC.

Example 8

N-(2-Bromo-4-(1-methyl)phenyl)-N-ethyl-6-methyl-4-(2 - thienyl)-2-pyrimidinamine.

Part A. 2-Chloropyrimidine (2.0 g) dissolved in diethyl ether (50 ml) and cooled to -30oC. Slowly add a solution metallice in ether (1.4 M, 15 ml) and stirred the reaction mixture at -30oC for 30 minutes, then at 0oC additional 30 minutes. To terminate the reaction, add a mixture of glacial acetic acid (1.2 ml), water (0.5 ml) and tetrahydrofuran (5 ml). Then add 2,3-sodium dichloro-5,6-dicyano-1,4-benzoquinone (4,79 g) in tetrahydrofuran (20 ml) and stirred the reaction mixture for 5 minutes at room temperature. The mixture is cooled to 0oC and add an aqueous solution of sodium hydroxide (3 M, 50 ml), stirred for 10 minutes. Separate the organic layer, washed with water and dried over magnesium sulfate. Concentrated in vacuo and the resulting residue chromatographic on silica gel (solvent-30% ethyl acetate, wcast Century To thiophene (0.66 g) in dry ether (25 ml) at 0oC add n-utility in hexane (1.6 M, 2.7 ml), the reaction mixture is stirred at 0oC for 15 minutes. After cooling to -30oC is added slowly a solution of 2 - chloro-4-methyl-pyrimidine (1.0 g) in ether (10 ml) and stirred the reaction mixture at -30oC for 30 minutes and at 0oC additional 30 minutes, then quenched with a mixture of glacial acetic acid (0.45 ml), water (0.5 ml) and tetrahydrofuran (1.0 ml). Add 2,3-sodium dichloro-5,6-dicyano-1,4-benzoquinone (1.77 g) in tetrahydrofuran (5 ml) and stirred at room temperature for 5 minutes, then cooled to 0oC and add aqueous sodium hydroxide solution (3 M, 50 ml). Separate the organic layer, washed with water and dried over magnesium sulfate. The solvent is evaporated and chromatographic the crude product (oil) on silica gel (30% ethyl acetate in hexane, Rf= 0,55) and get 2 - chloro-4-methyl-6-(2-thienyl) pyrimidine (0.21 g). Elemental analysis, calculated, %: C 51,46, H of 3.33, N 13,33. Found, %: C 51,77, H 3,35, N 12,97.

Part C. 2-Bromo-4-(1-methylethyl)aniline (0.26 g) and 2-chloro - 4-methyl-6-(2 - thienyl)pyrimidine (0.21 g) in ethylene glycol is heated under reflux for 24 hours. The reaction mixture was diluted with ethyl acetate, washing the I get the crude product is brown oil which is purified on silica gel using a 20% solution of ethyl acetate in hexane (Rf= 0,5) as eluent, and get N- (2-bromo-4-isopropyl)-4-methyl-6-(2-thienyl)-2-pyrimidinamine (0.1 g) as a solid substance, with a melting point 98-101oC. Mass spectrum (NH3-CI/DDIP): 390 (M + N)+.

Part D. the Product obtained by the method described in part C (0.1 g), is added slowly to the sodium hydride (50 mg) in dry tetrahydrofuran, and then add iodoethane (0.1 g) and heat the mixture under reflux for 24 hours. The reaction mixture is cooled and added to water (0.5 ml). The solvent is removed and the resulting product is placed in ethyl acetate, washed with water (I ml) and dried. The solvent is evaporated and chromatographic the crude product on silica gel using 10% ethyl acetate in hexane (Rf= 0.5), and get mentioned in the title compound 70 mg as free base.

Hydrochloric acid salt of this substance get, using the methodology described above; melting point 95-97oC. Mass spectrum (NH3-CI/DDIP): 417 (M+H+), elemental analysis, calculated for C20N22N3BrSHC, %: C 53,10, H 5,09, N 9,51, found, %: C 53,78, H 5,22, N 9,10.

Example 9

N is specified in the title compound get using 2-bromo-4-(1-petiatil)aniline (4.0 g) and 2 - chloro-4,6-demateriali specified in part A, to obtain the desired intermediate product of pyrimidinamine, mass spectrum (NH3-CI/DDIP): 321 (M+N)+. Using (bromomethyl)cyclopropane part In the same example, receive the necessary product of the mass spectrum (NH3-CI/DDIP): 374 (M+H+).

Get the salt is the hydrochloride of this free base with a melting point 146-148oC.

Example 10

N-(2-Bromo-4-(l-methylethyl)phenyl)-N-propargyl-4,6-dimethyl-2-pyrimidinamine.

Using 2-(2-bromo-4-(1-methylethyl)of aniline)-4,6-dimethylpyrimidin and specified in example 9 substituted propargylic, isolated in the form of a free base specified in the title compound, mass spectrum (NH3-CI/DDIP): 358 (M+H)+.

Get the salt is the hydrochloride of this free base.

Example 11

N-Ethyl-N-(2-iodide-4-(2-methoxyethyl)phenyl)-4,6-dimethyl-2-pyrimidinamine, hydrochloride.

Part A. 4-Hydroxyacetanilide coderoute manner similar to that described in example 6, in accordance with the order, as described in Tet. Lett.33: 373-376 (1992). Aniline (2 g, 14,58 mmol) dissolved in CH3CN (25 ml) and add water (15 ml) containing NaHCO3(1.68 g, 20 mmol). The mixture of the group of 16 hours and then separated between EtOAc (100 ml) and NaOH solution (20 ml, 1 M). EtOAc layer washed with brine, dried and concentrated in vacuo. The remainder chromatographic on silica gel using a mixture of EtOAc/hexane (1:1) and obtain 1.8 g of product, yield 47%.

Part B. the Product, the receipt of which is described in part A (6.3 g; 23,94 mmol), dissolved in a mixture of EtOAc (100 ml) and EtOH (10 ml) and added cyanamide (4.7 g, 112,5 mmol), then HCl in ether (31 ml, 1 M). Set the nozzle for distillation and distilled 50 ml of solvent. The remaining mixture is diluted with EtOH (15 ml) and heated under reflux for 5 hours. After cooling, add Et2O (100 ml), the precipitated salt was washed with EtOAc, and after drying receive the desired product (4.5 g) with a yield of 55%.

Part C. Salt guanidine, the receipt of which is described in part B (8.53 g, 24,95 mmol), potassium carbonate (3,84 g, 27,72 mmol) and 2,4-pentandiol (9 ml, 42,65 mmol) is heated under reflux in DMF (70 ml) for 16 hours. The reaction mixture was separated between EtOAc (150 ml) and water (50 ml), the organic layer washed with water (2 x 80 ml), with brine, dried and concentrated in vacuo. The remainder chromatographic on silica gel using a mixture of EtOAc/hexane (1: 1) and obtain the desired product (2.8 g) with 30% yield.

Part D. the product, obtaining kotorogo the mixture is stirred at 25oC for 16 hours. Add an additional portion of sulfuric acid (0.2 ml) and continue stirring for 3 hours. Add EtOAc (100 ml) and saturated NaHCO3(100 ml), separated layers. The aqueous layer was extracted with additional EtOAc (100 ml), the combined organic layers washed with NaHCO3, saline solution, dried and concentrated in vacuo. The remainder chromatographic on silica gel using 20% EtOAc/hexane to obtain the desired product (1.2 g) with a yield of 31%.

Part E. the Product, the receipt of which is described in part D, was dissolved in dry THF (15 ml) and add NaH (60% in oil, 220 mg, 5.5 mmol). The mixture is stirred at 25oC for 15 minutes and add Iodate (0.5 ml, 5.7 mmol). The mixture is stirred at 25oC for 16 hours and then heated under reflux for 2 hours. The reaction product is separated between EtOAc (100 ml) and NaOH (30 ml, 1 M). EtOAc layer washed with brine, dried and concentrated in vacuo. The rest is used in the following stage without further purification.

Part F. the Product, the receipt of which is described in part E (950 mg, 2.4 mmol) in dry THF (10 ml) is treated with NaH (60% in oil, 140 mg, 3.5 mmol) was stirred at 25oC for 15 min and add the in EtOAc (100 ml) and water (20 ml). The organic layer is washed with brine, dried and concentrated in vacuo. The remainder chromatographic on silica gel using 20% EtOAc/hexane, and get the desired product (500 mg), which was transferred to salt is the hydrochloride in the usual way, the melting point of 129-131oC.

Example 12

N-(2-Bromo-4-(1-methylethyl)phenyl-N-ethyl-4-methyl-2-pyrimidinamine.

Part A. the Product, the receipt of which is described in example 8, part a (0.2 g) and 2-bromo-4-(1-methylethyl) aniline is subjected to interaction, using the same method described in example 8, part C, and get N-(2-bromo-4-(1-methylethyl)phenyl)-4-methyl-2-pyrimidinamine (0.7 g) as a viscous oil. Mass spectrum (NH3-CI/DDIP): 307 (M+H).

Part B. the Product, the receipt of which is described in part A, the alkylate iodoethanol, using the same methodology described in example 8, part D, and provided with the necessary connection-N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4 - methyl-2-pyrimidinamine (0.3 g) in the form of free base.

Salt is a hydrochloride of this compound get the usual procedure, the melting point 145-147oC.

Mass spectrum (NH3-CI/DDIIP): 334 (M+N)+.

Example 13

N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(methylamino)ethanol (0.4 g) in ethanol (50 ml) is heated under reflux for 24 hours. The solvent is evaporated and get the remainder, which chromatographic on silica gel using 5% methanol in chloroform, to obtain 2-chloro-4-methyl-6-(N-methyl-2-hydroxyethylamino)pyrimidine (370 mg). Mass spectrum (NH3-CI/DDIP): 202 (M+N)+.

Part B. Hydroxyl group contained in the product, the receipt of which is described in part A, protects thus, to obtain methoxymethyl ether (MOM-ether), using N,N-di(1-methylethyl)ethylamine and bromonitromethane ether (0.35 g) in dry tetrahydrofuran have protected adduct (310 mg), mass spectrum: 246 (M+N)+, which is used without further purification.

Part C. Protected MOM-ether is subjected to interaction with 2-bromo-4-(1-methylethyl) aniline using the procedure described in example 8, part C. In these conditions also remove ethoxymethylene protective group receiving N-(2-bromo-4-(1-methylethyl)phenyl)-4-methyl-6-(N-methyl-2 - hydroxyethylamino)-2-pyrimidinamine (mass spectrum, NH3-CI/DDIP: 379, (M+N)+). These hydroxyl group re-protect for subsequent reactions, as described in part B (the mass spectrum for the MOM-ether (NH3-CI/DDIP): 453 (M+N)+). Alkylation of jumatano carried out using the method described in example 8, part D. the MOM-ether gr is Uchenie 24 hours. After highlighting receive specified in the title compound as free base.

Salt is a hydrochloride get, using previously described methodology. The mass spectrum of high resolution (msvr), 407, 144640 (M+N)+designed 407, 144648 (M+N)+.

Example 14

N-Ethyl-N-(2-iodide-4-(1-methylethyl)phenyl)-4-thiomorpholine-6-methyl-2 - pyrimidinamine, S-oxide.

The desired product is obtained by oxidation periodates sodium product, the receipt of which is described in example 22 by the method of J. H. Bushweller et al. J. Org. Chem. 54:2404 (1989).

Example 15

N-(2-Bromo-4-isopropoxy)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine.

Part A. Synthesis of 2-bromo-4-isopropoxyaniline carried out using the method of the synthesized 4-isopropoxyaniline published Kajigaeshi et al. Bull. Chem. Soc. Jpn. 61:597-599 (1988). Aniline, 1 EQ of benzyltrimethylammonium and g-equivalents of calcium carbonate is stirred at room temperature in a solution of MeOH: CH2Cl2(2:5) for one hour. The solid product removed by filtration, the filtrate is evaporated under vacuum. The residue is placed in water, and the mixture is extracted three times with CH2Cl2. The combined extracts are dried over MgSO4, filtered and evaporated in vacuum, get brown giddy, described in example 1, parts B-C, and substituted aniline described in part a, get mentioned in the title compound.

Example 16

N-(2-Bromo-4-(l-methylethyl)phenyl)-N-ethyl-4-methyl-6-(4-morpholinylcarbonyl)-2 - pyrimidinamine.

To a solution of sodium hydride (60% in oil, 0.24 g, 6.0 mmol) suspended in anhydrous THF (10 ml), added with stirring morpholine (0.52 g, 6.0 mmol), the reaction mixture is heated prior to the formation of phlegmy and stirred for 1 hour. Then the reaction mixture was cooled to ambient temperature and add 2-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino-4 - carbomethoxy-6-methylpyrimidin (2.0 g, 5.1 mmol). Stirring is continued for 26 hours. Then the reaction mixture was poured into 1 N NaOH solution, stirred and extracted 3 times with EtOAc. The combined organic layers dried over MgSO4, filtered and concentrated in vacuo. After column chromatography (Et2O) receive specified in the title compound as a solid (900 mg, yield 39%), melting point 145oC. NMR (CDCl3, 300 MHz) Delta: 7,5 (d, 1H, J=1), 7,21 (dd, 1H, J=7,1), and 7.1 (d, 1H, J=7), 6,8 (br s, 1H), from 4.3 to 4.15 (m, 1h), 3,9-3,3 (m, 11H), 3,1-3,0 (m, 1H), 2,9 (cenmem, 1H, J=7) and 1.3 (d, 6H, J=7), to 1.15 (t, 3H, J=7); elemental analysis for (C21H27BrN4O2), l)phenyl)-N-ethyl-6-methyl-4-(4-morpholinylmethyl)- 2-pyrimidinamine.

A solution of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(4-morpholinylcarbonyl)-2 - pyrimidinamine (750 mg, 1,72 mmol) in anhydrous THF (1.4 ml) was stirred at ambient temperature under nitrogen atmosphere. Add dropwise a solution of borane in THF (1 M, 3.6 ml, 3.6 mmol). Then the reaction mixture is heated to a temperature of education phlegmy and stirred for 20 hours. After cooling to room temperature, slowly add acetic acid and heat the mixture to a temperature of education phlegmy, stirred for 30 minutes. After cooling to room temperature the reaction mixture is poured into 3 N NaOH solution, stirred and 3 times extracted with EtOAc. The combined organic layers dried over MgSO4, filtered and concentrated in vacuo. After column chromatography receive specified in the title compound as an oil (300 mg, yield 39%, Rf=0,3); NMR (CDCl3, 300 MHz) Delta: 7,5 (S, 1H), 7,2 (d, 1H, J=7), to 7.15 (d, 1H, J=7), And 6.5 (S, 1H), from 4.3 to 4.1 (m, 1H) 3,8-3,6 (m, 7H), 3,5-3,3 (m, 2H), 2,9 (ceptet, 1H, J=7), 2,55 to 2.35 (br m, 3H), 2,35 was 2.25 (m, 2H) of 1.3 (d, 6H, J=7), and 1.2 (t, 3H, J=7); mass spectrum high-resolution chemical ionization calculated 433, 1603 (M+H), found 433, 1586.

Example 18

Methyl-2-((2-bromo-4-(1-methylethyl)phenyl)methylamino)-6-methyl-4 - pyrimidinecarboxylic.

To rest ablaut gradually over 30 minutes methyl-2-((2-bromo-4-(1-methylethyl)phenyl)amino)- 6-methyl-4-pyrimidinecarboxylic (42.8 g, 118 mmol). After the cessation of gassing add one portion of iodoethane (31,2 g, 16 ml, 200 mmol) and the reaction mixture was gently heated under reflux for 24 hours. After cooling to room temperature the reaction mixture was carefully quenched with water and extracted three times with ethyl acetate. The combined organic extracts washed twice with water, dried over magnesium sulfate and filtered. After removal of solvent in vacuo get a brown oil. Column chromatography of this oil (Et2O:hexane, 1:1) to give two fractions: (1) methyl 2-((2-bromo-4-(1-methylethyl)phenyl)amino)-6-methyl-4 - pyrimidinecarboxylic (4.6 g, yield 11%, Rf= 0,8) and (2) is specified in the title product (20 g, Rf= 0,7), crude oil. Specified in the title of the product is recrystallized from hexane and dried in vacuum, get a solid (18.0 g, yield 39%), melting point 81-82oC NMR (CDCl3, 300 MHz) Delta: (7,5, br s 1H), 7,25 (d, 1H, J=7), And 7.1 (S, 1H), 4,3,-4,l, (m, 1H), 4,05 of 3.75 (m, 4H), 2.95 and (septet, 1H, J=7), 2,3, (br S, 3H), 1,3, (d, 6H, J=7), 1,25 (t, 3H, J=7). The mass spectrum of high resolution. Chemical ionization calculated: 392, 0974, (M+H), found 392, 0960.

Example 19

N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(4 - methyldiisopropanolamine, get the desired product, melting point 81-82oC.

Example 20

N-(2-Bromo-4-(2-hydroxyethyl)phenyl-N-ethyl-4,6-dimethyl-2-pyrimidinamine.

TNR-hydroxylamine group, is removed by the action of HCl in ether product, as described earlier, and get mentioned in the title compound with melting point 58-60oC.

Example 21

N-Ethyl-N-(2-methoxy-4-(1-methylethyl)phenyl)-4,6-dimethyl-2-pyrimidinamine.

Part A. Using the procedure described in example 1, and 2-amino-5-METHYLPHENOL receive the intermediate secondary amine.

Part B. Double methylation of the amino and phenolic groups, using an excess of sodium hydride and iodomethane in THF, obtain the required product.

Example 22

N-Ethyl-N-(2-iodide-4-(1-methylethyl)phenyl)-4-thiomorpholine-6-methyl-2 - pyrimidinamine.

Using the methodology iodization shown in example 11, and a General synthesis method specified in example 4, to obtain the required compound, melting point 51-53oC.

Example 23

N-[2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(4-morpholinyl)- 1,3,5-triazine-2-amine.

Part A. Methylanisole (300 mmol, 3 M in ether, Aldrich) are added dropwise within 10 minutes to rest the C and continue stirring at this temperature for 4.5 hours. Added dropwise water (36 ml), maintaining the reaction temperature below -15oC. the Reaction mixture is allowed to warm to room temperature and add magnesium sulfate (40 g), allowed to stand for 1 hour. The reaction mixture is filtered and after evaporation of the solvent receives a yellow solid (11,06 g). This product is distilled flashamature (CH2Cl2, silica) and receive 2,4-d sodium dichloro-6-methyl-S-triazine as a white solid (7,44 g) with a yield of 65%.

Part B. 2,4-d sodium dichloro-6-methyl-S-triazine (3 g, 18,29 mmol), 2-bromo-N-ethyl-4-Isopropylamine (6,07 g, 25,07 mmol) and diisopropylethylamine (3.2 g, 25,07 mmol) in dioxane (60 ml) under nitrogen atmosphere is heated under reflux for three hours. Remove the solvent, and the residue purified using flashmemory (CH2Cl2, silica) to give the desired product (4,58 g) as a clear oil with a yield of 68%.

Part C. the Product, the receipt of which is described in part b, (500 mg, 1.35 mmol) dissolved in dioxane (20 ml) under nitrogen atmosphere at room temperature, and at once added morpholine (247 mg, 8,84 mmol). Continue stirring at room temperature for 17 hours. Remove solvent and the residue triturated with a mixture ethylacetoacetate oil (550 mg) with a yield of 97%, C19H26N3OBr.

Example 24

N-(2-Bromo-4-(1-methylethyl) phenyl)-N-ethyl-4-methyl-6-(hydroxymethyl)-2-pyrimidinamine.

Product, the receipt of which is described in example 18, and lithium borohydride (1.5 EQ) was stirred in dry tetrahydrofuran under nitrogen atmosphere for 50 hours. Then the reaction mixture was poured into water and extracted three times with CHCl3.

The combined extracts are dried over MgSO4, filtered and evaporated in vacuum, is obtained in almost quantitative yield the product as a light yellow liquid.

Example 25

N-(2-Bromo-4(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(methoxymethyl)- 2-pyrimidinamine.

To the product, the receipt of which is described in example 24, and sodium hydride (1.1 EQ) in dry THF under nitrogen atmosphere add logmean (1.1 EQ) and after 4 hours the reaction mixture was poured into water and extracted three times with CHCl3. The combined extracts are dried over MgSO4, filtered and evaporated in vacuum. The resulting product was then purified by chromatography on silica gel using 10% EtOAc in hexane and get a light yellow oil (Rf= 0,37).

Example 26

N-(2-Bromo-4-(1-methylethyl) phenyl)-N-ethyl-4 - methyl-6-(thiomethyl)-2-pyrimidinamine.

Part A. 2-B is nitrogen and heated at 190oC for 8 hours. The reaction mixture is cooled to room temperature. The residue is distilled flashamature (CH2Cl2/MeOH, 25:1, silica gel), and get 9,16 g (yield 89%) of white solid product.

Part C. the Product, the receipt of which is described in part A (6 g, of 18.6 mmol), POCl3(20 ml, 214 mmol) is heated in a nitrogen atmosphere for 15 minutes, the Reaction mixture was cooled to room temperature, slowly poured on ice (200 g), stirred for 30 min, before the ice melts, and the aqueous mixture extracted with ethyl acetate (3 x 100 ml). The combined organic extracts treated with water (100 ml) and with brine (100 ml), dried over anhydrous sodium sulfate, filtered and release of 6.1 g of oil. This product is distilled flashamature (CH2Cl2/hexane, 1:1, silicon dioxide), get 4,48 g of product (yield 70%) as a clear oil.

Part C. To the product, the receipt of which is described in part b (4.3 g, 12,65 mmol) in dimethylformamide (30 ml) in an atmosphere of nitrogen was added sodium hydride (658 mg, 16,45 mmol, 60% dispersion in oil) in small portions. After the addition is complete, stirred for 4 hours at room temperature. To the reaction mixture are added water (100 ml) and extracted with ethylacetate the sky layer is dried over anhydrous sodium sulfate, filtered, after allocating the gain of 4.8 g of a reddish-brown oil. This product is distilled flashamature (EtOAc/hexane, 1:6, silicon dioxide) and obtain 4.4 g (yield 95%) of oil.

Part D. the Product, the receipt of which is described in part C (2 g, 5.4 mmol), and thiamethoxam sodium (558 g, 7.6 mmol) in dioxane (50 ml) under nitrogen atmosphere is heated under reflux (20 hours). The solvent is removed and the residue purified by flashamature (CH2Cl2/hexane, 1:1, silica), and obtain 1.86 g (yield 91%) of a clear oil. Mass spectroscopy: (NH3-CI/DDI R): 380 (M + H)+.

Example 27

N-(2-Bromo-4-(1-methylethyl) phenyl)-N-ethyl-4 - methyl-6-(thiomethyl)-2-pyrimidinamine, S-dioxide.

To the product, the receipt of which is described in example 26 (1.8 g, 4.8 mmol) in CH2Cl2(100 ml) under nitrogen atmosphere added in small portions 3-chloroperbenzoic acid (3,16 g, 14,67 mmol, purity 80-85%) and then continue stirring for 30 minutes. Unreacted peroxide is removed using a 10% sodium sulfite (5 ml), and dilute the reaction mixture is CH2Cl2(150 ml) followed by washing with 5% sodium bicarbonate solution (100 ml) and salt solution (100 ml). The organic layer is dried over anhydrous sodium sulfate, f is) and obtain 1.6 g of an oil (yield 79%), mass spectrum: (NH3-CI/DDIP): 412 (M + H)+.

Example 28

N-(2-Bromo-4-(1-methylethyl) phenyl)-N-ethyl-4 - methyl-6-(thiomethyl)-2-pyrimidinamine, S-oxide.

To the product, the receipt of which is described in example 26 (770 mg, 2 mmol) in methanol (200 ml) is added at once periodate sodium (648 mg, 3 mmol) in water (10 ml) and stirred the reaction mixture at reflux for 28 hours. Remove the solvent, and the residue is divided between ethyl acetate (200 ml) and water (50 ml). Separate the organic layer and treated with brine (50 ml). The organic layer is dried over anhydrous sodium sulfate, filtered, isolated and obtain 820 mg reddish-brown product, which is purified by flashamature (EtOA/hexane, 1:1, silica), obtain 570 mg (71% yield) oil. Mass spectrum (NH3-CI/DDIP): 396 (M + H)+.

Example 29

N-[2-Bromo-4-(1-methylethyl) phenyl] -N-ethyl-4-methyl - 6-benzyloxy-1,3,5-triazine-2-amine.

Benzyl alcohol (197 mg, 1.82 mmol, 1.2 EQ) is slowly added to a solution of NaH (73 mg, 60% dispersion, 1.82 mmol) in dry DMF and stirred at room temperature for 15 minutes, add the product, the receipt of which is described in part b (560 mg, of 1.52 mmol) and the resulting mixture was stirred at room what cetecom. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The oil obtained chromatographic on silica, using as solvent 20% ethyl acetate in hexane and get listed in the title compound, C12H25N4Obr calculated, %: C 55,46, H 5,46, N 11,76, found, %: C 55,30, H 5,41, N 12,02.

Example 30

N-[2-Iodide-4-dimethylhydroxylamine-phenyl] -N-ethyl-4-6 - sodium dichloro-1,3,5-triazine-2-amine.

Part A. Ethyl-4-aminobenzoate (5.0 g, 30,27 mmol) and sodium bicarbonate (3,81 g, 45,40 mmol, 1.5 EQ) are added to a mixture of methylation-chloride and water (1: 1). The mixture is cooled to 0oC and gradually add I2(1,53 g, 45,40 mmol, 1.5 EQ). The reaction mixture is allowed to warm to room temperature and stirred for 72 hours. Then separate the layers and the aqueous layer was washed with dimethylaluminum. Organic products are combined and dried over magnesium sulfate, filtered and concentrated in vacuo. The oil obtained chromatographic on silica, using as solvent 30% ethyl acetate in hexane, to obtain ethyl-3-iodide-4-aminobenzoate, C9H10NO2I. Mass spectrum: 292 (M + NH4)+.

Part C. the Product, the receipt of which is described in part A (1.0 g, 3.4 mmol), add PR is ur 10 minutes. Then add ethyliodide (0.8 g, 5.2 mmol) and stirred for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting product chromatographic on silica, using as solvent 30% ethyl acetate and get 3-iodide-4-(N - ethyl)aminobenzoate, C11H14NO2I. Mass spectrum: 320 (M + H)+.

Part C. the Product, the receipt of which is described in part b (0.32 g 1.0 mmol), dissolved in dioxane and slowly add the acid chloride cyanuric acid (0.18 g, 1.0 mmol). The reaction mixture is heated under reflux for 4 hours, stirred at room temperature for 24 hours, then poured into water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting product chromatographic on silica, using as solvent a 10% ethyl acetate in hexane and receive N-[2-iodide-4 - ethyl-carbolit]-N-ethyl-4,6-sodium dichloro-1,3,5-triazine-2-amine. C14H13N4O2Cl2I. Mass spectrum: 467 (M + H)+.

Part D. the Product, the receipt of which is described in part C (0.26 g, 0.6 mmol), dissolved the 33 g, 3.0 mmol, 5 EQ). The reaction mixture is allowed to warm to room temperature and stirred for 4 hours, then poured into water and separate the layers. The aqueous layer was extracted with methylene chloride, the combined organic layers, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting product chromatographic on silica gel using as solvent 30% ethyl acetate in hexane, and get mentioned in the title compound, C15H18N4OICl. Mass spectrum: 453 (M + H)+.

Example 31

N-(2-Iodide-4-(1-methylethyl)phenyl)-N-allyl-4 - morpholino-6-methyl-2-pyrimidinamine.

Melting point 109-112oC. Elemental analysis for C12H27N4IOHCl calculated, %: C 48,99, H 5,48, I 24,65, Cl 6,89. Found, %: C 48,81, H 5,43, N 10,59, I 24,67, Cl 6,86.

Example 32

N-(2-Iodide-4-(1-methylethyl)- phenyl)-N-ethyl-4-chloro-6-methyl-2 - pyrimidinamine.

Guanidine, to 39.5 mmol, crude, obtained by processing K2CO3the corresponding salt guanidine, 15 ml (118 mmol) of ethylacetoacetate and 2.0 g (14,47 mmol) K2CO3in 120 ml of absolute ethanol is heated under reflux for 100 hours. Remove the solvent in vacuo and the residue chromatographic on silica gel, using pirimidine, obtained in accordance with the above-described reaction (2,47 g, 6,69 mmol), dissolved in 20 ml of POCl3and stirred at 25oC for 4 hours. The reaction mixture was poured onto ice, stirred for 30 minutes and extracted with 100 ml EtOAc. EtOAc extract was washed with brine, dried and concentrated in vacuo. The remainder chromatographic on silica gel using 20% EtOAc/hexane and obtain 1.64 g of the corresponding 4-chloropyrimidine (yield 63%).

1.6 g (4,13 mmol) of 4-chloropyrimidine, obtained as described above, and 0, 33 g (8.25 mmol) of NaH (60% in oil) in 10 ml dry DMF at 25oC mixed under stirring for 15 minutes Then add 0.7 ml (8,75 mmol) EtI, and conducting the reaction at 0oC within 2 hours and 25oC for 16 hours. Then the reaction mixture is divided between 100 ml EtOAc and 25 ml water and the EtOAc extract was washed with water (I ml), with brine, dried and concentrated in vacuo. The remainder chromatographic on silica gel using 8% EtOAc/hexane and get 1.2 product as a viscous liquid (yield 70%). Elemental analysis for C16H19N3ClI calculated, %: C 46,23, H br4.61, N 10,11, Cl 8,53, I 30,53, found, %: C 46,36, H of 4.57, N 9,89, Cl 8,79, I 30,38.

Example 33

N-(2-Methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4(S)-methyl-2'- pyrrolidin the oil) and to 0.19 ml (1.6 mmol) of (S)-N-methylpropanol in 10 ml of dry THF under nitrogen atmosphere is stirred at 25oC for 36 hours and then heated under reflux for 2 hours. The mixture is divided between 10 ml of EtOAc and 20 ml of water, and then EtOAc extract was washed with water, salt solution, dried and concentrated in vacuo. The remainder chromatographic on silica gel, using as eluent 0.5% of NH4OH/5% CH3OH/CH2Cl2and obtain 340 mg of product, which is then transferred to salt is a dihydrochloride by treatment of 1 M HCl in ether, melting point 101-103oC (decomp). Elemental analysis for C22H31N4IO 2HCl calculated, %: C 46,57, H 5,86, N 9,88, Cl 12,50, found, %: C 46,69, of 6.02 H, N 9,45, CI 12,69.

Example 34

N-(2,6-Dibromo-4-(1-methylethyl)phenyl)-4-thiomorpholine-6-methyl-2 - pyrimidinamine.

580 mg (2,46 mmol) 2-chloro-4-thiomorpholine-6-methylpyrimidine, 793 mg (2.7 mmol) of 2,6-dibromo-4-isopropylaniline and 216 mg (5.4 mmol) of NaH (60% in oil) are heated in toluene under reflux for 6 hours and purified by chromatography on silica gel using 25% EtOAc/hexane, yield 79%. tPL194-195oC. Elemental analysis for C18H22N4Br2S, calculated, %: C 44,46, H 4,56, N To 11.52, Br 32,87, S 6,59, found, %: C of 44.67, H of 4.54, N 11,24, Br 32,8, S 6,62.

Example 35

N-(2-Methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4, 6-dimethyl-2-pyrimidine is of yenilenebilir with n-BuLi in THF at 0oC followed by reaction with dimethyl sulfide. The resulting product was then purified by chromatography on silica gel, using as eluent 8% EtOAc/hexane, yield 37%, melting point 64-66oC. Elemental analysis for C18H25N3S; calculated, %: C 68,53, H 7,99, N 13,32, S 10,16. Found, %: C 68,43, H 7,94, N 13,16, S 10,02.

Example 36

N-(2-Methylthio-4- (1-methylethyl)phenyl-N-ethyl-4,6-dimethyl-2-pyrimidinamine.

Salt is a hydrochloride specified in example 35 connections receive the usual way, melting point 141-142oC. Elemental analysis for C18H25N3SHCl; calculated, %: C 61,43, H 7,45, N 11,94, S 9,11, Cl 10,07, found, %: C 61,07, H 7,40, N 11,80, S 9,37, Cl 9,77.

Example 37

N-(2-Methylsulfinyl-4-(1-methylethyl) phenyl)-N-ethyl-4,6-dimethyl-2 - pyrimidinamine.

Sulfide, the receipt of which is described in example 35 (300 mg, 0.95 mmol), reacts with 300 mg (1,41 mmol) NaIO4in 6 ml of MeOH and 3 ml of water at 25oC for 24 hours. The reaction mixture was separated between EtOAc and 25 ml of water, EtOAc extract was washed with water, salt solution, dried and concentrated in vacuo. The residue is purified by chromatography on silica gel, using as eluent EtOAc/hexane (1: 1) and obtain 220 mg of product (yield 70%), melting point 144 - 146o< 7,63, N 12,48, S 9,71.

Example 38

N-(2-Iodide-4-(1-methylethyl)phenyl) - N-ethyl-4-thiazolidine-6-methyl-2 - pyrimidinamine.

Specified in the title compound obtained as a viscous liquid. Elemental analysis for C19H25N4IS calculated, %: C 48,72, H 5,38, N 11,96, S 6,84, I 27,09. Found, %: C 48,80, H Are 5.36, N 11,84, S 6,95, I 27.05 Per.

Example 39

N-(2-Iodide-4-methoxymethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine.

Specified in the title compound obtained as a viscous liquid. Elemental analysis for C16H20N3IO, calculated, %: C 48,37, H 5,08, N of 10.58. Found, %: C 48,24, H 5,00, N 10,07.

Example 40

N-(4,6-Dimethyl-2-pyrimidinamine)-2,3,4,5-tetrahydro-4-(1-methylethyl)- 1,5-benzothiazepin.

To 4 g (15,32 mmol) 2-iodide-4-isopropylaniline and 2,53 g (18.4 mmol) of 4,6-dimethyl-2-mercaptopyridine in 30 ml of DMF is added 4.8 g (to 34.4 mmol) K2CO3and 600 mg (9.2 mmol) of copper powder, the resulting mixture was heated under reflux for 2 hours. After cooling, add 30 ml of EtOAc and filtered. The filtrate is divided between 200 ml of EtOAc and 50 ml of water, EtOAc layer washed with water (3 x 60 ml), with brine, dried and concentrated in vacuo, to obtain an oily residue which is used without further purification. Mass spec is added 132 mg (3.3 mmol) of NaH (60% in oil) and the mixture heated under reflux for 5 hours. Then add to 0.22 ml (2.2 mmol) of 1,3-dibromopropane and heated the reaction mixture for another 2 hours. Add the next portion (60 mg, 1.2 mmol) NaH (60% in oil) and continue heating for 3 hours. After cooling, filtered off solid foods, remove the solvent under vacuum, the filtrate chromatographic on silica gel using 8% EtOAc/hexane to obtain 220 mg of product (yield 32% over two stages). The mass spectrum of high resolution (msvr), calculated 314,169095 measured 314,168333. This compound was transferred to salt-hydrochloride treatment M HCl in ether, melting point 157-159oC.

Example 41

N-(2-Methylsulphonyl-4-(1-methylethyl)phenyl)-N - ethyl-4,6-dimethyl-2-pyrimidinamine.

Sulfoxide, the receipt of which is shown in example 37 (100 mg, 0.3 mmol), stirred in 4 ml of CH2Cl2and 8 ml of water with 20 mg (0.09 mmol) of benzyltriethylammonium 94.5 mg (0.6 mmol) KMnO4at 25oC for 16 hours. The mixture is divided between 60 ml of EtOAc and 40 ml of water, washed with EtOAc layer with water, salt solution, dried and concentrated in vacuo. The residue is purified by chromatography on silica gel using 25% EtOAc/hexane and obtain 85 mg of product (yield 81%), melting point which 174-175,3oC. Elemental analysis for C18>/BR>N-(2-Ethylthio-4-1-(1-methylethyl)phenyl)-N-ethyl - 4,6-dimethyl-2-pyrimidinamine.

Specified in the title compound receive the same manner as the product described in example 36. Melting point 128-130oC. Elemental analysis for C19H27N3SHCl, calculated, %: C 62,36, H 7,71, N 11,48, S 8,76, Cl RS 9.69. Found, %: C 62,64, H Of 7.75, N 11,43, S 8,59, Cl 9,58.

Example 43

N-(2-Ethylthio-4-methoxyaminomethyl)-N-ethyl-4,6-dimethyl-2 - pyrimidinamine.

Specified in the title compound receive the same manner as the product described in example 44, the melting point of 77-78oC. Elemental analysis for C19H26N4OS, calculated, %: C 63,66, H 7,31, N 15,63, S 8,95. Found, %: C 63,70 H 7,32, N 15,64, S 8,94.

Example 44

N-(2-Methylthio-4-methoxyaminomethyl)-N-ethyl-4,6 - dimethyl-2-pyrimidinamine.

To 4 g (29.6 mmol) of 41-aminoacetophenone in 20 ml of CH2Cl2and 50 ml of water containing 3.6 g (48 mmol) of NaHCO3add 9.0 g (of 35.4 mmol) I2. The mixture is stirred at 25oC for 20 hours. Then add 20 ml of a saturated aqueous solution of Na2SO3and the mixture is stirred for 10 minutes, divided between 120 ml of EtOAc and 10 ml of water. EtOAc extract was washed with brine, dried and con ucaut of 6.1 g of product (yield 79%).

To 3,05 g (of 11.69 mmol) 41-amino-31-iodoacetate in a mixture of 40 ml of ethanol and 10 ml of 3 M NaOH added 2.10 g (25,20 mmol) methoxyamine hydrochloride and heat the mixture under reflux for 2 hours. The ethanol is removed in vacuo, the residue is divided between 100 ml EtOAc and water (30 ml EtOAc layer washed with water, with brine and concentrated in vacuo. The obtained residue chromatographic on silica gel using 20% EtOAc/hexane to obtain 2.8 g of product (yield 83%).

The above product (1.5 g, 5.18 mmol) is subjected to interaction with 4,6-dimethyl-2-mercaptopyrimidine, as described above, receive the corresponding adduct with the release of 70% after chromatographic purification.

The above product, 1.1 g (of 3.64 mmol) is treated with 190 mg (4,73 mmol) NaOH (69% in oil) in 7 ml of dry xylene by heating under reflux for 5.5 hours. The reaction mixture was then divided between 100 ml EtOAc and 20 ml of water, EtOAc layer washed with water, salt solution, dried and concentrated in vacuo. The residue is purified by chromatography on silica gel using 25% EtOAc/hexane to obtain 900 mg of product (yield 82%).

The above product, 900 mg (2,98 mmol), handles 470 mg (3.4 mmol) of K2CO3and 0.22 ml (3.54 mmol) CH3Ut salt solution, dried and concentrated in vacuo. The rest is used for subsequent reactions without further purification.

The above product, 940 mg (2,97 mmol), treated with 160 mg (4.0 mmol) of NaH (60% in oil) in 7 ml of dry DMF for 20 minutes at 25oC, and then add of 0.32 ml (4.0 mmol) EtI. The mixture is stirred at 25oC for 16 hours and divide between 100 ml EtOAc and 20 ml of water, EtOAc layer washed with brine, dried, concentrated in vacuo and the residue chromatographic on silica gel using 20% EtOAc/hexane to obtain 600 mg of product (yield 58%), melting point 106-108oC. Elemental analysis for C18H24N4OS; calculated, %: C 62,76, H 7,02, N 16,27, S 9,31. Found, %: C 62,75, H 7.03 Is, N 16,12, S 9,45.

Example 45

N-(2-Methylsulphonyl-4-methoxyaminomethyl)-N-ethyl - 4,6-dimethyl-2-pyrimidinamine.

The sulfide obtained in the above sequence (0.3 g, 0.87 mmol), dissolved in 10 ml of CH2Cl2and type of 0.53 g (2,61 mmol) m-chloroperbenzoic acid (m SRVA, 85%), stirred mixture at 25oC for 16 minutes. The reaction mixture was quenched with Na2SO3and share between 40 ml of CH2Cl2and 30 ml of 5% NaHCO3. The organic layer is dried, concentrated in vacuo and the residue is s 151-154oC.

Elemental analysis for C18H24N4O3S, calculated, %: C 57,43, H 5,43, N 14,88, S charged 8.52. Found, %: C 57,24, H 6,40, N 14,18, S 8,60.

Example 46

N-(4-Bromo-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2 - pyrimidinamine.

2-Iodide-4-bromaniline subjected to interaction with 4,6-dimethyl-2-mercaptopyrimidine with the release of 93%. One gram of this adduct (3,22 mmol) dissolved in 10 ml of methanol and add 4 ml (4 mmol) of 1 M HCl in ether. The mixture is stirred at 25oC for 2 hours, the solvent is removed in vacuum, the residue is divided between 150 ml of a mixture of EtOAc and CH2Cl2(1:1) and 80 ml of saturated NaHCO3. The organic layer is dried and concentrated in vacuo receive 900 mg disulfide product which is dissolved in 10 ml of absolute ethanol and cooled to 0oC. To this solution was added 110 ml (2,92 mmol) NaBH4, allowed to warm to 25oC and stirred for 20 minutes, then add to 0.36 ml (USD 5.76 mmol) CH3I and stirred the mixture at 25oC for 2 hours. The solvent is removed in vacuum, the residue is divided between 100 ml EtOAc and 30 ml saturated NaHCO3. EtOAc layer washed with brine, and dried in vacuum. The remainder chromatographic on silica gel using 20% EtOAc/hexane and obtain 840 mg prod conditions, described above, with the release of 90%, the melting point of 91-93oC. Elemental analysis for C15H18BrN3S, calculated, %: C 51,15, H 5,15, N 11,93, Br 22,68, S 9,10. Found, %: C 51,25, H 5,15, N 11,89, Are 22.42 Br, S Which 9.22.

Example 47

N-(4-Ethyl-2-methylthiophenyl)-N-(1-methylethyl)-4,6-dimethyl-2 - pyrimidinamine.

Specified in the title compound obtained by method similar to that described in example 46, melting point 85-87oC. Elemental analysis for C18H25N3S, calculated, %: C 68,53, H 7,99, N 13,32, S 10,16, found, %: C 68,56, H 8,08, N 13,24, S 10,27.

Example 48

N-(-Ethyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine.

Specified in the title compound get by the method similar to the method of production of the product specified in example 46, so pl. 140-141oC. Elemental analysis for C17H23N3SHCl, calculated, %: C 60,43, H 7,16, to 12.44 N, S 9,49, Cl 10,49. Found, %: C 60,42, H 6,89, N 12,36, S Being 9.61, Cl 10,63.

Example 49

N-(2-Methylthio-4-(N-acetyl-N-methylamino)phenyl)-ethyl-4,6 - dimethyl-2-pyrimidinamine.

Specified in the title compound get by the method similar to the method of production of the product specified in example 46, so pl. 158-160oC. Elemental analysis for C18H24N4OS, calculated, %: C 62,76, H 7,02, N Il-2 - pyrimidinamine.

Specified in the title compound get by the method similar to the method of production of the product specified in example 46, so pl. 99-100oC. Elemental analysis for C18H23N3O2S, calculated, %: C 62,58, H of 6.71, N 12,16, S 9.28 are. Found, %: C 62,83, H Is 6.78, N 12,08, S 9,44.

Example 51

N-(4-Methoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidine.

A mixture of 352 g (1 mmol) 4-bromo-2-methylmercaptopropionaldehyde, 14.3 mg (0.1 mmol) CuBr and 0.5 ml (2.5 mmol) of a 25% weight/weight MeONa in MeOH is heated under reflux in 5 ml of dry DMF for 1.5 hours. The reaction mixture is divided between 100 ml EtOAc and 30 ml water and the EtOAc layer washed with water (2 x 30 ml), with brine, dried and concentrated in vacuo. The remainder chromatographic on silica gel using 20% EtOAc/hexane, and obtain 210 mg of product (yield 69%), so pl. 128-130oC. Elemental analysis for C16H21N3OS1/4H2O, calculated, %: C 62,41, N 7,07, N 13,64, S 10,41. Found, %: C 62,06, H 6,97, N 13,26, S 10,47.

Example 52

N-(4-Cyano-2-methylthiophenyl) -N-ethyl-4,6-dimethyl-2 - pyrimidinamine.

Specified in the title compound get by the method similar to the method of production of the product specified in example 51; T. pl. 112-113oC. Elemental analysis for C16H8N4enyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine.

To 0.5 g (1,68 mmol) of the nitrile specified in example 52, in 10 ml of dry C6H6add 1.1 ml (3.3 mmol) of a 3 M solution of CH3MgI in ether, the mixture is stirred at 25oC for 2 hours and heated under reflux for 1 hour. The reaction is quenched with water and 10% HCl and stirred for 20 minutes, then add 1 M NaOH until then, until the solution becomes alkaline and then extracted with 100 ml EtOAc. The organic layer is washed with water, salt solution, dried and concentrated in vacuo. The remainder chromatographic on silica gel using 20% EtOAc/hexane to obtain 370 mg of product (yield 70%), so pl. 125-126oC. Elemental analysis for C17H21N3OS, calculated, %: C 64,73, H of 6.71, N 13,32, S 10,10. Found, %: C 64,53, H 5,73, N 13,08, S 10,19.

Example 54

N-(4-Propionyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2 - pyrimidinamine.

Specified in the title compound get the technique similar to the product specified in example 53, so pl. 139-141oC. Elemental analysis for C17H21N3OS, calculated, %: C 65,62, H? 7.04 baby mortality, was 12.75 N, S 9,73. Found, %: C 65,53, H 7,19, N 12,51, S 9,62.

Example 55

N-(4-(1-Methoxyethyl)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2 - pyrimidinamine.

To 1.05 g of 3.33 mmol) of the ketone described in the bask to the 25oC and stirred for 16 hours. Then the solvent is removed in vacuum and the residue is divided between 100 ml EtOAc and 30 ml of 0.3 M NaOH. EtOAc layer washed with water, salt solution, dried and concentrated in vacuo. The remainder chromatographic on silica gel using EtOAc/hexane (2: 1) and obtain 1 g of the product, so pl. 46-49oC. the Above-mentioned alcohol, 0,72 g of 2.27 mmol) interacts with 108,09 mg (2.7 mmol) of NaH (60% in oil) in 5 ml dry DMF at 25oC for 20 minutes, and then add 0.3 ml (4.8 mmol) CH3I. the Mixture is stirred for 20 hours and add an additional amount (60 mg, 1,5 mmol) NaH (60%) and 0.1 ml of CH3I, the mixture is stirred for an additional 16 hours. Then the reaction mixture is divided between 100 ml EtOAc and 30 ml of water, EtOAc layer washed with water (2 x 30 ml), with brine, dried and concentrated in vacuo. The remainder chromatographic on silica gel using 20% EtOAc/hexane to obtain 600 mg of the product as a viscous liquid. This product was transferred to salt-hydrochloride by treatment of 1 M HCl in ether, so pl. 120-122oC.

Example 56

N-(4-(N-Methylamino)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine.

A solution of 0.2 g (of 0.58 mol) of 4-N-acetyl-N-methyl-2-methylmercaptopurine in 10 ml ethanol and 2 ml of water containing 272 continued for 3 hours. The ethanol was concentrated in vacuo and the residue separated between 100 ml EtOAc and 30 ml of water. The EtOAc extract was washed with brine, dried and concentrated in vacuo. The residue is subjected to chromatography on a column of silica gel using 1:1 EtOAc/hexane to obtain 140 ml of product with 80% output, so pl. 141 - 142oC. Elemental analysis for C16H22N4S, calculated, %: C 63,54, H 7,33, N Holds 18.52, S or 10.60. Found, %: C 63,63, H 7,41, N 18,55, S 10,80.

Example 57

N-(4-(N, N-Dimethylamino)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine.

K, 0.36 g (1.2 mmol) of 4-N-methyl-2-methylmercaptopropionaldehyde in 4 ml of dry DMF added 60 mg (1.5 mmol) of NaOH (60% in oil), the mixture is stirred for 20 minutes, then add 0.1 ml (1,67 mmol) CH3I and the reaction continued at a temperature of 25oC for 16 hours and Then share it between 100 ml EtOAc and 20 ml of water. The EtOAc extract was washed with water, brine, dried and concentrated in vacuo. The residue is subjected to chromatography on a column of silica gel using 20% EtOAc/hexane to obtain 150 mg of the product (40% yield); so pl. 119-120oC. Elemental analysis for C17H24N4S, calculated, %: C 64,52, H of 7.64, N 17,70, S 10,13. Found, %: C 64,55, H 7,65, N 17,50, S 10,31.

Example 58

N-(2-Bromo-4-(1-methylethyl)phenyl)-N-E. the NCA (1.7 g, 20 mmol) is heated under reflux in 25 ml of dichloromethane for 3 days. The reaction mixture was filtered through Celite, the filtrate was concentrated in vacuo and given a light yellow oil. This oil is purified by chromatography on silica gel using 10% ethyl acetate in hexane, and obtain 112 mg of a white solid product. The mass spectrum of the high-resolution chemical ionization calculated: 362, 0868 (M + H), found: 362, 0864.

Example 59

N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-hydroxyethoxymethyl-6 - methyl-2-pyrimidinamine.

Connection XLVII indicated on the above diagram 12 (0,41 g to 0.92 mmol) and sodium borohydride (76 mg, 2 mmol) in 10 ml of ethanol is stirred for 21 hours at room temperature. The reaction mixture is acidified with 1.0 N hydrochloric acid, stirred for 10 minutes, alkalinized with 1.0 N sodium hydroxide and extracted with dichloroethane. The combined extracts dried over magnesium sulfate and concentrated in vacuo, get a clear oil, which chromatographic on silica gel using 30% ethyl acetate in hexane, to obtain 345 mg of product (yield 92%). The mass spectrum of the high-resolution chemical ionization; calculated 408, 1287 (M + H), found: 408, 1284.

Example 60

N-(2-Bromo-6-hydroxy-4-methoxyp (214 mg, of 0.58 mmol) in 15 ml of dichloromethane in a nitrogen atmosphere is cooled in a bath of dry ice and acetone gradually add tribromide boron (1,0 M in dichloroethane, of 0.58 ml). The reaction mixture is allowed to gradually warm to room temperature, stirred under these conditions during the night. The reaction is quenched with water, the aqueous layer was alkalinized with a saturated solution of sodium bicarbonate and extracted with dichloroethane. The combined extracts dried over magnesium sulfate, concentrated in vacuo, get a reddish-brown solid, which is recrystallized from a mixture of ethyl acetate/hexane. Obtain 58 mg of the product, so pl. 157-160oC. Elemental analysis calculated, %: C 51,15, H 5,15, N 11,93, Br 22,69. Found, %: C 51,02, H 5,10, N 11,83, Br 22,52.

Example 61

N-(3-Bromo-4,6-acid)-N-ethyl-4,6-dimethyl-2-pyrimidinamine.

Part A. (Synthesis of 3-bromo-4,6-dimethoxyaniline). To a mixture of 2,4 dimethoxyaniline (5.0 g, 33 mmol) and potassium carbonate (10.4 g, 75 mmol) in 30 ml of chloroform is slowly added bromine (5.75 g, 33 mmol) in 20 ml of chloroform. After stirring for two hours the reaction mixture is washed three times with water, dried over magnesium sulfate, concentrated in vacuo and get a dark solid. The resulting material purified chrome the CSO solids (yield 23%).

Part C. Using the method described in example 1, parts B-C, and aniline, the receipt of which is described above in part A, get mentioned in the title compound.

Example 62

N-(2,3,-dibromo-4,6-acid)-N-ethyl-4,6-dimethyl-2 - pyrimidinamine.

Part A. (Synthesis of 2,3-dibromo-4,6-dimethoxyaniline). 2,4-dimethoxyaniline, 1 EQ. benzyltrimethylammonium and 2 EQ. calcium carbonate is stirred at room temperature in a solution of methanol and dichloromethane (2:5) for one hour. The solution is filtered, the filtrate is evaporated under vacuum and get a brown oil which is purified on silica gel using 20% ethyl acetate in hexane (Rf= 0,2).

Part C. Using the procedure described in example 1, parts B-C, and aniline, the receipt of which is described above in part A, get mentioned in the title compound.

Example 63

N-(2,6-Dibromo-4-(ethoxy)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine.

Part A. carry out the synthesis of 2,6-dibromo-4-ethoxyaniline, using the methodology of the synthesized 4-ethoxyaniline described Kajigaeshi et al., Bull. Chem. Soc. Jpn., 61:597-599 (1988). Aniline, 1 EQ. benzyltrimethylammonium, 2 EQ. calcium carbonate is stirred at room temperature in a solution of MeOH : CH2B H2O and extracted three times with CH2Cl2. The combined extracts are dried over MgSO4, filtered and evaporated under vacuum.

Get a brown oil which is purified on silica gel using 10% EtOAc in hexane.

Part C. Using the procedure described in example 1, part B-C, and aniline, the receipt of which is described above in part A, get mentioned in the title compound.

Example 64

1-(2-Bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole.

Part A. a Solution of 42,80 g (0,200 mol) of potassium salt of formulaction (K. Gewald, Z. Chem., 1 : 349 (1961)) and 29,20 g (0,200 mol) 2-bromo-4-isopropylaniline in a mixture of 50 ml of glacial acetic acid and 120 ml of ethanol is heated under reflux in nitrogen atmosphere for two hours. Remove most of the acetic acid and ethanol and place the residue in ethyl acetate. This solution was washed with 10% sodium bicarbonate solution, dried over anhydrous sodium sulfate and after removal of the solvent get dark oily residue, which chromatographic on silica gel using hexane/ethyl acetate (80:20). Get 24,23 g (40%) of N-(2-bromo-4-isopropylphenyl)-aminomethylenemalonate. Mass spectrum: (M + NH4)+= 321, 0 calculated: 321 is (3.65 mmol) of N-(2-bromo-4-isopropylphenyl)-aminomethylenemalonate (part a). The mixture is stirred for 16 hours under nitrogen atmosphere. The solvent is removed by evaporation. The residue is placed in ethyl acetate and washed successively 1 N hydrochloric acid, 10% sodium bicarbonate solution and saline. The solution is dried over anhydrous sodium sulfate and evaporated, to obtain a dark residue. The resulting residue is dissolved in dichloromethane, added 20 g of silica gel, the mixture is evaporated to dryness. This mixture is placed in the upper part of the chromatographic column filled with silica gel in hexane. The column is sequentially washed 10, 15, 20, 25, 30% the ethyl acetate in hexane and obtain 0.65 g (yield 59%) of 1-(2-bromo-4 - isopropylphenyl)-2-amino-4-cyanoferrate. Mass spectrum: (M + N)+=304,0; calculated: 304,0. Rf=0,22 (thin layer chromatography on silica gel, elution with hexane/ethyl acetate (70:30).

Part C. the Mixture 18,51 g (0,0609 mol) of 1-(2-bromo-4-isopropylphenyl)-2 - amino-4-cyanoprop, 300 ml of ethanol, 0.6 ml conc. hydrochloric acid and 10 ml (9.75 g, 0,0974 mol) of 2,4-pentanedione heated under reflux in nitrogen atmosphere for 4 hours. The mixture is cooled and the solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate and washed with 10% sodium bicarbonate solution and brine LASS="ptx2">

The remainder chromatographic on silica gel with a consistent gradient elution of 0, 10, 15, 20, 25 and 30% ethyl acetate in hexane. Get to 17.6 g (78%) of 1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7 - azaindole with so pl. 105,8oC. Mass spectrum (M + H)+= 368,0749 calculated, 368,0762 (79Br). Rf= 0,45 thin-layer chromatography on silicagel, elution with a mixture of hexane (ethyl acetate 70:30).

Example 65

1-(2-Bromo-4-isopropylphenyl)-4,6-dimethyl-7-azaindole.

A mixture of 4.00 g of 1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6 - dimethyl-7-azaindole and 40 ml of 65% sulfuric acid is heated under reflux for 1 hour. The solution is cooled and poured on ice. Add concentrated ammonium hydroxide until alkaline reaction of the indicator paper. The mixture is extracted with ethyl acetate. The solution is diluted with a mixture of hexane and ethyl acetate and passed through a short column with silica gel. The eluate evaporated, the residue is recrystallized from 20 ml of hexane, gain of 2.45 g (yield 66%) of 1-(2-bromo-4-isopropylphenyl)-4,6-dimethyl-7-azaindole. Mass spectrum: (M + H)+= 343,0818. Calculated: 343,0810. Rf=0,54 on silica gel (hexane/ethyl acetate, 70: 30).

Example 66

1-(2-Bromo-4-isopropylphenyl)-3-cyano-6-methyl-4-phenyl-7-azaindole.

See ewout in the flask, equipped with a water separator for 2 hours. The solvent is removed by evaporation, the residue chromatographic on silica gel performing a gradient elution of 0, 5, 10, 15% ethyl acetate in hexane. Receive 1-(2-bromo-4-isopropyl)-3-cyano-4-methyl-6-phenyl-7-azaindole and 1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-4-methyl-7-azaindole. The value of Rfequal respectively to 0.38 and 0.28 (silica gel, hexane/ethyl acetate, 80:20). The establishment of patterns is based on data from NMR spectroscopy decamillionaire compounds according to example 67.

Example 67

1-(2-Bromo-4-isopropylphenyl)-6-methyl-4-phenyl-7-azaindole.

A mixture of 130 mg (0,302 mmol) 1-(2-bromo-4-isopropylphenyl)-3-cyano-6 - methyl-4-phenyl-7-azaindole (example 66) and 10 ml of 0.65% sulfuric acid is heated under reflux for one hour. The mixture was poured on ice. Add concentrated ammonium hydroxide until alkaline reaction of the indicator paper. The mixture is extracted with ethyl acetate. The extract is evaporated and chromatographic on silica gel using hexane/ethyl acetate, 70:30. Obtain 112 mg (yield 92%) of 1-(2-bromo-4-isopropylphenyl)-6-methyl-4-phenyl-7-azaindole. Mass spectrum: (M + H)+= 405,10 calculated 405,10. In the same way obtain 1-(2-bromo-4-isopropylphenyl)-4-methyl shall indol.

Part A. N-(2-Bromo-4,6,-acid)-aminomethylenemalonate obtained from 2-bromo-4,6-dimethoxyaniline according to the method described in example 64, part A. Mass spectrum: (M + H)+= 322,0; calculated: 322,16. Rf=0,19 (silica gel, hexane/ethyl acetate, 60:40).

Part C. the Product, the receipt of which is described in part A, cyclist according to the method described in example 64, part b, receive 1-(2-bromo-4,6-acid)-2-amino-4-cyanoprop (yield 79%), Rf= 0,19 (silica gel, hexane/ethyl acetate, 60:40).

Part C. the Product, the receipt of which is described in part b, treated with 2,4-pentanedione as described in example 64, part C, and get 1-(2-bromo-4,6-acid)-3-cyano-4,6-dimethyl-7-azaindole get 1-(2-bromo-4,6-acid)-3-cyano-4,6-dimethyl-7-azaindole (yield 92%). Mass spectrum: (M + H)+= 388,0; calculated 388,0, Rf=0,44 (silica gel, hexane/ethyl acetate, 60:40).

Example 69

1-(2-Bromo-4,6-acid)-4,6 dimethyl-7-azaindole.

A mixture of 200 mg of 1-(2-bromo-4,6-acid)-3-cyano-4,6-dimethyl-7 - azaindole and 10 ml of 0.65% sulfuric acid is heated under reflux for one hour. The mixture is treated as described in example 65, and obtain 185 mg of the crude product. A portion (40 mg) of this product cleans WP5) and get 11 mg of 1-(2-bromo-4,6-acid) of 4,6-dimethyl-7-azaindole. Mass spectrum: (M + H)+= 360,9 calculated 361,1.

Example 70

1-(2-Bromo-4-isopropylphenyl)-6-chloro-3-cyano-methyl-7-azaindole.

Part A. a Solution of 30,04 g of the product obtained according to example 64, part b, 1.9 ml (1,94 g, 14.9 mmol) ethylacetoacetate and 0.1 ml of concentrated hydrochloric acid in 30 ml of ethanol is heated under reflux for 16 hours. Upon cooling, a precipitate, which is removed by filtration, and obtain 1.68 g of crystals with so pl. 202,4oC 1-(2-bromo-4-isopropylphenyl) -4-methyl-7-azaindole-6-he. TLC on silica gel using mixtures of hexane/ethyl acetate, 70: 30, gives a single spot, Rf= 0,29. Mass spectrum: (M + H)+= 370,5. Calculated 370,05 (79Br).

Part C. a Mixture of 185 mg of 7-azaindole-6-it (part a), 50 ml of POCl3heated in an autoclave at 180oC for 10 hours. Excess POCl3removed by distillation under reduced pressure. The residue is distributed between ethyl acetate and water. Separate an ethyl acetate layer and washed with 10% sodium bicarbonate solution, then with brine. The solution is dried (Na2SO4) and evaporated. TLC of the residue on silica gel using hexane/ethyl acetate (70:30) gives the main product (Rf= 0,52), with minor blemishes (Rf= 0.4 mg of product with Rf= 0,52, so pl. 123,8oC. This product represents 1-(2-bromo-4-isopropylphenyl)- 6-chloro-3-cyano-methyl-7-azaindole.

Example 71

1-(2-Bromo-4-isopropylphenyl)-6-chloro-4-methyl-7-azaindole.

A mixture of 50 mg of 1-(2-bromo-4-isopropylphenyl)-6-chloro-3-cyano-4-methyl-7 - azaindole and 10 ml of 65% sulfuric acid is heated under reflux for 1 hour. The cooled solution was poured on ice and add 17 ml of concentrated ammonium hydroxide. The alkaline mixture is extracted with ethyl acetate. The obtained extract was washed (brine), dried (Na2SO4) and evaporated. TLC of the residue on silica gel using mixtures of hexane/ethyl acetate (70: 30) gives the main new spot (Rf=0,58) and traces of the unchanged original product (Rf= 0,52). The crude product was purified preparative TLC and obtain 39 mg of non-crystalline product, which is slightly crystallizes during storage. Mass spectrum: (M + H)+= 363,0247 calculated 363,0264 (79Br35Cl).

Example 72

1-(2-Bromo-4-isopropylphenyl)-3-cyano-6-methyl-7-azaindole.

To a solution of 1,085 g (5,07 mmol) of the product obtained according to example 64 (part b), and 0.80 ml (0,797 g; 6,03 mmol) acetoacetanilide in 20 ml ethanol add 0,Hledat, evaporated and get dark heavy oil. TLC on silica gel using mixtures of hexane/ethyl acetate (70:30) gives two main spots with Rf= 0.47, and Rf= 0,41. The oil obtained is dissolved in ethyl acetate, add 20 ml of powder of silica gel, and evaporated to dryness. The powdered residue is loaded into the upper part of the column with 60 ml of silica gel in hexane. Column elute with step gradient using 0, 5, 10, 15, 20, 25% the ethyl acetate in hexane. Faction elwira first, give 0.32 g of the target 1-(2-bromo-4-isopropylphenyl)-3 - cyano-6-methyl-7-azaindole, Rf= 0,47. This product may crystallize from hexane, forming 176 mg of crystals, so pl. 176,0oC. Mass spectrum (M + H)+= 354,0595 calculated 354,0606.

Example 73

1-(2-Bromo-4-isopropylphenyl)-6-methyl-7-azaindole.

The product according to example 72 treated with 65% sulfuric acid as described in example 65, and receive the desired product as a viscous oil. TLC on silica gel with hexane and ethyl acetate (70:30) gives Rf= 0,57. Mass spectrum (M + H)+= 329,0641 calculated: 329,0653 (79Br).

Example 74

1-(2-Bromo-4-isopropylphenyl)-4-chloro-3-cyano-6-methyl-7-azaindole.

Part A. a Solution of 1.24 g of 1-(2-bromo-4-isopropylphenyl) -3-cyano-6 - methyl-7-azaindole the value of 6 hours. The mixture is cooled and washed first with 10% sodium bicarbonate solution, then with brine. The solution is dried (Na2SO4) and evaporated receive the remainder. TLC on silica gel with a mixture of dichloromethane/ethanol (95:5) gives the trace of the stain with Rf= 0.88 and the main spot with Rf= 0,34. This product is purified by chromatography on silica gel with dichloromethane, then with 1% methanol in dichloromethane get traces of unchanged 1-(2-bromo-4 - isopropylphenyl)-3-cyano-6-methyl-7-azaindole (Rf= 0,88) and 0, 92 g of 1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-7-azaindole-7-oxide (Rf= 0,34) so pl. 179,2oC. Mass spectrum: (M + H)+= 370,0559 calculated: 370,0555 (79Br).

Part C. a Mixture of 370 mg of 7-oxide (part a) and 5 ml of POCl3heated under reflux for two hours. The solution is cooled, poured on ice and stirred until a until a large part of the POCl3not hydrolyzed. The mixture is alkalinized with concentrated ammonium hydroxide and extracted with ethyl acetate. The extract was dried (Na2SO4), evaporated and obtain a viscous residue. TLC on silica gel with a mixture of dichloromethane/methanol gives the main spot with Rf= 0,79. The resulting product was then purified preparative TLC on silica gel using hexane/etelaat-methyl-7-azaindole, so pl. 123,3oC. Mass spectrum: (M + H)+=388,0197 calculated: 388,0216 (79Br,35Cl).

Example 75

1-(2-Bromo-4-isopropylphenyl)-4-chloro-6-methyl-7-azaindole.

A mixture of 190 mg of 3-cyano-7-azaindole (example 71) and 5 ml of 65% sulfuric acid is heated under reflux for 30 minutes. The solution was poured on ice and extracted with ethyl acetate. The extract is washed with brine, dried (Na2SO4), evaporated and get the rest. TLC of the residue on silica gel with a mixture of ethyl acetate/hexane (60:40) gives the main spot with Rf= 0,67. The residue is purified preparative TLC and obtain 130 mg of a viscous oil, which is 1-(2-bromo-4 - isopropylphenyl)-4-chloro-6-methyl-7-azaindole. Mass spectrum (M + H)+= 3636, 0246, calculated: 343, 0264 (79Br, 35Cl).

Example 76

N-[2-Bromo-6-methoxy-pyridin-3-yl]-N-ethyl-4,6-dimethyl-2 - pyrimidinamine.

Part A. To 3,18 g (of 25.6 mmol) of commercially available 5-amino-2-methoxypyridine in a solution of methylene chloride (50 ml) and methanol (20 ml) add benzyltrimethylammonium (10 g, 25.6 mmol), the mixture is stirred at room temperature for 24 hours. The solvent is removed, the resulting residue is placed into water and extracted with (3 x 100 ml) utilized the scientists of the product chromatographic on silica gel, using as solvent 30% ethyl acetate in hexane, to obtain 5-amino-2-bromo-6-methoxypyridine, C6H7N2OBr. Mass spectrum: 203 (M + H)+.

Part C. the Product described above in part A, enter into reaction with 2-chloro-4,6-dimethylpyrimidine (example 1, part a) using NaH (1.2 EQ) in DMF, and get N-[2-bromo-6-methoxypyridine-3-yl]- 4,6-dimethyl-2-pyrimidinamine, C12H13N4OBr, mass spectrum: 309 (M + H)+.

Part C. the Product obtained according to the methodology described above (part b), alkylate by the same method used in example 4, part C. Receive specified in the title compound, C14H17N4OBr. Mass spectrum: 337 (M + H)+.

Example 77

N-[3-Bromo-5-methylpyridin-2-yl]-N-ethyl-4,6-dimethyl-2-pyrimidinamine.

Part A. 1.0 g (to 5.35 mmol) of commercially available 2-amino-3 - bromo-5-methylpyridine is subjected to interaction with 2-chloro-4,6 - dimethylpyrimidine (example 1, part a) using NaH (1.2 EQ.) in DMF, and get N-[3-bromo-5-methylpyridin-2-yl] -4,6-dimethyl-2 - pyrimidinamine, C12H13N4Br. Mass spectrum: 293 (M + H)+.

Part C. the Product, the receipt of which is described in part A, alkylate using the same technique, which is used in the example CLASS="ptx2">

Example 78

N-[6-Methoxypyridine-3-yl]-N-ethyl-4,6-dimethyl-2-pyrimidinamine.

To 200 mg of N-[2-bromo-6-methoxypyridine-3-yl]-N - ethyl-4,6-dimethyl-2-pyrimidinamine in 25 ml of dry DMF is added 500 mg of K2CO3, 100 mg of CuI and 0.4 ml of the research, the reaction mixture is heated under reflux for 6 hours, the Reaction mixture is filtered and poured into water, then extracted with ethyl acetate (3 x 50 ml). The extracts are dried to remove the solvent, the residue chromatographic on silica gel using as solvent a 20% ethyl acetate in hexane (Rf=0,4), and get mentioned in the title compound, C14H18N4O. Mass spectrum: 259 (M + H)+.

Example 79

N-[2-Bromo-6-methoxypyridine-3-yl] -N-ethyl-4-methyl-6-(4-morpholinyl)- 1,3,5-triazine-2-amine.

Part A. To 2,4-d sodium dichloro-6-methyl-S-triazine (part A, example 23, 2.0 g, 12.3 mmol) in 50 ml of CH2Cl2cooled to 0oadd morpholine (1.1 ml, 12.3 mmol), the reaction mixture is allowed to warm to room temperature and stirred for 2 hours. Then the reaction mixture was poured into water and separate the layers. The aqueous layer was washed with CH2Cl2(3 x 50 ml), combine the organic layers and dried. Remove the solvent and the resulting material chromate is - morpholino)-6-methyl-S-triazine, C8H11N4OCl (M + H)+.

Part C. the Product, the receipt of which is described in example 76, part a (0.6 g, 3.0 mmol), and the product, the receipt of which is described in example 79, part a (to 0.63 g, 3.0 mmol), in dioxane is stirred at room temperature for 24 hours. The reaction mixture was poured into water, then extracted with ethyl acetate (3 x 50 ml). The extracts are dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting product chromatographic on silica, using as solvent 30% ethyl acetate in hexane, and get the product of accession, C14H17N6O2Br. Mass spectrum: 381 (M + H)+/

Part C. the Product obtained according to the above parts, alkylate by the same method used in example 5, part C, and get mentioned in the title compound, C16H21N6O2Br, mass spectrum: 409 (M + H)+.

Example 80

N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(N-(2-furylmethyl)-N - methylamino)carbonyl-6-methylpyrimidine.

Sodium hydride (60% in oil, 0.1 g, 2.4 mmol) was washed with hexane and double-decanted, suspended in anhydrous N,N-dimethylformamide (DMF, 5 ml) and dropwise with stirring astotnom DMF (5 ml). After 30 minutes add iodomethane (0,37 g, 2.6 mmol) and stirred the reaction mixture for 18 hours. Carefully add water (50 ml) and extracted with water, the mixture 3 times with chloroform. The combined organic layers dried over magnesium sulfate, filtered and concentrated in vacuo, get a brown oil. After column chromatography (ethyl acetate/hexane, 1:2) get listed in title product as a brown oil (850 mg, yield 82%, Rf= 0,35). NMR (CDCl3, 300 MHz): 7,5 (d, 1H, J=9), and 7.3 (d, 1H, J=12), 7,25 to 7.2 (m, 1H), 7,12 (dd, 1H, J= 8,1), 6,8 (s, 1H), and 6.3 (d, 1H, J=12), and 6.0 (br s, 0.5 H) and 5.9 (br s, 0.5 H) and 4.65 (br s, 2H), 4.2V (br s, 1H), 3,75 - 3,6 (m, 1H), from 3.0 to 2.8 (m, 4H), 2,4 (br s, 3H), of 1.40 (d, 6H, J=7), and 1.2 (t, 3H, J=8). The mass spectrum of the high-resolution chemical ionization, calculated (C23H27BrN4O2): 471,1396 (M + H), found: 471,1387.

Example 81

N-(2-Bromo-4-(1-methylethyl) phenyl)-N-ethyl-4- ((4,4-ethylenedioxythiophene)-carbonyl)-6-methylpyrimidine.

A solution of sodium hydride (60% in oil, 0.12 g, 3 mmol) was washed with hexane and double-decanted, suspended in anhydrous THF (5 ml) and dropwise with stirring a solution of 4-piperidin - etilenglikolya (of 0.43 g, 3 mmol) in anhydrous THF (5 ml). The reaction mixture is heated to a temperature of education phlegmy, mix the sludge)ethylamino)-6-methyl-4-pyrimidinecarboxylic (example 18), 1.0 g, 2.54 mmol in anhydrous THF (10 ml) and stirred the reaction mixture at room temperature for 98 hours, the Reaction mixture was poured into 1 N NaOH solution (100 ml), stirred and extracted 3 times with ethyl acetate, the combined organic layers dried over magnesium sulfate, filtered and concentrated in vacuo. Get a brown oil. After column chromatography (chloroform/methanol, 9: 1) to obtain N-(2-bromo-4-(1 - methylethyl)phenyl)-N-ethyl-4-(4,4-ethylene-dioxopiperidin)carbonyl-6 - methylpyrimidine in the form of an orange-yellow oil (260 mg, yield 52%, Rf=0,75). The mass spectrum of the high-resolution chemical ionization calculated for C24H31BrN4O3: 503,16578 (M + H), found: 503,16571.

Example 82

N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4- (4-oxopiperidine)carbonyl-6-methylpyrimidine.

A solution of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4,4 - ethylenedioxythiophene)carbonyl)-6-methylpyrimidine (260 mg) in a mixture of 1 N HCl solution (2.5 ml) and THF (2.5 ml) is stirred at a temperature of education phlegmy 20 hours, the Reaction mixture was poured into 1 N NaOH solution and extracted three times with ethyl acetate. The combined organic layers dried over MgSO4, filtered and concentrated in vacuo, get the uke is(s, 1H), 7,2 (d, 1H, J=8), and 7.1 (d, 1H, J=8), 6,8 (br s, 1H), from 4.3 to 4.1 (m, 1H), 3.95 to of 3.85 (m, 1H), 3.75 to 3.6V (m, 1H), 3,55-3,4 (m, 1H), 2,95-to 2.85 (m, 1H), 2,6-2,3 (m, 4H), of 2.0 to 1.6 (m, 2H), 1,4-of 1.15 (m, 12H). The mass spectrum of the high-resolution chemical ionization calculated for C22H27BrN4O2: 459,1396 (M + H); found: 459,1386.

Example 83

N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-oxopiperidine)methyl-6 - methylpyrimidine, salt is hydrochloride.

To a solution of borane in tetrahydrofuran (1 M, 29 ml, 29 mmol) is added dropwise a solution of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4,4 ethylenedioxythiophene)carbonyl-6-methylpyrimidine (1,67 g, 3.3 mmol) in anhydrous THF (7 ml) under stirring in nitrogen atmosphere. The reaction mixture is heated to a temperature of early education phlegmy and stirred for 20 h, then cooled to room temperature. Add dropwise a solution of glacial acetic acid, then the reaction mixture is heated to a temperature of education phlegmy and stirred for 4 hours, then cooled to room temperature. The reaction mixture was concentrated in vacuo, the residue is treated with excess 1 N NaOH solution and extracted three times with ethyl acetate. The combined organic layers dried over MgSO4, filtered and concentrated in vacuo, get the oil. After colonic the-6-methylpyrimidine in the form of a pale brown oil (860 mg). Mass spectrum (chemical ionization): 489,491 (M + H).

Ketal dissolved in a mixture of 33% HCl solution (10 ml) and THF (5 ml). The resulting solution was stirred at reflux for 65 hours, then cooled to room temperature and alkalinized 1 N NaOH solution. The aqueous mixture is extracted three times with ethyl acetate. The combined organic layers dried over MgSO4, filtered and concentrated in vacuo, get the oil. After column chromatography (ethyl acetate/hexane, 4:1) get listed in title product in the form of the free base as an oil (600 mg, total yield 41%). The mass spectrum of the high-resolution chemical ionization calculated for C22H29BrN4O: 444,1603 (M + H), found: 444,1594.

The above oil (0.55 g, 1,24 mmol) dissolved in ether (5 ml) and treated with 1 N HCl solution in ether. The precipitate is collected and rinsed with ether. After drying in vacuo get a white powder (500 mg, yield 84%), so pl. 186-188oC. Elemental analysis (C22H29BrN4O HCl), calculated, %: C 54,92, P 6,24, N 11,65, Br 16,64, Cl 7,39; found, %: C 54,62, H 6,37, N 11,41, Br 16,57, Cl 7,35.

Example 84

N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4- (4-imidazol-1-yl)methyl-6-methylpyrimidine.

To sodium hydride (60% in oil, 0.1 g, 2.4 mmol), washed with hexane and twice dekotirovaniem suspended in anhydrous THF (10 ml), add in one reception imidazole (146 mg, 2.14 mmol) and heated the reaction mixture to a temperature of education phlegmy with stirring for 2 hours the Solution nelfinavir (without purification) in anhydrous THF (10 ml) was added dropwise to cooled to room temperature the reaction mixture. The reaction mixture was stirred for 68 h, then poured into water and extracted three times with ethyl acetate. The joint organization of the intramural chromatography (ethyl acetate) receive: (1) N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4 - hydroxymethyl-6-methylpyrimidine (130 mg, the total yield of 8%, Rf= 0,7), (2) is specified in the title of the product (600 mg, total yield 59%, Rf= 0,007). The NMR spectrum (CDCl3, 300 MHz): 7,6 to 7.4 (m, 2H), 7,2 (dd, 1H, J=7,1), to 7.15 (d, 1H, J= 8), 7,05 (s, 1H), 7,0 to 6.8 (m, 1H), equal to 6.05 (s, 1H), 4.95 points and 4.8 (m, 2H), 4,25 to 4.1 (m, 1H), 3,8-3,6 (m, 1H), 3,0-to 2.85 (m, 1H), the 2.4-and 2.1 (br m, 3H) and 1.3 (d, 6H, J=8), and 1.2 (t, 3H, J=8). The mass spectrum of the high-resolution chemical ionization calculated for C20H24BrN5: 413,1293 (M + H), found: 413,1275.

Example 85

N-(2-Bromo-4-(1-methylethyl) phenyl)-N-ethyl-4-(3-(methoxyphenyl) methoxymethyl)-6-methylpyrimidine.

To a mixture of N-(2-bromo-4-(l-methylethyl)phenyl)-N-ethyl-4-hydroxy-methyl)-6 - methylpyrimidine (1.0 g, 2.7 mmol), triethylamine (1.4 ml, 10 mmol) and dichloromethane (20 ml) at 0oC in nitrogen atmosphere is added dropwise methanesulfonanilide (0.34 g, 3.0 mmol). The reaction is carried out as in example 84, except that the reaction time is 15 minutes

Sodium hydride (0.12 g, 3 mmol) and 3-methoxybenzyloxy alcohol (0,41 g, 3 mmol) is subjected to interaction in anhydrous THF (10 ml) as described in example 84. Added dropwise crude solution nelfinavir in anhydrous THF (10 ml). The reaction mixture is stirred at a temperature of education phlegmy 18 h, cooled to room temperature, poured into 1 N NaOH solution and three will rencontrera in vacuum and get the oil. After column chromatography (ethyl acetate/hexane, 1:1) get mentioned in the title compound as a viscous yellow liquid (800 mg, total yield 60%, Rf= 0,7). The NMR spectrum (CDCl3, 300 MHz): 7,5 (s, 1H), and 7.3, and 7.1 (m, 4H), 6,95-6,9 (m, 2H), 6,85 (br s, 1H, J=8), of 6.75 (s, 1H), 5,6 (br s, 2H), 4,45-4,3 (m, 2H), 4,25-of 4.05 (m, 1H), and 3.8 (s, 3H), 3,8-3,6 (m, 1H), 2,9 (septet, 1H, J= 7), 2,3 (br s, 3H) and 1.3 (d, 6H, J=7), and 1.2 (t, 3H, J=7). The mass spectrum of the high-resolution chemical ionization, calculated (C25H30BrN3O2): 484,1599 found: 484,1592.

Example 86

N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(thiazolyl)carbonyl)-6 - methylpyrimidine.

To a solution of n-utility in hexane (2.4 M, 1,34 ml, 3,24 mmol) in anhydrous THF (5 ml) at a temperature of -78oC is added dropwise 2-bromothiazole (0,49 g of 0.27 ml, 3.0 mmol). After the addition finished, the reaction mixture is stirred at a temperature of - 78oC for 30 minutes Then added dropwise a solution of methyl 2-(N-2-bromo-4-(1-methylethyl)-phenyl)-N-ethylamino)-6-methyl-4 - pyrimidinecarboxylic (example 18, 1.0 g, 2.5 mmol) in anhydrous THF solution (10 ml). Heated the reaction mixture to -60oC and stirred for 4 hours Add a saturated aqueous solution of NaHCO3give the reaction mixture to warm to ambient temperature. Then Tr is ω magnesium, filtered, concentrated in vacuo and get a dark brown oil. After column chromatography (ethyl acetate/hexane, 1: 1) get listed in title product, a brown solid (950 mg, yield 85%, Rf= 0,43), so pl. 97-98,5oC. the NMR spectrum (CDCl3, 300 MHz): 8,0 (s, 1H), 7,60 (s, 1H), and 7.4 to 7.2 (m, 4H, J=7), 3,05 is 2.9 (m, 1H), 2,8-2,7 (m, 1H), and 2.6 (br s, 3H), 1,4-1,2 (m, 9H). The mass spectrum of the high-resolution chemical ionization calculated: 445,0698 (M + H), found: 445,0699. Elemental analysis for C20H21BrN4S, calculated, %: C 54,05, H 4,73, N 12,61, Br 18,02, S 7,21, found, %: C 53,86, H 4,66, N 12,53, Br 18,20, S 7,46.

Example 87

N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-imidazole)carbonyl-6 - methylpyrimidine.

To a solution of 1-(dimethylaminomethyl)antifungals (to 0.63 g, 5 mmol) in anhydrous diethyl ether (5 ml) at a temperature of -78oC in nitrogen atmosphere is added dropwise a solution of n-utility in hexane (2.4 M, 2.1 ml, 5 mmol), and stirred pale yellow suspension at a temperature of - 78oC for 1 h Add in one scoop methyl-2-(N-(2-bromo - 4-(1-methylethyl)-phenyl)-N-ethylamino)-6-methyl-4-pyrimidinecarboxylic (example 18, 1.47 g, 5 mmol) and allow the reaction mixture to warm to room temperature for 23 hours Add 1 N HCl solution to pH = 1 (indicator paper), and lane is a). Extracted three times with ethyl acetate, dried the combined organic layers over magnesium sulfate, filtered, concentrated in vacuo and get oily solid product. After column chromatography (chloroform/methanol, 9: 1) get listed in title product, a yellow glassy substance (900 mg, yield 42%, Rf=0,43), so pl. 75-76oC. the NMR spectrum (CDCl3, 300 MHz): 12,2-12,1 (m, 1H), and 7.7 (d, 1H, J=1), 7,45-7,35 (m, 2H), 7,3 to 7.2 (m, 2H), 6,55 (br s, 1H), 4,3 (sextet, 1H, J=7), 3.8 (sextet, 1H, J=7), 3,05 (sextet, 1H, J=7), 2,65 (br s, 3H), and 1.4 (d, 6H, J= 7) and 1.3 (t, 3H, J=7). The mass spectrum of the high-resolution chemical ionization calculated: 428,1086 (M + H), found: 428,1089. Elemental analysis for C20H22BrN5O, calculated, %: C 56,08, H 5,18, N 16,35, Br 18,66, found, %: C 56,20, H 5,10, N 15,88, Br 18,73.

Example 88

N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(5 - indolocarbazole)-6-methylpyrimidine.

To a suspension of potassium hydride (35% in oil, 0.16 g, 1.4 mmol), washed with hexane and twice desantirovanii, in anhydrous ether (5 ml), cooled to 0oC, in an atmosphere of nitrogen was added a solution of 5-bromoindole (0.27 g, 1.4 mmol) in anhydrous ether. After stirring for 30 minutes the reaction mixture is cooled to -78oC and transferred via cannula to a pre-cooled (-78oSUP>C for 30 min and added dropwise a solution of 2-(N-(2-bromo-4(1-methylethyl)phenyl)-N-ethylamino)-6 - methyl-4-pyrimidinecarboxylic (example 18, 0.5 g, 1.25 mmol) in anhydrous ether (5 ml). After quenching the reaction mixture by the method described in example 87, the reaction mixture is extracted three times with ethyl acetate, then twice washed the combined organic layers with saturated solution of NaHCO3, dried over MgSO4, filtered and concentrated in vacuo.

Get a dark brown oil. After column chromatography (ethyl acetate/hexane, 1: 4) receive specified in the title of the product, a light brown solid (140 mg, yield 24%, Rf=0,2), so pl. 77-79oC. NMR spectrum (DMSO-d6, 400 MHz, 90oC): the 11.6-11,35 (br s, 1H), 8.30 to (s, 1H), of 7.75 (dd, 1H, J=8,1), at 7.55 (d, 1H), 7,47-7,35 (m, 2H), 7,35-7,25 (m, 2H), 6,9 (s, 1H), 6,60-6,55 (m, 1H), 4,1 to 3.7 (m, 2H), 2.95 and is 2.8 (m, 1H), 2,4 (br s, 3H), 1,25-1,1 (m, 9H). Elemental analysis for C25H25BrN4O, calculated, %: C 62,90, H 5,28, N 11,74, Br 16,74, found, %: C 63,13, H ceiling of 5.60, N 11,37, Br Ls 16.80.

Example 89

N-(2-Bromo-4-(1-methylethyl) phenyl)-N-ethyl-4-(4 - forfinal)carbonyl-6-methylpyrimidine.

To a suspension of N, O-dimethylhydroxylamine (of 1.46 g, 15 mmol) in benzene (20 ml) at 5-10oC in nitrogen atmosphere is added dropwise a solution of trimethyl is within 1 hour. The reaction mixture was transferred to a funnel and added dropwise to a solution of methyl 2-(N-(2-bromo-4-(1-methylethyl)phenyl)- N-ethylamino)-6-methyl-4-pyrimidinecarboxylic (example 18, 2.25 g, 5,73 mmol) in benzene (40 ml). The reaction mixture is heated under reflux with stirring. After cooling to room temperature the reaction mixture was poured into 5% HCl solution (100 ml), stirred and extracted three times with ethyl acetate. The combined organic layers dried over magnesium sulfate, filtered and concentrated in vacuo, get a dark brown oil. After column chromatography (ethyl acetate/hexane, 1:1) to obtain N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(N-methyl-N - methoxycarbonylamino)-6-methylpyrimidine (1.0 g, yield 41%, Rf= 0,4). Mass spectrum, chemical ionisation: 421,423 (M + H). The obtained amide is dissolved in anhydrous THF (10 ml). Add dropwise a solution of performancebased in ether (2 M, 1.25 ml, 2.5 mmol) and stirred the reaction mixture for 22 hours the Reaction is quenched, pouring the reaction mixture into 1 N NaOH solution (50 ml). The aqueous solution extracted three times with ethyl acetate. The combined organic layers dried over ethyl acetate, filtered, concentrated in vacuo and receives a yellow-orange oil. After column chromatograph%, Rf= 0,5), so pl. 70oC. the NMR spectrum (CDCl3, 300 MHz): 8,3-with 8.05 (m, 2H), 7,55 (d, 1H, J=1), 7,2 to 6.75 (m, 5H), 4,85 is 4.7 (m, 1H), from 4.3 to 4.15 (m, 1H), 2.95 and (septet, 1H, J=7), and 2.5 (br s, 3H), 1,4-of 1.15 (m, 9H). The mass spectrum of the high-resolution chemical ionization, calculated (C23H23BrFN3O): 456,1087 (M + H), found 456,1084.

Example 90

N-(2-Bromo-4-(1-methylethyl)phenyl-N-ethyl-4-carboxy-6-methylpyrimidine.

A mixture of methyl 2-(N-(2-bromo-4-(1-methylethyl)-phenyl)-N-ethylamino)-6 - methyl-4-pyrimidinecarboxylic (example 18, 10 g, 25 mmol), ethanol (100 ml) and 1 N NaOH solution (250 ml) is stirred at a temperature of education phlegmy 18 hours. After cooling to ambient temperature the reaction mixture is twice concentrated in vacuo and acidified with concentrated HCl solution. Extracted with chloroform three times, dried the combined organic layers over magnesium sulfate, filter and remove solvent under vacuum, to obtain a pale brown solid (9.0 g, yield 95%), so pl. 102 - 104oC. the NMR spectrum (CDCl3, 300 MHz): at 7.55 (d, 1H, J=1), 7,25-7,20 (m, 2H), 7,15 (d, 1H, J=7), 4,30-4,10 (m, 1H), 3,88-3,70 (m, 1H), 3.00 and-to 2.85 (m, 1H), 2,55 (br s, 3H), 2,30 (br s, 1H), of 1.30 (d, 6H, J=7), of 1.20 (t, 3H, J=7). The mass spectrum of the high-resolution chemical ionization calculated: (C17H20BrN3O): 378,0817 (M + H), found: 378,0813.

oC in vacuum for 4 hours After cooling to room temperature, placed in a nitrogen atmosphere and stirred solid product in anhydrous THF (50 ml) for 16 hours.

A solution of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-carboxy-6 - methylpyrimidine (3.7 g, 9.8 mmol) in anhydrous THF (25 ml) is cooled with stirring to -78oC in nitrogen atmosphere. Gradually add the solution metallice in ether (1.4 M, 7 ml, 9.8 mmol) and stirred the reaction mixture at -78oC for 1 hour. Suspension CeCl3transferred via cannula to the reaction mixture and continue stirring at -78oC for 5 hours. Add dropwise a solution of metallicy in ether (1.4 M, 7 ml, 9.8 mmol) and allow the reaction mixture gradually over 16 hours to warm to room temperature. After cooling the reaction mixture to -78oC the reaction is quenched with 1 N HCl solution and allowed to warm to room temperature. The resulting mixture was extracted three times with ethyl acetate. The combined organic layers dried over magnesium sulfate, filtered, concentrated in vacuo, get a yellow-orange oil. After column chromatography (ethyl acetate/hexane, 1:4) receive ukazanny,95 (s, 1H), 4,30-4,10 (m, 1H), 3,90-3,70 (m, 1H), 3.00 and-to 2.85 (m, 1H), 2,80-2,05 (m, 6H), 1,35-of 1.20 (m, 9H). The mass spectrum of the high-resolution chemical ionization, calculated (C18H22BrN3O): 376,1024 (M + H), found: 376,1042.

Example 92

N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(hydroxy-3-pyridylmethyl)-6 - methylpyrimidine (XU472).

Borohydride sodium (0.11 g, 2.8 mmol) are added to a solution of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-pyridylcarbonyl)-6 - methylpyrimidine (0.6 g, 1.4 mmol) in ethanol (5 ml). After stirring for 71 hours, the reaction mixture was concentrated in vacuo, treated with 1 N NaOH solution and extracted 3 times with ethyl acetate. The combined organic layers washed with brine, dried over magnesium sulfate, filtered, concentrated in vacuo and receive a colorless oil. After column chromatography (chloroform/methanol, 9:1) get listed in title product as an oil (600 mg, yield 96%, Rf=0,4). The NMR spectrum (CDCl3, 300 MHz): 8,65-to 8.45 (m, 2H), 7,55 (br s, 2H), 7.3 to a 7.1 (m, 2H), from 6.25 x 6.15 (m, 1H), 5,7-5,5 (m, 0.5 H), the 5.45 to 5.3 (m, 0.5 H), 5,15-of 4.95 (m, 1H), from 4.3 to 4.1 (m, 1H), from 3.9 to 3.7 (m, 1H), 3,0-to 2.85 (m, 1H), 2,45-2,2 (m, 3H), 2,3-2,2 (m, 1H), 1,35-1,2 (m, 9H). The mass spectrum of the high-resolution chemical ionization, calculated (C22H25BrN4O): 441,1290 (M + H), found: 444,1274.

Example 93

A solution of 4-bromoanisole (0.2 g, 1.1 mmol) in anhydrous THF (10 mmol) is cooled with stirring to -78oC in nitrogen atmosphere. Add dropwise a solution of tert-utility in pentane (1.7 M, and 1.4 ml, 2.4 mmol) and stirred the reaction mixture for 0.5 hours. Add dropwise a solution of N-(2-bromo-4-(1 - methylethyl)phenyl)-N-ethyl-4-(3-pyridylcarbonyl)-6 - methylpyridine (0.45 g, 1 mmol) in anhydrous THF (10 ml) and the reaction mixture is allowed to gradually warm to ambient temperature for 18 hours. The reaction mixture was poured into a saturated solution of NH4Cl and extracted three times with ethyl acetate. The combined organic layers dried over magnesium sulfate, filtered, concentrated in vacuo, get the oil. After column chromatography (ethyl acetate/hexane, 4:1) get listed in title product as a light brown glassy substance (170 mg, yield 31%, Rf= 0,2), so pl. 68 - 79oC NMR spectrum (CDCl3, 300 MHz): 8,6 an 8.4 (m, 2H), 7,7-7,5 (m, 1H), and 7.5 (s, 1H), 7,25-7,05 (m, 6H), 6,95 to 6.75 (m, 2H), 6,25 to 6.2 (m, 1H), 5,85-5,7 (m, 1H), 4,25-of 4.05 (m, 1H), 3,8 (br s, 3H), 3.95 to a 3.75 (m, 1H), from 3.0 to 2.8 (m, 1H), 2,45-2,1 (br s, 3H), 1,35-of 1.15 (m, 9H). The mass spectrum of the high-resolution chemical ionization, calculated (C29H31BrN4O2): 547,1709 (M + H), found: 547,1709.

Example 94

N-(2 and stirring sodium (0.08 g, 3.5 mmol). After the sodium will react, add a solution of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-acetyl-6-methylpyrimidine (1.0 g, to 2.67 mmol) in methanol (5 ml) and stirred the reaction mixture for 5 minutes. Add reagent gold (dimethylaminomethylphenol), dimethylammonium chloride (0.66 g, 4 mmol) and continue stirring for 19 hours. The reaction mixture was concentrated in vacuo, the residue is dissolved in chloroform, washed with a solution saturated solution of NaHCO3, dried over magnesium sulfate, and after filtration and removal of solvent in vacuo get a brown solid, which upon trituration with hexane gives N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl - 4-(3-dimethylaminopropanol)-6-methylpyrimidine in the form of a yellow solid substance (700 mg). The NMR spectrum (CDCl3, 300 MHz): 7,9-the 7.65 (br s, 1H), and 7.5 (s, 1H), 7,25 to 7.2 (m, 2H), 7,15 (s, 1H), 6,1-5,8 (br s, 1H), from 4.3 to 4.15 (m, 1H), 3,9-of 3.75 (m, 1H), 3,2-3,0 (br s, 3H), 3,0-to 2.85 (m, 1H), 2,8-2,6 (br s, 3H), 2,5-2,3 (br s, 3H), 1,35-1,2 (m, 9H). Mass spectrum, chemical ionisation: 431,433 (M + H).

The solution above winlogonexe amide and anhydrous hydrazine (0.15 g, 4.7 mmol) in toluene (15 ml) is stirred at a temperature of education phlegmy in nitrogen atmosphere for 16 hours. The reaction mixture was poured into water and three times the extras the shape in vacuum, get the oil. After column chromatography (ether) get mentioned in the title compound as a pale yellow glassy product (600 mg, total yield 59%, Rf=0,4). The NMR spectrum (CDCl3, 300 MHz): 7,6 (s, 1H), 7,55 (s, 1H), and 7.3 to 7.2 (m, 2H), 6,8 (s, 1H), 6.75 in and 6.6 (br s, 1H), from 4.3 to 4.15 (m, 1H), from 3.9 to 3.7 (m, 1H), 3.00 and-to 2.85 (m, 1H), 2,5-2,2 (br s, 3H) and 1.3 (d, 6H, J= 8), 1,25 (t, 3H, J=8). The mass spectrum of the high-resolution chemical ionization, calculated (C19H22BrN5): 399,1137 (M + H), found: 399,1140.

The obtained free base was dissolved in ether and treated with excess 1 N HCl in ether. After drying in vacuum at 60oC get listed in title product in the form of a powder (500 mg, yield 72%), so pl. 235-237oC. NMR spectrum (DMSO-d6, 300 MHz): of 7.9 to 7.7 (m, 1H), and 7.6 (s, 1H), between 7.4 and 7.3 (m, 2H), 7,2 (s, 1H), 7,05-6,85 (m, 1H), from 4.3 to 4.1 (m, 1H), 3,85-the 3.65 (m, 1H), 3,05 is 2.9 (m, 1H), 2,45 is 2.1 (br m, 3H), of 1.25 (d, 6H, J=8), and 1.2 (t, 3H, J=8). Elemental analysis for (C19H22BrN5-HCl), calculated, %: C 52,75, H 5,31, N 16,03, Br 18,29, Cl 8,12; found %: C 52,53, H 5,28, N 15,93, Br 18,44, Cl 8,17.

Example 95

N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-amino-ethyl)-6 - methylpyrimidine.

A mixture of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-acetyl-6 - pyrimidinamine (0.5 g, of 1.33 mmol), ammonium acetate (1.1 g, 14 mmol), cyanoborohydride sodium (59 mg, 0.9 mmol) and methanol (5 ml) th reaction solution (pH=2), then the reaction mixture was concentrated in vacuo. The residue is transferred into the water, alkalinized with concentrated NaOH solution and extracted three times with ether. The combined organic layers dried over magnesium sulfate, filtered, concentrated in vacuo and get the oil. After column chromatography (ethyl acetate/hexane, 1:1, then chloroform/methanol/NH4OH, 95: 5: 0.5 to) receive: (1) - N-2-bromo-4- (1-methylethyl)phenyl)-N-ethyl-4- (1-amino-ethyl)-6-methylpyrimidine (80 mg, yield 16%, Rf= 0,43, ethyl acetate/hexane, 1:1) and (2) is specified in the title product as a brown oil (180 mg, yield 36%, Rf= 0,34, chloroform/methanol/NH4OH, 95: 5:0.5 to). The NMR spectrum (CDCl3, 300 MHz): 7,5 (d, 1H, J= 1), to 7.2, and 7.1 (m, 2H), 6,4 (s, 1H), 4,25-of 4.05 (m, 1H), 3.9 to the 3.65 (m, 2H), 3,0-to 2.85 (m, 1H), 2,4-2,2 (br m, 3H), 1,9-1,6 (br m, 3H) and 1.3 (d, 6H, J=8), and 1.2 (t, 3H, J= 8). The mass spectrum of the high-resolution chemical ionization (C18H25BrN4): 377,1341 (M + H), found: 377,1330.

Example 96

N-(2-Bromo-4-(1-methylethyl) phenyl)-N-ethyl-4-(2-(4-tetrazolyl)-1 - methylethyl)-6-methylpyrimidine.

A mixture of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-hydroxyethyl)-6 - methylpyrimidine (1.1 g, 2.7 mmol), triethylamine (1.5 ml, 11 mmol) and dichloromethane (15 ml) stirred at 0oC in nitrogen atmosphere. Added dropwise to means is therefore washed with chilled on ice-1 N HCl solution, a saturated solution of NaHCO3and saturated NaCl solution. After drying over magnesium sulfate, filtration and removal of solvent in vacuo get N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4- (1-methanesulfonylaminoethyl)-6-methylpyrimidine in the form of a clear colorless oil (1.0 g). The NMR spectrum (CDCl3, 300 MHz): 7,5 (d, 1H, J=1), 7,25 to 7.1 (m, 2H), 6,55 (s, 1H), 4,3-of 4.05 (m, 1H), 3,85-3,6 (m, 1H), 3,0-2,5 (m, 4H), 2,5-2,05 (br m, 3H) and 1.3 (d, 6H, J=8), and 1.2 (t, 3H, J=8). Mass spectrum, chemical ionisation: 456,458 (M + H).

Mesilate (without further purification) is mixed with sodium cyanide (0.54 g, 11 mmol) in N,N-dimethylformamide (DMF, 20 ml) and stirred at a temperature of education phlegmy 67 hours. After cooling to room temperature the reaction mixture was poured into water, extracted three times with ethyl acetate. The combined organic layers dried over magnesium sulfate, filtered, concentrated in vacuo, get the oil. After column chromatography (ethyl acetate/hexane, 1:9) to obtain N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4- (1-cyanoethyl)-6-methylpyrimidine in the form of oil (440 mg, Rf= 0,24). The NMR spectrum (CDCl3, 300 MHz): 7,5 (d, 1H, J=1), 7,25 to 7.1 (m, 2H), 6,65-6,55 (m, 1H), 4,3-of 4.05 (m, 1H), 3,9-3,5 (m, 2H), 3,0-to 2.85 (m, 1H), 2,55-a 2.0 (br m, 3H), 1,8-1,4 (br m, 3H), 1.41 to 1,1 (m, 9H). Mass spectrum, chemical ionisation: 387, 389 (M + H).

The mixture qi is more at 100-105oC for 112 hours. After cooling to room temperature the reaction mixture was poured into water (200 ml), alkalinized 1 N NaOH solution (pH > 10) and three times extracted with chloroform. The combined organic layers dried over magnesium sulfate, filtered, concentrated in vacuo and get the oil. After column chromatography (chloroform/methanol, 9:1) get a brown solid (Rf= 0,22). After recrystallization from ether get listed in title product as a white solid (35 mg, total yield 3%), so pl. 127-129oC. the NMR spectrum (CDCl3, 400 MHz): 7,75 (s, 0,4 H), and 7.7 (s, 0,6 H), was 7.45 (d, 0,6 H, J=8), and 7.4 (d, 0,4 H, J=8), and 7.3 to 7.2 (m, 2H), 6,5 (s, 0,4 H), 6.48 in (s, 0,6 H), 4,28-4,0 (m, 1,4 H), 4,28-4,18 (m, 0,6 H), 3,94-3,82 (m, 0,6 H), of 3.8 to 3.7 (m, 0,4 H) and 3.1 to 3.0 (m, 1H), of 2.45 (s, 3H), 1.5 a (d, 3H, J=8), 1,4-1,3 (m, 5H), 1,3-1,2 (m, 4H). The mass spectrum of the high-resolution chemical ionization: 430,1355 (M + H); 430,1347.

Example 97

2-N-(2-Bromo-4-(2-propyl)phenyl)amino)-4-carbomethoxy-6 - methylpyrimidin.

A mixture of 2-chloro-4-carbomethoxy-6-methylpyrimidine (47,0 g, 252 mmol) and 2-bromo-4-(2-propyl)aniline (54,0 g, 252 mmol) in dioxane (400 ml) is stirred at a temperature of education phlegmy for 20 h under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and concentrated on a Roto what cetecom. The combined organic layers dried over magnesium sulfate and filtered. Remove the solvent in vacuo and get a red oil. After column chromatography (ethyl acetate/hexane, 1:1) get mentioned in the title substance in the form of dirty oil. After recrystallization from a mixture of ether and hexane, separation by filtration and drying in vacuo get mentioned in the title compound as a solid (42.8 g, yield 47%), so pl. 75-76oC. the NMR spectrum (CDCl3, 300 MHz): 8,4 (d, 1H, J=8), the 7.65 (br s, 1H), and 7.4 (d, 1H, J=1), and 7.3 (s, 1H), 7,2 (dd, 1H, J=8,1), 4,0 (s, 3H), 2,85 (septet, 1H, J=7), and 2.5 (br s, 3H), of 1.25 (d, 6H, J=7). Elemental analysis for C16H18BrN3O2calculated, %: C 52,76, H to 4.98, N 11,54, Br 21,94, found, %: C 52,71, H 4,99, N 11,38, Br 21,83.

Example 98

2-(N-2-Bromo-4-(2-propyl)phenyl)-N-ethylamino)-4-carbomethoxy-6 - methylpyrimidine.

To a solution of sodium hydride (60% in oil, 4.8 g, 120 mmol), washed twice with hexane and dekotirovaniem, in anhydrous tetrahydrofuran (150 ml) at ambient temperature under nitrogen atmosphere with stirring in parts 2-(N-(2-bromo)-4-(2-propyl)phenylamino)-4-carbomethoxy-6-methylpyrimidin (42.8 g, 118 mmol) within 30 minutes After the gas runs out, one portion of the injected iodoethane (31,2 g, Any and stirred for 24 hours. After cooling to room temperature the reaction mixture was carefully quenched with water and extracted three times with ethyl acetate. The combined organic layers washed twice with water, dried over magnesium sulfate and filtered. After removal of solvent in vacuo get a brown oil. Column chromatography (ether/hexane, 1:1) to give two fractions: (1) - 2-(N-(2-bromo-4-(2-propyl)phenylamino)-4-carbomethoxy - 6-methylpyridin (4.6 g, yield 11%, Rf= 0,8) and (2) is specified in the title product (20 g, Rf= 0,7) in the form of dirty oil.

Specified in the title of the product is recrystallized from hexane, dried in vacuum and get solid (18.0 g, yield 39%), so pl. 81-82oC. the NMR spectrum (CDCl3, 300 MHz): 7,5 (br s, 1H), 7,25 (d, 1H, J=7), to 7.15 (d, 1H, J=7), and 7.1 (s, 1H), from 4.3 to 4.1 (m, 1H), 4,05 of 3.75 (m, 4H), 2.95 and (septet, 1H, J= 7), 2,3 (br s, 3H) and 1.3 (d, 6H, J=7), 1,25 (t, 3H, J=7). The mass spectrum of the high-resolution chemical ionization calculated: 392,0974 (M + H), found: 392,0960.

Example 99

2-(N-(2-Bromo-4-(2-propyl) phenyl)-N-ethylamino) -6-methylpyrimidin-4-carboxylic acid, morpholine

To sodium hydride (60% in oil, 0.24 g, 6.0 mmol), washed twice with hexane, dekotirovaniem and suspended in anhydrous tetrahydrofuran (10 ml), add morpholine (0.52 g, 6.0 mmol) and najdat to ambient temperature, add 2-(N-(2-bromo-4-(2 - propyl)phenyl-N-ethylamino)-4-carbomethoxy-6-methylpyrimidin (2.0 g, 5.1 mmol), continue stirring for 26 hours. Then the reaction mixture was poured into 1 N NaOH solution, stirred, and extracted three times with ethyl acetate. The combined organic layers dried over magnesium sulfate, filtered and concentrated in vacuo. After column chromatography (ether) get mentioned in the title compound (900 mg, yield 39%), so pl. 145oC. the NMR spectrum (CDCl3, 300 MHz): 7,5 (d, 1H, J=1), 7,2 (dd, 1H, J=7,1), and 7.1 (d, 1H, J=7), 6,8 (br s, 1H), from 4.3 to 4.15 (m, 1H), 3,9-3,3 (m, 1H), 3,3-3,0 (m, 1H), 2,9 (septet, 1H, J= 7) and 1.3 (d, 6H, J=7) and 1.15 (t, 3H, J=7). Elemental analysis for C21H27BrN4O2calculated, %: C 56,38, H between 6.08, N To 12.52, Br 17,86; found, %: C 56,07, H 6,05, N 12,29, Br 18,08.

Example 100

2-(N-(2-Bromo-4-(2-propyl)phenyl-N-ethylamino)-4-(morpholinomethyl)-6 - methylpyrimidin.

To a solution of 2-(N-(2-bromo-4-(2-propyl)phenyl)N-ethylamino)-6 - methylpyrimidin-4-carboxylic acid, morphodynamics (750 mg, 1,72 mmol) in anhydrous tetrahydrofuran (1.4 ml) at ambient temperature under nitrogen atmosphere is added dropwise a solution of borane in tetrahydrofuran (1 M, 3.6 ml, 3.6 mmol), and the reaction mixture is heated under reflux for 20 hours After cooling to room After cooling to ambient temperature the reaction mixture is poured into 3 N NaOH solution and extracted three times with ethyl acetate. The combined organic layers dried over magnesium sulfate, filtered and concentrated under vacuum. After column chromatography (ethyl acetate) receive specified in the title compound as an oil (300 mg, yield 39%, Rf= 0,3). The NMR spectrum (CDCl3, 300 MHz): 7,5 (s, 1H), 7,2 (d, 1H, J=7), to 7.15 (d, 1H, J=7), and 6.5 (s, 1H), from 4.3 to 4.1 (m, 1H), 3,8-3,6 (m, 7H), 3,5-3,3 (m, 2H), 2,9 (septet, 1H, J= 7), 2,55 to 2.35 (br m, 3H), 2,35 was 2.25 (m, 2H), of 1.3 (d, 6H, J=7), and 1.2 (t, 3H, J= 7). The mass spectrum of the high-resolution chemical ionization calculated: 433,1603 (M + H), found: 433,1586.

Example 101

9[2-Bromo-4 (2-propyl)phenyl)-2-methyl-6-chloropurine.

Part A. To 4,6-dihydroxy-2-methylpyrimidine add parts of fuming nitric acid (40 ml), while cooling the flask with ice. After the addition finished, the reaction mixture is stirred for further 60 minutes under ice cooling, and then further 60 min at room temperature. Then the reaction mixture was poured on ice (60 g) and allow the ice to melt. Filtering emit a pale pink solid and washed with water (50 ml). The solid product is dried in vacuum over night and get to 22.6 g of substance.

Part C. the Product, the receipt of which is described in part a, parts add to POCl3(125 ml) under nitrogen atmosphere. Add postlady to room temperature. The reaction mixture was poured on ice (750 mg) and stirred for 1 hour. The aqueous layer was extracted with diethyl ether (4 x 400 ml), the extracts pooled. The combined extracts washed with brine (300 ml) and the organic layer is dried over Na2SO4. The dried organic layer was filtered and concentrated, emit reddish-brown solid (21,51 g).

Part C. the Product, the receipt of which is described in part b (3.0 g), is added to acetic acid (5.5 ml) and methanol (25 ml). This solution is added to the iron powder (3.0 g) and the reaction mixture is stirred at a temperature of 60-65oC for 2 h, the Reaction mixture was cooled to room temperature and filtered. From the filtrate allocate brown solid, which was extracted with ethyl acetate (CH ml). The combined organic extracts washed with NaOH (1 N, h ml), water (100 ml) and with brine (100 ml). The organic layer is dried over Na2SO4filter, after allocating the gain of 2.13 g of amber liquid, which hardens when cooled. Mass spectrum: (M + H)+178.

Part D. Mix the product, the receipt of which is described in part C (2.0 g), 2-bromo-4-isopropylaniline (2.4 g) and diisopropylethylamine (1.52 g), and reacciona 2
/MeOH, 50:1, silica), then allocate the receive of 1.45 g of a whitish solid. Mass spectrum (M + H)+356.

Part E. the Product, the receipt of which is described in part D (1,32 g), triethylorthoformate (10 ml) and acetic anhydride (10 ml) are mixed in a nitrogen atmosphere and heated under reflux for 4.5 hours, the Reaction mixture passes into a butter-like state, and then add water (50 ml). The aqueous layer was alkalinized (pH 8) solid Na2CO3and extracted with CHCl3(G ml). The combined organic layers are dried over Na2SO4filter, after highlighting receive amber oil (1.63 g). After cleaning flashamature (CH2Cl2/MeOH, 50: 1, silicon dioxide) receive light amber glassy substance 9[2-bromo-4(2-propyl)phenyl]-2-methyl-6-globulin (0,94 g), so pl. 49-52oC. Mass spectrum (M + H)+367.

Example 102

9[2-Bromo-4 (2-propyl) phenyl]-2-methyl-6-morpholinopropan.

9[2-Bromo-4(2-propyl)phenyl] -2-methyl-6-globulin (1.3 g) and morpholine (10 ml) are mixed in a nitrogen atmosphere and heated under reflux for 6 hours, the Reaction mixture was concentrated on a rotary evaporator, the residue is distilled flashamature (CH2Cl2/MeOH, 50: 1, Cremonese the-propyl)phenyl]-8-Aza-2-methyl-6-chloropurine.

Part A. To a 4.6-dihydroiso-2-methylpyrimidine add parts of fuming nitric acid (40 ml), while cooling the flask with ice. After the addition finished, the reaction mixture is additionally stirred for further 60 min, cooling on ice, and another 60 min at room temperature. The reaction mixture was poured on ice (60 g), and allow the ice to melt. Allocate filtering pale pink solid, washed with cold water (50 ml). The obtained solid is dried in vacuum over night and get to 22.6 g of the desired substance.

Part C. the Product, the receipt of which is described in part a, add parts to POCl3(125 ml) under nitrogen atmosphere, then add parts of N,N-diethylaniline (25 ml). The reaction mixture is heated under reflux for 150 min, cooled to room temperature, poured on ice (750 g) and stirred for 1 hour. The aqueous layer was extracted with diethyl ether (4x400 ml) and combine the extracts. The combined organic extracts washed with brine (300 ml), dried over Na2SO4filter and emit a reddish-brown solid (21,51 g).

Part C. the Product, the receipt of which is described in part In (6.5 g), is added to acetic acid (11 ml) and SUP>o
C, cooled to room temperature, filtered. From the filtrate allocate brown solid, which was extracted with ethyl acetate (CH ml). The combined organic layers washed with NaOH (1 N, h ml), water (100 ml) and with brine (100 ml). The organic layer is dried over Na2SO4filter, after allocating the gain of 4.75 g of amber liquid, which solidifies after standing. Mass spectrum (M + H)+178.

Part D. Mix the product, the receipt of which is described in part C and 4.75 g) and 2-bromo-4-isopropylaniline (5,71 g), the reaction mixture is heated to a temperature of 140oC for 60 minutes, the Reaction mass is suspended in CH2Cl2(300 ml), the organic solution was washed with NaOH (1 N, 3x250 ml) and with brine (250 ml). The organic phase is dried over Na2SO4get the dark liquid (9.28 are g). Purify the liquid flashamature (CH2Cl2/MeOH, 50: 1, silicon dioxide), get a light red solid. Mass spectrum (M + H)+356.

Part E. the Product, the receipt of which is described in part D (2.0 g), is added to acetic acid (50%, 20 ml) and then added dropwise sodium nitrite (0,407 g) in water (2.0 ml). After 4.25 hours, the reaction mixture is filtered, otdelemoe oil 9[2-bromo-4(2-propyl)phenyl]-8-Aza-2 - methyl-6-chloropurine (0.75 g). Mass spectrum (M + H)+368.

Example 104

9[2-Bromo-4(2-propyl)phenyl]-8-Aza-2-methyl-6-morpholinopropan.

9[2-Bromo-4(2-propyl)phenyl] -8-Aza-2-methyl-6-chloropurine (1,34 g) and morpholine (10 ml) are mixed in a nitrogen atmosphere, the resulting solution was washed with water (I ml) and with brine (100 ml). The organic phase is dried over sodium sulfate, concentrated on a rotary evaporator, the residue is distilled flashamature (CH2Cl2, silicon dioxide), get a solid yellow substance (0,62 g), so pl. 145-148oC. Mass spectrum (M + H)+: 417, 419.

Example 105

2(N-2,4-Dimethoxypyrimidine-5-yl)-N-ethylamino)-4,6-dimethylpyrimidin.

Part A. 5-Nitrouracil (25 g) is added to POCl3and N,N-diethyl-amine (32 ml), the reaction mixture is heated under reflux at a temperature of education phlegmy for 70 min in nitrogen atmosphere. After cooling to room temperature the reaction mixture was poured onto ice (600 mg) and stirred until the mixture reaches room temperature. The aqueous layer was extracted with diethyl ether (4x300 ml). The extracts are combined, washed with brine (200 ml), dried over sodium sulfate. Concentrate the organic layer and emit orange-red liquid (17,69 the t to the solution of sodium methoxide (30 wt.%, 38 ml) while cooling the flask in a bath with ice. After the addition finished, the reaction mixture is stirred over night at room temperature, then heated under reflux for 4 h After cooling to room temperature the reaction mixture was poured on ice (500 g), a white precipitate is formed (10,38 g), which is collected by filtration.

Part C. the Product, the receipt of which is described in part b (4.1 g) and Pd/C (10 weight. %, 0.15 g) is added to ethanol (70 ml), methanol (10 ml) and water (1 ml) in a Parr reactor. The reaction mixture is treated with hydrogen until, while according to the TLC will not remain of the original product. The reaction mass is filtered through Celite, the filtrate emit a reddish-brown solid (3,32 g).

Part D. the Product, the receipt of which is described in part C (1,086 g) and 2-chloro-4,6-dimethylpyrimidin (1.0 g) is dissolved in THF (50 ml) under nitrogen atmosphere. Add parts sodium hydride (0.33 g, 60 wt.%, dispersion in oil). After the addition, the reaction mixture was heated under reflux for 5.5 hours, cooled to room temperature and separating the solid product by filtration. The filtrate is concentrated and purified by flashamature (CH2Cl2/MeOH, 90:10, silicon dioxide), get a solid is (2.0 g), and iodoethane (1,49 g) dissolved in dimethylformamide (20 ml) under nitrogen atmosphere.

Parts added sodium hydride (0,383 g, 60 wt.%, dispersion in oil). After adding continue stirring at room temperature for 22 hours Add water (200 ml), the mixture is extracted with ethyl acetate (CH ml). The combined extracts washed with water (100 ml) and with brine (100 ml), dried over sodium sulfate, filtered and emit amber liquid 2-(N-(2,4-dimethoxypyrimidine-5-yl)-N-ethylamino)-4,6-dimethylpyrimidin (2,68 g). Mass spectrum (M + H)+290.

Many of the compounds described above, can be converted into their salts by the addition of the appropriate acid in a solution of the compound in organic solvent. The above-described salts do not limit the scope of the invention and are given only as illustrations of the General scheme of the synthesis. Physical properties of some compounds, which can be sintezirovany using the methods described above, are presented in tables 1 - 21. Column in the tables entitled "example N ...", refers to the syntheses described in the above examples 1 to 105. The designation "MC" and "SVR" refer to the usual mass-spectroscopy and mass spectroscopy high resolution suitable for the manufacture of the samples. Rats-males line Sprague Dawley (180-200 g) are killed by decapitation, open brain while cooling with ice, frozen whole in liquid nitrogen and to study stored at a temperature of 70oC. the day of the examination of frozen tissue was weighed and homogenized in 20 volumes of ice buffer containing 50 mm Tris, 10 mm MgCl2, 2 mm EGTA, pH 7.0 at 22oC using PoCytron (Brinkmann Instruments, Westbury, NY, setting 6) within 20 C. a Homogeneous product is centrifuged at 48000g for 10 minutes at 4oC. Separate the supernatant and the residue is re-homogenized in the same volume of buffer, then centrifuged at 48000g for 10 min at 4oC. Obtained after centrifugation clot again suspended in the above buffer to a final concentration of 20-40 mg of raw product/ml and used in the following studies. Determination of protein was carried out according to the method of Lowry (Zowry et al. , J. Biol. Chem 193: 265 (1951)), using as a standard bovine serum albumin.

The binding of ACTH (CRF) receptors.

Research associate receptors was carried out basically according to the method described by E. C. De Souza, J. Neurosci, 7:88 (1987).

Analysis of the saturation curves.

Pridemiami or not containing r/h CRF with final concentration 1 mm) to determine nonspecific binding, and 10 μl of membrane suspension (as described above) are added sequentially in a 1.5 ml polypropylene tube for microcentrifuge to a final volume of 300 ál. All samples brought to equilibrium for 2 hours at 22oC, as described E.B.De Souza, J. Neurosci, 7:88 (1987). The reaction is complete by centrifugation of the samples at microcentrifuge Beckmann for 5 min at 12000g. Take an aliquot of the supernatant to determine the "free" concentration of radioactive ligand. Remove the remaining supernatant and precipitate in the test tube gently washed with chilled on ice PBS containing addition of 0.01% Triton X-100, again centrifuged and measure "associated" with the concentration of radioactive ligand. The data obtained in the study of saturation, analyze using build non-linear relationships by the method of least squares LIGAND (P. J. Munson and D. Rodbavd, Anal Biochem. , 107:220 (1980)). This program has obvious advantages for processing of experimental data compared to the untransformed coordinate system, where suggest the most likely normal distribution and there is no correlation with the independent variable. The program LIGAND does not imply that the nonspecific binding is arbitrarily determined by the researcher, as it defines the independent variable of the whole set of data. The values of the affinity constants (KD) and the density of the receptor for the output data. This program is quite flexible and gives the possibility to analyze different curves, which increases the reliability of the analysis and, hence, allows to obtain correct values of the estimated values from the data of experiments on saturation.

Analysis of the competitive binding curves.

Studies of competitive binding 100 μl of [125I]-Ovine CRF (125I about CRF, the final concentration of 200-300 PM) incubated with 100 μl of buffer (in the presence of different numbers of competing ligands, usually from 1 PM to 10 PM) and 100 μl of membrane suspension obtained as described above, when the total volume of the reaction mixture, 300 μl. The reaction starts with the addition of membrane homogenate, incubated to equilibrium for 2 h at 22oC and finish by centrifugation (12000g) in microcentrifuge Beckmann, in order to separate the free radioactive ligand from the bound. Obtained after centrifugation the precipitate washed twice with the surface by centrifugation with 1 ml ice phosphate buffer and 0.01% Triton X-100, to separate the supernatant and the remaining residue is examined for radioactivity with approximately 80% efficiency.

The level of nonspecific binding of the statements analyze the program LIGAND. For each curve, competitive binding determine the affinity ligand with a radioactive label to the CRF receptor ([125I] CRF), regardless of experiments on the construction of curves of saturation, and these values are used in the analysis of the apparent constants of inhibition (Kifor the studied peptides. Typically, analysis of the data using a model involving one or two binding site, choosing the model that gives the best match with the experimental curve, in order to more accurately determine the value of Ki. Statistical analysis using the program LIGAND gives the opportunity to select the most appropriate model, namely the model, suggesting the presence of a single binding site, or model, suggesting the presence of two binding sites. For both peptides (a-helical CRF9-41and d-PheCRF12-41) as well as for all of the compounds of the present invention, the received data is more in line with the model, suggesting the presence of a single binding site model, suggesting the presence of two binding sites, is either impossible or does not correspond to the experimental points.

The results of the study of the compounds of the present invention in vitro prevedere free base or salt, in the study of binding were detected similar magnitude of inhibition.

A connection is considered active if the value of Kiless than about 10,000 nm for the inhibition of CRF. Table 22 shows the values of Kidefined in the above-described conditions. The following notation for values of Ki: +++ = < 500 nm; ++ = 501-2000 nm; + = 2001-10000 nm.

Inhibition of CRF-stimulated activity adenylate-cyclase activity

Inhibition of CRF-stimulated activity adenylate-cyclase activity were performed as described in: G. Battaglia et al., Synapse 1:572 (1987). The samples were kept for 10 min at 37oC in 200 ml of buffer containing 100 mm Tris-HCl (pH of 7.4 at 37oC), 10 mm MgCl2, 0.4 mm EGTA, 0.1% of BSA, 1 mm isobutylmethylxanthine (VMH), 250 u/ml phosphocreatine-kinase, 5 mm creatine phosphate, 100 mm guanosine-51-triphosphate, 100 nm oCRF, peptide antagonist (concentration of 10-9-10-6M) and 0.8 mg of sample raw fabric (approximately 40-60 mg protein). The reaction was initiated by adding 1 mm ART [32P] ATP (approximately 2-4 mcure per tube) and was finished by adding 100 ml of 50 mm Tris-HCl, 45 mm ATP and 2% sodium dodecyl sulfate. In order to measure the regeneration of camp in each tube was added 1 μl of [3H] camp (approximately 40000 minieval column. Separation of more than 80%.

Found that the compounds of the present invention are active in such conditions. IC50< 10000 nanomoles.

The research activity of the compounds in vivo

The activity of the compounds of the present invention in vivo can be studied using well-known specialists of biological tests. Models that can be used to test compounds of the present invention shown in: C. W. Berridge, A. J. Duhn. Brain Research Reviews 15:71 (1990), the Acoustic Startle Assay, the Stair Climbing Test, the Chronic Administration Assay.

Connections can be studied in rodents or small mammals, but these examples do not limit the scope of the invention.

The results of the above tests indicate that the compounds of the present invention can find use for the treatment of disorders associated with abnormal content of the releasing factor corticotropin in patients suffering from depression, emotional disturbance and/or symptoms of anxiety. The above tests illustrate the use of compounds of the present invention for the treatment of uterine contractions.

Compounds of the present invention can be introduced for l is s active agent in the body of a mammal. The compounds may be introduced by any known means used for introducing a pharmaceutical or individual therapeutic drugs, or in combination with therapeutic drugs. Connections can be entered alone, but usually introduced with a pharmaceutical carrier selected with the use of known rules and generally accepted pharmaceutical practice.

The dose used for the introduction, can vary widely depending on the destination and number of known factors such as the pharmacodynamic properties of the particular drug, the method and route of administration, patient's age, the nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, the desired effect. When used for treatment of the above diseases, the compounds can be administered orally with a daily dose of the active agent from 0.002 to 200 mg/kg of body weight. Usually to achieve the required pharmaceutical result use a dose amount of 0.01-10 mg/kg, divided into 1-4 servings per day, or maintenance dose.

Dosage forms (compositions) suitable for administration contain 1 mg to about 100 mg of active ingredient per unit. In such farmacia composition.

The active ingredient can be administered orally in solid dosage forms such as capsules, tablets or powders, or in liquid form, for example in the form of elixirs, syrups, and/or suspensions. Compounds of the present invention can also be administered orally in the form of a sterile liquid preparations.

For the introduction of the active ingredient can be used gelatin capsules and suitable carriers, such as lactose, starch, magnesium stearate, steric branched acids, derivatives of cellulose and other Similar solvents can be used for the manufacture of compressed tablets. As tablets and capsules can be manufactured with prolonged action. Molded tablets may be coated with sugar or film to mask any unpleasant taste or to protect the active ingredient from atmospheric effects or destructive effects in the gastrointestinal tract.

Liquid forms for oral administration may contain dyes or fragrances to enhance attractiveness.

As carriers for parenteral administration can be used water, pharmaceutically acceptable oils, physiological rainhill. Solutions for parenteral administration may contain a water-soluble salt of the active ingredient, suitable stabilizers and, if necessary, buffer substances. As stabilizing agents can be used antioxidants such as sodium bisulfite, sodium sulfite, ascorbic acid or mixtures thereof. You can also use citric acid or its salts, EDTA. In addition, parenteral solutions can contain preservatives, such as benzalconi chloride, methyl-or propylparaben, chlorobutanol.

Suitable pharmaceutical carriers are described in "Remington''s Pharmaceutical Sciences, A. Osol, a renowned leadership in this area.

Appropriate dosing forms for administration of the compounds can be the following:

Capsules

Prepared medicines in the form of multiple capsules by filling hard gelatin capsules consisting of two parts, 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft gelatin capsules

Prepare a mixture containing the active ingredient in easily digestible oil such as soybean oil, cottonseed oil or olive oil and injected into gelatin for receiving the 2">

Tablets

Was prepared a number of tablets according to standard techniques so that a single dosage included 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98,8 mg of lactose. To reduce the adhesive may be applied a suitable coating.

Compounds of the present invention can also be used as reagents or standards when conducting biochemical studies of neurological functions, dysfunctions and diseases.

1. 1-N-Alkyl-N-arylpyrimidines General formula I

< / BR>
in which J represents CX1where X1- H, halogen, C1-C6-alkyl, CHO, -OH or OC1-C4-alkyl;

K and L are N or CX1where X1- H, halogen or OC1-C4-alkyl;

M is CR5where R5- C1-C6-alkyl, halogen, -OC1-C4-alkyl, optionally substituted by 1 to 3 halogen, CN; C1-C4-halogenated, C3-C6-cycloalkyl, -C(= O)C1-C4-alkyl, -CO2C1-C4-alkyl, S(O)n(C1-C6-alkyl),

CN, n = 0 to 2, -C1-C4-alkyl-OR1where R1- H or C1-C15where R14and R15each C1-C14-alkyl;

V - N;

Y is N, CH, CCN, or CR29where R29together with R4forms a 5-membered ring and a is-C(R30)= or-N=, where R30- H or CN;

Z is N, CH or CCH3;

R4together with R29form a 5-membered ring and a is-CH= or-N=, or represents a group selected from C1-C4-alkyl, OC1-C4-alkyl, propargyl, allyl, -CH2C3-C6-cycloalkyl, -(CH2)nN(R1)2where R1- C1-C4alkyl, and n = 1 - 3;

X is halogen, halogenmethyl, -OC1-C4-alkyl, CN or S(O)nC1-C4-alkyl, where n = 0, 1, or 2;

R1- C1-C4-alkyl, C1-C4-alkoxy, halogen;

R3halogen, aryl, C1-C2-haloalkyl, CHO, C1-C4-alkyl, optionally substituted by CN, C1-C4-alkyl, C1-C4-alkoxy, OH; or C3-C6-cycloalkyl; S(O)nR8where R8is C1-C4-alkyl, C1-C4-alkoxy, optionally substituted C1-C4-alkoxy; morpholinyl; thienyl; pyrrolyl; picolyl; imidazolines; phenyl, substituted C1-C4-alkyl or C1-C4-al
)kOR8; (CHR16R25; (CHR16)NR6R7; -CH(CO2R16)2where R16- C1-C4alkyl, or-C(CN) (R25) (R16), where R16- H; R6and R7each independently represents hydrogen, with at least one of R6and R7different from H when R29and R4together denote-CH= or-N= , C3-C6-cycloalkyl; -(CH2)kR13; -(CHR16)pOR8where R8- H, C1-4-alkyl or (CH2)kR25where R25- phenyl, imidazolyl, furyl; or R6and R7together denote -(CH2)qA(CH2)r-; R8- C1-C6-alkyl; pyrimidinyl; pyridyl; furyl; phenyl, optionally substituted by 1 to 3 CH3or OCH3; (CH2)t-aryl or (CH2)t-heteroaryl with aryl or heteroaryl, optionally substituted CH3; (CH2)tR22or (CH2)kR25; R9- C1-C4alkoxy; R13- CN, C3-C6-cycloalkyl or or19where R19- C1-C6-alkyl; R16- H or C1-C4-alkyl; R22- C(O)R25, SR24, S(O)nR31, NR23R24or or24where each of R23and reel; tetrahydroquinoline; phenyl, optionally substituted C1-C4the alkyl or alkoxy; indolyl; pyridyl; pyrazolyl; furyl; pyrimidyl; pyrazinyl; piperidinyl; pyrrolidinyl, optionally substituted C1-C4-alkyl, or piperazinil, optionally substituted C1-C4-alkyl; R25A- H or R25; A represents O; NC(= O)R17with R17being H or C1-C4-alkyl; S(O)n; C(H) (OR20) with R20which is H; CH2or NR25; k = 1 to 4; t = 1 to 3; each p and n = 0 to 2; each q and r = 1 or 2

or their pharmaceutically acceptable salts.

2. N-Alkyl-N-arylpyrimidines General formula I

< / BR>
where Y is CH, CCN, or N;

R1, R3, R4, X, Z, V, J, K, L, M have the meanings specified in paragraph 1 of the formula

or their pharmaceutically acceptable salts.

3. Connection on p. 2, wherein R3- C1-C4-alkyl, phenyl, halogen, C1-C2-haloalkyl, NR6R7, OR8C(= O)R9C(O)NR6R7, (CH2)kOR8, NR10CH(R11)CO2R12, -(CHR16)pOR8, -C(OH) (R25)(R25A), -C(CN)(R25)(R16provided that if R25doesn't mean NH-containing ring, -C(=O)R C1-C4-alkoxy, C3-C6-cycloalkyl, phenyl, substituted C1-C4-alkoxy, phenyl, substituted C1-C4-alkyl, imidazolyl, 2-thienyl, 3-thienyl, morpholinyl, pyrrolidyl, J, K, L is independently chosen in each case from CX1; M - CR5, R1, R2and R30independently chosen in each case from the series comprising hydrogen or cyano, or R1- C1-C4-alkyl; X is halogen, aryl, S(O)2- C1-C4-alkyl, halogenmethyl, OC1-C4-alkyl, C1-C4-alkyl; R4has specified in paragraph (2 values; X1is hydrogen, halogen, -OC1-C4-alkyl, OH, C1-C4-alkyl; R5- halo, -C(=NOR16)-C1-C4-alkyl, C1-C4-alkyl, C1-C3-haloalkyl, C1-C4-alkoxy, optionally substituted by 1 to 3 halogen, S(O)nC1-C6-alkyl, n = 0 - 2, C3-C6-cycloalkyl, cyano, C1-C4-alkyl-OR1where R1- H or C1-C4-alkyl, C(O)C1-C4-alkyl; R6and R7independently chosen in each case from the group comprising hydrogen, C3-C6-cycloalkyl, (CHR16)pOR8or R6, R7together form a group -(CH2)qA(CH22)tR22, phenyl, optionally substituted by 1 to 3 CH3or OCH3; -NR16(CH2)nNR6R7, -(CH2)kR25, (CH2)4-heteroaryl or (CH2)4-aryl, where heteroaryl or each aryl may be substituted for CH3; R13not necessarily chosen in each case from a range that includes OR19and C3-C6-cycloalkyl; R14and R15independently chosen in each case from the series comprising hydrogen, C1-C6-alkyl; R17independently chosen in each case from the series comprising hydrogen, C1-C4-alkyl; R19independently chosen in each case from the series, including C1-C6-alkyl; R22independently chosen in each case from a range that includes OR24, SR24, NR23R24, -S(O)nR31and C(=O)R25; R25chosen in each case from the series comprising phenyl, optionally substituted C1-C4the alkyl or alkoxy, pyrazolyl, furyl; pyrazinyl, morpholinyl, piperazinil, optionally substituted C1-C4-alkyl, piperidinyl, pyridyl, pyrimidyl, pyrrolidinyl, optionally substituted C1-C4-alkyl, R25A, materialism, pyrazolyl, furyl, pyrazinyl, piperazinil, optionally substituted C1-C4-alkyl, piperidinyl, pteridinyl, purinol, pyranyl, pyrazolidine, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, optionally substituted C1-C4-alkyl; t is independently chosen in each case from 1 to 3.

4. Connection on p. 2, wherein R1independently chosen in each case from the series, including C1-C2-alkyl, C1-C4-alkoxy; R3independently chosen in each case from the group comprising C1-C4-alkyl, C1-C2-haloalkyl, NR6R7, OR8C(=O)R9C(=O)NR6R7, (CH2)kOR8, -C(CN) (R25) (R16), provided

if R25does not mean NH-containing ring, C(OH) (R25) (R25A), -C(= O)R25CH(CO2R16)22-thienyl, 3-thienyl, imidazolyl, morpholinyl, pyrrolidyl, R1A, R2and R3Aindependently chosen in each case from the series comprising hydrogen, methyl; X Is Cl, Br, I, OC1-C6-alkyl; X1is hydrogen, Cl, Br, I, OC1-C6-alkyl; R5- halo, C1-C6-alkyl, C1-C3-haloalkyl, C1-C6-alkoxy; R6and R7independently in 6-alkoxy, -(CH2)kR13or R6and R7taken together form the group -(CH2)qA(CH2)r; A IS O, S(O)nN(C(=O)R17), C(H) (OR20), NR25; R8independently chosen in each case from a range that includes-C1-C6-alkyl, (CH2)tR22and (CH2)kR25; R9- C1-C4-alkyl; R14, R15independently chosen in each case from the series comprising hydrogen, C1-C2-alkyl; R16is hydrogen; R19- C1-C3-alkyl; R22independently chosen in each case from a range that includes OR24, -C(= O)R25; R23and R24independently chosen in each case from the series comprising hydrogen, C1-C2-alkyl; R25independently chosen in each case from the series comprising phenyl, optionally substituted C1-C4the alkyl or alkoxy, pyrazolyl, furyl, 4-pyrazinyl, indolyl, morpholinyl, piperazinil, optionally substituted C1-C4-alkyl, piperidinyl, pyridyl, pyrrolidinyl, tetrahydrofuranyl, 1-tetrahydroquinoline; R25Aindependently chosen in each case from the series comprising hydrogen, phenyl, possibly substituted C1-C4the alkyl or alkoxy, the Ohm, pyridinyl, pyrimidinyl, pyrrolidinyl, possibly substituted C1-C4-alkyl, tetrahydrofuranyl, 1-tetrahydroquinoline; k = 1 to 3; p = 0 - 2; q = 1, 2; r = 1 - 2.

5. N-Alkyl-N-arylpyrimidines General formula I"

< / BR>
where Y is CR29where R29together with R4form a 5-membered ring and a is-C(R30)= or-N=;

R30is hydrogen or CN;

R1, R3, Z, V, K, L, M, and X have the meanings specified in paragraph 1 of the formula

or their pharmaceutically acceptable salts.

6. Connection on p. 5, wherein Z is CH; R1- C1-C2-alkyl; R3- C1-C4-alkyl, phenyl, halogen, NR6R7, OR8C(=O)R9C(=O)NR6R7, (CH2)kOR8, -C(OH) (R25) (R25A), -C(= O)R25, -CH(CO2R16)2substituted C1-C4-alkyl, C3-C6-cycloalkyl, phenyl-(substituted C1-C4)-alkyl, phenyl-(substituted C1-C4)-alkoxy, substituted C3-C6-cycloalkyl; J, K, L is independently chosen in each case from CX1; M means CR5; R4forms together with R29five-membered cycle and represents-CH=; X Is Br, I, S(O)nC1-C4-alkyl, OC1-C4-alkyl; X1is hydrogen, Br, B>-C6-alkoxy, NR14R15C3-C6-cycloalkyl, C(=O)C1-C4alkyl, C(=O)NR8R15; R6and R7independently chosen in each case from the series comprising hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, -(CH2)kR13, -(C1-C4-alkyl)phenyl, -(C1-C4-alkyl)-imidazolyl or furyl or R6and R7together form a group -(CH2)qA(CH2)r; A IS O, NR25or S(O)n; R8independently chosen in each case from the series, including C1-C6-alkyl, (CH2)tR22, phenyl, optionally substituted by 1 to 3 CH3, OCH3, -(CH2)kR25and (CH2-heteroaryl or (CH2)t-phenyl, each of which may be substituted CH3group; R14and R15independently chosen in each case from the series comprising hydrogen, C1-C2-alkyl; R16independently chosen in each case from the series comprising hydrogen, C1-C2-alkyl; R17independently chosen in each case from the series comprising hydrogen, C1-C2-alkyl; R22independently chosen in each case from a range that includes OR24, SR24, NR23R24-C2-alkyl; R25independently chosen in each case from the series comprising phenyl, optionally substituted C1-C4the alkyl or alkoxy, pyrazolyl, 4-pyrazinyl, morpholinyl, piperazinil, optionally substituted C1-C4-alkyl, piperidinyl, pteridinyl, purinol, pyranyl, pyrazolidine, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, optionally substituted C1-C4-alkyl, tetrahydrofuranyl, tetrahydropyranyl; R25Aindependently chosen in each case from the group comprising H and C1-C4-alkyl; R29together with R4form a 5-membered cycle and mean C(R30)=; R30is hydrogen, cyano; k = 1 to 3; p = 0 to 2; q and r = 2, t = 1 - 2.

7. Connection on p. 5, wherein R1is methyl; R3- C1-C2-alkyl, NR6R7, OR8C1-C2-alkyl or phenyl, substituted C1-C4-alkyl,

halogen or imidazolyl; X Is Br, I, S(O)nC1-C4-alkyl, NR14R15OC1-C4-alkyl; X1is hydrogen, Br, I, OH; R5- halogen, C1-C2-alkyl, C1-C2-alkoxy or-NR14R15; R6and R7independently chosen in each case from the group comprising hydrogen, C13, OCH3; R14and R15independently chosen in each case from the series comprising hydrogen, C1-C2-alkyl; R30is hydrogen or cyano.

8. Connection on p. 1, characterized in that it is a compound selected from the group

N-(2,4-acid)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromophenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-were)-N-methyl-4-morpholino-6-methyl-2-pyrimidinamine;

N-(2,4-acid)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,4-dibromophenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-ethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-tert-butylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-tert-butylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-triptoreline)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-triptoreline)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,4,6-trimethoxyphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,4,6-trimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimid is)phenyl-N-allyl-4-morpholino-6-methyl-2-pyrimidinamine;

N-(2-bromo-4-n-butylphenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-n-butylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-n-butylphenyl)-N-Protel-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-cyclohexylphenol)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-diethyl-2-pyrimidinamine;

N-(2-bromo-4-n-butylphenyl)-N-ethyl-4,6-diethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-formylpiperazine)-6-methyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-iodide-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-trifluoromethyl-2-pyrimidinamine;

N-(2-bromo-4-methoxyethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-iodide-4-(1-methylethyl)phenyl)-N-ethyl-morpholino-6-methyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(2-thiophene)-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-cyanomethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-cyclopropylmethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-propargyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-iodide-4-(1-is 2-pyrimidinamine;

N-(2-iodide-4-methoxyacetyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-iodide-4-methoxyacetyl)-N-ethyl-4-morpholino-6-methyl-2-pyrimidinamine;

N-(2-iodide-4-methoxyacetyl)-N-ethyl-4-morpholino-6-methyl-2-pyrimidinamine;

N-(2-methylthio-4-methoxymethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-dimethylamino-4-methoxymethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-methylthio-4-methoxymethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-dimethylamino-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,4-dimethylthiophenol)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-methylthio-4-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,6-dibromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,6-dibromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-thiomorpholine-2-pyrimidinamine;

N-(2,4-diiodophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,4-diiodophenyl)-N-ethyl-4-morpholino-6-methyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(N-methyl-2-hydroxyethylamino)-2-pyrimidinamine;

N-(2,6-dimethoxy-4-were)-N-ethyl-4,6-dimethyl-2-pyrimidine is Il-2,4-dimethoxy-6-pyrimidinamine;

2,6-dimethyl-4-(N-(2-bromo-4-(1-methylethyl)phenyl)amino)pyridine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(4-morpholinylcarbonyl)-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(morpholinylmethyl)-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(1-piperidinylcarbonyl)-2-pyrimidinamine;

methyl-2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-6-methyl-4-pyrimidinecarboxylic;

2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-N-cyclohexyl-6-methyl-4-pyrimidinecarboxylic;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(4-methyl-1-piperazinylcarbonyl)-2-pyrimidinamine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4,6-dimethyl-1,3,5-triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-methyl-6-(4-morpholinyl)-1,3,5-triazine-2-amine;

N-ethyl-N-[2-iodide-4-(1-methylethyl)phenyl] -4-methyl-6-(4-thiomorpholine)-1,3,5-triazine-2-amine;

N-ethyl-N-[2-iodide-4-(1-methylethyl)phenyl] -4-methyl-6-(4-morpholinyl)-1,3,5-triazine-2-amine;

N-ethyl-N-[2-iodide-4-(1-methylethyl)phenyl] -4-methyl-6-(1-piperidinyl)-1,3,5-triazine-2-amine;

1-(2-bromo-4-isopropylphenyl)-4,6-dimethyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-3-cyano-4-phenyl-6-methyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-4-phenyl-6-me-4,6-dimethyl-7-azaindole;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-N, N-diethylamino-6-methyl-1,3,5-triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4,6-sodium dichloro-1,3,5-triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4,6-dimethoxy-1,3,5-triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-imidazoline-6-methyl-1,3,5-triazine-2-amine;

N-[2-bromo-4,6-acid)-N-ethyl-4-morpholino-6-methyl-1,3,5-triazine-2-amine;

N-(2-bromo-4,6-acid)-N-ethyl-4-N, N-dimethylamino-6-methyl-1,3,5-triazine-2-amine;

N-(2,4,6-trimethoxyphenyl)-N-ethyl-4-morpholino-6-methyl-1,3,5-triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-N, N-dimethylamino-6-methyl-1,3,5-triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-thiazolidine-6-methyl-1,3,5-triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-benzyloxy-6-methyl-1,3,5-triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-phenyloxy-6-methyl-1,3,5-triazine-2-amine;

N-(2-bromo-4,6-acid)-N-ethyl-4-[4-(ethylpiperazine)] -6-methyl-1,3,5-triazine-2-amine;

N-(2-bromo-4,6-acid)-N-ethyl-4-[4-(piperazinone acid)]-6-methyl-1,3,5-triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-4-[3-(Malone-2-yl-diethyl ether)]-6-methyl-1,3,5-triazine-2-amine;

N-(2-bromo-4,6-acid)-N-ethyl-4-(1-cyano-1-phenylmethyl)-6-methyl-1,3,5-triaz ethylhydroxylamine)-N-ethyl-4,6-sodium dichloro-1,3,5-triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-methyl-6-(thiomethyl)-2-pyrimidinamine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-methyl-6-(methylsulfinyl)-2-pyrimidinamine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-methyl-6-(methylsulphonyl)-2-pyrimidinamine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-methyl-6-benzyloxy-1,3,5-triazine-2-amine;

N-(2-iodide-4-dimethylhydroxylamine)-N-ethyl-4,6-sodium dichloro-1,3,5-triazine-2-amine;

N-[2-iodide-4-(1-methylethyl)phenyl] -N-allyl-4-morpholino-6-methyl-2-pyrimidinamine;

N-[2-iodide-4-(1-methylethyl)phenyl]-N-ethyl-4-chloro-6-methyl-2-pyrimidinamine;

N-[2-methylthio-4-(1-methylethyl)phenyl] -N-ethyl-4-(S)-(N-methyl-2'-pyrrolidinyloxy)-6-methyl-2-pyrimidinamine;

N-[2,6-dibromo-4-(1-methylethyl)phenyl] -4-thiomorpholine-6-methyl-2-pyrimidinamine;

N-[2-methylthio-4-(1-methylethyl)phenyl]-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-[2-methylthio-4-(1-methylethyl)phenyl]-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-[2-methylsulfinyl-4-(1-methylethyl)phenyl] -N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-[2-iodide-4-(1-methylethyl)phenyl] -N-ethyl-4-thiazolidine-6-methyl-2-pyrimidinamine;

N-(2-iodide-4-methoxymethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4,6-dimethyl-2-pyrimidinamine)-2,3,4,5-tetrahydro-4-(1-methylethyl)-1,5-benzothiazepin;

N-[2-methylsulphonyl-4-(1-methylethyl)phenyl]N-(2-ethylthio-4-methoxyaminomethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-methylthio-4-methoxyaminomethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-methylsulphonyl-4-methoxyaminomethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-bromo-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-ethyl-2-methylthiophenyl)-N-(1-methylethyl)-4,6-dimethyl-2-pyrimidinamine;

N-(4-ethyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-[2-methylthio-4-(N-acetyl-N-methylamino)phenyl] -N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-carboethoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-methoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-cyano-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-acetyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-propionyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-[4-(1-methoxyethyl)-2-methylthiophenyl)] -N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-[4-(N-methylamino)-2-methylthiophenyl]-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-[4-(N, N-dimethylamino)-2-methylthiophenyl] -N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-formyl-6-methyl-2-pyrimidinamine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-hydroxy-ethoxymethyl-6-methyl-2-pyrimidinamine;

N-(2-bromo-6-hydroxy-4-methoxyphenyl)-N-ethyl-4,6-dime ethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,6-dibromo-4-(ethoxy)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-4,6-dimethyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-4-phenyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-6-methyl-4-phenyl-7-azaindole;

1-(2-bromo-4,6-acid)-3-cyano-4,6-dimethyl-7-azaindole;

1-(2-bromo-4,6-acid) of 4,6-dimethyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-6-chloro-3-cyano-4-methyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-6-chloro-4-methyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-4-chloro-3-cyano-6-methyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-4-chloro-6-methyl-7-azaindole;

N-(2-bromo-6-methoxypyridine-3-yl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(3-bromo-5-methylpyridin-2-yl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(6-methoxypyridine-3-yl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-6-methoxypyridine-3-yl)-N-ethyl-4-methyl-6-(4-morpholinyl)-1,3,5-triazine-2-amine;

N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-4-[N-(2-furylmethyl-N-methylamino] carbonyl-6-methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-[(4,4-ethylenedioxythiophene)carbonyl]-6-methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-(4-oxopiperidine)to inamin hydrochloride;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-(imidazol-1-yl)methyl-6-methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-4-[3-(methoxyphenyl)methoxymethyl] -6-methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-(2-thiazolyl)carbonyl-6-methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-(2-imidazolyl)carbonyl-6-methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-(5-indolocarbazole)-6-methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-(4-forefeel)carbonyl-6-materialization;

N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-4-carboxy-6-methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-4-acetyl-6-methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-(hydroxy-3-pyridylmethyl)-6-methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-[4-(methoxyphenyl)-3-pyridylcarboxylic]-6-methylpyrimidine;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-(3-pyrazolyl)-6-methapyrilene hydrochloride;

N-[2-bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-(1-amino-ethyl)-6-methylpyrimidine;

N-[2-[bromo-4-(1-methylethyl)phenyl] -N-ethyl-4-[2-(4-tetrazolyl)-1-methylethyl]-6-methylpyrimidine;

2-(N-[2-bromo-4-(2-propyl)phenyl]amino-4-carbomethoxy-6-methylpyrimidin;

2-(N-[2-bromo-4-(2-propamidine-4-morpholinoethyl;

9-[2-bromo-4-(2-propyl)phenyl]-2-methyl-6-morpholinopropan;

9-[2-bromo-4-(2-propyl)phenyl]-2-methyl-6-morpholino-8-agapurin;

1-[2-bromo-4-(2-propyl)phenyl]-6-methyl-4-morpholino-5,7-diakanda;

2-N[2-bromo-4-(2-propyl)phenyl] -N-ethylamino-4-(morpholinomethyl)-6-methylpyrimidin.

9. The method of treatment of diseases caused by the activity of CRF receptors in affective disorders, anxiety, depression, posttraumatic stress, appetite disorder, paralysis, syndrome of hypersensitivity of the gut, immune disorders, Alzheimer's disease, gastrointestinal disorders, anorexia, drug and alcohol abstinence, addiction to the excessive use of drugs, inflammatory processes and problems of fertility in mammals by introduction of active compounds, characterized in that the active compounds mammal is administered a therapeutically effective amount of the compounds according to paragraphs.1 - 8.

10. The pharmaceutical composition active in the CRF receptors, comprising an active compound and a carrier, wherein the active compounds it contains the connection PP.1 - 8 in an effective amount.1-C4-alkyl, OC1-C4-alkyl, propargyl, allyl, -CH2C3-C6-cycloalkyl, -(CH2)n-(R'2), where R' -C1-C4-alkyl and n = 1 - 3.

26.08.94 on p. 1: Y - CR29where R29together with R4means-CH= or-N=, and p. 3.

 

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