Pyrimidine derivatives with activity towards mch

FIELD: chemistry.

SUBSTANCE: in compounds of formula (I) , Q is: (IIa) or (IIb) , R1 is chosen from a group which consists of carboxylic aryl and carboxylic aryl which is substituted with substitute(s) independently chosen from a group which consists of halogen, cyano, nitro, C1-10alkyl, C1-10alkyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-9alkoxy, C1-9alkoxy which is substituted with substitute(s) independently chosen from a group which consists of halogen, mono-C1-5alkylamino, and heterocyclyl or heterocyclyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-5alkyl; R2 is C1-5alkyl, C1-5alkyl which is substituted with halogen, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, -N(R2a)(R2b); where R2a and R2b are each independently hydrogen, C1-5alkyl or C1-5alkyl, substituted with substitute(s) independently chosen from a group which consists of hydroxyl, carboxylic aryl; L represents formula (IIIa); , where R3 and R4 are each hydrogen; A is a single bond, and B is a single bond or -CH2-; Z1, Z3, and Z4 are each independently hydrogen, halogen, C1-5alkyl, C1-5alkyl, substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Z2 is hydrogen, C1-5alkyl, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Y is -C(O)NH-, -C(O)-, -C(S)NH-, -C(O)O- or -CH2-; where carboxylic aryl is phenyl; heterocyclyl is 1H-indolyl, 9H- xanthenyl, benzo[1,3]dioxolyl, furyl, imidazolyl, isoxazolyl, morpholinyl, piperazinyl, pyridyl, pyrrolidyl; halogen is fluorine, chlorine, bromine or iodine. The invention also relates to a pharmaceutical composition.

EFFECT: compounds can be used for treating central nervous system diseases, and for improving memory functioning, sleep, awakening, diabetes.

16 cl, 8 dwg, 4 tbl, 525 ex

 

The scope of the invention

The present invention relates to compounds that act as antagonists of the MCH receptor, and to the use of these compounds in pharmaceutical compositions.

Prior art

Melaninconcentrating hormone (MCH), a cyclic peptide, identified as the endogenous ligand associated with G-proteins organovo receptor SLC-1. See, for example, Shimomura et al., Biochem. Biophys. Res. Commun. 261, 622-26 (1999). Studies have shown that MCH acts as a neurotransmitter/neuromodulator to change the number of behavioral responses, such as dietary habits. For example, it was reported that injection of MCH in rats increases the consumption of food. The reports show that genetically modified mice with absence of MCH display lower body weight and enhanced metabolism. Cm. Saito et al., TEM, vol. 11, 299 (2000). Essentially, the literature data suggest that the opening of MCH antagonists that interact with expressing SCL-1 cells, will be useful in developing treatments for obesity. Cm. Shimomura et al., Biochem. Biophys. Res. Commun. 261, 622-26 (1999).

Associated with G protein-coupled receptor (GPCR) have a common structural motif. All of these receptors have seven sequences ranging in size from 22 to 24 hydrophobic amino acids that form seven alpha helices, each of which passes through the membrane. elverta and fifth transmembrane helix on the outer side of the cell membrane linked chain of amino acids, forming a relatively large loop. Another great loop, consisting mainly of hydrophilic amino acids, binds the fifth and sixth transmembrane helix on the inner side of the cell membrane. Carboxy-end of the receptor inside the cell, and amino end is located in the extracellular space. Suppose that the associated loop the fifth and sixth spirals, as well as carboxy-end interact with G-protein. Currently, as a possible proteins that interact with the receptor, identified G-protein Gq, Gs, Gi and Go.

Under physiological conditions GPCR are located in the cell membrane in equilibrium between two different States or conformations: an "inactive" status and the "active" state. The receptor in an inactive state is not able to contact by extracellular signal transmission for the formation of a biological response. The change in the conformation of the receptor in the active state of the network link by transmitting a signal and produces a biological response.

The receptor can be stabilized in an active state by endogenous or exogenous ligand ligand agonist. Recent studies, including, but without limitation, modification of the amino acid sequence of the receptor, has provided an alternative other than the ligands mechanisms for stabilizing conforma the AI active state. These approaches effectively stabilize the receptor in an active state, simulating the effect of binding of ligand to the receptor. Stabilization using such independent ligands approaches called "constitutive activation of the receptor". In contrast, antagonists can be competitive way to contact the receptor at the same site as the agonist, but does not activate the intracellular response initiated by the active form of the receptor, and, therefore, to inhibit the intracellular responses induced by agonists.

It was reported that some derivatives of 2-aminothiazoline are antagonists of NPY, which, as mentioned, are effective for treating disorders and diseases associated with subtype Y5 receptor NPY. Cm. patent application PCT 97/20823. Also found that derivatives of hintline suitable for enhancing antitumor activity. Cm. patent application PCT 92/07844. Also of the above patent applications WO03/070244, WO03/105850, WO03/45313, WO03/045920 and WO04/04726 known derivatives of quinoline, which have activity as antagonists of the MCH receptor.

In recent times the modern knowledge about the obese person has improved markedly. Previously, obesity was considered as the nature of the change, opposing inappropriate food options attractive food. Research the and models of obesity animals biochemical changes in humans and animals and the complex interactions of psychosocial and cultural factors, creating susceptibility to human obesity, showed that the disease in humans is complex and deeply rooted in biological systems. Thus, almost exactly determined that obesity has many causes, and that there are different types of obesity. MCHR1 antagonists have not only effective and long-term exposure to combat obesity in rodents, they also unexpectedly possess antidepressant and anxiolytic properties (Borowsky et al., Nature Medicine, 8, 825-830, 2002). It was reported that MCHR1 antagonists demonstrate the antidepressant and anxiolytic activity in these rodent models, as social interaction, the forced swimming test and ultrasonic alarm. These findings indicate that MCHR1 antagonists may be useful for the treatment of obese patients with multiple reasons. In addition, the MCHR1 antagonists can be used to treat subjects not only with obesity but also with depression and anxiety. These advantages distinguish them from the NPY receptor antagonists, for which you can expect similar entries as himself NPY has a similar anxiolytic effect.

Obesity is also considered as a chronic disease, and the likelihood of long-term treatment is a principle attractive gloss of leat is taking place more and more attention. In this context, it is noteworthy that the decline MCH leads to hypophagia, and depletion (Shimada et al., Nature, 396, 670-674, 1998). In contrast, mice with destroyed NPY (Erickson et al., Nature, 381, 415-418, 1996), as well as receptors Y1 (Pedrazzini et al., Nature Medicine, 4, 722-726, 1998) and Y5 (Marsh et al., Nature Medicine, 4, 718-721, 1998) maintained a stable body weight or quickly gained excessive weight. Considering the above documents MCHR1 antagonists may be more attractive than receptor antagonists Y1 or Y5 in respect of long-term treatment of obese patients.

Obesity, which is the result of imbalance between calorie intake and expenditure of energy in humans and experimental animals significantly correlated with insulin resistance and diabetes. However, the molecular mechanisms involved in the syndromes of obesity-diabetes, is not clear. During the early development of obesity increased secretion of insulin to compensate for insulin resistance and protects patients from hyperglycemia (Le Stunff et al.Diabetes43, 696-702 (1989)). However, after several decades of functioning β-cells deteriorates and approximately 20% suffering from obesity group is developing non-insulin dependent diabetes mellitus (NIDDM) (Pederson, P.Diab. Metab. Rev. 5, 505-509 (1989)) and (Brancati, F. L., et al.,Arch. Intern. Med.159, 957-963 (1999)). Given its high prevalence of the modern society, obesity, therefore, became the main risk factor for NIDDM (Hill, J.O., et al.,Science280, 1371-1374 (1998)). However, the causes that predispose some patients to changes in insulin secretion in response to the accumulation of fat, remain unknown.

When classifying someone as having overweight or suffering from obesity, typically determine the index of its body mass (BMI)calculated by dividing body mass (kg) by squared height (m2). Thus, BMI units are kg/m2and it is possible to calculate the range of BMI associated with minimum mortality rate in each decade of life. Excess weight is defined as BMI in the range of 25-30 kg/m2and obesity as BMI greater than 30 kg/m2(See table below). With this definition, there are problems in that it does not take into account the ratio of body weight represented by muscle, fat (adipose tissue). To account for this, obesity can also be defined on the basis of fat content in the body: more than 25% and 30% in men and women respectively.

CLASSIFICATION of WEIGHT BY BODY MASS INDEX (BMI)
BMIClassification
<18,5 Insufficient weight
18,5-24,9Norma
25,0-29,9Excess weight
30,0-34,9Obesity (Class I)
35,0-39,9Obesity (Class II)
>40Extreme obesity (class III)

As BMI increases, there is an increased risk of death from many causes, independent of other risk factors. The most common diseases to obesity are cardiovascular disease (particularly hypertension), diabetes (obesity increases the development of diabetes), gallbladder disease (especially malignant tumor) and diseases of the reproduction system. Research has shown that even moderate weight loss can correspond to a significant decrease in the risk of developing coronary heart disease.

Compounds marketed as anti-obesity include orlistat (Orlistat) (XENICAL™) and sibutramine (Sibutramine). Orlistat (a lipase inhibitor) directly inhibits the absorption of fat and high frequency leads to unpleasant (though relatively harmless) side effects such as diarrhea. Sibutra is in the combined inhibitor of the reuptake of 5-HT/noradrenaline) some patients may increase blood pressure and heart rate. It was reported that the funds release/reuptake inhibitors serotonin fenfluramine (Pondimin™) dexfenfluramin (Redux™) reduces food intake and body weight over an extended period (more than 6 months). However, both products were withdrawn after reports preliminary data about the anomalies of the heart valves associated with their use. Thus, there is a need for the development of safer anti-obesity.

Also obesity significantly increases the risk of developing cardiovascular disease. In the foreground induced obesity, cardiovascular complications are coronary insufficiency, atheromatous disease and heart failure. It is calculated that if the whole population would be the ideal weight, the risk of coronary heart disease could be reduced by 25% and the risk of heart failure and acute cerebral vascular disorders by 35%. In subjects aged less than 50 years with 30% overweight incidence of coronary heart disease is doubled. Patients with diabetes are faced with a 30% decrease in life expectancy. At the age of 45 years in people with diabetes are about three times more likely than people without diabetes, significant heart disease and up to size five times more likely to strike. E and opening emphasize the relationship between risk factors for NIDDM and coronary heart disease and the potential value of an integrated approach to the prevention of these conditions based on the prevention of these conditions on the basis of prevention of obesity (Perry, I.J., et al.,BMJ310, 560-564 (1995)).

Excessive weight is suffering an increasing number of children and adolescents. Although not all children with excessive weight will become adults with excess weight, increasing prevalence of obesity in childhood is likely to reflect in increasing obesity in the adult years. High prevalence of obesity in the adult population and the likelihood that the population in the future will become even more obese, requires re-validation of the consequences of this disease for health. See, Health Implications of Obesity. NIH Consens. Statement Online 1985 Feb 11-13; 5(9):1-7.

"Clinical obesity" is a measure of the excess of body fat relative to lean mass body mass, and is defined as body weight more than 20% above ideal body weight. Recent estimates suggest that 1 in 2 adults in the United States suffer from clinical obesity, an increase of more than 25% in the last decade. Flegal .D. et al., 22 Int.J. Obes. Relat. Metab. Disor.39 (1998). As a condition of excessive weight, and clinical obesity is an important health care around the world, in particular, because clinical obesity is often accompanied by many complications, i.e. hypertension and type II diabetes, which in turn can in order to predict the disease of the coronary arteries, stroke, complications of late-stage diabetes and premature death. (See, for example, Nishina R.M. et al., 43Metab.554 (1994)).

Although the etiologic mechanisms underlying obesity, require further clarification, the final effect of these mechanisms leads to an imbalance between intake and expenditure of energy. In the pathogenesis of obesity, probably involved and genetic factors, and environmental factors. They include excessive consumption of colonies, reduced physical activity and metabolic or endocrine abnormalities.

Treatment of conditions associated with excessive weight, and clinical obesity through pharmaceutical drugs are important not only in relation to the state, but also in relation to prevention of other diseases associated with, for example, clinical obesity and improve positive self-esteem, which is often characteristic of individuals with excessive weight or clinically obese and who have experienced significant weight loss. Given the above discussion, it is evident that the compounds contributing to the treatment of such diseases can be useful and can provide advancement in research and in clinical medicine. The present invention relates to him, as well as other important purposes.

The invention

Present from retina refers to compounds that associate with and modulate the activity of a GPCR, referred to in this description as MCH, and their application. As used in the present description, the term MCH includes a human sequence under inventory number Genbank NM_005297, natural allelic variants, orthologues in mammals, biologically active fragments and recombinant mutants.

One aspect of the present invention relates to certain compounds of the substituted pyrimidine represented by formula (I):

where Q represents:

or]

R1selected from the group consisting of:

(i) C1-16the alkyl and

C1-16the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

oxo,

C1-5alkoxy,

C1-5alkoxy substituted by substituent(s)independently selected from the group consisting of:

carbocyclic aryl,

heterocyclyl and

heterocyclyl, substituted C1-5ankylomon,

C1-5alkylcarboxylic,

carbocyclic,

carbocyclic, aryloxy,

carbocyclic, aryloxy substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy,

ka is samoila,

nitro,

cyano,

amino,

carbocyclic aryl,

carbocyclic aryl, substituted C1-5alkoxy,

C1-5alkoxy,

C1-5alkoxy substituted by halogen,

C1-5the alkyl and

C1-5the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy,

oxo,

mono-C1-5alkylamino,

di-C1-5alkylamino,

mono-C1-5alkylamino, is substituted by a carbocyclic aryl,

di-C1-5alkylamino, is substituted by a carbocyclic aryl,

mono-C1-5alkylamino, substituted by halogenated carbocyclic-aryl,

di-C1-5alkylamino, substituted by halogenated carbocyclic-aryl,

carbocyclic, arylcarboxamide and

carbocyclic, arylcarboxamide, substituted with halogen,

heterocyclics,

heterocyclic substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy,

carbamoyl,

nitro,

cyano,

amino,

carbocyclic aryl,

carbocyclic aryl, substituted C1-5alkoxy,

C1-5alkoxy,

C1-5alkoxy substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy and

carboxy,

C1-5the alkyl and

C1-5the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy and

carboxy,

replaced heterocyclizations,

C1-5alkoxycarbonyl,

C1-5alkoxycarbonyl, is substituted by a carbocyclic aryl,

mono-C1-5alkylaminocarbonyl,

di-C1-5alkylaminocarbonyl,

mono-C1-5alkylamino,

mono-C1-5alkylamino substituted by substituent(s)independently selected from the group consisting of:

cyano,

carbocyclic aryl, and

heterocyclyl,

di-C1-5alkylamino,

di-C1-5alkylamino substituted by substituent(s)independently selected from the group consisting of:

cyano,

carbocyclic aryl, and

heterocyclyl,

monocarbocyclic arylamino,

monocarbocyclic arylamino substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy,

carbamoyl,

nitro,

cyano,

amino,

carbocyclic aryl,

carbocyclic aryl, substituted C1-5alkoxy,

C1-5alkoxy,

C1-5alkoxy substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy and

carboxy,

C1-5alkyl and

C1-5the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy and

carboxy,

dicarbollide arylamino,

dicarbollide arylamino substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy,

carbamoyl,

nitro,

cyano,

amino,

carbocyclic aryl,

carbocyclic aryl, substituted C1-5alkoxy,

C1-5alkoxy,

C1-5alkoxy substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy and

carboxy,

C1-5the alkyl and

C1-5the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy and

carboxy,

monoethanolamine,

monoethanolamine substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy,

carbamoyl,

nitro,

cyano,

amino,

carbocyclic aryl,

carbocyclic aryl, substituted C1-5alkoxy,

C1-5alkoxy,

C1-5alkoxy substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy and

carboxy,

C1-5the alkyl and

C 1-5the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy and

carboxy,

diameterically,

diameterically substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy,

carbamoyl,

nitro,

cyano,

amino,

carbocyclic aryl,

carbocyclic aryl, substituted C1-5alkoxy,

C1-5alkoxy,

C1-5alkoxy substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy and

carboxy,

C1-5the alkyl and

C1-5the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy and

carboxy,

C1-5alkylcarboxylic,

C1-5alkylcarboxylic substituted by substituent(s)independently selected from the group consisting of:

C1-5alkylcarboxylic,

carbocyclic, arylcarboxamide and

heterocyclyl,

C1-5alkoxycarbonyl,

carbocyclic, arylcarboxamide,

geterotsiklicheskikh,

carbocyclic, arylsulfonamides,

carbocyclic, arylsulfonyl substituted by substituent(s)independently selected from the group consisting of:

nitro,

p> C1-5of alkyl,

mono-C1-5alkylamino and

di-C1-5alkylamino,

C1-5alkylthio,

C1-5alkylthio substituted by substituent(s)independently selected from the group consisting of:

monocarbocyclic of arylenecarborane,

monocarbocyclic of arylenecarborane, substituted with halogen,

dicarbollide of arylenecarborane,

dicarbollide of arylenecarborane, substituted with halogen,

monocarbocyclic arylamino,

monocarbocyclic arylamino, substituted with halogen,

dicarbollide arylamino,

dicarbollide arylamino, substituted with halogen,

carbocyclic aryl, and

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen and

C1-5alkoxy,

carbocyclic, aaltio,

carbocyclic, aaltio substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5the alkyl and

C1-5of alkyl, substituted with halogen,

carbocyclic arylsulfonyl

carbocyclic arylsulfonyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5the alkyl and

C1-5of alkyl, substituted with halogen,

carbocyclic arylsulfonyl,/p>

carbocyclic arylsulfonyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5the alkyl and

C1-5of alkyl, substituted with halogen,

heterocyclic,

heterocyclic substituted by substituent(s)independently selected from the group consisting of:

nitro and

C1-5of alkyl,

C3-6cycloalkyl,

C3-6cycloalkyl, substituted C1-5the alkyl,

C3-6cycloalkyl, is substituted by a carbocyclic aryl,

C3-6cycloalkenyl,

carbocycle,

carbocycle substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5of alkyl,

C1-5alkoxy,

C2-5alkenyl and

C2-5alkenyl substituted by substituent(s)independently selected from the group consisting of:

carbocyclic aryl, and

carbocyclic aryl, substituted C1-5alkylammonium,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy,

carbamoyl,

cyano,

nitro,

amino,

C1-5alkylcarboxylic,

C3-6cycloalkylcarbonyl,

C1-5of alkyl,

C1-5the alkyl substituted by substituent(s), an is isimo selected from the group consisting of:

halogen-free,

hydroxy,

carboxy,

carbamoyl,

oxo,

carbocyclic aryl,

heterocyclyl,

monocarbocyclic arylamino,

dicarbollide arylamino,

monocarbocyclic arylamino substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

nitro,

C1-5of alkyl,

C1-5alkoxy and

C1-5alkoxy substituted by halogen,

dicarbollide arylamino substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

nitro,

C1-5of alkyl,

C1-5alkoxy and

C1-5alkoxy substituted by halogen,

C2-5alkenyl,

C1-5alkoxy,

C1-5alkoxy substituted by substituent(s)independently selected from the group consisting of:

halogen and

carbocyclic aryl,

carbocyclic, aryloxy,

C1-5alkoxycarbonyl,

C1-5alkylcarboxylic,

mono-C1-5alkylamino,

di-C1-5alkylamino,

monocarbocyclic arylamino,

monocarbocyclic arylamino, substituted with halogen,

dicarbollide arylamino,

dicarbollide arylamino, substituted with halogen,

monocarbocyclic of arylenecarborane,

monocarbocyclic of arylenecarborane substituted by substituent(s), selected from the group consisting of:

halogen-free,

nitro,

C1-5of alkyl,

C1-5alkoxy and

C1-5alkoxy substituted by halogen,

dicarbollide of arylenecarborane,

dicarbollide of arylenecarborane substituted by substituent(s)selected from the group consisting of:

halogen-free,

nitro,

C1-5of alkyl,

C1-5alkoxy and

C1-5alkoxy substituted by halogen,

mercapto,

C1-5alkylthio,

C1-5alkylthio, substituted with halogen,

C1-5alkylsulfonyl,

C3-6cycloalkyl,

carbocyclic aryl, and

heterocyclyl,

heterocyclyl and

heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy,

carbamoyl,

cyano,

nitro,

amino,

C1-5of alkyl,

C1-5the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy and

carbamoyl,

C1-5of alkyl, substituted by a carbocyclic aryl,

C1-5alkoxy,

C1-5alkoxy substituted by halogen,

C1-5alkoxy, substituted by a carbocyclic aryl,

carbocyclic aryl, and

carbocyclic aryl substituted by halogen,

(ii) C2-8alkenyl and

C 2-8alkenyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

oxo,

C1-5alkoxy,

C1-5alkoxy, substituted by a carbocyclic aryl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

nitro,

C1-5of alkyl,

C1-5of alkyl, substituted with halogen,

C1-5alkoxy and

C1-5alkoxy substituted by halogen,

heterocyclyl and

heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

hydroxy,

nitro,

C1-5the alkyl and

C1-5alkoxy,

(iii) C2-5the quinil and

C2-5the quinil, is substituted by a carbocyclic aryl,

(iv) C3-12cycloalkyl and

C3-12cycloalkyl substituted by substituent(s)independently selected from the group consisting of:

C1-5of alkyl,

C1-5the alkyl substituted by substituent(s)independently selected from the group consisting of:

hydroxy,

oxo and

carbocyclic aryl,

mono-C1-5alkylamino,

mono-C1-5alkylamino, is substituted by a carbocyclic aryl,

di-C1-5alkylamino,

di-C1-5alkylamino, is substituted by a carbocyclic aryl,

carbocyclic the who arylcarboxamide,

carbocyclic aryl, and

carbocyclic aryl substituted by halogen,

(v) C3-6cycloalkenyl and

C3-6cycloalkenyl, substituted C1-5ankylomon,

(vi) carbocycle and

carbocycle substituted by substituent(s)independently selected from the group consisting of:

hydroxy and

nitro,

(vii) carbocyclic aryl, and

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

cyano,

nitro,

C1-10of alkyl,

C1-10the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy,

carbamoyl,

oxo,

C1-5alkoxy,

carbocyclic, aryloxy,

mono-C1-5alkylamino-N-oxy,

di-C1-5alkylamino-N-oxy,

mono-C1-5alkylamino,

di-C1-5alkylamino,

mono-C1-5alkylamino, is substituted by a carbocyclic aryl,

di-C1-5alkylamino, is substituted by a carbocyclic aryl,

monocarbocyclic arylamino,

dicarbollide arylamino,

carbacyclin,

carbacyclin, is substituted by a carbocyclic aryl,

monocarbocyclic arylamino,

dicarbollide arylamino,

monocarbocyclic arylamino, substituted C 1-5alkoxy,

dicarbollide arylamino, substituted C1-5alkoxy,

monocarbocyclic of arylenecarborane,

dicarbollide of arylenecarborane,

monocarbocyclic of arylenecarborane, substituted C1-5alkoxy,

dicarbollide of arylenecarborane, substituted C1-5alkoxy,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5the alkyl and

C1-5of alkyl, substituted with halogen,

heterocyclyl and

heterocyclyl, substituted C1-5ankylomon,

C2-5alkenyl,

C2-5alkenyl, is substituted by a carbocyclic aryl,

C1-9alkoxy,

C1-9alkoxy substituted by substituent(s)independently selected from the group consisting of:

hydroxy,

halogen-free,

carboxy,

mono-C1-5alkylamino,

di-C1-5alkylamino,

carbocyclic aryl,

halogenated carbocyclic aryl,

heterocyclyl,

heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

heterocyclyl and

heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5the alkyl and

C1-5is Lila, substituted with halogen,

C2-5alkenylacyl,

C3-6cycloalkane,

C1-5alkylcarboxylic,

carbocyclic, aryloxy,

carbocyclic, aryloxy substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy,

carbamoyl,

cyano,

nitro,

amino,

C1-5of alkyl,

C1-5the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy and

carbamoyl,

C1-5alkoxy and

C1-5alkoxy substituted by halogen,

heterocyclics,

heterocyclic substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy,

carbamoyl,

cyano,

nitro,

amino,

C1-5of alkyl,

C1-5the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy and

carbamoyl,

C1-5alkoxy and

C1-5alkoxy substituted by halogen,

(carbocyclic aryl)S(O)2O,

carboxy,

carbamoyl,

C1-5alkoxycarbonyl,

mono-C1-5alkylaminocarbonyl,

di-C1-5alkylaminocarbonyl,

mono-C1-5alkylaminocarbonyl, replaced by carbocyclization,

di-C1-5alkylaminocarbonyl, is substituted by a carbocyclic aryl,

monocarbocyclic of arylenecarborane,

dicarbollide of arylenecarborane,

monocarbocyclic of arylenecarborane, substituted C1-5ankylomon,

dicarbollide of arylenecarborane, substituted C1-5the alkyl,

amino,

mono-C1-5alkylamino,

di-C1-5alkylamino,

mono-C1-5alkylamino, substituted cyano,

di-C1-5alkylamino, substituted cyano,

monocarbocyclic arylamino,

dicarbollide arylamino,

C1-5alkylcarboxylic,

C3-6cycloalkylcarbonyl,

C2-5alkanolammonium,

C2-5alkanolammonium, is substituted by a carbocyclic aryl,

C1-5alkoxycarbonyl,

carbocyclic, arylsulfonamides,

carbocyclic, arylsulfonyl, substituted C1-5the alkyl,

(carbocyclic aryl)NHC(O)NH,

(carbocyclic aryl)NHC(O)NH, substituted C1-5alkoxy,

(carbocyclic aryl)NHC(O)NH, substituted halogenated C1-5alkoxy,

carbocyclic, arylazo,

carbocyclic, arylazo substituted mono-C1-5alkylamino,

carbocyclic, arylazo, substituted CI-C1-5alkylamino,

C1-5alkylthio,

C1-5alkisti is, substituted with halogen,

carbocyclic, aaltio,

carbocyclic, aaltio substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

nitro,

cyano and

C1-5of alkyl,

aminosulfonyl,

heterocyclic,

C1-5alkylsulfonyl,

mono-C1-5alkylaminocarbonyl,

di-C1-5alkylaminocarbonyl,

heterocyclisation,

C3-6cycloalkyl,

C3-6cycloalkyl, substituted C1-5the alkyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

C1-7the alkyl and

C1-7of alkyl, substituted with halogen,

heterocyclyl and

heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

C1-5of alkyl,

carbocyclic aryl, and

halogenated carbocyclic aryl,

C1-5alkoxycarbonyl, is substituted by a carbocyclic aryl, and

(viii) heterocyclyl and

heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy,

carbamoyl,

cyano,

nitro,

amino,

C1-5of alkyl,

C1-5the alkyl substituted by substituent(s)independently selected from the group SOS is oasa from:

halogen-free,

hydroxy,

carboxy,

carbamoyl,

oxo,

C1-5alkylcarboxylic,

carbocyclic, arylcarboxamide,

carbocyclic, arylcarboxamide, substituted with halogen,

C1-5alkoxycarbonyl,

C1-5alkylthio,

C1-5alkylthio, is substituted by a carbocyclic aryl,

C1-5alkylthio, substituted by halogenated carbocyclic-aryl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen and

nitro,

heterocyclyl and

heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5the alkyl and

C1-5of alkyl, substituted with halogen,

C1-5alkoxy,

C1-5alkoxy substituted by halogen,

C1-5alkoxy, substituted by a carbocyclic aryl,

carbocyclic, aryloxy,

carbocyclic, aryloxy substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

nitro,

cyano,

hydroxy,

carboxy,

carbamoyl,

amino,

C1-5of alkyl,

C1-5the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy and

carbamoyl is and,

mono-C1-5alkylamino,

di-C1-5alkylamino,

C1-5alkylcarboxylic,

C3-6cycloalkylcarbonyl,

C1-5alkoxy,

C1-5alkoxy substituted by halogen,

C3-6cycloalkyl,

C2-5alkenyl,

C2-5the quinil,

carboxy,

C1-5alkoxycarbonyl,

mono-C1-5alkylaminocarbonyl,

di-C1-5alkylaminocarbonyl,

mono-C3-6cycloalkylcarbonyl,

di-C3-6cycloalkylcarbonyl,

mono-C1-5alkylaminocarbonyl,

di-C1-5alkylaminocarbonyl,

mono-C3-6cycloalkylcarbonyl,

di-C3-6cycloalkylcarbonyl,

C1-5alkylthio,

C1-5alkylthio, substituted with halogen,

C1-5alkylsulfonyl,

C1-5alkylsulfonyl, substituted with halogen,

C1-5alkylsulfonyl and

C1-5alkylsulfonyl, substituted with halogen,

heterocyclics,

heterocyclic substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

nitro,

hydroxy,

carboxy,

carbamoyl,

cyano,

amino,

C1-5of alkyl,

C1-5the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy and

carbamoyl,/p>

C1-5alkoxy and

C1-5alkoxy substituted by halogen,

mono-C1-5alkylamino,

di-C1-5alkylamino,

C1-5alkylcarboxylic,

C1-5alkylthio,

C2-5alkanity,

carbocyclic, aaltio,

carbocyclic, aaltio, substituted with halogen,

carbocyclic, aaltio, substituted C1-5alkoxycarbonyl,

heterocyclic,

heterocyclic, substituted C1-5the alkyl,

C1-5alkylsulfonyl,

C1-5alkylsulfonyl,

carbocyclic arylsulfonyl

carbocyclic arylsulfonyl, substituted with halogen,

carbocyclic arylsulfonyl,

carbocyclic arylsulfonyl, substituted with halogen,

carbocyclic arylsulfonyl, substituted C1-5the alkyl,

C1-5alkoxycarbonyl,

C1-5alkoxycarbonyl, is substituted by a carbocyclic aryl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

nitro,

C1-5of alkyl,

C1-5of alkyl, substituted with halogen,

C1-5alkoxy and

C1-5alkoxy substituted by halogen,

heterocyclyl and

heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

halo is Jena,

C1-5of alkyl,

C1-5of alkyl, substituted with halogen,

C1-5alkoxy and

C1-5alkoxycarbonyl;

R2represents halogen, C1-5alkyl, C1-5alkyl substituted by halogen, C1-5alkyl, substituted hydroxy, C1-5alkyl, substituted by a carbocyclic aryl, C1-5alkyl, substituted by halogenated carbocyclic-aryl, C1-5alkyl, substituted heterocyclyl, C1-5alkyl, substituted halogenated heterocyclyl, C2-5alkenyl, C2-5quinil, C1-5alkoxy, C1-5alkoxy substituted by halogen, C1-5alkylthio, -N(R2a)(R2b); where R2aand R2beach independently represents hydrogen, C1-5alkyl or C1-5alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy,

carbamoyl,

C1-5alkoxy,

amino,

C3-6cycloalkyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5of alkyl,

C1-5alkoxy,

C1-5of alkyl, substituted with halogen,

C1-5alkoxy substituted by halogen, and

SO2NH2,

heterocyclyl and

heterocyclyl substituted by substituent(s), the independent is selected from the group consisting of:

halogen-free,

C1-5of alkyl,

C1-5alkoxy,

C1-5of alkyl, substituted with halogen, and

C1-5alkoxy substituted by halogen,

C3-6cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5of alkyl,

C1-5alkoxy,

C1-5of alkyl, substituted with halogen, and

C1-5alkoxy substituted by halogen,

heterocyclyl or heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5of alkyl,

C1-5alkoxy,

C1-5of alkyl, substituted with halogen, and

C1-5alkoxy substituted by halogen;

L is selected from the group consisting of formulas (III), (IIIa), (IIIb), (IV), (IVa) and (IVb);

where R3and R4each independently represents hydrogen or C1-5alkyl; and A and B each independently represents a single bond, -CH2- or -(CH2)2-;

Z1, Z2, Z3and Z4each independently represents hydrogen, halogen, C1-5alkyl, C1-5alkyl substituted by halogen, C1-5alkyl, substituted hydroxy, C1-5alkyl, substituted by a carbocyclic aryl, C1-5alkyl, substituted halogenated of carbon Klionsky-aryl, C1-5alkyl, substituted heterocyclyl, C1-5alkyl, substituted halogenated heterocyclyl, C2-5alkenyl, C2-5quinil, C3-6cycloalkyl, C1-5alkoxy, C1-5alkoxy substituted by halogen, mono-C1-5alkylamino, di-C1-5alkylamino, C1-5alkylthio, carbocyclic aryl, substituted carbocyclic aryl, heterocyclyl or substituted heterocyclyl; or

R2and Z2connected to each other to form a ring and-R2-Z2- represents -(CH2)n- or -(CH2)o-CH=CH-(CH2)p-; where one group-CH2- R2-Z2- may be optionally replaced with C(O)NR6, O, S, S(O) or S(O)2; where n equals 2, 3, 4, 5 or 6; o and p each independently 0, 1, 2, 3, or 4, provided that o+p=0, 1, 2, 3 or 4; and R6represents hydrogen, C1-5alkyl or substituted C1-5alkyl;

and

Y represents:

(i) -C(O)NR5-, -C(S)NR5-, -C(O)O-, -S(O)2-, -C(O)-, -C(S)- or -(CH2)m-when L is selected from the group consisting of formulas (III), (IIIa) and (IIIb); or

(ii) -C(O)NR5-, -C(S)NR5-, -C(O)O - or-OC(O)-when L is selected from the group consisting of formulas (IV), (IVa) and (IVb); where R5represents hydrogen or C1-5alkyl; and m is 0, 1, 2, 3, 4 or 5;

where carbocyclic aryl represents phenyl, naphthyl, anthranol, tenantry Il is biphenyl;

carbocyclic is a

10,11-dihydro-5-oxidant[a,d]cycloheptyl, 1-oxoindole,

7,7-dimethyl-2-oxobicyclo[2.2.1]heptyl, 9H-fluorenyl,

9-oxipurinol, acenaphthyl, anthrachinone,C-fluoren-9-ilidene,

indanyl, indenyl, mental, 1,2,3,4-tetrahydronaphthyl or

bicyclo[2.2.1]heptenyl;

heterocyclyl is a

1,2,3,4-tetrahydroisoquinoline, 1,2,3-thiadiazolyl,

1,2,3-triazolyl, 1,2-dihydro-3-oxadiazolyl, 1,3,4-thiadiazolyl,

1,3-dikshithar, 1,3-DIOXOLANYL, 1H-indolyl,

1H-pyrrolo[2,3-c]pyridyl, 1H-pyrrolyl,

1-oxo-3H-isobenzofuranyl, 2,2',5',2"-terthiophene,

2,2'-bithiophene, 2,3-dihydro-1-occaisonaly,

2,3-dihydrobenzo[1,4]dioxines, 2,3-dihydrobenzofuran,

2,4-dihydro-3-oxadiazolyl, 2H-benzopyranyl,

2-octoberapril, 2-oxopyrrolidin,

3,4-dihydro-2H-benzo[1,4]oxazinyl,

3,4-dihydro-2H-benzo[b][1,4]dioxyphenyl, 4H-benzo[1,3]dioxines,

4H-benzopyranyl, 4-oxo-1,5,6,7-tetrahydroindole,

4-oxo-3,4-dihydrophenazine, 4-octoberapril,

9,10,10-trioxatridecane, 9H-carbazolyl, 9H-xantener,

azetidinol, benzimidazolyl, benzo[1,3]dioxole,

benzo[2,1,3]oxadiazolyl, benzo[1,2,5]oxadiazolyl,

benzo[b]thienyl, benzofuran, benzothiazole, cannoli, furyl,

imidazo[2,1-b]thiazolyl, imidazolyl, isoxazolyl, morph the Lino,

morpholinyl, oxazolyl, oxolane, piperazin, piperidyl, pyridyl,

pyrazolo[5,1-b]thiazolyl, pyrazolyl, pyrazinyl, pyridyl,

pyrimidyl, pyrrolidyl, hinely, Minoxidil, thiazolidin,

thiazolyl, thienyl, tylenol, 2,3-dihydrobenzofuran,

tetrahydrothieno or benzofuranyl;

halogen represents fluorine, chlorine, bromine or iodine;

or their pharmaceutically acceptable salt, hydrate or MES.

One aspect of the present invention relates to pharmaceutical compositions containing a therapeutically effective amount of at least one specified in the description of the compounds in combination with a pharmaceutically acceptable carrier.

One aspect of the present invention relates to a method of prevention or treatment of conditions requiring improvements in functioning memory, sleeping and arousal, anxiety, depression, mood disorders, seizures, obesity, diabetes, disorders of appetite and eating behavior, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, disorders related to "binge" eating, including bulimia, anorexia, mental disorders including manic-depressive disorder, schizophrenia, delirium, dementia, stress, cognitive disorders, disorder attention deficit, drug abuse by realcool and dyskinesias, including Parkinson's disease, epilepsy, and addiction, including the introduction suffering from a specified state to the individual a therapeutically effective amount of a compound as described herein, or pharmaceutical compositions.

One aspect of the present invention relates to a method of treatment or prophylaxis of eating disorders, obesity or associated with obesity violations, including the introduction suffering from this state to the individual a therapeutically effective amount of a compound as described herein, or pharmaceutical compositions.

One aspect of the present invention relates to a method of treatment or prevention of anxiety, depression, schizophrenia, addiction or epilepsy, including the introduction suffering from this state to the individual a therapeutically effective amount of a compound as described herein, or pharmaceutical compositions.

One aspect of the present invention relates to compounds of the present invention, as described herein, or pharmaceutical compositions for use in the method of treatment of the human or animal body by therapy.

One aspect of the present invention relates to compounds of the present invention, as described herein, Il is to their pharmaceutical compositions for use in the method of prevention or treatment of eating disorders, obesity or associated with obesity disorders in human or animal body by therapy.

One aspect of the present invention relates to compounds of the present invention, as described herein, or pharmaceutical compositions for use in the method of prevention or treatment of anxiety, depression, schizophrenia, addiction or epilepsy human or animal body by therapy.

One aspect of the present invention relates to compounds of the present invention, as described herein, for the manufacture of a medicinal product for use in the prevention or treatment of eating disorders, obesity or obesity-related disorders.

One aspect of the present invention relates to compounds of the present invention, as described herein, for the manufacture of a medicinal product for use in the prevention or treatment of anxiety, depression, schizophrenia, addiction, or epilepsy.

One aspect of the present invention relates to a method of reducing food intake by the individual, including the introduction of a specified individual a therapeutically effective amount of a compound as described herein, or pharmaceutical compositions.

One aspect of the present invention relates to FPIC is BAM induction of satiety in an individual, includes introduction to the specified individual a therapeutically effective amount of a compound as described herein, or pharmaceutical compositions.

One aspect of the present invention relates to methods of controlling or decreasing weight gain in an individual, comprising the introduction of a specified individual a therapeutically effective amount of a compound as described herein, or pharmaceutical compositions.

One aspect of the present invention relates to methods of modulating MCH receptor in an individual comprising contacting the receptor with a compound as described herein. In some embodiments, the implementation of connection is an antagonist. In some embodiments, the implementation of the modulating MCH receptor intended for the prevention or treatment of eating disorders, obesity or associated with obesity disorders. In some embodiments, the implementation of the modulating MCH receptor reduces food intake by the individual. In some embodiments, the implementation of the modulating MCH receptor induces the individual satiety. In some embodiments, the implementation of the modulating MCH receptor controls and reduces the individual's weight gain. In some embodiments, the implementation of the modulation of receptor MCH intended is prohibited for the prevention or treatment of anxiety, depression, schizophrenia, addiction, or epilepsy.

In some embodiments, the implementation of the individual is a mammal.

In some embodiments, the implementation of the mammal is man.

In some embodiments, the implementation of the body mass index is from about 18.5 to about 45. In some embodiments, the implementation of the body mass index is from about 25 to about 45. In some embodiments, the implementation of the body mass index is from about 30 to about 45. In some embodiments, the implementation of the body mass index is from about 35 to about 45.

One aspect of the present invention relates to methods of producing a pharmaceutical composition, comprising mixing the compound, as described herein, and a pharmaceutically acceptable carrier.

Detailed description of the invention

One aspect of the present invention relates to certain compounds of the substituted pyrimidine represented by formula (I):

or their pharmaceutically acceptable salt, hydrate or solvate, where Q, L, Y, and R1are as described herein, above and below.

It is clear that certain features of the invention, which is snasti described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, described in the context of one possible implementation can also be provided separately or in any suitable podschitany.

In some embodiments, the communication of the present invention are compounds of formula (I), where Q represents the formula (IIa); Z1represents hydrogen, halogen, C1-5alkyl, C1-5alkyl substituted by halogen, C3-6cycloalkyl, C1-5alkoxy, C1-5alkoxy substituted by halogen, or C1-5alkylthio, or their pharmaceutically acceptable salt, hydrate or MES.

In some embodiments, the communication of the present invention are compounds of formula (I), where R1selected from the group consisting of:

(i) C1-10the alkyl and

C1-10the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

oxo,

C1-5alkoxy,

C1-5alkoxy, substituted by a carbocyclic aryl,

C1-5alkylcarboxylic,

C1-5alkoxycarbonyl,

C1-5alkoxycarbonyl, is substituted by a carbocyclic aryl,

carbocyclic, aryloxy and

carbocyclic, aryloxy, substituted mixing what ielem(s), independently selected from the group consisting of:

halogen-free,

nitro,

C1-5the alkyl and

C1-5of alkyl, substituted oxo,

heterocyclics,

heterocyclics, substituted C1-5the alkyl,

monocarbocyclic arylamino,

dicarbollide arylamino,

carbocyclic, arylsulfonamides,

carbocyclic, arylsulfonyl, substituted C1-5the alkyl,

C1-5alkylthio,

C1-5alkylthio, is substituted by a carbocyclic aryl,

carbocyclic, aaltio,

carbocyclic, aaltio, substituted with halogen,

carbocyclic, aaltio, substituted C1-5the alkyl,

carbocyclic arylsulfonyl,

carbocyclic arylsulfonyl, substituted with halogen,

heterocyclic,

heterocyclic, substituted C1-5the alkyl,

C3-6cycloalkyl,

C3-6cycloalkenyl,

carbocycle,

carbocycle, substituted C1-5alkoxy,

carbocyclic aryl, and

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

nitro,

C1-5the alkyl and

C1-5the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

carbocyclic aryl, and

heterocyclyl,

C1-5alkoxy

C1-5alkoxy substituted by halogen,

C1-5alkoxy, substituted by a carbocyclic aryl,

carbocyclic, aryloxy,

monocarbocyclic of arylenecarborane and

monocarbocyclic of arylenecarborane substituted by substituent(s)selected from the group consisting of:

halogen-free,

C1-5of alkyl,

C1-5alkoxy and

C1-5alkoxy substituted by halogen,

dicarbollide of arylenecarborane and

dicarbollide of arylenecarborane substituted by substituent(s)selected from the group consisting of:

halogen-free,

C1-5of alkyl,

C1-5alkoxy and

C1-5alkoxy substituted by halogen,

C1-5alkylthio,

C1-5alkylthio, substituted with halogen,

C1-5alkylsulfonyl,

carbocyclic aryl, and

heterocyclyl,

heterocyclyl and

heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

C1-5of alkyl,

C1-5alkoxy,

C1-5alkoxy, substituted by a carbocyclic aryl,

carbocyclic aryl, and

carbocyclic aryl substituted by halogen,

(ii) C2-5alkenyl and

C2-5alkenyl substituted by substituent(s)independently selected from the group consisting of:

carbocyclic aryl, and

carbocycles is aryl, substituted by substituent(s)independently selected from the group consisting of:

nitro,

halogen-free,

C1-5of alkyl,

C1-5of alkyl, substituted with halogen,

C1-5alkoxy and

C1-5alkoxy substituted by halogen,

(iii) C3-6cycloalkyl and

C3-6cycloalkyl substituted by substituent(s)independently selected from the group consisting of:

C1-5of alkyl,

C1-5of alkyl, substituted by a carbocyclic aryl,

carbocyclic, arylcarboxamide and

carbocyclic aryl,

(iv) carbocyclic and

carbocycle, substituted nitro,

(v) carbocyclic aryl, and

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

cyano,

nitro,

C1-9the alkyl and

C1-9the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

oxo,

monocarbocyclic of arylenecarborane,

dicarbollide of arylenecarborane,

monocarbocyclic of arylenecarborane, substituted C1-5alkoxy,

dicarbollide of arylenecarborane, substituted C1-5alkoxy,

carbocyclic, aryloxy,

carbocyclic aryl, and

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5the alkyl and

C1-5of alkyl, substituted with halogen,

heterocyclyl and

heterocyclyl, substituted C1-5the alkyl,

C2-5alkenyl,

C1-7alkoxy,

C1-7alkoxy substituted by halogen,

C1-7alkoxy, substituted by a carbocyclic aryl,

C3-6cycloalkane,

carbocyclic, aryloxy and

carbocyclic, aryloxy substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

nitro and

C1-5alkoxy

heterocyclics and

heterocyclic substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5the alkyl and

C1-5of alkyl, substituted with halogen,

C1-5alkoxycarbonyl,

mono-C1-5alkylaminocarbonyl,

di-C1-5alkylaminocarbonyl,

mono-C1-5alkylaminocarbonyl, is substituted by a carbocyclic aryl,

di-C1-5alkylaminocarbonyl, is substituted by a carbocyclic aryl,

monocarbocyclic of arylenecarborane,

dicarbollide of arylenecarborane,

monocarbocyclic of arylenecarborane, substituted C1-5the alkyl,

dicarbollide of arylenecarborane, substituted C1-5the alkyl,

mono-C1-5alkylamino,

di-C1-5al is ylamino,

C1-5alkylthio,

C1-5alkylthio, substituted with halogen,

C1-5alkylsulfonyl,

carbocyclic aryl, and

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

C1-7the alkyl and

C1-7of alkyl, substituted with halogen,

(vi) heterocyclyl and

heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5the alkyl and

C1-5the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

oxo,

carbocyclic aryl,

carbocyclic aryl substituted by halogen,

heterocyclyl and

heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5the alkyl and

C1-5of alkyl, substituted with halogen,

C1-5alkoxy,

C1-5alkylthio,

carbocyclic, aaltio,

C1-5alkylsulfonyl,

carbocyclic arylsulfonyl,

carbocyclic arylsulfonyl, substituted with halogen,

carbocyclic arylsulfonyl, substituted C1-5the alkyl,

C1-5alkoxycarbonyl,

carbocyclic aryl, and

carbocyclic aryl substituted by substituent(s)independently selected from the group status is the present of:

halogen-free,

nitro and

C1-5of alkyl,

heterocyclyl and

heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5the alkyl and

C1-5of alkyl, substituted with halogen;

where carbocyclic aryl represents phenyl, naphthyl or indranil;

carbocyclic is a 1-oxoindole, 9H-fluorenyl, 9-oxipurinol, anthrachinone,C-fluoren-9-ilidene, indanyl or mental;

heterocyclyl is a

1,2,3,4-tetrahydroisoquinoline, 1,2,3-thiadiazolyl,

1,2,3-triazolyl, 1,3-dikshithar, 1H-indolyl, 1H-pyrrolyl,

2,3-dihydro-1-occaisonaly, 2,3-dihydrobenzo[1,4]dioxines,

2H-benzopyranyl, 2-octoberapril, 2-oxopyrrolidin,

4-octoberapril, 9H-xantener, benzo[1,3]dioxole,

benzo[2,1,3]oxadiazolyl, benzo[1,2,5]oxadiazolyl,

benzo[b]thienyl, furyl, isoxazolyl, morpholinyl, oxazolyl,

pyrazolyl, pyridyl, pyrimidyl, pyrrolidyl, hinely, Minoxidil,

thiazolyl, thienyl, imidazolyl or piperonyl;

halogen represents fluorine, chlorine, bromine or iodine;

or their pharmaceutically acceptable salt, hydrate or MES.

In some embodiments, the communication of the present invention are compounds of formula (I), where R2represents halogen, C1-5alkyl, C1-5alkoxy, -N(R2a)(R2bor heterocyclyl; where R2aand R2beach independently represents hydrogen, C1-5alkyl, C1-5alkyl, substituted hydroxy, C1-5alkyl, substituted by a carbocyclic aryl, C1-5alkyl, substituted heterocyclyl, C3-6cycloalkyl or carbocyclic aryl; L is selected from the group consisting of formulas (IIIa) and (IVa); where R3and R4each independently represents hydrogen or C1-5alkyl; and A and B each independently represents a single bond, -CH2- or -(CH2)2-; Z1represents hydrogen, halogen, C1-5alkyl, C1-5alkyl substituted by halogen, C1-5alkoxy or C1-5alkylthio; Z2represents hydrogen, halogen or C1-5alkyl; or R2and Z2connected to each other to form a ring and-R2-Z2- represents-NR6-CH=CH-; where R6represents hydrogen or C1-5alkyl; and Y represents:

(i) -C(O)NR5-, -C(S)NR5-, -C(O)O-, -S(O)2-, -C(O)- or -(CH2)m-when L is selected from the group consisting of formulas (IIIa); or

(ii) -C(O)NR5- or-C(O)O-when L is selected from the group consisting of the formulas (IVa);

where R5represents hydrogen or C1-5alkyl; and m is 0, 1 or 2;

or their pharmaceutically acceptable the Yu salt, hydrate or MES.

In some embodiments, the communication of the present invention are compounds of formula (I), where R1selected from the group consisting of:

(i) C1-5the alkyl substituted by substituent(s)independently selected from the group consisting of:

hydroxy,

carbocyclic aryl,

carbocyclic aryl substituted by halogen, and

C1-5alkylthio,

(ii) C3-6cycloalkyl and

(iii) carbocyclic aryl, and

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

nitro,

cyano,

C1-5of alkyl,

C1-5of alkyl, substituted with halogen,

C1-5alkoxy,

C1-5alkoxy substituted by halogen,

C1-5alkoxy, substituted by a carbocyclic aryl,

carbocyclic, aryloxy and

carbocyclic, aryloxy, substituted C1-5alkoxy,

(iv) heterocyclyl and

heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5of alkyl,

carbocyclic aryl, and

carbocyclic aryl substituted by halogen;

R2represents-N(R2a)(R2bor heterocyclyl; where R2aand R2beach independently represents hydrogen or C1-5Ala is l;

Z1represents hydrogen, C1-5alkyl or C1-5alkylthio; Z2represents hydrogen or C1-5alkyl; or

R2and Z2connected to each other to form a ring and-R2-Z2- represents-NR6-CH=CH-; where R6represents hydrogen or C1-5alkyl;

L is formula (IIIa) or (IVa), where R3and R4represent hydrogen, A is single bond, and B is a single bond or-CH2-;

and

Y represents:

(i) -C(O)NH-, -C(S)NH, -C(O)- or-CH2-when L is selected from the group consisting of formulas (IIIa); or

(ii) -C(O)NH-, when L is selected from the group consisting of the formulas (IVa);

where carbocyclic aryl represents phenyl or naphthyl;

heterocyclyl represents furyl, 1H-indolyl, morpholinyl, oxazolyl, piperidyl, pyridyl, pyrrolidyl or 9H-xantener;

halogen represents fluorine, chlorine or bromine;

or their pharmaceutically acceptable salt, hydrate or MES.

In some embodiments, the communication of the present invention are compounds of formula (I), where R1selected from the group consisting of:

(i) carbocyclic aryl, and

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C-5 of alkyl,

C1-5of alkyl, substituted with halogen,

C1-5alkoxy and

C1-5alkoxy substituted by halogen,

(ii) heterocyclyl and

heterocyclyl, substituted with halogen;

and

Z1represents hydrogen, C1-5alkyl or C1-5alkylthio; Z2represents hydrogen or C1-5alkyl;

where carbocyclic aryl represents phenyl;

heterocyclyl represents furyl, pyridyl or pyrrolidyl;

halogen represents fluorine, chlorine or bromine;

or their pharmaceutically acceptable salt, hydrate or MES.

In some embodiments, the communication of the present invention are compounds of formula (I)where the compound is selected from the group consisting of:

N-(CIS-4-{[6-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-3,4-differentated;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-fermentated;

4-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-fermentated;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)for 3,5-differentated;

3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-(triptoreline)benzamide;

3-chloro-4-fluoro-N-(CIS-4-{[2-methyl-6-(methylamino)pyrimidine-4-yl]amino}C is clohessy)benzamide;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-fermentated;

4-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-fluoro-5-(trifluoromethyl)benzamide;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)for 3,5-bis(trifluoromethyl)benzamide;

3-chloro-4-fluoro-N-{CIS-4-[(2-methyl-6-piperidine-1-Yeremey-4-yl)amino]cyclohexyl}benzamide;

3-chloro-4-fluoro-N-{CIS-4-[(2-methyl-6-morpholine-4-Yeremey-4-yl)amino]cyclohexyl}benzamide;

3-chloro-4-fluoro-N-{CIS-4-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]cyclohexyl}benzamide;

3,4,5-Cryptor-N-{CIS-4-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]cyclohexyl}benzamide;

3,4,5-Cryptor-N-(CIS-4-{[2-methyl-6-(methylamino)pyrimidine-4-yl]amino}cyclohexyl)benzamide;

CIS-N-(3,4-differenl)-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexanecarboxylate;

1-(4-chlorophenyl)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)cyclopentanecarboxylate;

3-(2-chloro-6-forfinal)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-5-methylisoxazol-4-carboxamide;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin is n-4-yl]amino}cyclohexyl)-2-(4-methoxyphenoxy)-5-nitrobenzamide;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-5-iodine-2-furamide;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-(ethylthio)-2,2-diphenylacetamide;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-9H-xanthene-9-carboxamide;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-[1-(1-naphthyl)ethyl]urea;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-(3,4,5-trimethoxyphenyl)urea;

N-(5-chloro-2,4-acid)N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)urea;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-(2,4,6-tribromophenyl)urea;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'musicindiaonline;

N-(2,6-diethylphenyl)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiourea;

N-(2,4-dichloro-6-were)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiourea;

N-(5-chloro-2,4-acid)N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiourea;

N-[4-bromo-2-(trifluoromethyl)phenyl]-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin the-4-yl]amino}cyclohexyl)thiourea;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-nitrobenzamide;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-diethoxybenzene;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethoxybenzene;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-diethoxybenzene;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-isopropoxybenzoic;

3-bromo-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-fermentated;

4 deformedarse-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;

4-chloro-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-methylbenzamide;

3 deformedarse-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;

3-chloro-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-methylbenzamide;

4-bromo-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-dimethoxybenzamide;

4-cyano-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;

N[CIS-4-(6-dimethylamino-2-methylpr midin-4-ylamino)cyclohexyl]-4-methoxybenzamide;

3-cyano-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-methoxybenzamide;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-fluoro-3-methylbenzamide;

4-bromo-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-methylbenzamide;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-fluoro-4-methylbenzamide;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethylbenzamide;

3-bromo-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-fluoro-4-cryptomelane;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-triphtalocyaninine;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-methylbenzamide;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-methylbenzamide;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-cryptomelane;

[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]amide 2,2-debtorrent[1,3]dioxol-5-carboxylic acid;

N{CIS-4-[(1H -indol-2-ylmethyl)amino]cyclohexyl}-2,N',N'trimethylpyridine-4,6-diamine;

2,N,Ntrimethyl-N'-[CIS-4-(3-triphtalocyaninine)cyclohexyl]pyrimidine-4,6-diamine;

N[CIS-4-(3,4-diferentiating)cyclohexyl]-2,N',N'trimethylpyridine-4,6-diamine;

1-(3,4-acid)-3-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]urea;

1-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-(2-ethoxyphenyl)urea;

1-(4-benzyloxyphenyl)-3-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]urea;

3,5-dibromo-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;

3-bromo-4-chloro-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;

4-chloro-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-cryptomelane;

2-(3,5-bistrifluormethylbenzene)-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-2-hydroxyacetamido;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-fluoro-4-cryptomelane;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-triphtalocyaninine;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-methods dibenzamide;

4-chloro-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]benzamide;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-cryptomelane;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-4-cryptomelane;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-methylbenzamide;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]for 3,5-differentated;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-ethylbenzamide;

[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]amide 2,2-debtorrent[1,3]dioxol-5-carboxylic acid;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-fluoro-4-methylbenzamide;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-4-fermentated;

3,4-dichloro-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]benzamide;

4-bromo-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]benzamide;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3,4-differentated;

3,5-dichloro-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)Ziklag Kilmer]benzamide;

3-chloro-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-4-fermentated;

N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-4-fluoro-3-methylbenzamide and

3-chloro-N[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]benzamide;

or their pharmaceutically acceptable salt, hydrate or MES.

In some embodiments, the communication of the present invention are compounds of formula (I)where the compound is selected from the group consisting of:

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4-differentated;

N-(CIS-4-{[6-(dimethylamino)-2-ethylpyrimidine-4-yl]amino}cyclohexyl)-3,4-differentated;

3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-fermentated;

3,4-dichloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide;

3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-5-fermentated;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4,5-triterpenoid;

5-bromo-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)nicotinamide;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-ft is R-3-(trifluoromethyl)benzamide;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-(trifluoromethyl)benzamide;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-(triptoreline)benzamide;

3,5-dichloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide;

3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide;

3-chloro-4-fluoro-N-{CIS-4-[(2-methyl-6-pyrrolidin-1-Yeremey-4-yl)amino]cyclohexyl}benzamide;

N-(CIS-4-{[6-(dimethylamino)-2-ethylpyrimidine-4-yl]amino}cyclohexyl)-3,4,5-triterpenoid;

CIS-N-(3-chloro-4-forfinal)-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexanecarboxylate;

N-(CIS-4-{[2-benzyl-6-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-3-chloro-4-fermentated;

CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}-N-(3,4,5-tryptophanyl)cyclohexanecarboxylate;

N-(4-bromo-2,6-dimetilfenil)N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)urea;

N-(4-bromo-2,6-dimetilfenil)N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiourea;

N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-(3,4,5-trimethoxyphenyl)thiourea;

N-(CIS-4-{[6-(dimethylamino)-2-ethylpyrimidine-4-yl]amino}cyclohexyl)- N'-(2,4,6-tribromophenyl)thiourea;

[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]amide 5-bromofuran-2-carboxylic acid;

N-[CIS-4-(3,5-dimethoxyphenethylamine)cyclohexyl]-2,N',N'trimethylpyridine-4,6-diamine;

N-[CIS-4-(3-bromobenzylamine)cyclohexyl]-2,N',N'trimethylpyridine-4,6-diamine;

1-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-(3-methoxyphenyl)urea;

1-(3,5-differenl)-3-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]urea;

N-[CIS-4-(6-dimethylamino-2-methylsulfonylamino-4-ylamino)cyclohexyl]-3,4-differentated;

N-[CIS-4-(6-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-differentated;

N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]for 3,5-bitreversed and

N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-4-triphtalocyaninine;

or their pharmaceutically acceptable salt, hydrate or MES.

In some embodiments, the communication of the present invention are compounds of formula (I), where R1represents:

(i) hydrogen, -CO2tBu or-CO2Bn (Bn is a benzyl group), when L is selected from the group consisting of form is l (III), (IIIa) and (IIIb); or

(ii) hydrogen, C1-5alkyl, substituted C1-5alkyl, Bn or substituted Bn, when L is selected from the group consisting of formulas (IV), (IVa) and (IVb);

where R3and R4each independently represents hydrogen or C1-5alkyl; and A and B each independently represents a single bond, -CH2- or -(CH2)2-; R2represents halogen, C1-5alkyl, C1-5alkoxy, -N(R2a)(R2bor heterocyclyl; where R2aand R2beach independently represents hydrogen, C1-5alkyl, C1-5alkyl, substituted hydroxy, C1-5alkyl, substituted by a carbocyclic aryl, C1-5alkyl, substituted heterocyclyl, C3-6cycloalkyl or carbocyclic aryl; Z1represents hydrogen, halogen, C1-5alkyl, C1-5alkyl substituted by halogen, C1-5alkoxy or C1-5alkylthio; Z2represents hydrogen, halogen or C1-5alkyl; or R2and Z2connected to each other to form a ring, and R2-Z2- represents-NR6-CH=CH-; where R6represents hydrogen or C1-5alkyl; and Y represents:

(i) single bond when L is selected from the group consisting of formulas (III), (IIIa) and (IIIb); or

(ii) -C(O)O-when L is selected from the group consisting of formulas (IV), (IVa) and (IVb);

or farmatsevticheskii salt, hydrate or MES.

In some embodiments, the communication of the present invention are compounds of formula (I), where R1represents:

(i) hydrogen, -CO2tBu or-CO2Bn (Bn is a benzyl group), when L is selected from the group consisting of formulas (IIIa); or

(ii) hydrogen, C1-5alkyl, substituted C1-5alkyl, Bn or substituted Bn, when L is selected from the group consisting of the formulas (IVa);

where R3and R4each represents hydrogen; and A and B each independently represents a single bond or-CH2-; R2represents-N(R2a)(R2bor heterocyclyl; where R2aand R2beach independently represents hydrogen or C1-5alkyl; Z1represents hydrogen, C1-5alkyl or C1-5alkylthio; Z2represents hydrogen or C1-5alkyl; or R2and Z2connected to each other to form a ring and-R2-Z2- represents-NR6-CH=CH-; where R6represents hydrogen or C1-5alkyl; and Y represents:

(i) single bond when L is selected from the group consisting of formulas (IIIa); or

(ii) -C(O)O-when L is selected from the group consisting of the formulas (IVa);

heterocyclyl represents furyl, 1H-indolyl, morpholinyl, oxazolyl, piperidyl, who iridal, pyrrolidyl or 9H-xantener;

or their pharmaceutically acceptable salt, hydrate or MES.

In some embodiments, the communication of the present invention are compounds of formula (I), where Q is the formula (IIb); R2represents a C1-5alkyl, substituted hydroxy, C1-5alkyl, substituted by a carbocyclic aryl, C1-5alkyl, substituted by halogenated carbocyclic-aryl, C1-5alkyl, substituted heterocyclyl, C1-5alkyl, substituted halogenated heterocyclyl, C2-5alkenyl, C2-5quinil or-N(R2a)(R2b); where R2aand R2beach independently represents hydrogen, C1-5alkyl or C1-5alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

carboxy,

carbamoyl,

C1-5alkoxy,

amino,

C3-6cycloalkyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5of alkyl,

C1-5alkoxy,

C1-5of alkyl, substituted with halogen,

C1-5alkoxy substituted by halogen, and

SO2NH2,

heterocyclyl and

heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5of alkyl,

C1-5alkoxy,

C1-5of alkyl, substituted with halogen, and

C1-5alkoxy substituted by halogen,

carbocyclic aryl, carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5of alkyl,

C1-5alkoxy,

C1-5of alkyl, substituted with halogen, and

C1-5alkoxy substituted by halogen,

heterocyclyl, or heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5of alkyl,

C1-5alkoxy,

C1-5of alkyl, substituted with halogen, and

C1-5alkoxy substituted by halogen;

or their pharmaceutically acceptable salt, hydrate or MES.

In some embodiments, the communication of the present invention are compounds of formula (I), where R1selected from the group consisting of:

(i) C1-10the alkyl and

C1-10the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

hydroxy,

oxo,

C1-5alkoxy,

C1-5alkoxy, substituted by a carbocyclic aryl,

C1-5alkylcarboxylic,

C1-5alkoxycarbonyl,

C1-5alkoxycarbonyl, replaced carbocyclic the sky aryl,

carbocyclic, aryloxy and

carbocyclic, aryloxy substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

nitro,

C1-5the alkyl and

C1-5of alkyl, substituted oxo,

heterocyclics,

heterocyclics, substituted C1-5the alkyl,

monocarbocyclic arylamino,

dicarbollide arylamino,

carbocyclic, arylsulfonamides,

carbocyclic, arylsulfonyl, substituted C1-5the alkyl,

C1-5alkylthio,

C1-5alkylthio, is substituted by a carbocyclic aryl,

carbocyclic, aaltio,

carbocyclic, aaltio, substituted with halogen,

carbocyclic, aaltio, substituted C1-5the alkyl,

carbocyclic arylsulfonyl,

carbocyclic arylsulfonyl, substituted with halogen,

heterocyclic,

heterocyclic, substituted C1-5the alkyl,

C3-6cycloalkyl,

C3-6cycloalkenyl,

carbocycle,

carbocycle, substituted C1-5alkoxy,

carbocyclic aryl, and

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

nitro,

C1-5the alkyl and

C1-5the alkyl substituted by substituent(s)independently selected from the group, with Toyama from:

halogen-free,

carbocyclic aryl, and

heterocyclyl,

C1-5alkoxy,

C1-5alkoxy substituted by halogen,

C1-5alkoxy, substituted by a carbocyclic aryl,

carbocyclic, aryloxy,

monocarbocyclic of arylenecarborane and

monocarbocyclic of arylenecarborane substituted by substituent(s)selected from the group consisting of:

halogen-free,

C1-5of alkyl,

C1-5alkoxy and

C1-5alkoxy substituted by halogen,

dicarbollide of arylenecarborane and

dicarbollide of arylenecarborane substituted by substituent(s)selected from the group consisting of:

halogen-free,

C1-5of alkyl,

C1-5alkoxy and

C1-5alkoxy substituted by halogen,

C1-5alkylthio,

C1-5alkylthio, substituted with halogen,

C1-5alkylsulfonyl,

carbocyclic aryl, and

heterocyclyl,

heterocyclyl and

heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

C1-5of alkyl,

C1-5alkoxy,

C1-5alkoxy, substituted by a carbocyclic aryl,

carbocyclic aryl, and

carbocyclic aryl substituted by halogen,

(ii) C2-5alkenyl, and

C2-5alkenyl substituted by substituent(s), Nezavisimoye from the group consisting of:

carbocyclic aryl, and

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

nitro,

halogen-free,

C1-5of alkyl,

C1-5of alkyl, substituted with halogen,

C1-5alkoxy and

C1-5alkoxy substituted by halogen,

(iii) C3-6cycloalkyl and

C3-6cycloalkyl substituted by substituent(s)independently selected from the group consisting of:

C1-5of alkyl,

C1-5of alkyl, substituted by a carbocyclic aryl,

carbocyclic, arylcarboxamide and

carbocyclic aryl,

(iv) carbocyclic and

carbocycle, substituted nitro,

(v) carbocyclic aryl, and

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

cyano,

nitro,

C1-9the alkyl and

C1-9the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

oxo,

monocarbocyclic of arylenecarborane,

dicarbollide of arylenecarborane,

monocarbocyclic of arylenecarborane, substituted C1-5alkoxy,

dicarbollide of arylenecarborane, substituted C1-5alkoxy,

carbocyclic, aryloxy,

carbocyclic aryl, and

carbon Kochetkova aryl, substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5the alkyl and

C1-5of alkyl, substituted with halogen,

heterocyclyl and

heterocyclyl, substituted C1-5the alkyl,

C2-5alkenyl,

C1-7alkoxy,

C1-7alkoxy substituted by halogen,

C1-7alkoxy, substituted by a carbocyclic aryl,

C3-6cycloalkane,

carbocyclic, aryloxy and

carbocyclic, aryloxy substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

nitro and

C1-5alkoxy

heterocyclics and

heterocyclic substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5the alkyl and

C1-5of alkyl, substituted with halogen,

C1-5alkoxycarbonyl,

mono-C1-5alkylaminocarbonyl,

di-C1-5alkylaminocarbonyl,

mono-C1-5alkylaminocarbonyl, is substituted by a carbocyclic aryl,

di-C1-5alkylaminocarbonyl, is substituted by a carbocyclic aryl,

monocarbocyclic of arylenecarborane,

dicarbollide of arylenecarborane,

monocarbocyclic of arylenecarborane, substituted C1-5the alkyl,

dicarbollide of arylenecarborane, substituted C-5 the alkyl,

mono-C1-5alkylamino,

di-C1-5alkylamino,

C1-5alkylthio,

C1-5alkylthio, substituted with halogen,

C1-5alkylsulfonyl,

carbocyclic aryl, and

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

C1-7the alkyl and

C1-7of alkyl, substituted with halogen,

(vi) heterocyclyl and

heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5the alkyl and

C1-5the alkyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

oxo,

carbocyclic aryl,

carbocyclic aryl substituted by halogen,

heterocyclyl and

heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5the alkyl and

C1-5of alkyl, substituted with halogen,

C1-5alkoxy,

C1-5alkylthio,

carbocyclic, aaltio,

C1-5alkylsulfonyl,

carbocyclic arylsulfonyl,

carbocyclic arylsulfonyl, substituted with halogen,

carbocyclic arylsulfonyl, substituted C1-5the alkyl,

C1-5alkoxycarbonyl,

carbocyclic aryl, and

carbocyclic aryl is, substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

nitro and

C1-5of alkyl,

heterocyclyl and

heterocyclyl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

C1-5the alkyl and

C1-5of alkyl, substituted with halogen;

where carbocyclic aryl represents phenyl, naphthyl or indranil;

carbocyclic is a 1-oxoindole, 9H-fluorenyl, 9-oxipurinol, anthrachinone,C-fluoren-9-ilidene, indanyl or mental;

heterocyclyl is a

1,2,3,4-tetrahydroisoquinoline, 1,2,3-thiadiazolyl,

1,2,3-triazolyl, 1,3-dikshithar, 1H-indolyl, 1H-pyrrolyl,

2,3-dihydro-1-occaisonaly, 2,3-dihydrobenzo[1,4]dioxines,

2H-benzopyranyl, 2-octoberapril, 2-oxopyrrolidin,

4-octoberapril, 9H-xantener, benzo[1,3]dioxole,

benzo[2,1,3]oxadiazolyl, benzo[1,2,5]oxadiazolyl,

benzo[b]thienyl, furyl, isoxazolyl, morpholinyl, oxazolyl,

pyrazolyl, pyridyl, pyrimidyl, pyrrolidyl, hinely, Minoxidil,

thiazolyl or thienyl;

halogen represents fluorine, chlorine, bromine or iodine;

or their pharmaceutically acceptable salt, hydrate or MES.

In some embodiments, the communication of the present invention are sobesednike formula (I), where R2represents a C1-5alkyl, substituted by a carbocyclic aryl, C1-5alkyl, substituted by halogenated carbocyclic-aryl, C1-5alkyl, substituted heterocyclyl, C1-5alkyl, substituted halogenated heterocyclyl, carbocyclic aryl, carbocyclic aryl substituted by halogen, heterocyclyl, heterocyclyl, substituted with halogen, or-N(R2a)(R2b); where R2aand R2beach independently represents hydrogen, C1-5alkyl, C1-5alkyl, substituted hydroxy, or C1-5alkyl substituted by halogen; L is formula (IIIa); where R3and R4each independently represents hydrogen or C1-5alkyl; and A and B each independently represents a single bond, -CH2- or -(CH2)2-; Z3and Z4each independently represents hydrogen, halogen, C1-5alkyl, C1-5alkyl substituted by halogen, mono-C1-5alkylamino or di-C1-5alkylamino; and Y represents-C(O)-, -C(O)NR5-, -C(S)NR5- or -(CH2)m-; where R5represents hydrogen or C1-5alkyl; and m is 0, 1, or 2; Y is -(CH2)m-provided or R2aor R2bis hydrogen;

or their pharmaceutically acceptable salt, hydrate or MES.

In some embodiments, the OS is enforced compounds of the present invention are compounds of formula (I), where R1selected from the group consisting of:

(i) C1-5the alkyl substituted by substituent(s)independently selected from the group consisting of:

hydroxy,

carbocyclic aryl,

carbocyclic aryl substituted by halogen, and

carbocyclic aryl, substituted halogenated C1-5the alkyl,

(ii) carbocyclic aryl, and

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

cyano,

C1-5of alkyl,

C1-5of alkyl, substituted with halogen,

C1-5alkoxy and

C1-5alkoxy substituted by halogen,

(iii) heterocyclyl and

heterocyclyl, substituted with halogen;

R2represents a C1-5alkyl, substituted by a carbocyclic aryl, or-N(R2a)(R2b); where R2aand R2beach independently represents hydrogen or C1-5alkyl;

L is formula (IIIa); where R3and R4each represents hydrogen; and A and B each represents a single bond;

Z3and Z4each independently represents hydrogen, C1-5alkyl, mono-C1-5alkylamino or di-C1-5alkylamino;

and

Y represents-C(O)-;

where carbocyclic aryl represents phenyl;

heterocyclyl represents a furyl and the and pyridyl;

halogen represents fluorine, chlorine or bromine;

or their pharmaceutically acceptable salt, hydrate or MES.

In some embodiments, the communication of the present invention are compounds of formula (I), where R1selected from the group consisting of:

carbocyclic aryl, and

carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:

halogen-free,

cyano and

C1-5alkoxy;

Z3represents hydrogen when Z4represents a C1-5alkyl; or Z3represents a C1-5alkyl, mono-C1-5alkylamino or di-C1-5alkylamino, when Z4represents hydrogen;

or their pharmaceutically acceptable salt, hydrate or MES.

In some embodiments, the communication of the present invention are compounds of formula (I)where the compound is selected from the group consisting of:

3-chloro-N-(CIS-4-{[2-(dimethylamino)-6-methylpyrimidin-4-yl]amino}cyclohexyl)-4-fermentated;

N-(CIS-4-{[2-(dimethylamino)-6-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4-differentated;

N[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3-methoxybenzamide;

N[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3-Tr is formatively;

N[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-bitreversed;

[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]amide 2,2-debtorrent[1,3]dioxol-5-carboxylic acid;

4-cyano-N[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;

4-chloro-N[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;

N[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethylbenzamide;

N[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-differentated;

5-bromo-N[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]nicotinamide;

[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]amide 5-bromofuran-2-carboxylic acid;

3,5-dibromo-N[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;

N[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethoxybenzene;

2-(3,5-bistrifluormethylbenzene)-N[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-2-hydroxyacetamido;

2-(4-bromophenyl)-N[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-2-hydroxyacetamido;

N[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-dioxime Sumida;

3-bromo-N[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-4-fermentated;

N[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethoxybenzene;

N[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-3-cryptomelane;

N[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-bitreversed;

[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]amide 2,2-debtorrent[1,3]dioxol-5-carboxylic acid;

4-chloro-N[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;

N[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethylbenzamide;

N[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-4-methylbenzamide;

5-bromo-N[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]nicotinamide;

[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]amide 5-bromofuran-2-carboxylic acid;

3,5-dibromo-N[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;

N[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethoxybenzene;

2-(3,5-bistrifluormethylbenzene)-N[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-2-hydroxyacetamido;

2-(4-bromophenyl)-N[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-2-hydroxyacetamido;

N[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-diethoxybenzene and

3-bromo-N[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-4-fermentated;

or their pharmaceutically acceptable salt, hydrate or MES.

In some embodiments, the communication of the present invention are compounds of formula (I)where the compound is selected from the group consisting of:

3-chloro-N-(CIS-4-{[2-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-4-fermentated;

N-(CIS-4-{[2,6-bis(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-3,4-differentated;

N-(CIS-4-{[2-benzyl-6-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-3-chloro-4-fermentated;

3,4-dichloro-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;

4-cyano-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;

N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-diethoxybenzene;

3-chloro-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-5-fermentated;

N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-dimethoxybenzamide;

3-dichloro- N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;

N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-diethoxybenzene and

3-chloro-N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-5-fermentated;

or their pharmaceutically acceptable salt, hydrate or MES.

In some embodiments, the communication of the present invention are compounds of formula (I), where R1selected from hydrogen, -CO2tBu or-CO2Bn (Bn represents a benzyl group; R2represents a C1-5alkyl, substituted by a carbocyclic aryl, C1-5alkyl, substituted by halogenated carbocyclic-aryl, C1-5alkyl, substituted heterocyclyl, C1-5alkyl, substituted halogenated heterocyclyl, carbocyclic aryl, carbocyclic aryl substituted by halogen, heterocyclyl, heterocyclyl, substituted with halogen, or-N(R2a)(R2b); where R2aand R2beach independently represents hydrogen, C1-5alkyl, C1-5alkyl, substituted hydroxy, or C1-5alkyl substituted by halogen; L is formula (IIIa); where R3and R4each independently represents hydrogen or C1-5alkyl; and A and B each independently represents a single the ligature, -CH2- or -(CH2)2-; Z3and Z4each independently represents hydrogen, halogen, C1-5alkyl, C1-5alkyl substituted by halogen, mono-C1-5alkylamino or di-C1-5alkylamino; and Y represents a single bond;

or their pharmaceutically acceptable salt, hydrate or MES.

In some embodiments, the communication of the present invention are compounds of formula (I), where R2represents a C1-5alkyl, substituted by a carbocyclic aryl, or-N(R2a)(R2b); where R2aand R2beach independently represents hydrogen or C1-5alkyl; L is formula (IIIa); where R3and R4each represents hydrogen; and A and B each represents a single bond; and Z3and Z4each independently represents hydrogen, C1-5alkyl, mono-C1-5alkylamino or di-C1-5alkylamino;

where carbocyclic aryl represents phenyl;

heterocyclyl represents a furyl or pyridyl;

halogen represents fluorine, chlorine or bromine;

or their pharmaceutically acceptable salt, hydrate or MES.

One aspect of the present invention relates to pharmaceutical compositions containing a therapeutically effective amount of at least one the of soedineniya, as described herein, in combination with a pharmaceutically acceptable carrier.

One aspect of the present invention relates to a method of prevention or treatment of conditions requiring improvements in functioning memory, sleeping and arousal, anxiety, depression, mood disorders, seizures, obesity, diabetes, disorders of appetite and eating behavior, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, disorders related to "binge" eating, including bulimia, anorexia, mental disorders including manic-depressive disorder, schizophrenia, delirium, dementia, stress, cognitive disorders, disorder attention deficit, drug or alcohol abuse and dyskinesias, including disease Parkinson's disease, epilepsy and addiction, including the introduction suffering from a specified state to the individual a therapeutically effective amount of a compound as described herein, or pharmaceutical compositions.

One aspect of the present invention relates to a method of treatment or prophylaxis of eating disorders, obesity or obesity-related disorders, including the introduction of suffering from the condition an individual a therapeutically effective amount of a compound as described in this OPI is assured, or pharmaceutical compositions.

One aspect of the present invention relates to a method of treatment or prevention of anxiety, depression, schizophrenia, addiction or epilepsy, including the introduction of suffering from the condition an individual a therapeutically effective amount of a compound as described herein, or pharmaceutical compositions.

One aspect of the present invention relates to compounds of the present invention, as described herein, or pharmaceutical compositions for use in the method of treatment of the human or animal body by therapy.

One aspect of the present invention relates to compounds of the present invention, as described herein, or pharmaceutical compositions for use in the method of prevention or treatment of eating disorders, obesity or obesity-related violations of the human or animal body by therapy.

One aspect of the present invention relates to compounds of the present invention, as described herein, or pharmaceutical compositions for use in the method of prevention or treatment of anxiety, depression, schizophrenia, addiction or epilepsy in humans or animals through therapy.

One aspect of the present invented the I relates to the compounds of the present invention, as described herein, for the manufacture of a medicinal product for use in the prevention or treatment of eating disorders, obesity or obesity-related disorders.

One aspect of the present invention relates to compounds of the present invention, as described herein, for the manufacture of a medicinal product for use in the prevention or treatment of anxiety, depression, schizophrenia, addiction, or epilepsy.

One aspect of the present invention relates to a method of decreasing food intake in an individual, comprising an introduction to the individual a therapeutically effective amount of a compound as described herein, or pharmaceutical compositions.

One aspect of the present invention relates to a method of inducing satiety in an individual, comprising the introduction of a specified individual a therapeutically effective amount of a compound as described herein, or pharmaceutical compositions.

One aspect of the present invention relates to methods of controlling or decreasing weight gain in an individual, comprising the introduction of a specified individual a therapeutically effective amount of a compound as described herein, or pharmaceutical compositions.

One aspect of altoadige invention relates to methods of modulating MCH receptor in an individual, comprising contacting the receptor with a compound as described herein. In some embodiments, the implementation of connection is an antagonist. In some embodiments, the implementation of the modulating MCH receptor intended for the prevention or treatment of eating disorders, obesity or obesity-related disorders. In some embodiments, implementation, modulation of MCH receptor reduces food intake by the individual. In some embodiments, the implementation of the modulating MCH receptor induces the individual satiety. In some embodiments, the implementation of the modulating MCH receptor controls and reduces the individual's weight gain. In some embodiments, the implementation of the modulating MCH receptor intended for the prevention or treatment of anxiety, depression, schizophrenia, addiction, or epilepsy.

In some embodiments, the implementation of the individual is a mammal.

In some embodiments, the implementation of the mammal is man.

In some embodiments, the implementation of the body mass index is from about 18.5 to about 45. In some embodiments, the implementation of the body mass index is from about 25 to about 45. In some embodiments, the implementation of the body mass index of a person extending t is from about 30 to about 45. In some embodiments, the implementation of the body mass index is from about 35 to about 45.

One aspect of the present invention relates to methods of producing a pharmaceutical composition, comprising mixing the compound, as described herein, and a pharmaceutically acceptable carrier.

One of the embodiments of the invention include any compound according to the invention, which selectively binds with the receptor, MCH, where such selective binding preferably shown by the Kione or more other GPCR, preferably NPY, which is at least 10 times greater than the Kifor any specific MCH receptor, preferably MCHR1.

As used herein, the term "alkyl" is intended to refer to hydrocarbon compounds, including non-branched chain and unbranched chain, including, but without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, etc.

The term "alkoxy" is intended to refer to substituents of the formula-O-alkyl.

In various places in the present description, the substituents of the compounds according to the invention described in groups. This specifically means that the invention included each and every individual podschitana present is Italy such groups.

Associated with G protein-coupled receptor (GPCR) represent a large class of cell surface receptors, which for mediating their effects interact with many neurotransmitters. Predicted GPCR have a family crossing the membrane domains and coupled to their effectors by G-protein that links the activation of receptors with intracellular biochemical events, such as stimulation of adenylate cyclase. Melaninconcentrating hormone (MCH), a cyclic peptide, identified as the endogenous ligand associated with G-proteins organovo receptor SLC-1. See, for example, Shimomura et al., Biochem. Biophys. Res. Commun. 261, 622-26 (1999). Studies have shown that MCH acts as a neurotransmitter/modulator/regulator with a change in the number of behavioral reactions.

MCH mammals (19 amino acids) is highly conservative in rats, mice and people, showing 100% identity of amino acids, but its physiological role is less clear. It was reported that MCH is involved in many processes, including food, water balance, energy metabolism, General state of arousal/attention, memory and cognitive functions and psychiatric disorders. For reviews, See. 1. Baker, Int. Rev. Cytol. 126:1-47 (1991); 2. Baker, TEM 5:120-126 (1994); 3. Nahon, Critical Rev. in Neurobiol 221:221-262, (1994); 4. Knigge et al., Peptides 18(7):1095-1097, (1996). The role of MCH in the regulation of feeding the sludge is body mass is supported in Qu et al., Nature 380:243-247, (1996), showing that MCH sverkhekspressiya in the hypothalamus of mice ob/ob compared with mice ob/+, and that starvation additionally increased MCH mRNA in obese or normal mice during fasting. MCH also stimulates feeding in normal rats when injected into the lateral ventricles according to Rossi et al., Endocrinology 138:351-355, (1997). Also it is shown that MCH is a functional antagonist of the behavioral effects of α-MSH; See: Miller et al., Peptides 14:1-10, (1993); Gonzalez et al, Peptides 17:171-177, (1996) and Sanchez et al., Peptides 18:3933-396, (1997). In addition, it is shown that stress increases the levels of POMC mRNA, thus reducing the mRNA levels of the MCH precursor of prepress (ppMCH); Presse et al., Endocrinology 131:1241-1250, (1992). Thus, the MCH can serve as an integrative neuropeptide involved in stress response and in the regulation of feeding and sexual activity; Baker, Int. Rev. Cytol. 126:1-47, (1991); Knigge et al., Peptides 17:1063-1073, (1996).

Localization and biological activity of MCH peptide suggests that the modulation of the activity of MCH receptor may be suitable in a number of therapeutic applications. MCH is expressed in the lateral hypothalamus, the brain area involved in the regulation of hunger and thirst: Grillon et al., Neuropeptides 31:131-136, (1997); it was recently shown that orexin A and B, which are causing strong appetite means, have a very similar MCH localization of the lateral hypothalamus; Sakurai et al., Cell 92:573-585 (1998). Levels of MCH mRNA in this brain areas increased in rats 24 hours after deprivation of food; Herve and Fellmann, Neurpeptides 31:237-242 (1997); after the injection of insulin, together with a significant increase in the mRNA level MCH observed a significant increase in the relative intensity of the immunoreactive staining for MCH of perikaryon and fibers; Bahjaoui-Bouhaddi et al., Neuropeptides 24:251-258, (1994). Consistent with the ability of MCH to stimulate feeding in rats; Rossi et al., Endocrinology 138:351-355, (1997); there is the observation that the levels of MCH mRNA increased in hypothalamus fat mice ob/ob; Qu et al., Nature 380:243-247, (1996); and reduced hypothalamus rats treated with leptin, whose food consumption and weight gain was also decreased; Sahu, Endocrinology 139:795-798, (1998). Apparently, the MCH acts as a functional antagonist exposure system melanocortin on food intake and secretion of hormones in the HPA (hypothalamic-pituitary-adrenal system); Ludwig et al., Am. J. Physiol. Endocrinol. Metab. 274:E627-E633, (1998). Together, these data indicate the role of endogenous MCH in the regulation of energy balance and stress responses and give the rationale for development of specific compounds acting on the MCH receptor, for use in the treatment of obesity and stress-related disorders.

Thus, the MCH receptor antagonist desirable to profile the tick or treating obesity or obesity-related disorders. Associated with obesity violation is a violation, directly or indirectly associated with obesity, such as diabetes type II, X-syndrome, impaired glucose tolerance, dyslipidemia, hypertension, coronary heart disease and other cardiovascular disorders, including atherosclerosis, insulin resistance associated with obesity and psoriasis; for the treatment of diabetic complications and other diseases such as polycystic ovary syndrome (PCOS), certain renal diseases including diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal failure and microalbuminuria, and some eating disorders.

We investigated to date kinds of most neurons in the group of cells MCH takes quite a permanent position in the areas of the lateral hypothalamus and the hypothalamus, where they are located and can be part of the soma of the so-called "extrapyramidal" motor pathways. They include fundamental striata and pallidipennis way, including the thalamus and the cerebral cortex, hypothalamus and reciprocal connections with hypothalamic nuclei, black substance and centers in the midbrain; Bittencourt et al., J. Comp. Neurol. 319:218-245, (1992). In your location the research group of cells MCH can provide a bridge or a mechanism for the manifestation of hypothalamic visceral activity together with appropriate and coordinated motor activity. This may have some clinical value in order to consider the involvement of this system MCH in motor disorders such as Parkinson's disease and Huntington's chorea, which are known to be involved extrapyramidal path.

Research on the genetic coupling in humans given the opportunity to localize authentic loci hMCH on chromosome 12 (12q23-24) and the variant loci hMCH on chromosome 5 (5q12-13) (Pedeutour et al., 1994). Locus 12q23-24 coincides with the locus in which mapped autosomal dominant cerebellar ataxia type II (SCA2); Auburger et al., Cytogenet. Cell. Genet. 61:252-256, (1992); Twells et al., Cytogenet. Cell. Genet. 61:262-265, (1992). This disease is neurodegenerative disorders, including olivopontocerebellar atrophy. In addition, the locus 12q23-24 gene mapped disease Daria; Craddock et al., Hum. Mol. Genet. 2:1941-1943, (1993). Disease Daria is characterized by abnormalities of adhesion of keratinocytes and I mental illness in some families. Due to functional and neuro-anatomical features of the nervous system MCH in the brain of rat and human gene MCH may be a good candidate for SCA2 or illness Daria. Interestingly, this locus mapped diseases with high social impact. Indeed, using the analysis of genetic clutch on chromosome 5q12-13 mapped the gene responsible for chronic is a severe form of spinal muscular atrophy; DRO! d et al., Nature (London) 344:767-768, (1990); Westbrook et al., Cytogenet. Cell. Genet. 61:225-231, (1992). In addition, a number of independent evidence shows localization to chromosome 5q11.2-13.3 main locus of schizophrenia; Sherrington et al., Nature (London) 336:164-167, (1988); Bassett et al., Lancet 1:799-801, (1988); Gilliam et al., Genomics 5:940-944, (1989). The above studies suggest that MCH may play a role in neurodegenerative diseases and emotional disorders.

Additional therapeutic applications for communicating with MCH connections are available when considering the actions of MCH in other biological systems. For example, the MCH may regulate reproductive function in female and male rats. Transcripts of MCH and MCH peptide found in germ cells in testes of adult rats, indicating that MCH may participate in the renewal of stem cells and/or differentiation of early spermatocyte; Hervieu et al., Biology of Reduction 54:1161-1172, (1996). MCH, injected directly into the middle prezritelnoe field (MPOA) or ventromedial nucleus (VMN), stimulated sexual activity in female rats; Gonzalez et al., Peptides 17:171-177, (1996). Ovariectomised rats, prestimulation estradiol, MCH stimulated the release of luteinizing hormone (LH), whereas anticavity against MCH inhibited LH release; Gonzalez et al., Neuroendocrinology 66:254-262, (1997). Zona incerta, containing a large group of t is l cells MCH, was previously identified as a regulatory region preovulatory release of LH; MacKenzie et al., Neuroendocrinology 39:289-295, (1984). It was reported that MCH affects release of pituitary hormones, including ACTH and oxytocin. The MCH analogs can also be suitable for the treatment of epilepsy. On seizure model with PTZ injection of MCH before the onset of seizures prevented seizures in rats and Guinea pigs, indicating that MCH neurons may participate in neural pathways underlying PTZ induced convulsions; Knigge and Wagner, Peptides 18:1095-1097, (1997). It was also observed that MCH affects behavioral based cognitive functions. Processing MCH accelerates the extinction of passive avoidance in rats; McBride et al., Peptides 15:757-759, (1994); increasing the likelihood that the MCH receptor antagonists may be useful for the accumulation and/or retention of memory. The possible role of MCH in the modulation or pain perception is supported by a dense innervation allowedprogram gray matter (PAG) is positive on MCH fibers. Finally, the MCH may participate in the regulation of fluid intake. ICV-infusion of MCH in consciousness sheep led to changes in diuresis, natriuresis and calibrations changes in response to increased plasma volume; Parkes, J. Neuroendocrinol. 8:57-63, (1996). Together with anatomical data show them of the presence of MCH in the areas of the brain, regulating the fluid, these results indicate that MCH may be an important peptide involved in the Central control of fluid homeostasis in mammals.

In the last link MCHR1 antagonists unexpectedly showed its use as antidepressants and/or anti-anxiety. It was reported that MCHR1 antagonists showed activity as antidepressants or anxiolytics in rodent models, such as social interaction, the forced swimming test and ultrasonic irradiation. Thus, MCHR1 antagonists may be suitable for independent treatment of subjects with depression and/or anxiety. Also MCHR1 antagonists may be suitable for treatment of subjects suffering from depression and/or anxiety and obesity.

This invention relates to a method of treatment of a disorder of a subject, where the violation is facilitated by reducing the activity of the MCH1 receptor mammal, where the method comprises the administration to a subject of a certain number of connections, which the MCH1 receptor antagonist mammal, is effective for the treatment of disorders. In some cases, the implementation of the violation is a regulation disorders of steroid hormones and pituitary hormones, impaired release of epinephrine, anxiety disorder, genta gastro-intestinal disorder, heart with udeste violation, the imbalance of electrolytes, hypertension, diabetes, respiratory disturbance, asthma, impaired reproductive function, immune disturbance, endocrine disruption, violation of the musculoskeletal system, neuroendocrine disturbance, cognitive disorder, memory loss, impaired sensory modulation and transmission, impaired motor coordination, impaired sensory integration, motor integration, impaired dopaminergic function, impaired sensory transmission, impaired sense of smell, impaired sympathetic innervation, affective disorder associated with stress disturbance, disturbance of fluid balance, seizures, pain, psychotic behavior, tolerance to morphine, opiate dependence or migraine.

The composition of the invention can easily enter in unit dosage form and may be obtained by any of the methods well known in the pharmaceutical field, for example, as described in Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1980).

Compounds according to the invention can be used as the sole active tool in the pharmaceutical vehicle or they can be used in combination with other active ingredients that may contribute to therapeutic effect of the compound.

Compounds of the present invention, or their solvate, or physiologically functional is optional derivatives can be used as active ingredients in pharmaceutical compositions, particularly as antagonists of the MCH receptor. The term "active ingredient" is defined in relation to the "pharmaceutical compositions", and he means a component of a pharmaceutical composition, providing the main favorable pharmaceutical effects, in contrast to the "inactive ingredient", which, in General, is considered not to have beneficial pharmaceutical effects. The term "pharmaceutical composition" means a composition that contains one active ingredient and at least one ingredient that is not the active ingredient (for example, and without limitation, filler, dye or remedy for slow release), according to which the composition is suitable for use with obtaining specific effective result in a mammal (for example, and without limitation, a human).

Pharmaceutical compositions, including, but without limitation, a pharmaceutical composition containing at least one compound of the present invention and/or an acceptable salt or MES (for example, pharmaceutically acceptable salt or MES) as the active ingredient in combination with at least one carrier or excipient (for example, the pharmaceutical carrier or excipient), can be used for the treatment of clinical conditions for which illustrates the ant who honest MCH receptor. At least one compound of the present invention can be combined with a carrier in solid or liquid form in a single dosage composition. The pharmaceutical carrier must be compatible with other ingredients of the composition and must be tolerated by the host recipient. Other physiologically active ingredients can be included in the pharmaceutical composition according to the invention, if desired, and if such ingredients are compatible with other ingredients in the composition. The composition can be obtained by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers or both, in the required proportions, and then, if necessary, converting the resulting mixture into a desired shape.

Tablets and capsules for oral administration can be used conventional excipients such as binding agents, fillers, acceptable moisturizers, lubricants for tabletting and disintegrant. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oil suspensions, and syrups. Alternative oral drugs may be in the form of a dry powder, which can be restored with water or other suitable liquid medium before use. Liquid drugs the the ATA, you can add additional additives, such as suspendresume or emulsifying means, nonaqueous media (including edible oils), preservatives and flavorings and colorings. Parenteral dosage forms can be obtained by dissolving the compound according to the invention in a suitable liquid medium and sterilizing the solution by filtration prior to filling and sealing of the respective vial or ampoule. This represents only a small number of examples of a variety of suitable methods well known in the field of production of dosage forms.

It should be noted that when the MCH receptor antagonists are used in pharmaceutical compositions as active ingredients, they are not intended to apply only to humans but also to other mammals, other than humans. Indeed, recent advances in the field of medical care these animals require that consideration was given to the application of MCH receptor antagonists for the treatment of obesity in domestic animals (e.g. cats and dogs) and antagonists of the MCH receptor for other domestic animals, where the disease or disorder is not obvious (such as those in food animals such as cows, chickens, fish etc). Specialists in this field will be obvious and understood the usefulness of such compounds in such conditions.

Pharmaceutically acceptable salts with which dinani according to the invention can be obtained by reaction of the form of free acids or bases of these compounds with the appropriate base or acid in water, in an organic solvent or their mixture; typically, the preferred non-aqueous environment, such diethyl ether, ethyl acetate, ethanol, isopropanol, dioxane or acetonitrile. For example, when compound (I) has an acidic functional group, it can form an inorganic salt such as a salt of alkali metal (e.g. sodium salt, potassium salt etc), salt, alkaline earth metal (e.g. calcium salt, magnesium salt, barium salt etc) and ammonium salt. When compound (I) has a basic functional group, it can form an inorganic salt (e.g. hydrochloride, sulfate, phosphate, Hydrobromic etc) or organic salt (e.g. acetate, maleate, fumarate, succinate, methanesulfonate, p-toluensulfonate, citrate, tartrate and so on).

When the connection according to the invention contains optical isomers, stereoisomers, regioisomers, rotary isomers, one compound or a mixture thereof are included in this description as the connection according to the invention. For example, when a chemical formula is presented in the form that does not indicate the stereochemical designation(s), such as formula (III), then all possible stereoisomers, optical isomers and their mixtures are considered as being within the scope of this formula. Accordingly, the formula (IIIa) specifically refers to the CIS-relationship between the two amino groups n is tsiklogeksilnogo ring, and therefore, this formula is also fully covered by the formula (III).

Obtaining the compounds of formula (I) General methods of synthesis

New substituted pyrimidines of the present invention can easily obtain a variety of synthetic methods, all of them well-known to specialists in this field. Preferred methods of making compounds of the present invention include, but without limitation, methods of preparation, are described in schemes 1-8.

A pyrimidine (C) can be obtained as shown in scheme 1. 4,6-dihydroxypyrimidine (A), which is commercially available or obtained by the condensation of derivatives of malonic acid and derivatives of amidine, where Z1and Z2are as defined above, is converted into 4,6-dehalogenation (B) with a halogenation reagent with the addition of a base or without it (where X is a halogen, such as chlorine, bromine or iodine). Halogenation reagent includes phosphorus oxychloride (POCl3), oxybromide phosphorus (POBr3or pentachloride phosphorus (PCl5). The base includes a tertiary amine (preferablyN,N-diisopropylethylamine etc) or an aromatic amine (preferablyN,N-dimethylaniline etc). The reaction temperature is in the range from about 100°C to 200°C, preferably from about 140°C to 180°C. Put the e substituent R 24.6-dehalogenation (B) results in a pyrimidine (C). Also a pyrimidine (C) can be obtained from commercially available 2,4,6-trigalogenmetany (D), where Z2is the same as defined above, and X represents a halogen, such as chlorine, bromine or iodine, with the subsequent introduction of a substituent R2Deputy and Deputy Z1.

Scheme 1

Total intermediate compound (H) new substituted pyrimidines can be obtained as shown in scheme 2. A pyrimidine (C) in an inert solvent with addition of a base or without it replaces monosubstituted by diamine (F), where R3, R4, A, and B are as defined above, and P represents a protective group, to obtain the adduct combinations (G). The base includes a carbonate of an alkali metal (preferably sodium carbonate or potassium carbonate, etc.), hydroxide of alkali metal (preferably sodium hydroxide, etc.) or tertiary amine (preferablyN,N-diisopropylethylamine, triethylamine orN-methylmorpholin etc). The inert solvent includes lower alkalemia alcohol solvents (preferably methanol, ethanol, 2-propanol or butanol, etc.) or amide solvents (preferablyN,N-dimethylformamide or 1-methylpyrrolidine-2-it, etc.). The reaction temperature is in the range from about 50°C to 200°C, preferably from about 80°C to 150°C. this reaction can be carried out in conditions of the microwave oven.

Typical protective group suitable for a wide range of synthetic transformations described by Greene and Wuts, Protective Groups in Organic Synthesis, second edition, John Wiley & Sons, New York, 1991, the description of which is included in this description in its entirety. The removal of the protective group gives the opportunity to obtain a common intermediate compound (H) new substituted pyrimidines.

Scheme 2

The conversion of the common intermediate of the compound (H) to new substituted pyrimidines (I), (J) and (V)to(X) of the present invention is shown in scheme 3.

Amin (H) is subjected to interaction with the carboxylic acid (R1CO2H) and a dehydrating condensing reagent in an inert solvent with addition of a base with or without obtaining a new amide (I) of the present invention. Dehydrating condensing agent includes dicyclohexylcarbodiimide (DCC), the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC•HCl), hexaflurophosphate bromo-Tris-pyrrolidinone (PyBroP), hexaflurophosphateO-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium (HATU) or 1-cyclohexyl-3-methylolacrylamide. The base includes a tertiary amine (preferablyN,N-diisopropylethylamine or triethyl is in etc). The inert solvent includes a solvent, which represents a lower halogenated hydrocarbon, preferably dichloromethane, dichloroethane or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), nitrile solvents (preferably acetonitrile, etc.) or amide solvents (preferablyN,N-dimethylformamide and so on). If needed as a reagent can be used 1-hydroxybenzotriazole (HOBT), HOBT-6-carboxamidotryptamine or 1-hydroxy-7-asobancaria (HOAT). The reaction temperature is in the range of approximately -20°C to 50°C, preferably about 0°C to 40°C.

Alternative new amide (I) of the present invention can be obtained by amidation reaction using the acid chloride (R1COCl) and base in an inert solvent. The base includes a carbonate of an alkali metal (preferably sodium carbonate or potassium carbonate, etc.), bicarbonate of an alkali metal (preferably sodium bicarbonate or potassium bicarbonate, etc.), hydroxide of alkali metal (preferably sodium hydroxide or potassium hydroxide, etc.), tertiary amine (preferablyN,N-diisopropylethylamine, triethylamine orN-methylmorpholin etc), or an aromatic amine (preferably pyridine, imidazole, poly(-vinylpyridine) etc). The inert solvent includes a solvent, which represents a lower halogenated hydrocarbon, preferably dichloromethane, dichloroethane or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), amide solvents (preferablyN,N-dimethylformamide, etc. or aromatic solvents (preferably toluene or pyridine, etc.). The reaction temperature is in the range of approximately -20°C to 50°C, preferably about 0°C to 40°C.

New amide (I) of the present invention is subjected to interaction with a reducing agent in an inert solvent to obtain a new amine (J) of the present invention. The reducing agent includes alumoweld alkali metal (preferably of alumoweld lithium), borhydride alkali metal (preferably lithium borohydride), trielaxhillshire alkali metal (preferably threetert-butoxyaniline lithium), dialkylamide (preferably diisobutylaluminium), borohydride, dialkylacrylamide (preferably dietarily borohydride), trialkylborane alkali metal (preferably triethylborohydride lithium). The inert solvent includes ether solvents (preferably tetrahydrofuran or dioxane) or aromatic solvents (preferably the toluene etc). The reaction temperature is in the range of from about -78°C to 200°C, preferably from about 50°C to 120°C.

Alternative new Amin (J) of the present invention can be obtained by the reaction of reductive amination using an aldehyde (R1CHO) and a reducing agent in an inert solvent with addition of acid or without it. The reducing agent includes triacetoxyborohydride sodium, cyanoborohydride sodium, sodium borohydride or complex borohydride-pyridine, preferably triacetoxyborohydride sodium or cyanoborohydride sodium. The inert solvent includes lower alkalemia alcohols (preferably methanol or ethanol etc), solvents, representing a lower halogenated hydrocarbon, preferably dichloromethane, dichloroethane or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane) or aromatic solvents (preferably toluene, etc.). The acid includes inorganic acid (preferably hydrochloric acid or sulfuric acid) or organic acid (preferably acetic acid). The reaction temperature is in the range of approximately -20°C to 120°C, preferably about 0°C to 100°C. this reaction can be carried out in conditions of the microwave oven.

Amin (I) is subjected to interact the Oia with sulphonylchloride (R 1SO2X), where X is a halogen, such as chlorine, bromine or iodine, and a base in an inert solvent with a new sulfanilamide (V) of the present invention. The base includes a carbonate of an alkali metal (preferably sodium carbonate or potassium carbonate, etc.), bicarbonate of an alkali metal (preferably sodium bicarbonate or potassium bicarbonate, etc.), hydroxide of alkali metal (preferably sodium hydroxide or potassium hydroxide, etc.), tertiary amine (preferablyN,N-diisopropylethylamine, triethylamine orN-methylmorpholin etc) or an aromatic amine (preferably pyridine or imidazole, and so on). The inert solvent includes a solvent, which represents a lower halogenated hydrocarbon, preferably dichloromethane, dichloroethane or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), an alcohol solvent (preferably 2-propanol, etc.) or aromatic solvents (preferably toluene or pyridine, etc.). The reaction temperature is in the range of approximately -20°C to 50°C, preferably about 0°C to 40°C.

New urea (W) or thiourea (W) according to the present invention can be obtained urea reaction or thiocarbamide reaction using isocyanate R 1NCO) or isothiocyanate (R1NCS) in an inert solvent with addition of a base or without him. The base includes a carbonate of an alkali metal (preferably sodium carbonate or potassium carbonate, etc.), bicarbonate of an alkali metal (preferably sodium bicarbonate or potassium bicarbonate, etc.), hydroxide of alkali metal (preferably sodium hydroxide or potassium hydroxide, etc.), tertiary amine (preferablyN,N-diisopropylethylamine, triethylamine orN-methylmorpholin etc) or an aromatic amine (preferably pyridine or imidazole, and so on). The inert solvent includes a solvent, which represents a lower halogenated hydrocarbon, preferably dichloromethane, dichloroethane or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), aromatic solvents (preferably benzene or toluene, etc. or polar solvents (preferablyN,N-dimethylformamide or dimethyl sulfoxide and so on). The reaction temperature is in the range of approximately -20°C to 120°C, preferably about 0°C to 100°C.

New urethane (X) according to the present invention can be obtained urethane reaction using R1OCOX, where X is a halogen, such as chlorine, bromine or iodine, in an inert solvent with EXT is the free base or without. The base includes a carbonate of an alkali metal (preferably sodium carbonate or potassium carbonate, etc.), bicarbonate of an alkali metal (preferably sodium bicarbonate or potassium bicarbonate, etc.), hydroxide of alkali metal (preferably sodium hydroxide or potassium hydroxide, etc.), tertiary amine (preferablyN,N-diisopropylethylamine, triethylamine orN-methylmorpholin etc) or an aromatic amine (preferably pyridine, imidazole or poly(4-vinylpyridine) etc). The inert solvent includes a solvent, which represents a lower halogenated hydrocarbon, preferably dichloromethane, dichloroethane or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), aromatic solvents (preferably benzene or toluene, etc. or polar solvents (preferablyN,N-dimethylformamide or dimethyl sulfoxide and so on). The reaction temperature is in the range of approximately -20°C to 120°C, preferably about 0°C to 100°C.

Scheme 3

Also you can get a new one substituted pyrimidine (M) of the present invention, as shown in figure 4.

First of 4,6-dehalogenation (B) replace Amin (K), to which is attached the desired substituent R1where R3 , R4, A, B, Y, and R1are as defined above, with the addition of a base or without it, in an inert solvent to obtain the adduct combinations (L). The base includes a carbonate of an alkali metal (preferably sodium carbonate or potassium carbonate, etc.), hydroxide of alkali metal (preferably sodium hydroxide, etc.) or tertiary amine (preferablyN,N-diisopropylethylamine, triethylamine orN-methylmorpholin etc). The inert solvent includes lower alkalemia alcohols (preferably methanol, ethanol, 2-propanol or butanol, etc.) or amide solvents (preferablyN,N-dimethylformamide or 1-methylpyrrolidine-2-it, etc.). The reaction temperature is in the range from about 50°C to 200°C, preferably from about 80°C to 150°C. this reaction can be conducted under conditions of a microwave oven. Introduction of the substituent R2provides the ability to get new substituted pyrimidine (M) according to the present invention.

Scheme 4

Total intermediate compound (R) of new substituted pyrimidines can be obtained as shown in scheme 5.

Commercially available 2,4-dihydroxypyrimidine (N), where Z3and Z4are as defined above, is converted into 2,4-dehalogenation (O) halogenation reagent with d is the addition of a base or without it (where X represents halogen, such as chlorine, bromine or iodine). Halogenation reagent includes phosphorus oxychloride (POCl3), oxybromide phosphorus (POBr3or pentachloride phosphorus (PCl5). The base includes a tertiary amine (preferablyN,N-diisopropylethylamine etc) or an aromatic amine (preferablyN,N-dimethylaniline etc). The reaction temperature is in the range from about 100°C to 200°C, preferably from about 140°C to 180°C. the Introduction of the substituent R22.4-dehalogenation (O) gives the opportunity to get pyrimidine (P). The pyrimidine (P) with the addition of a base or without it, in an inert solvent replaces monogamists-diamine (F), where R3, R4, A, and B are as defined above, and P represents a protective group, to obtain the adduct combinations (Q). The base includes a carbonate of an alkali metal (preferably sodium carbonate or potassium carbonate, etc.), hydroxide of alkali metal (preferably sodium hydroxide, etc.) or tertiary amine (preferablyN,N-diisopropylethylamine, triethylamine orN-methylmorpholin etc). The inert solvent includes lower alkalemia alcohols (preferably methanol, ethanol, 2-propanol or butanol, etc.) or amide solvents (preferablyN,N-dimethylformamide or 1-methylpyrrolidine-2-it, etc.). Tempera is ur reaction is in the range from about 50°C to 200°C, preferably from about 80°C to 150°C. this reaction can be carried out in conditions of the microwave oven.

It is clear that using some described in this description of ways, such as in scheme 5, you can get the regioisomers, and that these regioisomers can be separated by applying a well-known expert in the field of methods.

Typical protective group suitable for a wide range of synthetic transformations described in Greene and Wuts, Protective Groups in Organic Synthesis, second edition, John Wiley & Sons, New York, 1991, the description of which is included in this description in its entirety. The removal of the protective group gives the opportunity to obtain a common intermediate compound (R) of new substituted pyrimidines.

Scheme 5

The total conversion of the intermediate (R) in new substituted pyrimidines (S), (T) and (V)to(A') of the present invention is shown in scheme 6.

Amin (R) is subjected to interaction with the carboxylic acid (R1CO2H) and a dehydrating condensing reagent in an inert solvent with addition of a base with or without obtaining a new amide (S) of the present invention. Dehydrating condensing agent includes dicyclohexylcarbodiimide (DCC), the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC•HCl), hexaflurophosphate bromo-Tris-pyrrolidino is a phosphonium (PyBroP), hexaphosphateO-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium (HATU) or 1-cyclohexyl-3-methylolacrylamide. The base includes a tertiary amine (preferablyN,N-diisopropylethylamine or triethylamine, etc.). The inert solvent includes a solvent, which represents a lower halogenated hydrocarbon, preferably dichloromethane, dichloroethane or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), nitrile solvents (preferably acetonitrile, etc.) or amide solvents (preferablyN,N-dimethylformamide and so on). If needed as a reagent can be used 1-hydroxybenzotriazole (HOBT), HOBT-6-carboxamidotryptamine or 1-hydroxy-7-asobancaria (HOAT). The reaction temperature is in the range of approximately -20°C to 50°C, preferably about 0°C to 40°C.

Alternative new amide (S) of the present invention can be obtained by amidation reaction using the acid chloride (R1COCl) and base in an inert solvent. The base includes a carbonate of an alkali metal (preferably sodium carbonate or potassium carbonate, etc.), bicarbonate of an alkali metal (preferably sodium bicarbonate or potassium bicarbonate, etc.), hydroxide of alkaline metal (suppose the equipment sodium hydroxide or potassium hydroxide, etc.), tertiary amine (preferablyN,N-diisopropylethylamine, triethylamine orN-methylmorpholin etc) or an aromatic amine (preferably pyridine, imidazole, poly(4-vinylpyridine) etc). The inert solvent includes a solvent, which represents a lower halogenated hydrocarbon, preferably dichloromethane, dichloroethane or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), amide solvents (preferablyN,N-dimethylformamide, etc. or aromatic solvents (preferably toluene or pyridine, etc.). The reaction temperature is in the range of approximately -20°C to 50°C, preferably about 0°C to 40°C.

New amide (S) of the present invention is subjected to interaction with a reducing agent in an inert solvent to obtain a new amine (T) according to the present invention. The reducing agent includes alumoweld alkali metal (preferably of alumoweld lithium), borhydride alkali metal (preferably lithium borohydride), trielaxhillshire alkali metal (preferably threetert-butoxyaniline lithium), dialkylamide (preferably diisobutylaluminium), borohydride, dialkylacrylamide (preferably dietarily borohydride), alkali metal trialkylborane the (preferably triethylborohydride lithium). The inert solvent includes ether solvents (preferably tetrahydrofuran or dioxane) or aromatic solvents (preferably toluene, etc.). The reaction temperature is in the range of from about -78°C to 200°C, preferably from about 50°C to 120°C.

Alternative new Amin (T) according to the present invention can be obtained by the reaction of reductive amination using an aldehyde (R1CHO) and a reducing agent in an inert solvent with addition of acid or without it. The reducing agent includes triacetoxyborohydride sodium, cyanoborohydride sodium, detribalized or complex borohydride-pyridine, preferably triacetoxyborohydride sodium or cyanoborohydride sodium. The inert solvent includes lower alkalemia alcohols (preferably methanol or ethanol etc), solvents, representing a lower halogenated hydrocarbon, preferably dichloromethane, dichloroethane or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane) or aromatic solvents (preferably toluene, etc.). The acid includes inorganic acid (preferably hydrochloric acid or sulfuric acid) or organic acid (preferably acetic acid). The reaction temperature is in the range of approx is Ino -20°C to 120°C, preferably from about 0°C to 100°C. this reaction can be carried out in conditions of the microwave oven.

Amin (R) is subjected to interaction with sulphonylchloride (R1SO2X), where X is a halogen, such as chlorine, bromine or iodine, and a base in an inert solvent with a new sulfanilamide (Y) according to the present invention. The base includes a carbonate of an alkali metal (preferably sodium carbonate or potassium carbonate, etc.), bicarbonate of an alkali metal (preferably sodium bicarbonate or potassium bicarbonate, etc.), hydroxide of alkali metal (preferably sodium hydroxide or potassium hydroxide, etc.), tertiary amine (preferablyN,N-diisopropylethylamine, triethylamine orN-methylmorpholin etc) or an aromatic amine (preferably pyridine or imidazole, and so on). The inert solvent includes a solvent, which represents a lower halogenated hydrocarbon, preferably dichloromethane, dichloroethane or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), an alcohol solvent (preferably 2-propanol, etc.) or aromatic solvents (preferably toluene or pyridine, etc.). The reaction temperature is in the range of approximately -20°C to 50°C, preferably priblizitel is but from 0°C to 40°C.

New urea (Z) or thiourea (Z) according to the present invention can be obtained urea reaction or thiocarbamide reaction using isocyanate (R1NCO) or isothiocyanate (R1NCS) in an inert solvent with addition of a base or without him. The base includes a carbonate of an alkali metal (preferably sodium carbonate or potassium carbonate, etc.), bicarbonate of an alkali metal (preferably sodium bicarbonate or potassium bicarbonate, etc.), hydroxide of alkali metal (preferably sodium hydroxide or potassium hydroxide, etc.), tertiary amine (preferablyN,N-diisopropylethylamine, triethylamine orN-methylmorpholin etc) or an aromatic amine (preferably pyridine or imidazole, and so on). The inert solvent includes a solvent, which represents a lower halogenated hydrocarbon, preferably dichloromethane, dichloroethane or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), aromatic solvents (preferably benzene or toluene, etc. or polar solvents (preferablyN,N-dimethylformamide or dimethyl sulfoxide and so on). The reaction temperature is in the range of approximately -20°C to 120°C, preferably about 0°C to 100°C.

New urethane (A') under this breath is retenu you can get urethane reaction using R 1OCOX, where X is a halogen, such as chlorine, bromine or iodine, in an inert solvent with addition of a base or without him. The base includes a carbonate of an alkali metal (preferably sodium carbonate or potassium carbonate, etc.), bicarbonate of an alkali metal (preferably sodium bicarbonate or potassium bicarbonate, etc.), hydroxide of alkali metal (preferably sodium hydroxide or potassium hydroxide, etc.), tertiary amine (preferablyN,N-diisopropylethylamine, triethylamine orN-methylmorpholin etc) or an aromatic amine (preferably pyridine, imidazole or poly(4-vinylpyridine) etc). The inert solvent includes a solvent, which represents a lower halogenated hydrocarbon, preferably dichloromethane, dichloroethane or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), aromatic solvents (preferably benzene or toluene, etc. or polar solvents (preferablyN,N-dimethylformamide or dimethyl sulfoxide and so on). The reaction temperature is in the range of approximately -20°C to 120°C, preferably about 0°C to 100°C.

Scheme 6

Alternative new pyrimidines (M) and (U) according to the present invention is directly synthesized and the pyrimidine nucleus (C), which are synthesized according to scheme 1, and pyrimidine nucleus (P), which are synthesized according to scheme 5, as shown in scheme 7. This combination is carried out with addition of a base or without an inert solvent. The base includes a carbonate of an alkali metal (preferably sodium carbonate or potassium carbonate, etc.), hydroxide of alkali metal (preferably sodium hydroxide, etc.) or tertiary amine (preferablyN,N-diisopropylethylamine, triethylamine orN-methylmorpholin etc). The inert solvent includes lower alkalemia alcohols (preferably methanol, ethanol, 2-propanol or butanol, etc.) or amide solvents (preferablyN,N-dimethylformamide or 1-methylpyrrolidine-2-it, etc.). The reaction temperature is in the range from about 50°C to 200°C, preferably from about 80°C to 180°C. this reaction can be carried out in conditions of the microwave oven.

Scheme 7

Total intermediate compound (C') of the new amide (D') and a new complex of ester (E') of the present invention is obtained by condensation of the pyrimidine nucleus (C), which are synthesized according to scheme 1, the carboxylic acid (B'), where R3, A, and B are as defined above, as shown in figure 8.

Carboxylic acid, (C') is subjected to interaction with the amine (R1Other4 and dehydrating condensing reagent in an inert solvent with addition of a base with or without obtaining a new amide (D') of the present invention. Dehydrating condensing agent includes dicyclohexylcarbodiimide (DCC), the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC•HCl), hexaflurophosphate postreperfusion (PyBroP), hexaflurophosphateO-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium (HATU) or 1-cyclohexyl-3-methylolacrylamide. The base includes a tertiary amine (preferablyN,N-diisopropylethylamine or triethylamine, etc.). The inert solvent includes a solvent, which represents a lower halogenated hydrocarbon, preferably dichloromethane, dichloroethane or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), nitrile solvents (preferably acetonitrile, etc.) or amide solvents (preferablyN,N-dimethylformamide and so on). If needed as a reagent can be used 1-hydroxybenzotriazole (HOBT), HOBT-6-carboxamidine polystyrene or 1-hydroxy-7-asobancaria (HOAT). The reaction temperature is in the range of approximately -20°C to 50°C, preferably about 0°C to 40°C.

Alternative new amide (D') of the present invention can in order to alocate amidation reaction using the acid chloride, derived from carboxylic acids (C'), and base in an inert solvent. The base includes a carbonate of an alkali metal (preferably sodium carbonate or potassium carbonate, etc.), bicarbonate of an alkali metal (preferably sodium bicarbonate or potassium bicarbonate, etc.), hydroxide of alkali metal (preferably sodium hydroxide or potassium hydroxide, etc.), tertiary amine (preferablyN,N-diisopropylethylamine, triethylamine orN-methylmorpholin etc) or an aromatic amine (preferably pyridine, imidazole, poly(4-vinylpyridine) etc). The inert solvent includes a solvent, which represents a lower halogenated hydrocarbon, preferably dichloromethane, dichloroethane or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), amide solvents (preferablyN,N-dimethylformamide, etc. or aromatic solvents (preferably toluene or pyridine, etc.). The reaction temperature is in the range of approximately -20°C to 50°C, preferably about 0°C to 40°C.

Carboxylic acid, (C') is subjected to interaction with alcohol (R1OH and dehydrating condensing reagent in an inert solvent with addition of a base or without it to obtain a new complex ether (E') for the present the invention. Dehydrating condensing agent includes dicyclohexylcarbodiimide (DCC), the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC•HCl), hexaflurophosphate postreperfusion (PyBroP), hexaflurophosphateO-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium (HATU) or 1-cyclohexyl-3-methylolacrylamide. The base includes a tertiary amine (preferablyN,N-diisopropylethylamine or triethylamine, etc.). The inert solvent includes a solvent, which represents a lower halogenated hydrocarbon, preferably dichloromethane, dichloroethane or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), nitrile solvents (preferably acetonitrile, etc.) or amide solvents (preferablyN,N-dimethylformamide and so on). If needed as a reagent can be used 1-hydroxybenzotriazole (HOBT), HOBT-6-carboxamidine polystyrene or 1-hydroxy-7-asobancaria (HOAT). The reaction temperature is in the range of approximately -20°C to 50°C, preferably about 0°C to 40°C.

Alternative new ester (E') of the present invention can be obtained by esterification using acid chloride derived from carboxylic acids (C'), and base in an inert solvent. The base includes CT is ONAT alkali metal (preferably sodium carbonate or potassium carbonate, etc.), bicarbonate of an alkali metal (preferably sodium bicarbonate or potassium bicarbonate, etc.), hydroxide of alkali metal (preferably sodium hydroxide or potassium hydroxide, etc.), tertiary amine (preferablyN,N-diisopropylethylamine, triethylamine orN-methylmorpholin etc) or an aromatic amine (preferably pyridine, imidazole, poly(4-vinylpyridine) etc). The inert solvent includes a solvent, which represents a lower halogenated hydrocarbon, preferably dichloromethane, dichloroethane or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), amide solvents (preferablyN,N-dimethylformamide, etc. or aromatic solvents (preferably toluene or pyridine, etc.). The reaction temperature is in the range of approximately -20°C to 50°C, preferably about 0°C to 40°C.

Alternative new pyrimidines (D') and (E') according to the present invention is directly synthesized from the pyrimidine nucleus (C), which are synthesized according to scheme 1. This connection is carried out with addition of a base or without an inert solvent. The base includes a carbonate of an alkali metal (preferably sodium carbonate or potassium carbonate, etc.), hydroxide of alkaline metal (preferably a hydroxide n is sodium etc) or tertiary amine (preferably N,N-diisopropylethylamine, triethylamine orN-methylmorpholin etc). The inert solvent includes lower alkalemia alcohols (preferably methanol, ethanol, 2-propanol or butanol, etc.) or amide solvents (preferablyN,N-dimethylformamide or 1-methylpyrrolidine-2-it, etc.). The reaction temperature is in the range from about 50°C to 200°C, preferably from about 80°C to 180°C. this reaction can be carried out in conditions of the microwave oven.

Scheme 8

EXAMPLES

Compounds according to the invention and their synthesis are additionally illustrated by the following examples. The following examples are provided to further define the invention, but without limiting the invention specifically these examples. As indicated in the following examples, "ambient temperature" means a temperature in the range from 0°C to 40°C. the Following compounds are named using Beilstein Auto Nom Version 4.0, CS Chem Draw Ultra Version 7.0.1, CS Chem Draw Ultra Version 6.0.2, CS Chem Draw Ultra Version 6.0 or ACD Name Version 7.0.

Abbreviations used in the present description, specifically in the schemes and examples, are as follows:

1H NMR spectrum, the proton nuclear magnetic resonance

AcOH: acetic acid

APCI: chemical ionization at atmospheric d is no

(Boc)2O: di-tert-BUTYLCARBAMATE

BuLi: utility

BuOH: butanol

Cbz: carbobenzoxy

CDCl3: deuterated chloroform

CH2Cl2: dichloromethane

CHCl3: chloroform

CI: chemical ionization

DCM: dichloromethane

DIEA: diisopropylethylamine

DMSO: dimethyl sulfoxide

EDC-HCl: hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

EI: ionization electrons

ESI: electrospray ionization

Et3N: triethylamine

Et2O: diethyl ether

EtOAc: ethyl ester of acetic acid

EtOH: ethanol

FAB: the bombardment of accelerated atoms

HOBt-H2O: hydrate of 1-hydroxybenzotriazole

H2SO4: sulfuric acid

HCl: hydrogen chloride

IPA: isopropanol

iPr2NEt: diisopropylethylamine

K2CO3: potassium carbonate

Me2NH: dimethylamine

MeNH2: methylamine

MeOH: methanol

MgSO4: magnesium sulfate

NaBH(OAc)3: triacetoxyborohydride sodium

NaBH3CN: cyanoborohydride sodium

NaBH4: sodium borohydride

NaH: sodium hydride

NaHCO3: sodium bicarbonate

NH3: ammonia

NH4Cl: ammonium chloride

Pd/C: palladium on carbon

POCl3: phosphorus oxychloride

SOCl2: thionyl chloride

TFUCK: triperoxonane acid

THF: tetrahydrofuran

ZCl: benzyloxy vanilloid

ZnBr2: zinc bromide

s: singlet

d: doublet

t: triplet

square: Quartet

DD: doublet of doublets

dt: the triplet of doublets

DDD: doublet of doublets of doublets

users: broad singlet

m: multiplet

J: binding constant of

Hz: Hertz

Example 1

The dihydrochlorideN'-(CIS-4-{[4-bromo-2-(triptoreline)benzyl]amino}cyclohexyl)-N,N-dimethylpyrimidin-4,6-diamine

Stage A: Synthesis of (6-chloropyrimidine-4-yl)dimethylamine.

To a solution of 4,6-dichloropyrimidine (10.0 g) in THF (10 ml) was added iPr2NEt (10.4 g) and 50% aqueous Me2NH (6,05 g). The mixture was stirred at ambient temperature for 28 hours and was poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue is suspended in Et2O. the Precipitate was collected by filtration, washed with Et2O and dried under reduced pressure to obtain (6-chloropyrimidine-4-yl)dimethylamine (6,37 g).

ESI MS m/e 157, M+;1H NMR (300 MHz, CDCl3) δ of 3.12 (s, 6H), 6,41 (s, 1H), of 8.37 (s, 1H).

Stage B: Synthesis ofN-(CIS-4-bromo-2-cryptomaterial)cyclohexane-1,4-diamine.

To a solution oftert-butyl methyl ether(4-aminocyclohexane)carbamino acid (6,72 g) in CHCl3(67 ml) we use the 4-bromo-2-triphtalocyaninine (8.44 grams), acetic acid (1.88 g) and

NaBH(OAc)3(becomes 9.97 g). The mixture was stirred at ambient temperature for 4 hours and poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure, and purified flash chromatography (silica gel, 33% EtOAc in hexane) to give thetert-butyl ether [CIS-4-(4-bromo-2-triphtalocyaninine)cyclohexyl]carbamino acid. To the solution obtained above substances (3.00 g) in EtOAc (30 ml) was added 4M hydrogen chloride in EtOAc (60 ml). The mixture was stirred at ambient temperature for 1 hour and concentrated under reduced pressure. The residue was podslushivaet saturated aqueous NaHCO3and the aqueous layer was extracted with CHCl3(seven times). The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to getN-(CIS-4-bromo-2-cryptomaterial)cyclohexane-1,4-diamine (2,39 g).

ESI MS m/e 367, M+;1H NMR (300 MHz, CDCl3) δ 1,22 is 1.96 (m, 8H), of 2.51-2.71 to (m, 1H), 2,87-3,13 (m, 1H), 3,74 (users, 2H), 7,28-to 7.50 (m, 3H).

Stage C: Synthesis dihydrochlorideN'-(CIS-4-{[4-bromo-2-(triptoreline)benzyl]amino}cyclohexyl)-N,N-dimethylpyrimidin-4,6-diamine.

The mixture ofN-(CIS-4-bromo-2-triptime kribensis)cyclohexane-1,4-diamine (466 mg), (6-chloropyrimidine-4-yl)dimethylamine (200 mg) and ethylene glycol (0.5 ml) was stirred at the boiling point under reflux for 4 hours in a sealed tube. The mixture was poured into saturated aqueous NaHCO3and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure, and purified flash chromatography (NH-silica gel, 50% EtOAc in hexane and silica gel, 5% MeOH in CHCl3with gettingN'-(CIS-4-{[4-bromo-2-(triptoreline)benzyl]amino}cyclohexyl)-N,N-dimethylpyrimidin-4,6-diamine. To the solution obtained above substances in EtOAc (2 ml) was added 4M hydrogen chloride in EtOAc (10 ml). The mixture was stirred at ambient temperature for 1 hour and concentrated under reduced pressure. The residue is suspended in Et2O (20 ml) and the suspension was stirred at ambient temperature for 4 hours. The precipitate was collected by filtration, washed with Et2O and dried under reduced pressure to obtain dihydrochlorideN'-(CIS-4-{[4-bromo-2-(triptoreline)benzyl]amino}cyclohexyl)-N,N-dimethylpyrimidin-4,6-diamine (67 mg).

ESI MS m/e 488, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,64 is 1.86 (m, 2H), 1,96-of 2.34 (m, 8H), 2,98-3,44 (m, 8H), 4,27 (s, 2H), 7,40-to 7.59 (m, 3H), 8,06-8,24 (m, 2H).

Example 2

HydrochlorideN-(CIS -4-{[6-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-3,4-differentated

Stage A: Synthesis oftert-butyl ether (CIS-4-{[1-(3,4-differenl)methanol]amino}cyclohexyl)carbamino acid.

To a solution of 3,4-diferential acid (4,10 g) andtert-butyl ether (CIS-4-aminocyclohexane)carbamino acid (of 5.05 g) in DMF (50 ml) was added

Et3N (90 ml), HOBt-H2O (5,41 g) and EDC-HCl (equal to 4.97 g). The mixture was stirred at ambient temperature for 17 hours. To the reaction mixture were added water (200 ml) and the suspension was stirred at ambient temperature for 10 minutes the Precipitate was collected by filtration, washed with H2O and EtOH and dried at 80°C under reduced pressure to gettert-butyl ether (CIS-4-{[1-(3,4-differenl)methanol]amino}cyclohexyl)carbamino acid (5.20 g).

ESI MS m/e 377, M+Na+;1H NMR (300 MHz, CDCl3) δ 1,45 (s, 9H), 1,53-of 1.95 (m, 8H), 3,60-3,74 (m, 1H), 4,00-4,16 (m, 1H), 4,50-and 4.68 (m, 1H), 5,95-6,09 (m, 1H), 7,15-7,28 (m, 1H), 7,43-to 7.68 (m, 2H).

Stage B: Synthesis ofN-(CIS-4-aminocyclohexane)-3,4-differentated.

Solutiontert-butyl ether (CIS-4-{[1-(3,4-differenl)methanol]amino}cyclohexyl)carbamino acid (5.20 g) in EtOAc (52 ml) was cooled in an ice bath was added 4M hydrogen chloride in EtOAc (104 ml). The mixture was stirred at ambient temperature for 1 hour and who has koncentrirebuli under reduced pressure. The residue was dissolved in 1M aqueous NaOH and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and dried at 60°C under reduced pressure to getN-(CIS-4-aminocyclohexane)-3,4-differentated (3.00 g).

ESI MS m/e 255, M+H+;1H NMR (300 MHz, CDCl3) δ 1,15-of 1.52 (m, 3H), 1,59-1,89 (m, 5H), 2,94-of 3.06 (m, 1H), 4,06-4,20 (m, 1H), 6,01-6,18 (m, 1H), 7,13-7,26 (m, 1H), 7,43-to 7.50 (m, 1H), EUR 7.57-to 7.67 (m, 1H).

Stage C: Synthesis of hydrochlorideN-(CIS-4-{[6-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-3,4-differentated.

To a solution ofN-(CIS-4-aminocyclohexane)-3,4-differentated (442 mg) was added (6-chloropyrimidine-4-yl)dimethylamine obtained in stage A of example 1 (250 mg). The mixture was stirred at 180°C for 8 hours in a sealed tube. To the mixture was added saturated aqueous NaHCO3and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure, and purified flash chromatography (NH-silica gel, 33% to 50% EtOAc in hexane and silica gel, 3% MeOH in CHCl3with gettingN-(CIS-4-{[6-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-3,4-differentated. To the solution obtained above substances in EtOAc (10 ml) was added 4M hydrogen chloride in EtOAc (0.2 ml). The mixture was stirred p. and ambient temperature for 1 hour and concentrated under reduced pressure. The residue is suspended in Et2O (20 ml) and the suspension was stirred at ambient temperature for 4 hours. The precipitate was collected by filtration, washed with Et2O and dried at 70°C under reduced pressure to obtain hydrochlorideN-(CIS-4-{[6-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-3,4-differentated (99 mg).

ESI MS m/e 398, M(free)+Na+;1H NMR (300 MHz, CDCl3) δ 1,69-of 2.15 (m, 8H), 3.00 and-of 3.42 (m, 6H), 3,69-3,81 (m, 1H), 4,03-is 4.21 (m, 1H), 5,26 (s, 1H), 6,66-to 6.80 (m, 1H), 7,13-7,26 (m, 1H), 7,51 to 7.62 (m, 1H), 7.68 per-7,80 (m, 1H), 8,01 (s, 1H), 8,68-8,91 (m, 1H), at 13.84-14,09 (m, 1H).

Example 3

HydrochlorideN-[CIS-4-({[6-(dimethylamino)pyrimidine-4-yl]amino}methyl)cyclohexyl]-3,4-differentated

Stage A: Synthesis oftert-butyl ether (CIS-4-hydroxymethylcellulose)carbamino acid.

SuspensionCIS-4-aminocyclohexanecarboxylic acid (244 g) in MeOH (2,45 l) was cooled to -8°C. was Added dropwise thionyl chloride (45,0 ml). The mixture was stirred at ambient temperature for 4.5 hours and then concentrated under reduced pressure to obtain white solid. To the suspension obtained above solids in CHCl3(3,00 l) was slowly added triethylamine (261 ml) and (Boc)2O (409 g). The mixture was stirred at ambient temperature for 5 hours and poured into water. The aqueous layer was extracted with CHCl3(three times is). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure, and purified flash chromatography (silica gel, CHCl3to 10% MeOH in CHCl3) to obtain a colorless oil (531 g). To a suspension, cooled at -4°C lithium aluminum hydride (78,3 g) Et2O (7,9 l) was added to the solution obtained above oil (530,9 g) Et2O (5.3 l) below 0°C. the resulting suspension was stirred at ambient temperature for 2 hours. The mixture was cooled in an ice bath, put cold water and filtered through a layer of celite. The filtrate was dried over MgSO4, filtered and concentrated under reduced pressure. Sediment suspended in hexane (300 ml), filtered, washed with hexane and dried under reduced pressure to gettert-butyl ether (CIS-4-hydroxymethylcellulose)carbamino acid (301 g).

ESI MS m/e 252, M+Na+;1H NMR (300 MHz, CDCl3) δ 1,16-of 1.36 (m, 2H), 1,45 (s, 9H), of 1.52-1.77 in (m, 7H), 3,51 (d, J=6.2 Hz, 2H), 3,75 (users, 1H), 4,30-4,82 (m, 1H).

Stage B: Synthesis oftert-butyl ether [CIS-4-(benzyloxycarbonylamino)cyclohexyl]carbamino acid.

To a solution oftert-butyl ether (CIS-4-hydroxymethylcellulose)carbamino acid (17,7 g) in THF (245 ml) was gradually added triphenylphosphine (20.2 g) and phthalimide (11.4 g). The resulting suspension was cooled to Ladan the th bath and for 1 hour was added 40% diethylazodicarboxylate in toluene (33.6 ml). The mixture was stirred at ambient temperature for 2.5 hours, concentrated under reduced pressure, and purified flash chromatography (silica gel, 33% EtOAc in hexane) to give white solid. To the suspension obtained above solid (27.5 g) in EtOH (275 ml) was added hydrazinehydrate (USD 5.76 g). The mixture is stirred at the boiling point under reflux for 2.25 hours, cooled to ambient temperature and concentrated under reduced pressure. The precipitate was dissolved in 10% aqueous sodium hydroxide (350 ml). The aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. To a solution of the above residue in CHCl3(275 ml) was added triethylamine (8,54 g). The resulting solution was cooled to 0°C and added ZCl2(14.4 g) below 5°C. the Mixture was stirred at ambient temperature for 16 hours and was poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure, and purified flash chromatography (silica gel, 2% MeOH in CHCl3with gettingtert-butyl ether [CIS-4-(benzyloxycarbonylamino)cyclohexyl]carbamino acid (25,3 g).

ES-MS m/e 385, M+Na+;1H NMR (300 MHz, CDCl3) δ of 1.13 to 1.31 (m, 2H), of 1.44 (s, 9H), 1,48 is 1.75 (m, 7H), 3,10 (t, J=6.4 Hz, 2H), 3.72 points users, 1H), 4,42 was 4.76 (m, 1H), 4,76 to 4.92 (m, 1H), 5,09 (s, 2H), 7,27-7,38 (m, 5H).

Stage C: Synthesis of benzyl ether (CIS-4-aminocyclohexanol)carbamino acid.

To a solution oftert-butyl ether [CIS-4-(benzyloxycarbonylamino)cyclohexyl]carbamino acid (12.9 g) in EtOAc (129 ml) was added 4M hydrogen chloride in EtOAc (129 ml). The mixture was stirred at ambient temperature for 3 hours, filtered, washed with EtOAc and dried under reduced pressure. To the residue was added saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3(five times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and dried under reduced pressure to obtain benzyl ether (CIS-4-aminocyclohexanol)carbamino acid (8,88 g).

ESI MS m/e 263, M+H+;1H NMR (300 MHz, CDCl3) δ 1,36-to 1.98 (m, 9H), 2,96-of 3.32 (m, 3H), 5,12 (users, 3H), of 7.36 (s, 5H).

Stage D: Synthesis of benzyl ether [CIS-4-(3,4-differentiating)cyclohexylmethyl]carbamino acid.

To a solution of benzyl ether (CIS-4-aminocyclohexanol)carbamino acid (2.00 g) in CHCl3(16 ml) was added Et3N (2,23 ml) and 3,4-differentiald (1.48 g) in CHCl3(4 ml). The mixture was stirred PR the ambient temperature for 12 hours and poured into saturated aqueous NaHCO 3. The aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, 20% to 50% EtOAc in hexane) to give the benzyl ether [CIS-4-(3,4-differentiating)cyclohexylmethyl]carbamino acid (2.66 g).

ESI MS m/e 425, M+;1H NMR (300 MHz, CDCl3) δ 1,22-of 1.44 (m, 2H), 1,57-of 1.88 (m, 6H), 3,07-of 3.25 (m, 2H), 4,08-to 4.28 (m, 1H), 4,78-is 4.93 (m, 1H), 5,10 (s, 2H), 6,02-6,24 (m, 1H), 7,13-7,39 (m, 6H), 7,43-7,52 (m, 1H), 7,58-to 7.68 (m, 1H).

Stage E: Synthesis ofN-(CIS-4-aminoethylthiomethyl)-3,4-differentated.

To a solution of benzyl ether [CIS-4-(3,4-differentiating)cyclohexylmethyl]carbamino acid (2,60 g) in MeOH (26 ml) was added 10% Pd/C (260 mg). The mixture was stirred at ambient temperature in an atmosphere of hydrogen within 84 hours. The mixture was filtered through a layer of celite, concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, from 9% to 17% EtOAc in hexane and silica gel, 1% MeOH in CHCl3with gettingN-(CIS-4-aminoethylthiomethyl)-3,4-differentated (1,43 g).

ESI MS m/e 269, M+H+;1H NMR (300 MHz, CDCl3) δ 1,13-to 1.86 (m, 9H), of 2.64 (d, J=6,5 Hz, 2H), 4,16-to 4.28 (m, 1H), 6,09-6,30 (m, 1H), 7,15-7,27 (m, 1H), 7,46-7,53 (m, 1H), 7,58-to 7.67 (m, 1H).

Stage F: Synthesis of hydrochlorideN-[CIS -4-({[6-(dimethylamino)pyrimidine-4-yl]amino}methyl)cyclohexyl]-3,4-differentated.

To a solution ofN-(CIS-4-aminoethylthiomethyl)-3,4-differentated (373 mg) in BuOH (1 ml) was added (6-chloropyrimidine-4-yl)dimethylamine obtained in stage A of example 1 (200 mg). The mixture was heated in a microwave synthesizer at 220°C for 20 minutes To the mixture was added saturated aqueous NaHCO3and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, 20% to 50% EtOAc in hexane) to give theN-[CIS-4-({[6-(dimethylamino)pyrimidine-4-yl]amino}methyl)cyclohexyl]-3,4-differentated. To the solution obtained above substances in EtOAc (10 ml) was added 4M hydrogen chloride in EtOAc (0.5 ml). The mixture was stirred at ambient temperature for 30 min and concentrated under reduced pressure. The suspension obtained above substances in Et2O (12 ml) was stirred at ambient temperature for 2 hours. The precipitate was collected by filtration, washed with Et2O and dried at 70°C under reduced pressure to obtain hydrochlorideN-[CIS-4-({[6-(dimethylamino)pyrimidine-4-yl]amino}methyl)cyclohexyl]-3,4-differentated (106 mg).

ESI MS m/e 390, M(free)+H+;1H YAM who (300 MHz, CDCl3) δ 1,31 with 2.14 (m, 8H), 2,96-of 3.46 (m, 8H), 4,40-br4.61 (m, 1H), 5,18 (s, 1H), 7,14-7,35 (m, 2H), 7,83-of 8.09 (m, 3H), 8,79-9,14 (m, 1H).

Example 4

HydrochlorideN-[(CIS-4-{[6-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)methyl]-3,4-differentated

Stage A: Synthesis oftert-butyl ether {CIS-4-[(3,4-differentiating)methyl]cyclohexyl}carbamino acid.

To a solution oftert-butyl ether [CIS-4-(benzyloxycarbonylamino)cyclohexyl]carbamino acid obtained in stage B of example 3 (5,00 g)in MeOH (50 ml) was added 10% Pd/C (500 mg). The mixture was stirred at ambient temperature in an atmosphere of hydrogen for 84 hours, filtered through a layer of celite and concentrated under reduced pressure to obtain a light brown oil. To the solution obtained above oil in CHCl3(40 ml) was added Et3N (a 4.03 ml) and 3,4-differentiald (2,68 g) in CHCl3(10 ml). The mixture was stirred at ambient temperature for 12 hours. To the mixture was added saturated aqueous NaHCO3and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, 50% EtOAc in hexane) to give thetert-butyl ether {CIS-4-[(3,4-differentiating)methyl]C is logaxis}carbamino acid (3,48 g).

ESI MS m/e 391, M+Na+;1H NMR (300 MHz, CDCl3) δ 1,19-of 1.81 (m, 16H), 3,33-of 3.43 (m, 2H), 3,68-with 3.79 (m, 1H), 4,54-to 4.73 (m, 1H), 6,10-6,21 (m, 1H), 7,17-7,27 (m, 1H), 7,46-rate of 7.54 (m, 1H), to 7.59-to 7.68 (m, 1H).

Stage B: Synthesis ofN-(CIS-4-aminocyclohexanol)-3,4-differentated.

To a solution oftert-butyl ether {CIS-4-[(3,4-differentiating)methyl]cyclohexyl}carbamino acid (3,48 g) in EtOAc (35 ml) was added 4M hydrogen chloride in EtOAc (35 ml). The mixture was stirred at ambient temperature for 12 hours and then concentrated under reduced pressure. The residue was dissolved in 1M aqueous NaOH and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure to getN-(CIS-4-aminocyclohexanol)-3,4-differentated (2.50 g).

ESI MS m/e 269, M+H+;1H NMR (300 MHz, CDCl3) δ 1,16-of 1.81 (m, 9H), 2,93-is 3.08 (m, 1H), 3,32-of 3.42 (m, 2H), 6,41-to 6.57 (m, 1H), 7,14-7,27 (m, 1H), of 7.48-EUR 7.57 (m, 1H), 7,60-7,71 (m, 1H).

Stage C: Synthesis of hydrochlorideN-[(CIS-4-{[6-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)methyl]-3,4-differentated.

To a solution ofN-(CIS-4-aminocyclohexanol)-3,4-differentated (469 mg) in BuOH (1 ml) was added (6-chloropyrimidine-4-yl)dimethylamine obtained in stage A of example 1 (250 mg). The mixture was heated in a microwave synthesizer at 220°C for 20 minutes To the mixture was added n is sydeny aqueous NaHCO 3and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, 20% to 50% EtOAc in hexane) to give theN-[(CIS-4-{[6-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)methyl]-3,4-differentated. To the solution obtained above substances in EtOAc (10 ml) was added 4M hydrogen chloride in EtOAc (0.5 ml). The mixture was stirred at ambient temperature for 30 min and concentrated under reduced pressure. A suspension of the residue in Et2O (12 ml) was stirred at ambient temperature for 2 hours. The precipitate was collected by filtration, washed with Et2O and dried at 70°C under reduced pressure to obtain hydrochlorideN-[(CIS-4-{[6-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)methyl]-3,4-differentated (82 mg).

ESI MS m/e 390, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,50-2,04 (m, 9H), 2.93 which is 3.57 (m, 8H), 3,67-of 3.85 (m, 1H), 5,23 (s, 1H), 6,85-7,35 (m, 2H), 7,73-with 8.05 (m, 3H), 8,75-9,01 (m, 1H), 13,64-13,95 (m, 1H).

Example 5

HydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4-differentated

Stage A: Synthesis of 4,6-dichloro-2-methylpyrimidine.

A suspension of 2-methylpyrimidine-4,6-diol (20,0 g) in POCl3(162 ml) was stirred while the temperature is the boiling point under reflux for 4 hours and cooled to ambient temperature. The mixture was poured into ice water (3 l). The aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to obtain 4,6-dichloro-2-methylpyrimidine (22,37 g).

CI MS m/e 163, M+;1H NMR (300 MHz, CDCl3) δ a 2.71 (s, 3H), 7,25 (s, 1H).

Stage B: Synthesis of (6-chloro-2-methylpyrimidin-4-yl)dimethylamine.

To a solution of 4,6-dichloro-2-methylpyrimidine (11.1 g) in THF (110 ml) was added iPr2NEt (of 14.2 ml) and 50% aqueous Me2NH (8.5 ml). The mixture was stirred at ambient temperature for 2 hours. To the mixture was added 50% aqueous Me2NH (3.5 ml) and stirred at ambient temperature for 7 hours and concentrated under reduced pressure. To the residue was added saturated aqueous NaHCO3and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and dried under reduced pressure to obtain (6-chloro-2-methylpyrimidin-4-yl)dimethylamine (11.6 g).

ESI MS m/e 172 M+H+;1H NMR (300 MHz, CDCl3) δ 2.49 USD (s, 3H), 3,10 (s, 6H), 6,24 (s, 1H).

Stage C: Synthesis of hydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4-differentated.

To a solution ofN-(CIS-4-aminocyclohexane)-3,4-differentated, polucen is th at stage B of example 2 (407 mg), in BuOH (1 ml) was added (6-chloro-2-methylpyrimidin-4-yl)dimethylamine (250 mg). The mixture was heated in a microwave synthesizer at 200°C for 20 min and 230°C for 20 minutes To the mixture was added saturated aqueous NaHCO3and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, 20% to 50% EtOAc in hexane) to give theN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4-differentated.To the solution obtained above substances in EtOAc (10 ml) was added 4M hydrogen chloride in EtOAc (0.2 ml). The mixture was stirred at ambient temperature for 1 hour and concentrated under reduced pressure. A suspension of the residue in Et2O (12 ml) was stirred at ambient temperature for 2 hours. The precipitate was collected by filtration, washed with Et2O and dried at 70°C under reduced pressure to obtain hydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4-differentated (325 mg).

ESI MS m/e 412, M(free)+Na+;1H NMR (300 MHz, CDCl3) δ 1,63-2,03 (m, 8H), 2.49 USD (s, 3H), 2.91 in-3,43 (m, 6H), 3,67-with 3.79 (m, 1H), 4,03-4,22 (m, 1H), 5,15 (s, 1H), 6.89 in-7,02 (m, 1H), 7,14-7,27 (m, 1H), 7,56-to 7.64 (m, 1H), 7,69-7,81 (m, 1H), 8,40-8,55 (m, 1H).

Example 6

Hydrochloride 3-PI is p- N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-

4-yl]amino}cyclohexyl)-4-fermentated

Stage A: Synthesis ofCIS-N-benzylchloride-1,4-diamine.

To a solution oftert-butyl ether (CIS-4-aminocyclohexane)carbamino acid (5,00 g) in CHCl3(100 ml) was added benzaldehyde (2,48 g) and acetic acid (1.40 g). The mixture was stirred at ambient temperature for 1 hour. To the mixture was added NaBH(OAc)3(7,42 g) and the mixture was stirred at ambient temperature for 15 hours. The reaction extinguished saturated aqueous NaHCO3and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (silica gel, 2% to 9% MeOH in CHCl3with gettingtert-butyl ether (CIS-4-benzylaminocarbonyl)carbamino acid (76.9 g). To the solution obtained above substances (76.9 g) in EtOAc (77 ml) was added 4M hydrogen chloride in EtOAc (38,5 ml). The mixture was stirred at ambient temperature for 10 hours and then concentrated under reduced pressure. The residue was dissolved in 2M aqueous NaOH (150 ml) and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated at the pony who hinnon pressure and dried under reduced pressure to get CIS-N-benzylchloride-1,4-diamine (4.12 g).

ESI MS m/e 205, M+H+;1H NMR (300 MHz, CDCl3) δ 1,42-1,72 (m, 8H), 2,63-to 2.74 (m, 1H), 2,80-only 2.91 (m, 1H), of 3.77 (s, 2H), 7,20-7,39 (m, 5H).

Stage B: Synthesis ofN-(CIS-4-benzylaminocarbonyl)-2,N',N'-trimethylpyridine-4,6-diamine.

To a solution of (6-chloro-2-methylpyrimidin-4-yl)amine, obtained in stage B of example 5 (763 mg)in BuOH (0.8 ml) was addedCIS-N-benzylchloride-1,4-diamine (1,00 g). The mixture was heated in a microwave synthesizer at 220°C for 25 minutes To the mixture was added saturated aqueous NaHCO3and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, from 9% to 60% EtOAc in hexane) to give theN-(CIS-4-benzylaminocarbonyl)-2,N',N'-trimethylpyridine-4,6-diamine (952 mg).

ESI MS m/e 340, M+H+;1H NMR (300 MHz, CDCl3) δ 1,47-of 1.92 (m, 8H), to 2.35 (s, 3H), 2,63-to 2.74 (m, 1H), 3.04 from (s, 6H), 3,56 at 3.69 (m, 1H), 3,79 (s, 2H), 4,67-4,80 (m, 1H), 5,14 (s, 1H), 7,20 was 7.36 (m, 5H).

Stage C: the Synthesis ofN-(CIS-4-aminocyclohexane)-2,N',N'-trimethylpyridine-4,6-diamine.

To a solution ofN-(CIS-4-benzylaminocarbonyl)-2,N',N'-trimethylpyridine-4,6-diamine (940 mg) in MeOH (9.4 ml) was added 20% Pd(OH)2(188 mg). A mixture of AC is stirred at 50°C in hydrogen atmosphere for 10 hours. The mixture was filtered through a layer of celite, concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, 2%→5% MeOH in CHCl3with gettingN-(CIS-4-aminocyclohexane)-2,N',N'-trimethylpyridine-4,6-diamine (566 mg).

ESI MS m/e 250, M+H+;1H NMR (300 MHz, CDCl3) δ 1,05-1,89 (m, 10H), to 2.35 (s, 3H), of 2,75 2,90 (m, 1H), 3,05 (s, 6H), 3,54-3,70 (m, 1H), 4,68-4,82 (m, 1H), 5,14 (s, 1H).

Stage D: Synthesis of hydrochloride of 3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-fermentated.

To a solution of 3-chloro-4-fermenting acid (192 mg) andN-(CIS-4-aminocyclohexane)-2,N',N'-trimethylpyridine-4,6-diamine (250 mg) in DMF (4 ml) was added Et3N (0,34 ml), HOBt-H2O (230 mg) and EDC-HCl (211 mg). The mixture was stirred at ambient temperature for 12 hours. To the mixture was added water (20 ml) and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, 25% to 50% EtOAc in hexane) to give 3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-fermentated. To the solution obtained above substances in EtOAc (10 ml) was added 4M hydrogen chloride in EtOAc (0.2 ml). The mixture was stirred at same time is the temperature value to the environment for 1 hour and concentrated. The residue is suspended in Et2O (20 ml) and the suspension was stirred at ambient temperature for 2 hours. The precipitate was collected by filtration, washed with Et2O and dried at 70°C under reduced pressure to obtain hydrochloride of 3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-fermentated (196 mg).

ESI MS m/e 406, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,62 is 2.00 (m, 8H), 2.49 USD (s, 3H), 2,99 is 3.40 (m, 6H), 3,67-with 3.79 (m, 1H), was 4.02-4,20 (m, 1H), 5,15 (s, 1H), 6,59-6,70 (m, 1H), 7,11-7,26 (m, 1H), to 7.67-7,79 (m, 1H), 7,89-8,02 (m, 1H), 8,48-8,61 (m, 1H).

Example 7

HydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-fermentated

To a solution ofN-(CIS-4-aminocyclohexane)-2,N',N'-trimethylpyridine-4,6-diamine obtained in stage C of example 6 (250 mg)in CHCl3(3 ml) was added Et3N (0,29 ml) and 4-perbenzoate (174 mg). The mixture was stirred at ambient temperature for 12 hours. The reaction extinguished saturated aqueous NaHCO3and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, 25% to 50% EtOAc in hexane) to give theN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-tormented. To the solution obtained above substances in EtOAc (10 ml) was added 4M hydrogen chloride in EtOAc (0.2 ml). The mixture was stirred at ambient temperature for 1 hour and concentrated under reduced pressure. The residue is suspended in Et2O (20 ml) and the suspension was stirred at ambient temperature for 2 hours. The precipitate was collected by filtration, washed with Et2O and dried at 70°C under reduced pressure to obtain hydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-fermentated (255 mg).

ESI MS m/e 372, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,66-2,03 (m, 8H), 2.49 USD (s, 3H), 2,93-of 3.43 (m, 6H), 3,64-of 3.78 (m, 1H), 4.04 the-4,20 (m, 1H), 5,14 (s, 1H), to 6.43-6,56 (m, 1H), 7,05-to 7.15 (m, 2H), 7,75-to $ 7.91 (m, 2H), of 8.47-8,63 (m, 1H).

Example 8

Hydrochloride 3,4-dichloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide

Specified in the title compound was obtained using the methodology of stage A of example 7.

ESI MS m/e 422, M(free)+;1H NMR (300 MHz, CDCl3) δ 1,63-2,02 (m, 8H), 2.49 USD (s, 3H), 2,96-to 3.38 (m, 6H), 3,67-of 3.80 (m, 1H), was 4.02-is 4.21 (m, 1H), 5,14 (s, 1H), 6,69-to 6.80 (m, 1H), 7,47-7,53 (m, 1H), 7,62-of 7.70 (m, 1H), 7,93-of 8.00 (m, 1H), 8,48-8,59 (m, 1H), 13,70-13,90 (m, 1H).

Example 9

Hydrochloride 4-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-fermentated

Specified in the title compound was obtained IP is the use of techniques of stage D of example 6.

ESI MS m/e 406, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,66-2,07 (m, 8H), 2,48 (s, 3H), 2,94 is 3.40 (m, 6H), 3,66-with 3.79 (m, 1H), 4,00-is 4.21 (m, 1H), 5,14 (s, 1H), 6,88-7,00 (m, 1H), 7,40-of 7.48 (m, 1H), 7,52-of 7.60 (m, 1H), 7,65-7,73 (m, 1H), 8,45-8,54 (m, 1H), 13,66-13,86 (m, 1H).

Example 10

The hydrochloride of 3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-5-fermentated

Specified in the title compound was obtained using the methodology of stage D of example 6.

ESI MS m/e 406, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,61-2,07 (m, 8H), 2.49 USD (s, 3H), 2,96-to 3.41 (m, 6H), 3,65-with 3.79 (m, 1H), 4,00-4,22 (m, 1H), 5,14 (s, 1H), 6,78-to 6.88 (m, 1H), 7,16-of 7.23 (m, 1H), 7,42-to 7.50 (m, 1H), 7,60-to 7.64 (m, 1H), at 8.36-to 8.62 (m, 1H), of 13.75-13,95 (m, 1H).

Example 11

HydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4,5-triterpenoid

Specified in the title compound was obtained using the methodology of stage D of example 6.

ESI MS m/e 408, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,64-2,04 (m, 8H), 2,48 (s, 3H), 2,92-of 3.42 (m, 6H), 3,65-with 3.79 (m, 1H), 4,00-4,20 (m, 1H), 5,15 (s, 1H), 6.73 x-6,84 (m, 1H), of 7.48-7,58 (m, 2H), of 8.47 at 8.60 (m, 1H), 13,70-13,86 (m, 1H).

Example 12

The dihydrochloride of 5-bromo-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)nicotinamide

Specified in the title compound was obtained using the methodology of stage D of example 6.

ESI MS m/e 433, M(free)+;1H NMR (300 MHz, CDCl3) δ 1,67-2,8 (m, 8H), 2.49 USD (s, 3H), 2.91 in is-3.45 (m, 6H), 3,60-of 3.80 (m, 1H), 4,10-to 4.28 (m, 1H), 5,11-5,20 (m, 1H), 7,70-7,87 (m, 1H), 8,33-8,49 (m, 1H), 8,60-8,67 (m, 1H), 8,90-of 9.02 (m, 1H), 9,17-of 9.30 (m, 1H).

Example 13

HydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)for 3,5-differentated

Specified in the title compound was obtained using the methodology of stage A of example 7.

ESI MS m/e 390, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,63-2,03 (m, 8H), 2,48 (s, 3H), 2,99 is-3.45 (m, 6H), 3,69-with 3.79 (m, 1H), 4,03-4,19 (m, 1H), 5,14 (s, 1H), 6,58-of 6.71 (m, 1H), 6,86-6,98 (m, 1H), 7,28-7,44 (m, 2H), 8,50-8,64 (m, 1H), of 13.75-13,93 (m, 1H).

Example 14

HydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-fluoro-3-(trifluoromethyl)benzamide

Specified in the title compound was obtained using the methodology of stage A of example 7.

ESI MS m/e 440, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,65-2,03 (m, 8H), 2.49 USD (s, 3H), 2,97 is 3.40 (m, 6H), 3,67-3,81 (m, 1H), was 4.02-to 4.23 (m, 1H), 5,15 (s, 1H), 6,63-6,79 (m, 1H), 7,19-7,31 (m, 1H), 7,97-8,08 (m, 1H), 8,13-to 8.20 (m, 1H), 8,50 at 8.60 (m, 1H), 13,74-13,88 (m, 1H).

Example 15

HydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-fluoro-4-(trifluoromethyl)benzamide

Specified in the title compound was obtained using the methodology of stage A of example 7.

ESI MS m/e 462, M(free)+Na+;1H NMR (300 MHz, CDCl3) δ 1,64-to 2.06 (m, 8H), 2.49 USD (s, 3H), 2,97-3,39 (m, 6H), 3,67-3,81 (m, 1H), was 4.02-to 4.23 (m, 1H), 5,15 (s,1H), 6,76-to 6.95 (m, 1H), 7,52-7,81 (m, 2H), of 8.47-to 8.62 (m, 1H), 13,71-13,85 (m, 1H).

Example 16

The hydrochloride of 3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-(triptoreline)benzamide

Specified in the title compound was obtained using the methodology of stage A of example 7.

ESI MS m/e 494, M(free)+Na+;1H NMR (300 MHz, CDCl3) δ 1.60-to to 2.06 (m, 8H), 2.49 USD (s, 3H) 2,95 is 3.40 (m, 6H), 3,70-of 3.78 (m, 1H), was 4.02-4,24 (m, 1H), 5,15 (s, 1H), 6,59-6,72 (m, 1H), 7,34-7,41 (m, 1H), 7,71-7,80 (m, 1H), of 7.96-of 8.04 (m, 1H), 8,48-to 8.62 (m, 1H), of 13.75-13,90 (m, 1H).

Example 17

HydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-(trifluoromethyl)benzamide

Specified in the title compound was obtained using the methodology of stage A of example 7.

ESI MS m/e 444, M(free)+Na+;1H NMR (300 MHz, CDCl3) δ 1,66-2,17 (m, 8H), 2.49 USD (s, 3H), 2,97-to 3.38 (m, 6H), 3,65-of 3.80 (m, 1H), 4,06-to 4.23 (m, 1H), 5,15 (s, 1H), 6,59-of 6.71 (m, 1H), 7,52 to 7.62 (m, 1H), 7,69-7,80 (m, 1H), 7,93-8,02 (m, 1H), 8,13 (s, 1H), 8,51-8,68 (m, 1H), 13,81-13,96 (m, 1H).

Example 18

HydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-(triptoreline)benzamide

Specified in the title compound was obtained using the methodology of stage A of example 7.

ESI MS m/e 438, M(free)+Na+;1H NMR (300 MHz, CDCl3) δ 1,68-to 2.06 (m, 8H), 2.49 USD (s, 3H), 2,94-3,44 (m, 6H) ,3,67-3,81 (m, 1H), 4,03-to 4.23 (m, 1H), 5,14 (s, 1H), 6,51 of 6.66 (m, 1H), 7,29-7,37 (m, 1H), 7,42-7,53 (m, 1H), 7,65 to 7.4 (m, 2H), 8,46-8,69 (m, 1H), 13,79-13,95 (m, 1H).

Example 19

HydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-(trifluoromethyl)benzamide

Specified in the title compound was obtained using the methodology of stage A of example 7.

ESI MS m/e 422, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,64-to 2.06 (m, 8H), 2.49 USD (s, 3H), 2,97-3,39 (m, 6H), 3,65-3,81 (m, 1H), 4,05-to 4.23 (m, 1H), 5,15 (s, 1H), of 6.71-6,84 (m, 1H), 7,69 (d, J=8,2 Hz, 2H), 7,95 (d, J=8,2 Hz, 2H), 8,48-to 8.62 (m, 1H).

Example 20

HydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-(triptoreline)benzamide

Specified in the title compound was obtained using the methodology of stage A of example 7.

ESI MS m/e 460, M(free)+Na+;1H NMR (300 MHz, CDCl3) δ 1,63-2,02, (m, 8H), 2,48 (s, 3H), 2,89-of 3.42 (m, 6H), 3,66-of 3.78 (m, 1H), 4,03-of 4.25 (m, 1H), 5,14 (s, 1H), 6,72-6,86 (m, 1H), 7,26 (d, J=7,6 Hz, 2H), 7,89 (d, J=8,9 Hz, 2H), 8,45-8,59 (m, 1H).

Example 21

Hydrochloride 3,5-dichloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide

Specified in the title compound was obtained using the methodology of stage A of example 7.

ESI MS m/e 444, M(free)+Na+;1H NMR (300 MHz, CDCl3) δ 1,65-2,02 (m, 8H), 2.49 USD (s, 3H), 2,93-of 3.42 (m, 6H), 3,68-with 3.79 (m, 1H), was 4.02-4,19 (m, 1H), 5,14 (s, 1H), 6,47-to 6.57 (m, 1H), 7,45-of 7.48 (m, 1H), 7,68 (d, J=1.8 Hz, 2H), charged 8.52-8,65 (m, 1H).

Example 22

HydrochlorideN-(CIS-4-{[6-(Dima is ylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-fermentated

Specified in the title compound was obtained using the methodology of stage A of example 7.

ESI MS m/e 394, M(free)+Na+;1H NMR (300 MHz, CDCl3) δ 1,65-to 2.06 (m, 8H), 2,48 (s, 3H), 2.93 which is 3.40 (m, 6H), 3,63-3,71 (m, 1H), 4,08-4,24 (m, 1H), 5,12 (s, 1H), 6,69-6,85 (m, 1H), 7,06-7,30 (m, 2H), 7,39-7,53 (m, 1H), 7.95 is-with 8.05 (m, 1H), 8,51-8,61 (m, 1H).

Example 23

HydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-fermentated

Specified in the title compound was obtained using the methodology of stage A of example 7.

ESI MS m/e 394, M(free)+Na+;1H NMR (300 MHz, CDCl3) δ 1,64-2,05 (m, 8H), 2.49 USD (s, 3H), 2,99 is-3.45 (m, 6H), 3,66-of 3.77 (m, 1H), 4.04 the-to 4.23 (m, 1H), 5,14 (s, 1H), 6,40-6,53 (m, 1H), 7,13-7,22 (m, 1H), 7,34 was 7.45 (m, 1H), 7,52-7,58 (m, 2H), charged 8.52-to 8.62 (m, 1H).

Example 24

The hydrochloride of 3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide

Specified in the title compound was obtained using the methodology of stage A of example 7.

ESI MS m/e 388, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,68-2,03 (m, 8H), 2.49 USD (s, 3H), 2,97-3,37 (m, 6H), 3,66-of 3.77 (m, 1H), was 4.02-is 4.21 (m, 1H), 5,14 (s, 1H), 6.48 in-to 6.57 (m, 1H), 7,32-7,49 (m, 2H), 7,63-of 7.69 (m, 1H), 7,81-a 7.85 (m, 1H), 8,53-to 8.62 (m, 1H), 13,86-13,97 (m, 1H).

Example 25

Hydrochloride 4-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide

Specified in the title compound was obtained using method A stage when the EPA 7.

ESI MS m/e 388, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,67-2,07 (m, 8H), 2.49 USD (s, 3H), 2,98-to 3.38 (m, 6H), 3,67-with 3.79 (m, 1H), 4,01-is 4.21 (m, 1H), 5,14 (s, 1H), 6.42 per-6,55 (m, 1H), 7,37-the 7.43 (m, 2H), 7,73-7,80 (m, 2H), charged 8.52-8,63 (m, 1H), 13,82-13,98 (m, 1H).

Example 26

HydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-fluoro-5-(trifluoromethyl)benzamide

Specified in the title compound was obtained using the methodology of stage A of example 7.

ESI MS m/e 462, M(free)+Na+;1H NMR (300 MHz, CDCl3) δ 1.70 to 2.05 is (m, 8H), 2,48 (s, 3H), 2.93 which is-3.45 (m, 6H), 3,67-with 3.79 (m, 1H), 4.04 the-to 4.23 (m, 1H), 5,15 (s, 1H), of 6.71-6,84 (m, 1H), 7,40-7,47 (m, 1H), 7,72-7,79 (m, 1H), of 7.90 (s, 1H), 8,49-8,63 (m, 1H).

Example 27

HydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)for 3,5-bis(trifluoromethyl)benzamide

Specified in the title compound was obtained using the methodology of stage A of example 7.

ESI MS m/e 512, M(free)+Na+;1H NMR (300 MHz, CDCl3) δ 1,66-of 2.09 (m, 8H), 2,48 (s, 3H), 2.91 in-3,44 (m, 6H), 3,67-a 3.83 (m, 1H), 4.04 the-4,27 (m, 1H), 5,15 (s, 1H), 6,92-7,05 (m, 1H), 7,98 (s, 1H), 8,32 (s, 2H), 8,50-8,64 (m, 1H).

Example 28

HydrochlorideN-[CIS-4-({[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}methyl)cyclohexyl]-3,4-differentated

Specified in the title compound was obtained using the methodology of stage F of example 3.

ESI MS m/e 404, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,50-of 2.08 (m, 9H),2,46 (s, 3H), 2,88 (s, 8H), 4,43-4,58 (m, 1H), is 5.06 (s, 1H), 7,10-7,35 (m, 2H), 7,88-8,08 (m, 2H), 8,58-8,78 (m, 1H), 13,44-13,62 (m, 1H).

Example 29

HydrochlorideN-[(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)methyl]-3,4-differentated

Specified in the title compound was obtained using the methodology of stage C of example 4.

ESI MS m/e 404, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1.50 is for 2.01 (m, 9H), 2,47 (s, 3H), 2,89 of 3.56 (m, 8H), 3,66-3,86 (m, 1H), 5,12 (s, 1H), 6,82-6,98 (m, 1H), 7,11-7,32 (m, 1H), 7,72-of 7.97 (m, 2H), 8,61 is 8.75 (m, 1H), 13,61-13,89 (m, 1H).

Example 30

Hydrochloride 3,4-debtor-N-(CIS-4-{[2-methyl-6-(methylamino)pyrimidine-4-yl]amino}cyclohexyl)benzamide

Stage A: Synthesis of (6-chloro-2-methylpyrimidin-4-yl)methylamine.

To a solution of 4,6-dichloro-2-methylpyrimidine obtained in stage A of example 5 (11.1 g)in THF (110 ml) was added iPr2NEt (of 14.2 ml) and 40% aqueous MeNH2(10.1 ml). The mixture was stirred at ambient temperature for 7 hours and concentrated under reduced pressure. To the residue was added saturated aqueous NaHCO3and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and dried under reduced pressure to obtain (6-chloro-2-methylpyrimidin-4-yl)methylamine (10.7 g).

ESI MS m/e 157, M+;1H NMR (200 MHz, CDCl3) δ 2,48 (s, 3H), of 2.93 (d, J=5,2 G is, 3H), 5,20-5,70 (m, 1H), 6,18 (s, 1H).

Stage B: Synthesis of hydrochloride 3,4-debtor-N-(CIS-4-{[2-methyl-6-(methylamino)pyrimidine-4-yl]amino}cyclohexyl)benzamide.

Specified in the title compound was obtained using the methodology of stage C of example 5.

ESI MS m/e 376, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,58 and 2.13 (m, 8H), is 2.37 (s, 3H), 2,82-3,19 (m, 3H), 3,56-3,86 (m, 1H), 3,98-4,27 (m, 1H), 5,03-and 5.30 (m, 1H), 6,07-of 6.52 (m, 1H), of 6.71-of 6.96 (m, 1H), 7,11-7,33 (m, 1H), 7,49-of 7.82 (m, 2H), 8.34 per at 8.60 (m, 1H).

Example 31

The hydrochloride of 3-chloro-4-fluoro-N-(CIS-4-{[2-methyl-6-(methylamino)pyrimidine-4-yl]amino}cyclohexyl)benzamide

Stage A: Synthesis ofN-(CIS-4-aminocyclohexane)-3-chloro-4-fermentated.

To a solution of 3-chloro-4-fermenting acid (26,9 g) andCIS-tert-butyl ether (4-aminocyclohexane)carbamino acid (30.0 g) in DMF (300 ml) was added Et3N (46,8 ml), HOBt-H2O (32,2 g) and EDC-HCl (29.5 g). The mixture was stirred at ambient temperature for 20 hours. To the mixture was added water (1.20 l) and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. A solution of the residue in EtOAc (650 ml) was cooled in an ice bath was added 4M hydrogen chloride in EtOAc (325 ml). The mixture was stirred at ambient temperature for 16 hours and then concentrated under reduced is the making. The residue was dissolved in 1M aqueous NaOH (300 ml) and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and dried under reduced pressure to getN-(CIS-4-aminocyclohexane)-3-chloro-4-fermentated (44.4 g).

ESI MS m/e 271, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,37-of 1.92 (m, 8H), 2,94-is 3.08 (m, 1H), 4,06-4,22 (m, 1H), 6,13 of 6.31 (m, 1H), 7,19 (t, J=8.5 Hz, 1H), to 7.61-of 7.70 (m, 1H), 7,79-7,87 (m, 1H).

Stage B: Synthesis of hydrochloride of 3-chloro-4-fluoro-N-(CIS-4-{[2-methyl-6-(methylamino)pyrimidine-4-yl]amino}cyclohexyl)benzamide.

To a solution ofN-(CIS-4-aminocyclohexane)-3-chloro-4-fermentated (472 mg) in BuOH (1 ml) was added (6-chloro-2-methylpyrimidin-4-yl)methylamine obtained in stage A of example 30 (250 mg). The mixture was heated in a microwave synthesizer at 220°C for 20 minutes To the mixture was added saturated aqueous NaHCO3and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, 50% EtOAc in hexane) to give 3-chloro-4-fluoro-N-(CIS-4-{[2-methyl-6-(methylamino)pyrimidine-4-yl]amino}cyclohexyl)benzamide.To the solution obtained above substances in EtOAc (10 ml) was added 4M chloride odor the d in EtOAc (0.2 ml). The mixture was stirred at ambient temperature for 1 hour and concentrated under reduced pressure. A suspension of the residue in Et2O (12 ml) was stirred at ambient temperature for 2 hours. The precipitate was collected by filtration, washed with Et2O and dried at 70°C under reduced pressure to obtain hydrochloride of 3-chloro-4-fluoro-N-(CIS-4-{[2-methyl-6-(methylamino)pyrimidine-4-yl]amino}cyclohexyl)benzamide (64 mg).

ESI MS m/e 392, M(free)+H+;1H NMR (300 MHz, DMSO-d6) δ 1,54-1,90 (m, 8H), 2,29 is 2.43 (m, 3H), 2,74-to 2.94 (m, 3H), 3,80-of 3.96 (m, 2H), 5,44-5,64 (m, 1H), 7,53 (t, J=8,9 Hz, 1H), 7,86-7,94 (m, 2H), 8.07-a 8,13 (m, 2H), 8,31-of 8.47 (m, 1H).

Example 32

HydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-ethylpyrimidine-4-yl]amino}cyclohexyl)-3,4-differentated

Stage A: Synthesis of (2,6-dichloropyrimidine-4-yl)dimethylamine.

To a solution of 2,4,6-trichloropyridin (10.0 g) in THF (50 ml) was added 50% aqueous Me2NH (4,92 g) and iPr2NEt (8,46 g). The mixture was stirred at ambient temperature for 1.5 hours and concentrated under reduced pressure. The residue was poured into saturated aqueous NaHCO3and the aqueous layer was extracted with

CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure, and purified flash chromatography (NH-silica gel, 3% EtOAc in hexane) to give (2,6-d is chloropyrimidine-4-yl)dimethylamine (6,03 g).

ESI MS m/e 192, M+H+;1H NMR (300 MHz, CDCl3) δ 2.77-to of 3.46 (m, 6H), 6,34 (s, 1H).

Stage B: Synthesis of (6-chloro-2-ethylpyrimidine-4-yl)dimethylamine.

The solution ZnBr2(a 3.87 g) in THF (60 ml) was cooled to -60°C was added 1M EtMgBr in THF (17,2 ml). The mixture was stirred at -60°C for 1 hour and warmed up to ambient temperature. To the mixture was added tetrakis(triphenylphosphine)palladium (903 mg) and (2,6-dichloropyrimidine-4-yl)dimethylamine in THF (60 ml) and the mixture was stirred at the boiling point under reflux for 5 days. To the mixture was added saturated aqueous NH4Cl and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (silica gel, 17% to 33% EtOAc in hexane) to give (2-chloro-6-ethylpyrimidine-4-yl)dimethylamine (352 mg) and (6-chloro-2-ethylpyrimidine-4-yl)dimethylamine (622 mg).

(2-chloro-6-ethylpyrimidine-4-yl)dimethylamine:

ESI MS m/e 208, M(free)+Na+;1H NMR (300 MHz, CDCl3) δ 1,25 (t, J=7,6 Hz, 3H), 2,54-of 2.66 (m, 2H), 3,11 (s, 6H), x 6.15 (s, 1H).

(6-chloro-2-ethylpyrimidine-4-yl)dimethylamine:

ESI MS m/e 186, M+H+;1H NMR (300 MHz, CDCl3) δ of 1.29 (t, J=7,6 Hz, 3H), 2,74 (sq, J=7.7 Hz, 2H), 3,10 (s, 6H), 6,24 (s, 1H).

Stage C: Synthesis of hydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-ethylpyrimidine-4-yl]amine is}cyclohexyl)-3,4-differentated.

Specified in the title compound was obtained using the methodology of stage C of example 5.

ESI MS m/e 404, M(free)+H+;1H NMR (300 MHz, CDCl3) δ of 1.37 (t, J=7.5 Hz, 3H), 1,64-2,03 (m, 8H), was 2.76 (sq, J=7.5 Hz, 2H), 2,97-of 3.42 (m, 6H), 3,65-of 3.80 (m, 1H), was 4.02-is 4.21 (m, 1H), 5,14 (s, 1H), 6.42 per of 6.66 (m, 1H), 7,12-7,27 (m, 1H), 7,45-of 7.60 (m, 1H), 7,65-7,81 (m, 1H), 8,60-8,73 (m, 1H), 13,61-13,77 (m, 1H).

Example 33

HydrochlorideN-(CIS-4-{[2,6-bis(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-3,4-differentated

Stage A: Synthesis of 6-chloro-N,N,N',N'tetramethylpiperidine-2,4-diamine.

To a suspension of (2,6-dichloropyrimidine-4-yl)amine, obtained in stage A of example 32 (1.60 g)in IPA (2 ml) was added 50% aqueous Me2NH (789 mg). The mixture is stirred at the boiling point under reflux for 3.5 hours in a sealed tube. The mixture was poured into saturated aqueous NaHCO3and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (silica gel, 20% EtOAc in hexane) to give 2-chloro-N,N,N',N'tetramethylpiperidine-4,6-diamine (203 mg) and 6-chloro-N,N,N',N'tetramethylpiperidine-2,4-diamine (1,43 g).

2-chloro-N,N,N',N'tetramethylpiperidine-4,6-diamine:

ESI MS m/e 201, M(free+H +;1H NMR (300 MHz, CDCl3) δ 3,05 (s, 12H), of 5.15 (s, 1H).

6-chloro-N,N,N',N'tetramethylpiperidine-2,4-diamine:

ESI MS m/e 201 M+H+;1H NMR (300 MHz, CDCl3) δ 3.04 from (s, 6H), of 3.13 (s, 6H), USD 5.76 (s, 1H).

Stage B: Synthesis of hydrochlorideN-(CIS-4-{[2,6-bis(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-3,4-differentated.

Specified in the title compound was obtained using the methodology of stage C of example 5.

ESI MS m/e 419, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,58-of 2.16 (m, 8H), 2,97 is-3.45 (m, 12H), 3,62-3,74 (m, 1H), 4,03-is 4.21 (m, 1H), 4,81 (s, 1H), 6,76-of 6.90 (m, 1H), 7,13-7,26 (m, 1H), 7,55-to 7.64 (m, 1H), 7,70-7,79 (m, 1H), 8,57-to 8.70 (m, 1H), up 11,86-11,94 (m, 1H).

Example 34

HydrochlorideN-(CIS-4-{[2-(ethylamino)pyrimidine-4-yl]amino}cyclohexyl)-3,4-differentated

Stage A: Synthesis of (4-chloropyrimidine-2-yl)ethylamine.

To a solution of 2,4-dichloropyrimidine (of 5.00 g) in THF (50 ml) was added 70% aqueous EtNH2(of 5.40 g). The mixture was stirred at ambient temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in CHCl3and the solution was poured into saturated aqueous NaHCO3. Separated the two layers and the aqueous layer was extracted with CHCl3(twice). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure, and purified flash chromatography (silica gel, 17% to 50% EtOAc in hexa is e) to obtain (2-chloropyrimidine-4-yl)ethylamine (3,69 g) and (4-chloropyrimidine-2-yl)ethylamine (1.28 g).

(2-chloropyrimidine-4-yl)ethylamine:

ESI MS m/e 157, M+;1H NMR (500 MHz, CDCl3) δ of 1.26 (t, J=7,3 Hz, 3H), 3,16-3,62 (m, 2H), 4.80 to 5,95 (m, 1H), 6,23 (d, J=5.8 Hz, 1H), 8,02 is 8.22 (m, 1H).

(4-chloropyrimidine-2-yl)ethylamine:

CI MS m/e 158, M+H+;1H NMR (500 MHz, CDCl3) δ of 1.23 (t, J=7.5 Hz, 3H), 3,42-to 3.49 (m, 2H), and 5.30-5,62 (m, 1H), is 6.54 (d, J=5,2 Hz, 1H), 8,02 is 8.22 (m, 1H).

Stage B: Synthesis of hydrochlorideN-(CIS-4-{[2-(ethylamino)pyrimidine-4-yl]amino}cyclohexyl)-3,4-differentated.

Specified in the title compound was obtained using the methodology of stage C of example 5.

ESI MS m/e 376, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,22 (t, J=7,1 Hz, 3H), 1.61 of (s, 8H), 3,31 of 3.56 (m, 2H), 4,05-4,47 (m, 2H), of 6.31-6,56 (m, 1H), 6.75 in-to 6.95 (m, 1H), 7,07-7,34 (m, 2H), of 7.48-7,87 (m, 3H), 8,01-8,24 (m, 1H), KZT 12.39-to 12.52 (m, 1H).

Example 35

HydrochlorideN-[CIS-4-({2-[ethyl(methyl)amino]pyrimidine-4-yl}amino)cyclohexyl]-3,4-differentated

Stage A: Synthesis of (4-chloropyrimidine-2-yl)ethylmethylamine.

To a solution of 2,4-dichloropyrimidine (of 5.00 g) in THF (50 ml) was added ethylmethylamine (2,08 g). The mixture was stirred at ambient temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in CHCl3and the solution was poured into saturated aqueous NaHCO3. Separated the two layers and the aqueous layer was extracted with CHCl3(twice). The combined organic layer was dried over MgSO4that was filtered, koncentrira is whether under reduced pressure, and purified flash chromatography (silica gel, from 17% to 50% EtOAc in hexane) to give (2-chloropyrimidine-4-yl)ethylmethylamine (4,49 g) and (4-chloropyrimidine-2-yl)ethylmethylamine (0,91 g).

(2-chloropyrimidine-4-yl)ethylmethylamine:

CI MS m/e 172, M(free)+H+;1H NMR (500 MHz, CDCl3) δ of 1.18 (t, J=3.0 Hz, 3H), 3,06 (users, 3H), 3,35-3,70 (m, 2H), 6,29 (d, J=4,8 Hz, 1H), to 7.99(d, J=6,1 Hz, 1H).

(4-chloropyrimidine-2-yl)ethylmethylamine:

CI MS m/e 172 M+H+;1H NMR (500 MHz, CDCl3) δ of 1.17 (t, J=3.0 Hz, 3H), 3,10 (s, 3H), 3,66 (sq, J=7,0 Hz, 2H), 6,45 (d, J=5.0 Hz, 1H), 8,14 (d, J=5.0 Hz, 1H).

Stage B: Synthesis of hydrochlorideN-[CIS-4-({2-[ethyl(methyl)amino]pyrimidine-4-yl}amino)cyclohexyl]-3,4-differentated.

Specified in the title compound was obtained using the methodology of stage C of example 5.

ESI MS m/e 390, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,11-of 1.29 (m, 3H), 1,63-of 2.20 (m, 8H), 3,23 (users, 3H), 3,61 is 3.76 (m, 2H), 4,06 was 4.42 (m, 2H), 6,53 of 6.68 (m, 1H), 6,88-7,24 (m, 2H), 7,39-7,52 (m, 1H), to 7.59-7,86 (m, 2H), 8,39-8,54 (m, 1H), of 12.26-to 12.44 (m, 1H).

Example 36

Hydrochloride 3,4-debtor-N-[CIS-4-({2-[(2-hydroxyethyl)(methyl)amino]pyrimidine-4-yl}amino)cyclohexyl]benzamide

Stage A: Synthesis of 2-[(4-chloropyrimidine-2-yl)methylamino]ethanol.

To a solution of 2,4-dichloropyrimidine (of 5.00 g) in THF (50 ml) was added 2-methylaminoethanol (2.65 g). The mixture was stirred at ambient temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in CHCl3the solution was poured into saturated aqueous NaHCO 3. Separated the two layers and the aqueous layer was extracted with CHCl3(twice). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure, and purified flash chromatography (silica gel, 17% to 50% EtOAc in hexane) to give 2-[(2-chloropyrimidine-4-yl)methylamino]ethanol (3.50 g) and 2-[(4-chloropyrimidine-2-yl)methylamino]ethanol (827 mg).

2-[(2-chloropyrimidine-4-yl)methylamino]ethanol:

ESI MS m/e 188, M(free)+H+;1H NMR (500 MHz, CDCl3) δ 2.91 in (users, 3H), of 3.13 (s, 3H), 3,64-to 3.92 (m, 4H), 6,46-of 6.49 (m, 1H), to 7.99 (d, J=6,1 Hz, 1H).

2-[(4-chloropyrimidine-2-yl)methylamino]ethanol:

ESI MS m/e 210, M+Na+;1H NMR (500 MHz, CDCl3) δ of 3.23 (s, 3H), 3,76-to 3.92 (m, 4H), of 6.52 (d, J=5,2 Hz, 1H), 8,12 (d, J=4,6 Hz, 1H).

Stage B: Synthesis of hydrochloride 3,4-debtor-N-[CIS-4-({2-[(2-hydroxyethyl)(methyl)amino]pyrimidine-4-yl}amino)cyclohexyl]benzamide.

Specified in the title compound was obtained using the methodology of stage C of example 5.

ESI MS m/e 406, M(free)+H+;1H NMR (300 MHz, DMSO-d6) δ 1,59 is 1.96 (m, 8H), and 3.16 (s, 3H) 3,57-3,71 (m, 2H), 3,80-4,07 (m, 3H), 4,20-4,30 (m, 1H), 6,20-6,34 (m, 1H), 7,49-7,80 (m, 3H), 7,88-to 7.99 (m, 1H), 8,31-to 8.40 (m, 1H), 8,64-8,79 (m, 1H).

Example 37

The hydrochloride of 3-chloro-4-fluoro-N{CIS-4-[(2-methyl-6-piperidine-1-Yeremey-4-yl)amino]cyclohexyl}benzamide

To a solution of 4,6-dichloro-2-methylpyrimidine obtained in stage A of example 5 (3.00 g)in THF (3 ml) was added N-(CIS-4-aminocyclohexane)-3-chloro-4-perbenzoic obtained in stage A of example 31 (5,98 g), and iPrNEt2(of 3.85 ml). The mixture is stirred at the boiling point under reflux for 60 hours and was poured into saturated aqueous NaHCO3.The aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, 20% EtOAc in hexane) to give 3-chloro-N-[CIS-4-(6-chloro-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-fermentated (6,34 g). To the solution obtained above solid (250 mg) in BuOH (1 ml) was added piperidine (80 mg) and iPrNEt2(121 mg). The mixture was heated in a microwave synthesizer at 220°C for 10 min and 230°C for 20 min and poured into saturated aqueous NaHCO3.The aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, 20% EtOAc in hexane) to give 3-chloro-4-fluoro-N{CIS-4-[(2-methyl-6-piperidine-1-Yeremey-4-yl)amino]cyclohexyl}benzamide. To the solution obtained above substances in EtOAc (10 ml) was added 4M hydrogen chloride in EtOAc (0.2 ml). The mixture was stirred at the temperature of environment the environment for 1 hour and concentrated under reduced pressure. A suspension of the residue in Et2O (12 ml) was stirred at ambient temperature for 2 hours. The precipitate was collected by filtration, washed with Et2O and dried at 70°C under reduced pressure to obtain hydrochloride of 3-chloro-4-fluoro-N{CIS-4-[(2-methyl-6-piperidine-1-Yeremey-4-yl)amino]cyclohexyl}benzamide (6 mg).

ESI MS m/e 446, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,28 is 2.10 (m, 14H), to 2.46 (s, 3H), 2,92-3,11 (m, 1H), 3.27 to the 3.89 (m, 4H), 4,00-is 4.21 (m, 1H), 5,16-5,31 (m, 1H), 6,69-to 6.88 (m, 1H), 7,13-7,27 (m, 1H), 7,60-8,03 (m, 2H), 8,40-8,55 (m, 1H).

Example 38

The dihydrochloride of 3-chloro-4-fluoro-N-(CIS-4-{[6-(1H-imidazol-1-yl)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide

Specified in the title compound was obtained using the methodology of stage A of example 37.

ESI MS m/e 451, M(free)+Na+;1H NMR (300 MHz, CDCl3) δ 1,69-of 2.21 (m, 8H), 2,56-2,87 (m, 3H), 4.04 the-4,58 (m, 2H), 6,41-6,70 (m, 1H), 7,10-7,25 (m, 1H), 7,42-7,51 (m, 1H), 7,58-7,80 (m, 1H), 7,84 is 8.22 (m, 3H).

Example 39

The hydrochloride of 3-chloro-4-fluoro-N-{CIS-4-[(2-methyl-6-morpholine-4-Yeremey-4-yl)amino]cyclohexyl}benzamide

Specified in the title compound was obtained using the methodology of stage A of example 37.

ESI MS m/e 470, M(free)+Na+;1H NMR (300 MHz, CDCl3) δ 1,65-2,02 (m, 8H), 2.49 USD (s, 3H), to 3.58-to 3.92 (m, 9H), a 4.03-4,22 (m, 1H), 5.25 in (s, 1H), 6,51-6,62 (m, 1H), 7,18 (t, J=8.5 Hz, 1H), to 7.67-7,74 (m, 1H), to $ 7.91-of 7.96 (m, 1H), 8,63 is 8.75 (m, 1H).

Example 40

<> The hydrochloride of 3-chloro-4-fluoro-N-{CIS-4-[(2-methyl-6-pyrrolidin-1-Yeremey-4-yl)amino]cyclohexyl}benzamide

Specified in the title compound was obtained using the methodology of stage A of example 37.

ESI MS m/e 432, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1.41 to 2,24 (m, 12H), 2,48 (s, 3H), 3,09 of 3.56 (m, 3H), 3,60-of 3.78 (m, 2H), 3,99-4,18 (m, 1H), 5,02 (s, 1H), 6,52 of 6.66 (m, 1H), 7,18 (t, J=8.6 Hz, 1H), 7,63-to 7.77 (m, 1H), 7,88-to 7.99 (m, 1H), 8,40-8,55 (m, 1H).

Example 41

The dihydrochloride of 3-chloro-4-fluoro-N-(CIS-4-{[2-methyl-6-(4-methylpiperazin-1-yl)pyrimidine-4-yl]amino}cyclohexyl)benzamide

Specified in the title compound was obtained using the methodology of stage A of example 37.

ESI MS m/e 461, M(free)+H+;1H NMR (300 MHz, DMSO-d6) δ 1,63-of 1.88 (m, 8H), 2,37 is 2.46 (m, 3H), 2,73-and 2.83 (m, 3H), 2,97 is 3.15 (m, 2H), 3,24-3,62 (m, 6H), 3,78-4,01 (m, 2H), of 5.99 (s, 1H), 7,52 (t, J=8,9 Hz, 1H), 7,81-of 7.97 (m, 1H), 8,04-8,16 (m, 2H), 8,40-8,54 (m, 1H).

Example 42

The dihydrochlorideN4-(CIS-4-{[4-bromo-2-(triptoreline)benzyl]amino}cyclohexyl)-N2,N2-dimethylpyrimidin-2,4-diamine

Stage A: Synthesis of (4-chloropyrimidine-2-yl)dimethylamine.

To a solution of 2,4-dichloropyrimidine (15.0 g) in THF (150 ml) was added 50% aqueous

Me2NH (22,7 g). The mixture was stirred at ambient temperature for 2 hours and poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3(three is Aza). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure, and purified flash chromatography (NH-silica, 20% EtOAc in hexane) to give (2-chloropyrimidine-4-yl)dimethylamine (8,66 g) and (4-chloropyrimidine-2-yl)amine (0.87 g).

(2-chloropyrimidine-4-yl)dimethylamine:

CI MS m/e 158, M+H+;1H NMR (300 MHz, CDCl3) δ of 3.12 (s, 6H), 6,32 (d, J=6,1 Hz, 1H), 8,00 (d, J=6,1 Hz, 1H).

(4-chloropyrimidine-2-yl)dimethylamine:

ESI MS m/e 157, M+;1H NMR (300 MHz, CDCl3) δ is 3.21 (s, 6H), of 6.50 (d, J=5,1 Hz, 1H), 8,18 (d, J=5,1 Hz, 1H).

Stage B: Synthesis dihydrochlorideN4-(CIS-4-{[4-bromo-2-(triptoreline)benzyl]amino}cyclohexyl)-N2,N2-dimethylpyrimidin-2,4-diamine.

The mixture ofN-(CIS-4-bromo-2-cryptomaterial)cyclohexane-1,4-diamine obtained in stage B of example 1 (466 mg), (4-chloropyrimidine-2-yl)dimethylamine (200 mg) and BuOH (1 ml) was stirred at the boiling point under reflux for 13 hours. The mixture was poured into saturated aqueous NaHCO3and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure, and purified flash chromatography (NH-silica gel, 20% EtOAc in hexane) to give theN4-(CIS-4-{[4-bromo-2-(triptoreline)benzyl]amino}cyclohe the forces)- N2,N2-dimethylpyrimidin-2,4-diamine. To the solution obtained above substances in EtOAc (2 ml) was added 4M hydrogen chloride in EtOAc (10 ml). The mixture was stirred at ambient temperature for 1 hour and concentrated under reduced pressure. The residue is suspended in Et2O (20 ml) and the suspension was stirred at ambient temperature for 4 hours. The precipitate was collected by filtration, washed with Et2O and dried under reduced pressure to obtain dihydrochlorideN4-(CIS-4-{[4-bromo-2-(triptoreline)benzyl]amino}cyclohexyl)-N2,N2-dimethylpyrimidin-2,4-diamine (294 mg).

ESI MS m/e 488, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,42-to 1.67 (m, 2H), 2,03-2,39 (m, 6H), 2,79-to 3.38 (m, 7H), 4,13 is 4.36 (m, 3H), 6.89 in-7,00 (m, 1H), 7,42-7,46 (m, 1H), 7,50-EUR 7.57 (m, 1H), of 7.90 shed 8.01 (m, 1H), 8,12 (d, J=8,4 Hz, 1H), 8,90-9,00 (m, 1H), 9,98-10,18 (m, 2H), 12,21-12,37 (m, 1H).

Example 43

HydrochlorideN-(CIS-4-{[2-(dimethylamino)-6-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4-differentated

Stage A: Synthesis of (4-chloro-6-methylpyrimidin-2-yl)dimethylamine.

To a solution of 2,4-dichloro-6-methylpyrimidine (20,0 g) in THF (200 ml) was added 50% aqueous Me2NH (13.3 g) and the mixture was stirred at ambient temperature for 24 hours. To the mixture was added saturated aqueous NaHCO3and the aqueous layer was extracted with CHCl3(three times). United'or is anceschi layer was dried over MgSO 4was filtered , concentrated under reduced pressure, and purified flash chromatography (NH-silica gel, 5% to 16% EtOAc in hexane) to give (2-chloro-6-methylpyrimidin-4-yl)dimethylamine (14.4 g) and (4-chloro-6-methylpyrimidin-2-yl)dimethylamine (6,57 g).

(2-chloro-6-methylpyrimidin-4-yl)dimethylamine:

ESI MS m/e 194, M++Na+;1H NMR (300 MHz, CDCl3) δ of 2.34 (s, 3H), 3,10 (s, 6H), 6,16 (s, 1H).

(4-chloro-6-methylpyrimidin-2-yl)dimethylamine:

CI MS m/e 172 M+H+;1H NMR (300 MHz, CDCl3) δ to 2.29 (s, 3H), and 3.16 (s, 6H), 6,34 (s, 1H).

Stage B: Synthesis of hydrochlorideN-(CIS-4-{[2-(dimethylamino)-6-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4-differentated.

To a solution ofN-(CIS-4-aminocyclohexanol)-3,4-differentated (652 mg) in BuOH (1 ml) was added (4-chloro-6-methylpyrimidin-2-yl)dimethylamine (400 mg). The mixture is stirred at the boiling point under reflux for 8 days. To the mixture was added saturated aqueous NaHCO3and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, 10% to 20% EtOAc in hexane) to give theN-(CIS-4-{[2-(dimethylamino)-6-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4-differentated. To the solution obtained above substances in EtOAc (5 m is) was added 4M hydrogen chloride in EtOAc (10 ml). The mixture was stirred at ambient temperature for 1 hour and concentrated under reduced pressure. A suspension of the residue in Et2O (20 ml) was stirred at ambient temperature for 4 hours. The precipitate was collected by filtration, washed with Et2O and dried at 80°C under reduced pressure to obtain hydrochlorideN-(CIS-4-{[2-(dimethylamino)-6-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4-differentated (507 mg).

1H NMR (300 MHz, CDCl3) δ 1,62-of 2.21 (m, 8H), 2,39 (s, 3H), 3.15 and is-3.45 (m, 6H), 4.09 to 4,43 (m, 2H), 6,28-6,37 (m, 1H), 7,06-7,24 (m, 1H), to 7.61-7,87 (m, 2H), 8,24-of 8.37 (m, 1H), 11,55-11,67 (m, 1H).

Example 44

The hydrochloride of 3-chloro-N-(CIS-4-{[2-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-4-fermentated

Specified in the title compound was obtained using the methodology of stage B of example 31.

ESI MS m/e 392, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,58-of 2.20 (m, 8H), of 3.07 (s, 6H), a 4.03-4,48 (m, 2H), 6,52-of 6.73 (m, 1H), 6,95-to 6.95 (m, 2H), was 7.36-7,51 (m, 1H), 7,72-a 7.85 (m, 1H), 7,94-with 8.05 (m, 1H), 8,50-8,69 (m, 1H), 12,20-12,41 (m, 1H).

Example 45

The hydrochloride of 3-chloro-N-(CIS-4-{[2-(dimethylamino)-6-methylpyrimidin-4-yl]amino}cyclohexyl)-4-fermentated

Specified in the title compound was obtained using the methodology of stage B of example 31.

ESI MS m/e 406, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1.56 to 2,22 (m, 11H), 3,05 is-3.45 (m, 6H), 4,07 was 4.42 (m, 2H), 6,25-6,40 (m, 1H), 7.03 is-7,26 (m, 2H), ,73-8,07 (m, 2H), 8.30 to-8,44 (m, 1H), 11,51-11,64 (m, 1H).

Example 46

The hydrochloride of 3-chloro-N-(CIS-4-{[2-(dimethylamino)-5-methylpyrimidin-4-yl]amino}cyclohexyl)-4-fermentated

Stage A: Synthesis of 4-chloro-2-dimethylamino-5-methylpyrimidine.

To a solution of 2,4-dichloro-5-methylpyrimidine (20,0 g) in THF (200 ml) was added 50% aqueous Me2NH (13.3 g). The mixture was stirred at ambient temperature for 5 hours and concentrated under reduced pressure. The residue was poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure, and purified flash chromatography (NH-silica gel, 2% EtOAc in hexane) to give 2-chloro-4-dimethylamino-5-methylpyrimidine (19.9 g) and 4-chloro-2-dimethylamino-5-methylpyrimidine (1,53 g).

2-chloro-4-dimethylamino-5-methylpyrimidin:

ESI MS m/e 172 M+H+;1H NMR (300 MHz, CDCl3) δ, and 2.27 (s, 3H), 3.15 in (s, 6H), of 7.82 (s, 1H).

4-chloro-2-dimethylamino-5-methylpyrimidin:

ESI MS m/e 194, M+Na+;1H NMR (300 MHz, CDCl3) δ and 2.14 (s, 3H), 3.15 in (s, 6H), of 8.06 (s, 1H).

Stage B: Synthesis of hydrochloride of 3-chloro-N-(CIS-4-{[2-(dimethylamino)-5-methylpyrimidin-4-yl]amino}cyclohexyl)-4-fermentated.

Specified in the title compound was obtained using the methodology of stage B of example 31.

ESI MS m/e 406, M(free)+H+/sup> ;1H NMR (300 MHz, DMSO-d6) δ 1.56 to 2,02 (m, 8H), 2,04 (s, 3H), and 3.16 (s, 6H), 3,90-4,18 (m, 2H), 7,47-7,66 (m, 3H), to $ 7.91-of 8.00 (m, 1H), 8,13-8,21 (m, 1H), 8,28-at 8.36 (m, 1H), KZT 12.39-12,48 (m, 1H).

Example 47

The hydrochloride of 3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-(trifluoromethyl)pyrimidine-4-yl]amino}cyclohexyl)-4-fermentated

Stage A: Synthesis of 2-cryptomaterial-4,6-diol.

To a suspension of 60% NaH in oil (11.7 g) in toluene (98 ml) was added BuOH (21.8 g). The mixture was stirred at ambient temperature for 16 hours. To the mixture was added malonamide (10.0 g) and ethyl ether triperoxonane acid (13,9 g). The mixture was stirred at 100°C for 3.5 hours and ambient temperature for 16 hours. The organic layer was extracted with water (twice) and the aqueous layer was filtered through activated charcoal. To the aqueous layer was added concentrated HCl (pH 1) and the suspension was stirred at 4°C for 2 hours. The precipitate was collected by filtration and dried at 80°C under reduced pressure to obtain 2-cryptomaterial-4,6-diol (3.25 g).

ESI MS m/e 178, M-H+;1H NMR (300 MHz, CDCl3) δ 6,00 (s, 1H), 12,48 (users, 2H).

Stage B: Synthesis of (6-chloro-2-cryptomaterial-4-yl)dimethylamine.

To a suspension of 2-cryptomaterial-4,6-diol (3.25 g) in POCl3(7,89 ml) was added Et3N (5,00 ml). The mixture was stirred at 120°C for 3 hours, cooled to ambient temperature the Reda and poured into ice-cold water. The aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to obtain 4,6-dichloro-2-cryptomaterial. To the solution obtained above substances (1,00 g) in THF (10 ml) was added iPr2NEt (0,98 ml) and 50% aqueous Me2NH (0,48 ml). The mixture was stirred at ambient temperature for 60 hours. To the solution was added saturated aqueous NaHCO3and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (silica gel, 5%→25% EtOAc in hexane) to give (6-chloro-2-cryptomaterial-4-yl)dimethylamine (728 mg).

ESI MS m/e 225 M+;1H NMR (300 MHz, CDCl3) δ 2.77-to 3,61 (m, 6H), of 6.50 (s, 1H).

Stage C: Synthesis of hydrochloride of 3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-(trifluoromethyl)pyrimidine-4-yl]amino}cyclohexyl)-4-fermentated.

Specified in the title compound was obtained using the methodology of stage B of example 31.

ESI MS m/e 482, M(free)+H+;1H NMR (300 MHz, CDCl3) δ 1,66-of 2.08 (m, 8H), 3,20 (s, 6H), 3,68-a 3.83 (m, 1H), 4.04 the-is 4.21 (m, 1H), and 5.30 (s, 1H), 6,34-6,46 (m, 1H), 7,18 (t, J=8.5 Hz, 1H), 7,63-7,73 (m, 2H), 7,87-to 7.93 (m, 1H).

Example 48

Triptorelin [CIS-4-(6-dimethylamino-2-methylpyrimidin-ylamino)cyclohexyl]amide 5-bromofuran-2-carboxylic acid

Stage A: Synthesis oftert-butyl ether [CIS-4-(6-chloro-2-methylpyrimidin-4-ylamino)cyclohexyl]carbamino acid.

To a solution of 4,6-dichloro-2-methylpyrimidine (4,87 g, being 0.030 mol) in 50 ml MeOH was added DIEA (10.4 ml, 0,059 mol) andCIS-tert-butyl ether (4-aminocyclohexane)carbamino acid (6.4 g, being 0.030 mol). The mixture is stirred at the boiling point under reflux overnight and the solution was concentrated. The resulting oil was subjected to chromatography (0-70% ethyl acetate in hexane) to give thetert-butyl ether [CIS-4-(6-chloro-2-methylpyrimidin-4-ylamino)cyclohexyl]carbamino acid (9.7 g, 0,028 mol, 95%) as a white solid.

ESI MS (M+H)+;1H NMR (400 MHz, CD3OD) δ 6,38 (s, 1H), 4,14 (m, 1H), of 3.56 (m, 1H), 2.40 a (s, 3H), 1,78-to 1.63 (m, 8H), of 1.47 (s, 9H).

Stage B: Synthesis oftert-butyl ether [CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]carbamino acid.

To a solution oftert-butyl ether [CIS-4-(6-chloro-2-methylpyrimidin-4-ylamino)cyclohexyl]carbamino acid (0.5 g, 0,0015 mol) in 2 ml of 2-propanol was added dimethylamine (2.20 ml, 0,0044 mol) and DIEA (511 μl, 0,0029 mol). The mixture was heated in a microwave synthesizer at 160°C for 2 hours. The reaction was repeated 17 times (9 g total solids) and the reaction mixture is combined. The solvent is evaporated and the substance, for example, the Ali chromatography (2-4% 2M NH 3in MeOH/CH2Cl2with gettingtert-butyl ether [CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]carbamino acid (7.5 g, 0,021 mol, 81%) as a white solid.

ESI MS 350,4 (M+H)+;1H NMR (400 MHz, CD3OD) δ to 5.35 (s, 1H), and 3.72 (m, 1H), 3,54 (m, 1H), 3,05 (s, 6H), is 2.30 (s, 3H), 1,75-to 1.61 (m, 8H), of 1.47 (s, 9H).

Stage C: the Synthesis ofN-(CIS-4-aminocyclohexane)-2,N',N'trimethylpyridine-4,6-diamine.

To a solution oftert-butyl ether [CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]carbamino acid (7.5 g, 0,021 mol) in 50 ml of CH2Cl2added TFOC (3,3 ml 0,043 mol). The solution was stirred at room temperature for 4 hours (or until the reaction is completed according to TLC). The excess solvent is evaporated and the oil obtained was dissolved in 30 ml of CH2Cl2. The organic layer was extracted with 30 ml of the diluted NaOH solution (aq.)/NaHCO3(water) (maintaining the basicity of the aqueous layer during the extraction was confirmed using paper pH indicator). The aqueous layer was twice subjected to back extraction with the use of CH2Cl2and the organic layers were combined, dried over MgSO4and concentrated to obtainN-(CIS-4-aminocyclohexane)-2,N',N'trimethylpyridine-4,6-diamine (5.3g, 0,021 mol, 99%) as white is solid substances.

ESI MS 250,2 (M+H)+;1H NMR (400 MHz, CD3OD) δ lower than the 5.37 (s, 1H), 3,78 (m, 1H), 3,06 (s, 6H), 2,84 (m, 1H), 2,30 (s, 3H), 1,82 was 1.69 (m, 6H), 1,55 of 1.50 (m, 2H).

Stage D: Synthesis of triptoreline [CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]amide 5-bromofuran-2-carboxylic acid.

To a solution ofN-(CIS-4-aminocyclohexane)-2,N',N'trimethylpyridine-4,6-diamine (30 mg, 0.12 mmol) in 0.5 ml DMF was added 5-bromo-2-frankenboob acid (23 mg, 0.12 mmol), pyridine (14,6 μl, 0.18 mmol) and HATU (54.9 mg, 0.14 mmol). The reaction mixture was stirred over night and then to the mixture was added 0.5 ml of DMSO. Then the connection was subjected to preparative purification IHMS with getting trifenatate [CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]amide 5-bromofuran-2-carboxylic acid (25 mg, 0,047 mmol, 39%) as a white solid salt TFUCK.

ESI MS 422,2 (M+H)+;1H NMR (400 MHz, CD3OD) δ to 7.15 (d, 1H, J=3.6 Hz), only 6.64 (d, 1H, J=3.6 Hz), the ceiling of 5.60 (s, 1H), 4,01 (m, 1H), a 3.87 (m, 1H), and 3.16 (s, 6H), 2.49 USD (s, 3H), 1,89 and 1.80 (m, 8H).

Example 49

Triptorelin 5-bromo-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]nicotinamide

Specified in the title compound as a white solid substance was obtained using the methodology of stage D of example 48 (35 mg, 53%).

ESI MS 433,0 (M+H)+;1H NMR (400 MHz, CD3OD) δ of 8.95 (d, 1H, J=1.6 Hz), 8,84 (d, 1H, J=2.0 Hz), 8,58 (m, 1H), 8,43 (t, 1H, J=2 Hz), the ceiling of 5.60 (s, 1H), of 4.05 (m, 1H), 3,88 (m, 1H), up 3.22 (s, 6H), 2.49 USD (s, 3H), 1.93 and-of 1.84 (m, 8H).

Example 50

TriptorelinN-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-bis-cryptomelane

To a solution ofN-(CIS-4-aminocyclohexane)-2,N',N'trimethylpyridine-4,6-diamine (30 mg, 0.12 mmol) in 0.5 ml DMF was added pyridine (14,6 μl, 0.18 mmol) and 3,5-bis(trifluoromethyl)benzoyl chloride (21,8 μl, 0.12 mmol). The reaction mixture was stirred over night and then to the mixture was added 0.5 ml of DMSO. The compound was subjected to preparative purification IHMS with getting trifenatateN-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-bitreversed (12 mg, at 0.020 mmol, 17%) as a white solid salt TFUCK.

ESI MS 490,4 (M+H)+;1H NMR (400 MHz, CD3OD) δ 8,46 (s, 2H), 8,19 (s, 1H), 5,42 (s, 1H), 4,06 (m, 1H), 3,86 (m, 1H), 3,09 (s, 6H), was 2.34 (s, 3H), 1.93 and-to 1.79 (m, 9H).

Example 51

TriptorelinN-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-differentated

Specified in the title compound as a white solid substance was obtained using the methodology of stage A of example 50 (22 mg, 0,044 mmol, 36%).

ESI MS 390,2 (M+H)+;1H NMR (400 MHz, CD3OD) δ 7,50-7,46 (m, 2H), 7,22-7,16 (m, 1H), ceiling of 5.60 (s, 1H), was 4.02 (m, 1H), a 3.87 (m, 1H), up 3.22 (s, 6H), 2.49 USD (s, 3H), 1,90-of 1.81 (m, 8H).

Example 52

BestrefiratecomN-[CIS-4-(3,5-DiMeo is dibenzylamino)cyclohexyl]-2, N',N'trimethylpyridine-4,6-diamine

To a solution ofN-(CIS-4-aminocyclohexane)-2,N',N'trimethylpyridine-4,6-diamine (24,9 mg, 0.1 mmol) in 0.5 ml of MeOH was added 3,5-dimethoxybenzaldehyde (16.6 mg, 0.1 mmol). The mixture was stirred at room temperature for half an hour and then was added triacetoxyborohydride sodium (84,8 mg, 0.4 mmol). The mixture was stirred at room temperature over night and then to the mixture was added 0.5 ml of DMSO. The compound was subjected to preparative purification IHMS with getting bestreferat.ruN-[CIS-4-(3,5-dimethoxyphenethylamine)cyclohexyl]-2,N',N'trimethylpyridine-4,6-diamine (27 mg, 0,043 mmol, 43%) as a white solid salt TFUCK.

ESI MS 400,5 (M+H)+;1H NMR (400 MHz, CD3OD) δ 6,72 (d, 2H, J=2.0 Hz), 6,59 (t, 1H, J=2.0 Hz), 5,59 (s, 1H), 4,22 (s, 2H), 3,97 (m, 1H), 3,84 (m, 1H), 3,79 (s, 6H), up 3.22 (s, 6H), 2,48 (s, 3H), 2,11-2,02 (m, 4H), 1,95-of 1.81 (m, 4H).

Example 53

BestrefiratecomN-[CIS-4-(3-bromobenzylamine)cyclohexyl]-2,N',N'trimethylpyridine-4,6-diamine

Specified in the title compound as a white solid substance was obtained using the methodology of stage A of example 52 (35 mg, 0,054 mmol, 54%).

ESI MS 418,0 (M+H)+;1H NMR (400 MHz, CD3OD) δ for 7.78 (s, 1H), 7,68 (d, 1H, J=8.0 Hz), 7,55 (d, 1H, 7,6 Hz), the 7.43 (t, 1H, J=8.0 Hz), the ceiling of 5.60 (s, 1H), 4,29 (s, 2H), 3,21 (s, 6H), 2,48 (s, 3H), 2,12-2,03 (m, 4H), 1,95-of 1.85 (m, 4H).

Example 54

Triforce is at 1-[ CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-(3-methoxyphenyl)urea

To a solution ofN-(CIS-4-aminocyclohexane)-2,N',N'trimethylpyridine-4,6-diamine (24,9 mg, 0.1 mmol) in 0.5 ml of DMSO was added 3-methoxyphenylalanine (11,8 μl, 0.09 mmol). The mixture was stirred at room temperature over night and then to the mixture was added 0.5 ml of DMSO. The compound was subjected to preparative purification IHMS with getting trifenatate 1-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-(3-methoxyphenyl)urea (19 mg, 0,037 mmol, 41%) as a white solid salt TFUCK.

ESI MS 399,2 (M+H)+;1H NMR (400 MHz, CD3OD) δ to 7.15 (s, 1H), 7,14 (t, 1H, J=2,4 Hz), 6,86 (DD, 1H, J1=8.0 Hz, J2=2,0Hz), to 6.57 (DD, 1H, J1=8.0 Hz, J2=2,4 Hz), to 5.57 (s, 1H), 3,84 (m, 1H), 3,79 (s, 3H), of 3.78 (m, 1H), 3,21 (s, 6H), 2,47 (s, 3H), 1,90 is 1.75 (m, 8H).

Example 55

Triptorelin 1-(3,5-differenl)-3-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]urea

Specified in the title compound as a white solid substance was obtained using the methodology of stage A of example 54 (22 mg, 0,043 mmol, 47%).

ESI MS 405,4 (M+H)+;1H NMR (400 MHz, CD3OD) δ 7,07? 7.04 baby mortality (m, 2H), 6,54-6,50 (m, 1H), ceiling of 5.60 (s, 1H), 3,83 (m, 1H), 3,82 (m, 1H), 3,18 (s, 6H), 2,48 (s, 3H), 1,90 of-1.83 (m, 4H), 1,79 is 1.75 (m, 4H).

Example 56

TriptorelinN-[CIS-4-(6-dimethylamino-2-methylsulfonylamino-4 and the amino)cyclohexyl]-3,4-differentated

Stage A: Synthesis oftert-butyl etherCIS-[4-(3,4-differentiating)cyclohexyl]carbamino acid.

To a solution ofCIS-tert-butyl ether (4-aminocyclohexane)carbamino acid (3 g, 0.014 mol) in CH2Cl2(50 ml) was added DIEA (3.6 ml, 0,021 mol). The mixture was cooled in an ice bath and slowly added 3,4-differentiald (1.9 ml, 0.015 mol). The mixture was brought to room temperature and was stirred for 1 hour. Then the solvent was concentrated and the oil obtained was subjected to chromatography (0-70% ethyl acetate in hexane). After evaporation of the solvents the residue was rasmalai, was filtered and was washed with 70% cold ether in hexane to obtaintert-butyl etherCIS-[4-(3,4-differentiating)cyclohexyl]carbamino acid (4.4 g, 0.012 mol, 89%) as a white solid.

ESI 355,4 M+H+;1H NMR (400 MHz, CD3OD) δ 7,78-7,72 (m, 1H), 7.68 per-to 7.64 (m, 1H), 7,39-7,33 (m, 1H), 3,93 (m, 1H), 3,61 (m, 1H), 1,78 by 1.68 (m, 8H), 1,45 (s, 9H).

Stage B: Synthesis ofCIS-N-(4-aminocyclohexane)-3,4-differentated.

To a solution oftert-butyl etherCIS-[4-(3,4-differentiating)cyclohexyl]carbamino acid (4.4 g, 0.012 mol) in CH2Cl2(50 ml) was added TFOC (1.9 ml of 0.025 mol). The solution was stirred at room temperature for 4 hours (or until the reaction is completed, according to the SH). The excess solvent is evaporated and the oil obtained was dissolved in 30 ml of CH2Cl2. The organic layer was extracted with 30 ml of the diluted NaOH solution (aq.)/NaHCO3(aq.) (maintaining the basicity of the aqueous layer during the extraction was confirmed using paper pH indicator). The aqueous layer was twice subjected to back extraction with CH2Cl2and the organic layers were combined, dried over MgSO4and concentrated to obtainCIS-N-(4-aminocyclohexane)-3,4-differentated (2.9 g, to 0.011 mol, 90%) as a white solid.

ESI 255,4 M+H+;1H NMR (400 MHz, CD3OD) δ 8.17 and (d, 1H, J=4,8 Hz), 7,93-7,88 (m, 1H), 7,80-of 7.70 (m, 4H), 7,58-7,51 (m, 1H), 3,86 (m, 1H), 3,12 (m, 1H), 1,91-to 1.87 (m, 2H), 1,73 is 1.60 (m, 6H).

Stage C: the Synthesis ofCIS-N-[4-(6-chloro-2-methylsulfonylamino-4-ylamino)cyclohexyl]-3,4-differentated.

To a solution of 4,6-dichloro-2-(methylthio)pyrimidine (19.5 mg, 0.1 mmol) in IPA (0.6 ml) was added DIEA (35 μl, 0.2 mmol) andCIS-N-(4-aminocyclohexane)-3,4-diflorasone (to 25.4 mg, 0.1 mmol). Then the mixture was heated in a microwave oven at 170°C for 30 minutes. The reaction mixture was cooled, concentrated and the resulting oil was purified on column (0-100% ethyl acetate in hexane) to give theCIS-N-[4-(6-chloro-2-methylsulfonylamino-4-ylamino)cyclohexyl]-3,4-differentated (37 mg, 0,090 mmol, 90%) as a colourless oil.

ESI MS 413,2 (M+H)+;1H YAM who (400 MHz, CD3OD) δ 8,23 (m, 1H), 7,81-7,76 (m, 1H), 7,72-to 7.68 (m, 1H), 7,43 and 7.36 (m, 1H), 6,27 (s, 1H), 4,17 (m, 1H), 4.00 points (m, 1H), of 2.51 (s, 3H), 1,94-to 1.79 (m, 8H).

Stage D: Synthesis of triptorelineN-[CIS-4-(6-dimethylamino-2-methylsulfonylamino-4-ylamino)cyclohexyl]-3,4-differentated.

To a solution ofCIS-N-[4-(6-chloro-2-methylsulfonylamino-4-ylamino)cyclohexyl]-3,4-differentated (73 mg, 0.18 mmol) in IPA (0.8 ml) was added DIEA (62 μl, 0.35 mmol) and dimethylamine (265 μl, of 0.53 mmol). Then the mixture was heated in a microwave oven at 170°C for 1 hour. The reaction mixture was cooled and concentrated, the resulting oil was again dissolved in 1 ml DMSO and purified preparative IHMS with getting trifenatateN-[CIS-4-(6-dimethylamino-2-methylsulfonylamino-4-ylamino)cyclohexyl]-3,4-differentated (18,4 mg 0,034 mmol, 19%) as a salt of TFWC.

ESI MS 422,2 (M+H)+;1H NMR (400 MHz, CD3OD) δ of 8.28 (m, 1H), 7,82-7,76 (m, 1H), 7,73-of 7.69 (m, 1H), 7,43 and 7.36 (m, 1H), 4,88 (s, 1H), was 4.02 (m, 1H), with 3.89 (m, 1H), 3,11 (s, 6H), to 2.66 (s, 3H), 1,92-to 1.79 (m, 8H).

Example 57

TriptorelinN-[CIS-4-(6-dimethylaminopyridine-4-ylamino)cyclohexyl]-3,4-differentated

To a solution of 4,6-dichloropyrimidine (14,9 mg, 0.1 mmol) in IPA (1 ml) was added DIEA (35 μl, 0.2 mmol) andCIS-N-(4-aminocyclohexane)-3,4-diflorasone with stage B of example 56 (to 25.4 mg, 0.1 mmol). Then the mixture was heated in a microwave oven at 170°C for 15 minutes. The reaction to shift the ü cooled and then added DIEA (35 μl, 0.2 mmol) and dimethylamine (150 μl, 0.3 mmol). Then the mixture was heated in a microwave oven at 170°C for 1 hour. The reaction mixture was cooled, concentrated, the resulting oil was again dissolved in 1 ml DMSO and purified preparative IHMS with getting trifenatateN-[CIS-4-(6-dimethylaminopyridine-4-ylamino)cyclohexyl]-3,4-differentated (11.7 mg, 0,024 mmol, 24%) as a salt of TFWC.

ESI MS 376.3 on (M+H)+;1H NMR (400 MHz, CD3OD) δ of 8.27 (m, 1H), 8,18 (s, 1H), 7,82-7,76 (m, 1H), 7,73-of 7.69 (m, 1H), 7,43 and 7.36 (m, 1H), 5,71 (s, 1H), was 4.02 (m, 1H), 3,88 (m, 1H), 3,23 (s, 6H), 1,90-of 1.84 (m, 8H).

Example 58

TriptorelinN-[CIS-4-(6-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-differentated

To a solution of 2-methyl-4,6-dichloropyrimidine (32,6 mg, 0.2 mmol) in IPA (1 ml) was added DIEA (70 μl, 0.4 mmol) andCIS-N-(4-aminocyclohexane)-3,4-diflorasone with stage B of example 56 (or 50.8 mg, 0.2 mmol). Then the mixture was heated in a microwave oven at 170°C for 15 minutes. The reaction mixture was cooled and then added DIEA (70 μl, 0.4 mmol) and dimethylamine (300 μl, 0.3 mmol). Then the mixture was heated in a microwave oven at 170°C for 1 hour. The reaction mixture was cooled, concentrated, the resulting oil was again dissolved in 1 ml DMSO and purified preparative IHMS with getting trifenatateN-[CIS-4-(6-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-differentated (2.2 mg, 0,064 mmol, 64%) as a salt of TFWC.

ESI MS 390,2 (M+H)+;1H NMR (400 MHz, CD3OD) δ to 8.20 (s, 1H), 8,17 (m, 1H), 7,81 for 7.78 (m, 1H), 7,72-7,71 (m, 1H), 7,42-7,40 (m, 1H), 4,10 (m, 1H), 4.09 to (m, 1H), and 3.16 (s, 6H), of 2.16 (s, 3H), 2,02-to 1.82 (m, 8H).

Example 59

Triptorelin 3,4-dichloro-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]benzamide

Stage A: Synthesis oftert-butyl etherCIS-[4-(2-chloro-6-methylpyrimidin-4-ylamino)cyclohexyl]carbamino acid.

To a solution of 2,4-dichloro-6-methylpyrimidine (3.7 g, is 0.023 mol) in 30 ml of methanol was added DIEA (of 5.89 ml, 0,034 mmol) andCIS-tert-butyl ether (4-aminocyclohexane)carbamino acid (5.3g, 0,025 mol). The mixture was heated under reflux overnight, cooled and concentrated. The resulting oil was subjected to chromatography (0-100% ethyl acetate in hexane) to give thetert-butyl etherCIS-[4-(2-chloro-6-methylpyrimidin-4-ylamino)cyclohexyl]carbamino acid (5.1 g, 0.015 mol, 66%) as a white solid.

ESI MS 341,4 (M+H)+;1H NMR (400 MHz, CD3OD) δ of 6.31 (s, 1H), 4,12 (m, 1H), of 3.56 (m, 1H), and 2.26 (s, 3H), 1,78-to 1.67 (m, 8H), to 1.48 (s, 9H).

Stage B: Synthesis oftert-butyl etherCIS-[4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]carbamino acid.

To a solution oftert-butyl etherCIS-[4-(2-chloro-6-methylpyrimidin-4-ylamino)cyclohexyl]carbamino to the slots (0.5 g, 0,0015 mol) in 2 ml of 2-propanol was added dimethylamine (1,47 ml, 0,0029 mol) and DIEA (511 μl, 0,0029 mol). The mixture was heated in a microwave synthesizer at 170°C for 1 hour. The reaction was repeated 9 more times (5 g total solids) and the reaction mixture is combined. The solvent is evaporated and the substance was subjected to chromatography (2-4% 2M NH3in MeOH/CH2Cl2with gettingtert-butyl etherCIS-[4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]carbamino acid (2.2 g, 0,0063 mol, 43%) as a white solid.

ESI MS 350,2 (M+H)+;1H NMR (400 MHz, CD3OD) δ of 5.68 (s, 1H), 3,95 (m, 1H), 3,54 (m, 1H), 3,11 (s, 6H), of 2.16 (s, 3H), 1.77 in-of 1.64 (m, 8H), of 1.47 (s, 9H).

Stage C: the Synthesis ofCIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)-1-aminocyclohexane.

To a solution oftert-butyl etherCIS-[4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]carbamino acid (2.2 g, 0,0063 mol) in 15 ml of CH2Cl2added TFOC (0,97 ml of 0.013 mol). The solution was stirred at room temperature for 4 hours (or until the reaction is completed according to TLC). The excess solvent is evaporated and the oil obtained was dissolved in 30 ml of CH2Cl2. The organic layer was extracted with 30 ml of the diluted NaOH solution (aq.)/NaHCO3(aq.) (maintaining the basicity of the aqueous layer during the extraction was confirmed using boom is iny indicator pH). The aqueous layer was twice subjected to back extraction with CH2Cl2and the organic layers were combined, dried over MgSO4and concentrated to obtainCIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)-1-aminocyclohexane (1.3 g, 0,0052 mol, 83%) as a white solid.

ESI MS 250,2 (M+H)+;1H NMR (400 MHz, CD3OD) δ 5,70 (s, 1H), 4.00 points (m, 1H), 3,11 (s, 6H), 2,84 (m, 1H), 2,16 (s, 3H), 1,86 and 1.80 (m, 2H), 1,76-of 1.66 (m, 4H), 1,57-1,49 (m, 2H).

Stage D: Synthesis of triptoreline 3,4-dichloro-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]benzamide.

To a solution ofCIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)-1-aminocyclohexane (20 mg, 0,080 mmol) in 0.5 ml DMF was added pyridine (9,7 μl, 0.12 mmol) and 3,4-dichlorobenzophenone (11,1 μl, 0,076 mmol). The reaction mixture was stirred over night and then to the mixture was added 0.5 ml of DMSO. The compound was subjected to preparative purification IHMS with getting trifenatate 3,4-dichloro-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]benzamide (10 mg, 0.019 mmol, 24%) as a salt of TFWC.

ESI MS 422,2 (M+H)+;1H NMR (400 MHz, CD3OD) δ of 8.00 (d, 1H, J=2.0 Hz), 7,76 (DD, J1=8,4 Hz, J2=2.0 Hz), the 7.65 (d, 1H, J=8,4 Hz), 6,01 (s, 1H), 4,23 (m, 1H), 4.00 points (m, 1H), 3,26 (s, 6H), was 2.34 (s, 3H), 1,98-of 1.81 (m, 8H).

Example 60

Triptorelin 4-cyano-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]benzo is foreign

Specified in the title compound was obtained using the methodology of stage D of example 59 (11 mg, of 0.022 mmol, 29%).

ESI MS to 379.2 (M+H)+;1H NMR (400 MHz, CD3OD) δ of 7.97 (d, 2H, J=8.0 Hz), 7,86 (d, 2H, J=8,4 Hz), 6,01 (s, 1H), 4,23 (m, 1H), a 4.03 (m, 1H), 3,26 (s, 6H), was 2.34 (s, 3H), 1,99-to 1.82 (m, 8H).

Example 61

TriptorelinN-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-diethoxybenzene

To a solution ofCIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)-1-aminocyclohexane (20 mg, 0,080 mmol) in 0.5 ml DMF was added 3,4-diethoxybenzoic acid (16.0 mg, 0,076 mmol), pyridine (9,7 μl, 0.12 mmol) and HATU (36,6 mg, 0,096 mmol). The reaction mixture was stirred over night and then to the mixture was added 0.5 ml of DMSO. The compound was subjected to preparative purification IHMS with getting trifenatateN-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-diethoxybenzene (11 mg, at 0.020 mmol, 26%) as a salt of TFWC.

ESI MS 442,4 (M+H)+;1H NMR (400 MHz, CD3OD) δ 7,47-7,44 (m, 2H), 7,02-7,00 (m, 1H), 6,01 (s, 1H), 4,23 (m, 1H), 4,15 (square, 4H, J=7.0 Hz), 4.00 points (m, 1H), 3,26 (s, 3H), of 2.34 (s, 3H), 1,99-of 1.81 (m, 8H), 1,45 (t, 6H, J=7.2 Hz),

Example 62

Triptorelin 3-chloro-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-5-fermentated

Specified in the title compound was obtained using the methodology of stage A of example 61 (12 mg, is 0.023 mmol, 30%).

ESI MS of 406.4 (M+H) +;1H NMR (400 MHz, CD3OD) δ 7,71 (s, 1H), EUR 7.57-7,53 (m, 1H), 7,45-7,42 (m, 1H), 6,00 (s, 1H), 4,23 (m, 1H), 4.00 points (m, 1H), 3,26 (s, 6H), was 2.34 (s, 3H), 1,99-to 1.82 (m, 8H).

Example 63

TriptorelinN-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-dimethoxybenzamide

Stage A: Synthesis oftert-butyl etherCIS-[4-(2-chloro-5-methylpyrimidin-4-ylamino)cyclohexyl]carbamino acid.

To a solution of 2,4-dichloro-5-methylpyrimidine (1.0 g, 6,13 mmol) in 2 ml of 2-propanol was added DIEA (1.6 ml, 9,20 mmol) andCIS-tert-butyl ether (4-aminocyclohexane)carbamino acid (1.45 g, of 6.75 mmol). The mixture was heated in a microwave synthesizer at 150°C for 15 minutes. The solvent is evaporated and the substance was subjected to chromatography (0-70% ethyl acetate in hexane) to give thetert-butyl etherCIS-[4-(2-chloro-5-methylpyrimidin-4-ylamino)cyclohexyl]carbamino acid (1.7 g, a 4.86 mmol, 79%) as a white solid.

ESI MS 341,2 (M+H)+;1H NMR (400 MHz, CD3OD) δ 7,76 (s, 1H), 4,12 (m, 1H), to 3.67 (m, 1H), 2.05 is (s, 3H), 1,82 is 1.70 (m, 8H), to 1.48 (s, 9H).

Stage B: Synthesis oftert-butyl etherCIS-[4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]carbamino acid.

To a solution oftert-butyl etherCIS-[4-(2-chloro-5-methylpyrimidin-4-ylamino)cyclohexyl]carbamino acid (0.5 g, 0,0015 mol) in 2 ml of 2-propanol was added on the methylamine (1,47 ml, 0,0029 mol) and DIEA (511 μl, 0,0029 mol). The mixture was heated in a microwave synthesizer at 170°C for 1 hour. The reaction was repeated 3 more times (1.5 g total solids) and the reaction mixture is combined. The solvent is evaporated and the substance was subjected to chromatography (2-4% 2M NH3in MeOH/CH2Cl2with gettingtert-butyl etherCIS-[4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]carbamino acid (1.3 g, 0,0037 mol, 85%) as a white solid.

ESI MS 350,2 (M+H)+;1H NMR (400 MHz, CD3OD) δ 7,53 (s, 1H), 4,13 (m, 1H), 3,63 (m, 1H), 3,09 (s, 6H), was 1.94 (s, 3H), 1,83 is 1.70 (m, 8H), to 1.48 (s, 9H).

Stage C: the Synthesis ofCIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)-1-aminocyclohexane.

To a solution oftert-butyl etherCIS-[4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]carbamino acid (1.3 g, 0,0037 mol) in 10 ml of CH2Cl2added TFOC (or 0.57 ml, 0,0074 mol). The solution was stirred at room temperature for 4 hours (or until the reaction is completed according to TLC). The excess solvent is evaporated and the oil obtained was dissolved in 30 ml of CH2Cl2. The organic layer was extracted with 30 ml of the diluted NaOH solution (aq.)/NaHCO3(aq.) (maintaining the basicity of the aqueous layer during the extraction was confirmed using paper pH indicator). The aqueous layer was twice subjected to arr is based extraction CH 2Cl2and the organic layers were combined, dried over MgSO4and concentrated to obtainCIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)-1-aminocyclohexane (0.88 g, 0,0035 mol, 95%) as a white solid.

ESI MS 250,2 (M+H)+;1H NMR (400 MHz, CD3OD) δ 7,53 (s, 1H), 4,17 (m, 1H), 3,09 (s, 6H), to 2.94 (m, 1H), 1,96 (s, 3H), 1,86-1,71 (m, 6H), 1,62-to 1.59 (m, 2H).

Stage D: Synthesis of triptorelineN-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-dimethoxybenzamide.

To a solution ofCIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)-1-aminocyclohexane (20 mg, 0,080 mmol) in 0.5 ml DMF was added pyridine (9,7 μl, 0.12 mmol) and 3,5-dimethoxybenzoate (15.3 mg, 0,076 mmol). The reaction mixture was stirred over night and then to the mixture was added 0.5 ml of DMSO. The compound was subjected to preparative purification IHMS with getting trifenatateN-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-dimethoxybenzamide (14 mg, or 0.027 mmol, 35%) as a salt of TFWC.

ESI MS 414,4 (M+H)+;1H NMR (400 MHz, CD3OD) δ of 8.00 (s, 1H), of 7.48 (s, 1H), 7,19 (d, 1H, J=2.4 Hz), 6,69 (t, 1H, J=2.4 Hz), or 4.31 (m, 1H), 4,10 (m, 1H), 3,85 (s, 6H), 3,23 (s, 6H), 2,32 (s, 3H), 2,10-to 1.82 (m, 8H).

Example 64

Triptorelin 3,4-dichloro-N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]benzamide

Specified in the title compound was obtained using IU Tiki stage D of example 63 (15 mg, 0,028 mmol, 37%).

ESI MS 422,2 (M+H)+;1H NMR (400 MHz, CD3OD) δ 8,24 (m, 1H), 8,02 (d, 1H, J=2.0 Hz), 7,78 (DD, 1H, J1=8,4 Hz, J2=2.0 Hz), to 7.67 (d, 1H, J=8,4 Hz), of 7.48 (s, 1H), or 4.31 (m, 1H), 4,10 (m, 1H), 3,23 (s, 6H), 2,10 (s, 3H), 2.00 in to 1.82 (m, 8H).

Example 65

TriptorelinN-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-diethoxybenzene

To a solution ofCIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)-1-aminocyclohexane (20 mg, 0,080 mmol) in 0.5 ml DMF was added 3,4-diethoxybenzoic acid (16.0 mg, 0,076 mmol), pyridine (9,7 μl, 0.12 mmol) and HATU (36,6 mg, 0,096 mmol). The reaction mixture was stirred over night and then to the mixture was added 0.5 ml of DMSO. The compound was subjected to preparative purification IHMS with getting trifenatateN-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-diethoxybenzene (12 mg, of 0.022 mmol, 28%) as a salt of TFWC.

ESI MS 442,4 (M+H)+;1H NMR (400 MHz, CD3OD) δ 7,49-7,46 (m, 3H), 7,02 (d, 1H, J=8.0 Hz), or 4.31 (m, 1H), 4,16 (square, 4H, J=7.0 Hz), 4,10 (m, 1H), 3,23 (s, 6H), 2,10 (s, 3H), 2,01-of 1.81 (m, 8H), 1,46 (t, 6H, J=7.0 Hz),

Example 66

Triptorelin 3-chloro-N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-5-fermentated

Specified in the title compound was obtained using the methodology of stage A of example 65 (12 mg, is 0.023 mmol, 30%).

ESI MS 406,2 (M+H)+;1H NMR (400 MHz, CD3OD) δ 7,73 (s, 1H), to 7.59-7,56 (m, 1H, of 7.48 (s, 1H), 7,46-the 7.43 (m, 1H), or 4.31 (m, 1H), 4,10 (m, 1H), 3,23 (s, 6H), 2,10 (s, 3H), 2,03-of 1.81 (m, 8H).

Example 67

TriptorelinN-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]for 3,5-bitreversed

Stage A: Synthesis of benzyl etherCIS-(4-aminocyclohexanol)carbamino acid.

To a solution oftert-butyl etherCIS-(4-aminoethylthiomethyl)carbamino acid (25 g, 0.11 mol) in CH2Cl2(300 ml) was added DIEA (22.9 ml, 0.13 mol). The mixture was cooled in an ice bath and slowly added benzylchloride (17.3 ml, 0.12 mol). The mixture was removed from ice bath and stirred overnight. The solvent was removed in vacuum and the oil obtained was dissolved in MeOH (250 ml). To the mixture under stirring was slowly added concentrated HCl (75 ml). The reaction mixture was left to mix for more than 4 hours and then the solvent was removed in vacuum to obtain a residue. For dissolving the obtained residue HCl salt was added large amount of water (2 l), which is then made basic by slow addition of concentrated NaOH solution. The aqueous layer 3 times were extracted with ethyl acetate (1 liter). The organic layers were combined, dried over MgSO4and concentrated to obtain benzyl etherCIS-(4-aminocyclohexanol)carbamino acid (24.5 g, 0,093 mol, 85%) as oil.

EI MS m/e 263,2 (M+H) +;1H NMR (400 MHz, DMSO-d6) δ of 7.36-7,25 (m, 5H), at 4.99 (s, 2H), 2,90 (t, J=6.4 Hz, 2H), 2,81 (m, 1H), 143-1,34 (m, 8H).

Stage B: Synthesis of benzyl etherCIS-[4-(6-chloro-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]carbamino acid.

To a solution of 4,6-dichloro-2-methylpyrimidine (1.0 g, 6.1 mmol) in 2 ml of 2-propanol was added DIEA (1.6 ml, 9.2 mmol) and benzyl etherCIS-(4-aminocyclohexanol)carbamino acid (1.8 g, 6.7 mmol). The mixture was heated in a microwave synthesizer at 160°C for 20 minutes. The reaction was repeated 2 more times (3 g total solids) and the reaction mixture is combined. The solvent is evaporated and the substance was subjected to chromatography (0-100% ethyl acetate in hexane) to give the benzyl etherCIS-[4-(6-chloro-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]carbamino acid (6.5 g, is 0.017 mol, 91%) as a white solid.

ESI MS m/e 389,2 (M+H)+;1H NMR (400 MHz, CDCl3) δ 7,35-7,26 (m, 5H), 6,17 (s, 1H), 5,09 (s, 2H), 4,89 (m, 1H), 3,10 (t, J=6.0 Hz, 2H), 2,46 (s, 3H), 1,80-to 1.67 (m, 2H), 1,66-to 1.60 (m, 4H), 1,30-1,22 (m, 2H).

Stage C: Synthesis of benzyl etherCIS-[4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]carbamino acid.

To a solution of benzyl etherCIS-[4-(6-chloro-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]carbamino acid (0.5 g, 1.3 mmol) in 2 ml of 2-propanol was added DIEA (224 μl, 1.3 mmol) and dimethylamine (1.3 ml, 2.6 mmol). The mixture naked is evali in a microwave synthesizer at 170°C for 30 minutes. The reaction was repeated 7 more times (8 g total solids) and the reaction mixture was combined. The solvent is evaporated and the substance was subjected to chromatography (0-100% ethyl acetate in hexane to remove the original substance with the subsequent <5% MeOH in CH2Cl2) to give the benzyl etherCIS-[4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]carbamino acid (3.8 g, 9.6 mmol, 94%) as a white solid.

ESI MS m/e 398,2 (M+H)+;1H NMR (400 MHz, CDCl3) δ 7,6-7,26 (m, 5H), 5,10 (s, 1H), 5,09 (s, 2H), is 5.06 (m, 1H), 3,69 (m, 1H), 3,09 (m, 8H), 2.40 a (s, 3H), 1,87 of-1.83 (m, 2H), 1,65-of 1.56 (m, 4H), 1,42-of 1.36 (m, 2H).

Stage D: Synthesis ofCIS-N-(4-aminoethylthiomethyl)-2,N',N'trimethylpyridine-4,6-diamine.

To a solution of benzyl etherCIS-[4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]carbamino acid (3.8 g, 9.6 mmol) in EtOH (100 ml) was added 10% Pd/C (380 mg). The reaction mixture was stirred at room temperature in an atmosphere of H2(g) for 15 hours. The atmosphere of H2(g) was removed and the mixture was washed through a layer of celite with ethyl acetate. The solvent was concentrated and the product was subjected to chromatography (2-4% 2M NH3in MeOH/CH2Cl2with gettingCIS-N-(4-aminoethylthiomethyl)-2,N',N'trimethylpyridine-4,6-diamine (1.7 g, 6.5 mmol, 64%) as a white solid.

ESI MS m/e AZN 264.2 (M+H)+;1H I Is R (400 MHz, DMSO) δ of 6.29 (m,1H), 5,33 (s, 1H), a 3.87 (m, 1H), 2.91 in (s, 6H), 2,42 (s, 2H), of 2.15 (s, 3H), 1,55-of 1.29 (m, 8H).

Stage E: Synthesis of triptorelineN-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]for 3,5-bitreversed

To a solution ofCIS-N-(4-aminoethylthiomethyl)-2,N',N'trimethylpyridine-4,6-diamine (26 mg, 0.10 mmol) in 0.5 ml DMF was added pyridine (12,1 μl, 0.15 mmol) and 3,5-bis(trifluoromethyl)benzoyl chloride (18,1 μl, 0.10 mmol). The reaction mixture was stirred over night and then to the mixture was added 0.5 ml of DMSO. The compound was subjected to preparative purification IHMS with getting trifenatateN-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]for 3,5-bitreversed (to 11.9 mg, 0.019 mmol, 19%) as a white solid salt TFUCK.

ESI MS m/e 504,2 (M+H)+;1H NMR (400 MHz, CD3OD) δ 9,03 (m, 1H), of 8.47 (s, 2H), to 8.20 (s, 1H), 5,58 (s, 1H), 3,88 (s, 1H), 3.43 points (t, J=6.4 Hz, 2H), 3,20 (s, 6H), 2,48 (s, 3H), 1,90 is 1.75 (m, 6H), 1,54 of 1.46 (m, 2H).

Example 68

TriptorelinN-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-4-triphtalocyaninine

Specified in the title compound as a white solid substance was obtained using the methodology of stage E of example 67 (18.7 mg, 0,033 mmol, 33%).

ESI MS m/e 452,2 (M+H)+;1H NMR (400 MHz, CD3OD) δ 8,65 (m, 1H), of 7.96 (d, J=9.4 Hz, 2H), 7,40 (d, J=8,4 Hz), to 5.58 (s, 1H), a 3.87 (s, 1H), 3,39 (t, J=6.4 Hz), 3,19 (who, 6H), 2,48 (s, 3H), 1,88 is 1.75 (m, 6H), 1,53-of 1.44 (m, 2H).

Examples 69-72

Connection 69-72 was obtained by a similar procedure as described in example 48, using an appropriate carboxylic acid and amine intermediate from step D.

Examples 73-107

Connection 3-107 was obtained by a similar procedure as described in example 50, using the appropriate acid chloride and amine intermediate from step A.

Examples 108-110

Connection 108-110 was obtained by a similar procedure as described in example 52, using the appropriate aldehyde and amine intermediate from step A.

Examples 111-113

Connection 111-113 was obtained by a similar procedure as described in example 54, using the appropriate isocyanate and amine intermediate from step A.

Examples 114-117

Connection 114-117 was obtained by a similar procedure as described in example 48, using an appropriate carboxylic acid and amine intermediate from step D.

Examples 118-125

Connection 118-125 was obtained by a similar procedure as described in example 63, using the appropriate acid chloride and amine intermediate from step D.

Examples 126-133

Connection 126-133 was obtained by a similar procedure as described in example 65, using the appropriate carboxylic acid and amine intermediate from step A.

Examples 134140

Connection 134-140 was obtained by a similar procedure as described in example 59, using the appropriate acid chloride and amine intermediate from step D.

Examples 141-148

Connection 141-148 was obtained by a similar procedure as described in example 61, using the appropriate carboxylic acid and amine intermediate from step A.

Examples 149-167

Connection 149-167 was obtained by a similar procedure as described in example 67, using the appropriate acid chloride and amine intermediate from step E.

tr>
No.
Ave
Connection nameMS
69N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-diethoxybenzene442,4 (M+H)
70N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethoxybenzene398,2 (M+H)
71N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-diethoxybenzene442,2 (M+H)
72N-[CIS-4-(6-dimethylamino-2-methylpyrene the Jn-4 ylamino)cyclohexyl]-3-isopropoxybenzoic 412,4 (M+H)
733-bromo-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-perbenzoic450,2 (M+H)
744 deformedarse-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide420,2 (M+H)
754-chloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-methylbenzamide402 (M+H)
763-chloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-5-perbenzoic406,2 (M+H)
773 deformedarse-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide420,2 (M+H)
783-chloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-methylbenzamide402,2 (M+H)
794-bromo-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide432,2 (M+H)
80N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-dimethoxybenzamide414,6 (M+H)
813,4-dichloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide422,2 (M+H)
824-cyano-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamideto 379.2 (M+H)
83N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-methoxybenzamide384,2 (M+H)
843-cyano-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamideto 379.2 (M+H)
853,5-dichloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide422,2 (M+H)
86N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-methoxybenzamide384,2 (M+H)
87N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)is illogical]-4-fluoro-3-methylbenzamide 386,2 (M+H)
88N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-fluoro-5-cryptomelane440,4 (M+H)
89N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-perbenzoic372,2 (M+H)
904-bromo-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-methylbenzamide446,2 (M+H)
91N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-fluoro-4-methylbenzamide386,2 (M+H)
924-chloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamideof 388.4 (M+H)
93N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-perbenzoic372,2 (M+H)
94N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-cryptomaterial438,4 (M+H)
9 N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethylbenzamide382,4 (M+H)
963-bromo-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide432,3 (M+H)
97N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-cryptomelane422,1 (M+H)
98N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-fluoro-4-cryptomelane440,6 (M+H)
993-chloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide388,5 (M+H)
100N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-fluoro-3-cryptomelane440,6 (M+H)
101N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-diflorasone390,2 (M+H)
1023-chloro-N-[CIS-4-(6-dimethylamino-2-IU is Yeremey-4-ylamino)cyclohexyl]-4-perbenzoic 406,3 (M+H)
103N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-cryptomaterial438,1 (M+H)
104N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-methylbenzamide368,3 (M+H)
105N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-methylbenzamide368,2 (M+H)
106N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-cryptomelane422,3 (M+H)
107[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]amide 2,2-debtorrent[1,3]dioxol-5-carboxylic acidof 434.1 (M+H)
108N-{CIS-4-[(1H-indol-2-ylmethyl)amino]cyclohexyl}-2,N',N'-trimethylpyridine-4,6-diamine379,4 (M+H)
1092,N,N-trimethyl-N'-[CIS-4-(3-triphtalocyaninine)cyclohexyl]pyrimidine-4,6-diamine424,2 (M+H)
110N-[CIS-4-(3,4-diferentiating)cyclohexyl]-2,N',N'-trimethylpyridine-4,6-diamineUSD 376.6 (M+H)
1111-(3,4-acid)-3-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]urea429,4 (M+H)
1121-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-(2-ethoxyphenyl)urea413,5 (M+H)
1131-(4-benzyloxyphenyl)-3-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]urea475,5 (M+H)
1143,5-dibromo-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide510,2 (M+H)
1153-bromo-4-chloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide466,2 (M+H)
1164-chloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-cryptomelane456,2 (M+H)
117 2-(3,5-bistrifluormethylbenzene)-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-2-hydroxyacetamido520,2 (M+H)
118N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3-methoxybenzamide384,2 (M+H)
119N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3-cryptomelane422,2 (M+H)
120N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-bistrifluormethylbenzene490,4 (M+H)
121[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]amide 2,2-debtorrent[1,3]dioxol-5-carboxylic acid434,2 (M+H)
1224-cyano-N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]benzamide379,4 (M+H)
1234-chloro-N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]benzamide388,2 (M+H)
124N-[CIS 4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethylbenzamide382,4 (M+H)
125N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-diflorasoneRUR 390.4 (M+H)
1265-bromo-N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]nicotinamide433,2 (M+H)
127[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]amide 5-bromofuran-2-carboxylic acid422,2 (M+H)
1283,5-dibromo-N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]benzamide510,2 (M+H)
129N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethoxybenzene398,2 (M+H)
1302-(3,5-bistrifluormethylbenzene)-N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-2-hydroxyacetamido520,4 (M+H)
1312-(4-bromophenyl)-N-[CIS-4-(2-dimethylamino-5-meth is pyrimidin-4-ylamino)cyclohexyl]-2-hydroxyacetamido 462,2 (M+H)
132N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-diethoxybenzeneTP 442.6 (M+H)
1333-bromo-N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-4-perbenzoic450 (M+H)
134N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethoxybenzene384,2 (M+H)
135N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-3-cryptomelane422,2 (M+H)
136N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-bistrifluormethylbenzene490,4 (M+H)
137[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]amide 2,2-debtorrent[1,3]dioxol-5-carboxylic acid434,4 (M+H)
1384-chloro-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]benzamide388,2 (M+H)/td>
139N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethylbenzamide382,4 (M+H)
140N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-4-methylbenzamide368,2 (M+H)
1415-bromo-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]nicotinamide433,2 (M+H)
142[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]amide 5-bromofuran-2-carboxylic acid422 (M+H)
1433,5-dibromo-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]benzamide510 (M+H)
144N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethoxybenzene398,2 (M+H)
1452-(3,5-bistrifluormethylbenzene)-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-2-hydroxyacetamido520,4 (M+H)
146 2-(4-bromophenyl)-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-2-hydroxyacetamido462,2 (M+H)
147N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-diethoxybenzene442,4 (M+H)
1483-bromo-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-4-perbenzoic450 (M+H)
149N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-fluoro-4-cryptomelane454,2 (M+H)
150N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-cryptomaterial452,2 (M+H)
151N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-methoxybenzamide398,2 (M+H)
1524-chloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]benzamide402,2 (M+H)
153N-[CIS-4-(6-dimethy is amino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-cryptomelane 436,2 (M+H)
154N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-4-cryptomelane436,2 (M+H)
155N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-methylbenzamide382,4 (M+H)
156N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]for 3,5-diflorasone404 (M+H)
157N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-ethylbenzamide396,2 (M+H)
158[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]amide 2,2-debtorrent[1,3]dioxol-5-carboxylic acidUSD 448,2 (M+H)
159N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-fluoro-4-methylbenzamide400,2 (M+H)
160N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-4-perbenzoic 386,2 (M+H)
1613,4-dichloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]benzamide436,2 (M+H)
1624-bromo-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]benzamide446,2 (M+H)
163N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3,4-diflorasone404,2 (M+H)
1643,5-dichloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]benzamide436,2 (M+H)
1653-chloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-4-perbenzoic420,2 (M+H)
166N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-4-fluoro-3-methylbenzamide400,2 (M+H)
1673-chloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]benzamide402 (M+H)

Example 168

HydrochlorideN-{CIS-4-[(6-amino-2-methylpyrimidin-4-yl)amino]cyclohexyl}-3,4,5-triterpenoid

Stage A: SynthesisN-(CIS-4-aminocyclohexane)-3,4,5-triterpenoid.

To a solution oftert-butyl(CIS-4-aminocyclohexane)carbamate (44,3 g) in DMF (450 ml) was added 3,4,5-triptoreline acid (40,1 g), Et3N (69,2 ml), HOBt-H2O (47,5 g) and EDC-HCl (43,6 g). The mixture was stirred at ambient temperature for 12 hours. To the mixture was added water (1 l) and the suspension was stirred at ambient temperature for 2 hours. The precipitate was collected by filtration, washed with water and hexane and dried at 80°C under reduced pressure to obtain a light brown solid (82.7 g). To the suspension obtained above solid in EtOAc (800 ml) was added 4M hydrogen chloride in EtOAc (600 ml) at 10°C. the Mixture was stirred at ambient temperature for 6 hours and concentrated under reduced pressure. The residue was dissolved in CHCl3(300 ml) and poured into 1M aqueous NaOH (500 ml). The aqueous layer three times was subjected to extraction with CHCl3. The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to obtain specified in the connection header (65,3 g).

1H NMR (300 MHz, CDCl3, δ): 1,38 is 1.91 (m, 8H), 2,97-to 3.09 (m, 1H), 4.04 the-4,20 (m, 1H), 6,15-6,27 (m, 1H), 7,35 is 7.50 (m, 2H); ESI is With m/z 273 (M ++1, 100%).

Stage B: Synthesis of 6-chloro-2-methylpyrimidin-4-amine.

To a solution of 4,6-dichloro-2-methylpyrimidine obtained in stage A of example 5 (15.0 g)in 2-propanol (30 ml) was added 28% aqueous NH3(30 ml). The mixture is stirred at the boiling point under reflux for 6 hours in a sealed tube was cooled to ambient temperature. The precipitate was collected by filtration, washed with 2-propanol and dried at 80°C under reduced pressure to obtain specified in the connection header (7,58 g).

1H NMR (300 MHz, DMSO-d6, δ): to 2.29 (s, 3H), 6,27 (s, 1H), 7,12 (users, 2H); ESI MS m/z 144 (M++1, 100%).

Stage C: Synthesis of hydrochloride {CIS-4-[(6-amino-2-methylpyrimidin-4-yl)amino]cyclohexyl}-3,4,5-triterpenoid.

To a suspension ofN-(CIS-4-aminocyclohexane)-3,4,5-triterpenoid (1.20 g) in BuOH (2 ml) was added 6-chloro-2-methylpyrimidin-4-amine (534 mg). The mixture was heated in a microwave synthesizer at 220°C for 30 minutes the Mixture was diluted with CHCl3and added to saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, 20%→80% EtOAc in hexane) to obtain the oil. To the solution obtained above oil in EtOAc (10 ml) to relax is whether 4M hydrogen chloride in EtOAc (0.5 ml). The mixture was stirred at ambient temperature for 30 min and concentrated under reduced pressure. A suspension of the residue in Et2O (10 ml) was stirred at ambient temperature for 2 hours. The precipitate was collected by filtration, washed with Et2O and dried at 80°C under reduced pressure to obtain specified in the title compound (627 mg).

1H NMR (300 MHz, DMSO-d6, δ): 1,60-1,75 m, 8H), a 2.36 (s, 3H), 3,80 is 4.13 (m, 2H), 5,43-5,78 (m, 1H), 7,16-of 7.70 (m, 1H), 7,74-to 7.95 (m, 2H), of 8.37-8,48 (m, 1H) ,to 13.29-13,55 (m, 1H); ESI MS m/z 380 [M (free)++1, 100%].

Example 169

Hydrochloride 3,4,5-Cryptor-N-(CIS-4-{[2-methyl-6-(methylamino)pyrimidine-4-yl]amino}cyclohexyl)benzamide

Stage A: Synthesis of 6-chloro-N2-dimethylpyrimidin-4-amine.

To a solution of 4,6-dichloro-2-methylpyrimidine obtained in stage A of example 5 (15.0 g)in THF (150 ml) was added 40% aqueous MeNH2(17.9 g) and the mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with CHCl3and added to saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and dried under reduced pressure to obtain specified in the connection header (13,6 g).

1H NMR (300 MHz, CDCl3, δ): 2,48 (s, 3H), of 2.93 (d, J=5,1 Hz, 3H), 5,02-of 5.29 (m, 1H), 618 (s, 1H); ESI MS m/z 158 (M++1, 100%).

Stage B: Synthesis of hydrochloride 3,4,5-Cryptor-N-(CIS-4-{[2-methyl-6-(methylamino)pyrimidine-4-yl]amino}cyclohexyl)benzamide.

Specified in the title compound (312 mg) was obtained fromN-(CIS-4-aminocyclohexane)-3,4,5-triterpenoid obtained in stage A of example 168 (952 mg)and 6-chloro-N2-dimethylpyrimidin-4-amine (500 mg) using the technique of stage C of example 168.

1H NMR (300 MHz, CDCl3, δ): 1.55V is 1.91 (m, 8H), 2,22 is 2.46 (m, 3H), 2.71 to to 2.94 (m, 3H), of 3.73-4,11 (m, 2H), are 5.36-5,67 (m, 2H), 7,74-of 7.90 (m, 2H), 8,09-charged 8.52 (m, 2H); ESI MS m/z 394 [M (free)++1, 100%].

Example 170

MethanesulfonateN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4,5-triterpenoid

To a solution ofN-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4,5-triterpenoid (3.00 g)obtained in example 11, in EtOH (21 ml) was added MsOH (743 mg). The mixture was stirred at ambient temperature for 1 hour and 4°C for 4 hours. The precipitate was collected by filtration, washed with cold EtOH and dried at 80°C under reduced pressure to obtain specified in the connection header (3,16 g).

1H NMR (300 MHz, CDCl3, δ): 1,60-of 2.08 (m, 8H), 2,48 (s, 3H), of 2.92 (s, 3H), 3,07 (users, 3H), 3,30 (users, 3H), 3,71-of 3.80 (m, 1H), 4,07-4,24 (m, 1H), 5,18 (s, 1H), 7,65-7,83 (m, 4H), 12,63 (users, 1H); ESI MS m/z 408 [M (free)++1, 100%].

Example 171

Guide klorid 3-chloro- N-{CIS-4-[(2,6-dimethylpyrimidin-4-yl)amino]cyclohexyl}-4-fermentated

Stage A: Synthesis of 4-chloro-2,6-dimethylpyrimidine.

The solution ZnBr2(4,14 g) in THF (15 ml) was cooled to -60°C was added 3M methyl magnesium in Et2O (6,13 ml). The mixture was stirred at -60°C for 1 hour and warmed up to ambient temperature. To the mixture was added tetrakis(triphenylphosphine)palladium (1.06 g) and 4,6-dichloro-2-methylpyrimidin obtained in stage A of example 5 (3.0 g)in THF (15 ml). The mixture was stirred at 60°C for 8 hours. To the mixture was added saturated aqueous NH4Cl and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (silica gel, 5%→16% EtOAc in hexane) to obtain the specified title compound (940 mg).

1H NMR (300 MHz, CDCl3, δ): 2.49 USD (s, 3H), 2,68 (s, 3H), 7,05 (s, 1H); CI MS m/z 143 (M++1, 100%).

Stage B: Synthesis of hydrochloride of 3-chloro-N-{CIS-4-[(2,6-dimethylpyrimidin-4-yl)amino]cyclohexyl}-4-fermentated.

Specified in the title compound (454 mg) was obtained fromN-(CIS-4-aminocyclohexane)-3-chloro-4-fermentated obtained in stage A of example 31 (520 mg)and 4-chloro-2,6-dimethylpyrimidine (250 mg) using the technique of stage C of example 168.

1H YAM who (600 MHz, CDCl3, δ): 1,68-of 2.16 (m, 8H), 2,38 (users, 3H), 2,62 (s, 3H), 4,10-4,22 (m, 1H), 4,43-a 4.53 (m, 1H), 6,80-6,91 (m, 1H), 7,08-to 7.18 (m, 2H), 7,75-7,86 (m, 1H), 7,92-to 8.12 (m, 1H), 8,90-9,06 (m, 1H); ESI MS m/z 377 [M (free)++1, 100%].

Example 172

N-{CIS-4-[(6-chloro-2-methylpyrimidin-4-yl)amino]cyclohexyl}-3,4,5-triterpenoid

To a suspension ofN-(CIS-4-aminocyclohexane)-3,4,5-triterpenoid obtained in stage A of example 168 (16.7 g)in BuOH (9.1 ml) was added 4,6-dichloro-2-methylpyrimidin obtained in stage A of example 5 (9,10 g), and iPrNEt2(to 10.7 ml). The mixture is stirred at the boiling point under reflux for 1.5 hours. The mixture was diluted with CHCl3and added to saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, 33%→66% EtOAc in hexane) to obtain specified in the connection header (21,0 g).

1H NMR (300 MHz, CDCl3, δ): 1,56-2,03 (m, 8H), 2,47 (s, 3H), 3,74-to 3.92 (m, 1H), 4,03-4,18 (m, 1H), 5.08 to 5,24 (m, 1H), between 6.08 (d, J=7,3 Hz, 1H), 6,18 (s, 1H), 7,33-to 7.50 (m, 2H); ESI MS m/z 399 (M++1, 100%).

Example 173

HydrochlorideN-(CIS-4-{[6-(cyclopropylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4,5-triterpenoid

To a suspension ofN-{CIS-4-[(6-chloro-2-methylpyrimidin-4-yl)amino]cyclohex the Il}-3,4,5-triterpenoid, obtained in example 172 (250 mg), 3-methylbutane-1-Ola (0.5 ml) was added cyclopropylamine (43 mg). The mixture was stirred at 190°C for 1.5 hours in a sealed tube. The mixture was diluted with CHCl3and added to saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, 20%→50% EtOAc in hexane and silica gel, 2%→9% MeOH in CHCl3) to obtain a colorless oil. To the solution obtained above oil in EtOAc (10 ml) was added 4M hydrogen chloride in EtOAc (0.5 ml). The mixture was stirred at ambient temperature for 30 min and concentrated under reduced pressure. A suspension of the residue in Et2O (10 ml) was stirred at ambient temperature for 2 hours. The precipitate was collected by filtration, washed with Et2O and dried at 80°C under reduced pressure to obtain specified in the title compound (90 mg).

1H NMR (300 MHz, CDCl3, δ): 0,62-0,74 (m, 2H), 0.88 to 1.00 and (m, 2H), 1,72-2,02 (m, 8H), of 2.45 (s, 3H), 2,50-of 2.64 (m, 1H), 3,71-a 3.87 (m, 1H), 4,03-4,19 (m, 1H), 5,52 (s, 1H), 6,80-of 6.96 (m, 1H), of 7.48 to 7.62 (m, 2H); ESI MS m/z 420 [M (free)++1, 100%].

Example 174

Hydrochloride 3,4,5-Cryptor-N-[CIS-4-({2-methyl-6-[methyl(phenyl)amino]pyrimidine-4-yl}amino)cyclohexyl]benzamide

The criminal code is related to the title compound (210 mg) was obtained from N-{CIS-4-[(6-chloro-2-methylpyrimidin-4-yl)amino]cyclohexyl}-3,4,5-triterpenoid obtained in example 172 (250 mg), andN-methylaniline (81 mg) using the method of example 173.

1H NMR (300 MHz, CDCl3, δ): 1,50 is 1.91 (m, 8H), to 2.55 (s, 3H), 3,31 is 3.40 (m, 1H), 3,54 (s, 3H), 3.95 to 4.09 to (m, 1H), 4,96 (s, 1H), for 6.81 (d, J=8,4 Hz, 1H), 7,21-7,27 (m, 2H), 7,40-7,58 (m, 4H), 8,43 (d, J=8,4 Hz, 1H); ESI MS m/z 470 [M (free)++1, 100%].

Example 175

HydrochlorideN-[CIS-4-({6-[benzyl(methyl)amino]-2-methylpyrimidin-4-yl}amino)cyclohexyl]-3,4,5-triterpenoid

Specified in the title compound (121 mg) was obtained fromN-{CIS-4-[(6-chloro-2-methylpyrimidin-4-yl)amino]cyclohexyl}-3,4,5-triterpenoid obtained in example 172 (250 mg), andN-methylbenzylamine (91 mg) using the method of example 173.

1H NMR (300 MHz, CDCl3, δ): 1,57-2,07 (m, 8H), of 2.51 (s, 3H), 2,98 (s, 3H), 3,28 is-3.45 (m, 1H), 3,68-3,81 (m, 1H), 3,98-4,20 (m, 1H), 4,94-5,23 (m, 2H), 6,93? 7.04 baby mortality (m, 1H), 7,12-7,24 (m, 2H), 7,30-7,42 (m, 3H), of 7.48-to 7.61 (m, 2H), 8,54-8,67 (m, 1H), 13,78-13,89 (m, 1H); ESI MS m/z 484 [M (free)++1, 100%].

Example 176

HydrochlorideN-[CIS-4-({6-[ethyl(methyl)amino]-2-methylpyrimidin-4-yl}amino)cyclohexyl]-3,4,5-triterpenoid

Specified in the title compound (71 mg) was obtained fromN-{CIS-4-[(6-chloro-2-methylpyrimidin-4-yl)amino]cyclohexyl}-3,4,5-triterpenoid obtained in example 172 (250 mg), andN-ethylmethylamine (44 mg) using IU Tiki example 173.

1H NMR (300 MHz, CDCl3, δ): 1,06-of 1.35 (m, 3H), 1,62-2,11 (m, 8H), 2,48 (s, 3H), 2,96-to 3.49 (m, 4H), 3,67-of 3.85 (m, 2H), 4,01-4,20 (m, 1H), 5,04-5,20 (m, 1H), 6,98 (d, J=8.5 Hz, 1H), 7,47-7,63 (m, 2H), at 8.36-8,55 (m, 1H), 13,57-13,77 (m, 1H); ESI MS m/z 422 [M (free)++1, 100%].

Example 177

HydrochlorideN-(CIS-4-{[6-(dimethylamino)-2-ethylpyrimidine-4-yl]amino}cyclohexyl)-3,4,5-triterpenoid

Specified in the title compound (126 mg) was obtained fromN-{CIS-4-[(6-chloro-2-methylpyrimidin-4-yl)amino]cyclohexyl}-3,4,5-triterpenoid obtained in stage A of example 168 (403 mg), and (6-chloro-2-ethylpyrimidine-4-yl)amine, obtained in stage B of example 32 (250 mg), using the technique of stage C of example 168.

1H NMR (300 MHz, CDCl3, δ): 1,36 (t, J=7.5 Hz, 3H), 1,65-2,02 (m, 8H), 2,75 (sq, J=7.5 Hz, 2H), 2,97-to 3.41 (m, 6H), 3,68-of 3.77 (m, 1H), was 4.02-4,17 (m, 1H), 5,15 (s, 1H), 6.89 in (d, J=8.7 Hz, 1H), of 7.48-of 7.60 (m, 2H), 8,58 (d, J=8,5 Hz, 1H), 13,48-13,72 (m, 1H); ESI MS m/z 422 [M (free)++1, 100%].

Example 178

The hydrochloride of 3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-phenylpyrimidine-4-yl]amino}cyclohexyl)-4-fermentated

Stage A: Synthesis of 6-chloro-N,N-dimethyl-2-phenylpyrimidine-4-amine.

To a solution of 4,6-dichloro-2-phenylpyrimidine (2.00 g) in THF (10 ml) was added 50% aqueous Me2NH (2.30 ml) and the mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with CHCl3and added to saturated aqueous

NaHCO3. Water is Loy was extracted with CHCl 3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and dried under reduced pressure to obtain specified in the connection header (2,05 g).

1H NMR (300 MHz, CDCl3, δ): 3,19 (users, 6H), 6,34 (s, 1H), 7,39-7,49 (m, 3H), 8,35-to 8.45 (m, 2H); ESI MS m/z 234 (M++1, 100%).

Stage B: Synthesis of hydrochloride of 3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-phenylpyrimidine-4-yl]amino}cyclohexyl)-4-fermentated.

Specified in the title compound (85 mg) was obtained from 6-chloro-N,N-dimethyl-2-phenylpyrimidine-4-amine (250 mg) andN-(CIS-4-aminocyclohexane)-3-chloro-4-fermentated obtained in stage A of example 31 (319 mg), using the technique of stage C of example 168.

1H NMR (300 MHz, CDCl3, δ): 1,69-to 2.13 (m, 8H), 3,05-of 3.53 (m, 6H), 3.75 to-a-3.84 (m, 1H), 4,07-to 4.23 (m, 1H), 5,26 (s, 1H), 6,56 is 6.67 (m, 1H), 7,18 (t, J=8.6 Hz, 1H), 7,51 to 7.75 (m, 4H), 7,95 (d, J=8.5 Hz, 1H), 8,48 (d, J=6,5 Hz, 2H), 9,25-9,37 (m, 1H), 13,71-13,88 (m, 1H); ESI MS m/z 468 [M (free)++1, 100%].

Example 179

HydrochlorideN-(CIS-4-{[2-benzyl-6-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-3-chloro-4-fermentated

Stage A: Synthesis of 2-benzyl-6-chloro-N,N-dimethylpyrimidin-4-amine.

Specified in the header connection (2,02 g) was obtained from 2-benzyl-4,6-dichloropyrimidine (2.00 g) and 50% aqueous Me2NH (2,20 ml) using the technique of stage A of example 178.

1H NMR (300 MHz, CDCl3, δ): a 3.06 (s, 6H), was 4.02 (s, 2H), 6,23 (s, 1H), 7,16-the 7.43 (m, 5H); ESI MS m/z 248 (M++1, 100%).

Stage B: Synthesis of hydrochlorideN-(CIS-4-{[2-benzyl-6-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-3-chloro-4-fermentated.

Specified in the title compound (132 mg) was obtained from 2-benzyl-6-chloro-N,N-dimethylpyrimidin-4-amine (250 mg) andN-(CIS-4-aminocyclohexane)-3-chloro-4-fermentated obtained in stage A of example 31 (301 mg), using the technique of stage C of example 168.

1H NMR (300 MHz, CDCl3, δ): 1,65-2,04 (m, 8H), 2,94-to 3.38 (m, 6H), 3,63 of 3.75 (m, 1H), 3,98 (s, 2H), was 4.02-is 4.21 (m, 1H), 5,11 (s, 1H), 6,63 (d, J=8,1 Hz, 1H), 7,14-7,38 (m, 4H), 7,46-rate of 7.54 (m, 2H), to 7.67 to 7.75 (m, 1H), to $ 7.91-of 7.97 (m, 1H), to 8.57 (d, J=7.9 Hz, 1H); ESI MS m/z 482 [M (free)++1, 100%].

Example 180

The hydrochloride of 3-chloro-N-(CIS-4-{[6-(dimethylamino)-2,5-dimethylpyrimidin-4-yl]amino}cyclohexyl)-4-fermentated

Stage A: Synthesis of 2,5-dimethylpyrimidin-4,6-diol.

To a solution of Na (1.39 g) in EtOH (42 ml) was added diethylmalonate (5,00 g), and hydrochloride of acetamidine (2,71 g). The mixture is stirred at the boiling point under reflux for 2.5 hours and cooled to ambient temperature. The precipitate was collected by filtration, washed with EtOH and dried at 80°C under reduced pressure to obtain white solid. To the solution obtained above solids in H2O (30 ml) was added koncentrira is nnow HCl (2.5 ml) and the mixture was stirred at 4°C for 1 hour. The precipitate was collected by filtration, washed with H2O (twice), EtOH (twice) and Et2O (twice) and dried at 80°C under reduced pressure to obtain specified in the connection header (3,02 g).

1H NMR (300 MHz, DMSO-d6, δ): 1.69 in (s, 3H), 2,19 (s, 3H), 11,42-11,66 (m, 2H); ESI MS m/z 139 (M--1, 100%).

Stage B: Synthesis of 4,6-dichloro-2,5-dimethylpyrimidine.

A mixture of 2,5-dimethylpyrimidin-4,6-diol (3,02 g), POCl3(4,2 ml) andN,N-dimethylaniline (3.0 ml) was stirred at the boiling point under reflux for 1.5 hours and cooled to ambient temperature. The mixture was poured into ice water (20 ml) and was stirred for 2 hours. The precipitate was collected by filtration, washed with H2O and hexane and dried at 60°C with obtaining specified in the title compound (1.66 g).

1H NMR (300 MHz, CDCl3, δ): 2,45 (s, 3H), of 2.66 (s, 3H); CI MS m/z 177 (M+, 100%).

Stage C: Synthesis of 6-chloro-N,N,2,5-tetramethylpiperidine-4-amine.

Specified in the title compound (1.65 g) was obtained from 4,6-dichloro-2,5-dimethylpyrimidine (1.66 g) and 50% aqueous Me2NH (2,40 ml) using the technique of stage A of example 178.

1H NMR (300 MHz, CDCl3, δ): of 2.25 (s, 3H), 2,48 (s, 3H), to 3.02 (s, 6H); ESI MS m/z 186 (M++1, 100%).

Stage D: Synthesis of hydrochloride of 3-chloro-N-(CIS-4-{[6-(dimethylamino)-2,5-dimethylpyrimidin-4-yl]amino}cyclohexyl)-4-fermentated.

Listed is in the title compound (231 mg) was obtained from 6-chloro- N,N,2,5-tetramethylpiperidine-4-amine (300 mg) andN-(CIS-4-aminocyclohexane)-3-chloro-4-fermentated obtained in stage A of example 31 (481 mg), using the technique of stage C of example 168.

1H NMR (300 MHz, CDCl3, δ): 1,63-2,19 (m, 11H), 2,56 (users, 3H), 3,18 (s, 6H), 3,92-4,27 (m, 2H), 6,82-6,94 (m, 1H), 7,10-7,25 (m, 2H), 7,80-7,88 (m, 1H), 8,03 (d, J=6.2 Hz, 1H); ESI MS m/z 420 [M (free)++1, 100%].

Example 181

The hydrochloride of 3-chloro-N-(CIS-4-{[6-(dimethylamino)-5-fluoro-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-fermentated

Stage A: Synthesis of 5-fluoro-2-methylpyrimidine-4,6-diol.

Specified in the header connection (3,21 g) was obtained from diethylformamide (5,27 g), and hydrochloride of acetamidine (2,80 g) using the technique of stage A of example 180.

1H NMR (300 MHz, DMSO-d6, δ): 2,22 (d, J=0.9 Hz, 3H); ESI MS m/z 143 (M--1, 100%).

Stage B: Synthesis of 4,6-dichloro-5-fluoro-2-methylpyrimidine.

Specified in the title compound (3.13 g) was obtained from 5-fluoro-2-methylpyrimidine-4,6-diol (3,20 g) using the technique of stage B of example 180.

1H NMR (200 MHz, CDCl3, δ): 2,69 (d, J=1.3 Hz, 3H); CI MS m/z 181 (M++1, 100%).

Stage C: Synthesis of 6-chloro-5-fluoro-N,N2-trimethylpyridine-4-amine.

Specified in the header connection (2,02 g) was obtained from 4,6-dichloro-5-fluoro-2-methylpyrimidine (3,10 g) using the technique of stage C of example 180.

1H NMR (300 MHz, CDClsub> 3, δ): 2,44 (d, J=0.9 Hz, 3H), up 3.22 (d, J=2,5 Hz, 6H); ESI MS m/z 190 (M++1, 100%).

Stage D: Synthesis of hydrochloride of 3-chloro-N-(CIS-4-{[6-(dimethylamino)-5-fluoro-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-fermentated.

Specified in the title compound (135 mg) was obtained from 6-chloro-5-fluoro-N,N2-trimethylpyridine-4-amine (300 mg) andN-(CIS-4-aminocyclohexane)-3-chloro-4-fermentated obtained in stage A of example 31 (471 mg), using the technique of stage C of example 168.

1H NMR (300 MHz, CDCl3, δ): 1.70 to a 2.13 (m, 8H), 2,48 (s, 3H), 3,29 (d, J=3.1 Hz, 6H), 4,06-is 4.21 (m, 2H), 6,52-6,70 (m, 1H), 7,12-7,25 (m, 1H), 7,66-8,02 (m, 3H); ESI MS m/z 424 [M (free)++1, 100%].

Example 182

The hydrochloride of 3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-forbindelsesfaneblad

Specified in the title compound (271 mg) was obtained fromN-(CIS-4-aminocyclohexane)-2,N',N'-trimethylpyridine-4,6-diamine obtained in stage C of example 6 (250 mg)and 3-chloro-4-forbindelsesfaneblad (275 mg) using the method of example 7.

1H NMR (300 MHz, CDCl3, δ): 1,57 is 1.96 (m, 8H), 2,47 (s, 3H), 2,94-3,39 (m, 7H), 3,50-3,61 (m, 1H), 5,08 (s, 1H), of 5.83 (d, J=6,7 Hz, 1H), 7,21-7,31 (m, 1H), 7,85-to 7.93 (m, 1H), 8,00-of 8.06 (m, 1H), scored 8.38 (d, J=8,2 Hz, 1H); ESI MS m/z 442 [M (free)++1, 100%].

Example 183

HydrochlorideN-(3-chloro-4-forfinal)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]am is but}cyclohexyl)thiourea

To a solution ofN-(CIS-4-aminocyclohexane)-2,N',N'-trimethylpyridine-4,6-diamine obtained in stage C of example 6 (250 mg)in DMSO (2 ml) was added 3-chloro-4-perteneciente (206 mg) in DMSO (1 ml). The mixture was stirred at ambient temperature for 14 hours and poured into water. The precipitate was collected by filtration, washed with water and purified liquid medium pressure chromatography (NH-silica gel, 20%→50% EtOAc in hexane). To the solution obtained above substances in EtOAc (10 ml) was added 4M hydrogen chloride in EtOAc (0.5 ml). The mixture was stirred at ambient temperature for 1 hour and concentrated under reduced pressure. A suspension of the residue in Et2O (10 ml) was stirred at ambient temperature for 3 hours. The precipitate was collected by filtration, washed with Et2O and dried at 80°C under reduced pressure to obtain specified in the title compound (186 mg).

1H NMR (300 MHz, CDCl3, δ): 1.70 to a 2.12 (m, 8H), 2.40 a (s, 3H), 2.95 and is 3.40 (m, 6H), 3.46 in-3,61 (m, 1H), to 4.38-of 4.54 (m, 1H), 5,09 (users, 1H), 6,99-7,13 (m, 1H), 7,37-EUR 7.57 (m, 2H), 7,65-to 7.77 (m, 1H), 7,88 shed 8.01 (m, 1H), 9,16-9,29 (m, 1H), 13,26-13,42 (m, 1H); ESI MS m/z 437 [M (free)++1, 100%].

Example 184

4-bromophenyl(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate

To a solution ofN-(CIS-4-aminocyclohexane)-2,N',N'-trimethylpyridine-4,6-diamine obtained n the stage C of example 6 (250 mg), in CHCl3(3 ml) was added Et3N (of 0.21 ml) and 4-bromophenylacetate (283 mg). The mixture was stirred at ambient temperature for 14 hours. The reaction extinguished saturated aqueous NaHCO3and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (silica gel, 2% to 9% MeOH in CHCl3) obtaining specified in the title compound (100 mg).

1H NMR (300 MHz, CDCl3, δ): 1,54-of 1.95 (m, 8H), a 2.36 (s, 3H), 3,06 (s, 6H), to 3.58-3,81 (m, 2H), 4,66-of 4.77 (m, 1H), 4,96-5,04 (m, 1H), 5,15 (s, 1H), 7,03 (d, J=9.0 Hz, 2H), 7,46 (d, J=8,9 Hz, 2H); ESI MS m/z 448 (M++1, 100%).

Example 185

The hydrochloride of 3-chloro-N-{CIS-4-[(2,6-dimethoxypyrimidine-4-yl)amino]cyclohexyl}-4-fermentated

Specified in the title compound (16 mg) was obtained from 6-chloro-2,4-dimethoxypyrimidine (250 mg) andN-(CIS-4-aminocyclohexane)-3-chloro-4-fermentated obtained in stage A of example 31 (426 mg), using the technique of stage C of example 168.

1H NMR (300 MHz, CDCl3, δ): 1,66-2,04 (m, 8H), 3,64-of 3.78 (m, 1H), a 4.03 (s, 3H), 4,06-4,22 (m, 4H), 5,52 (s, 1H), of 6.71-6,86 (m, 1H), 7,12-7,24 (m, 1H), 7.68 per-7,79 (m, 1H), 7,95 (d, J=8,2 Hz, 1H), 9,14-9.28 are (m, 1H); ESI MS m/z 409 [M (free)++1, 40%], 423 [M (free)++15, 100%].

Example 186

The hydrochloride of 3-chloro-4-fluoro-N-[CIS-4-(7H-pyrrolo[2,3-d]feast midin-4-ylamino)cyclohexyl]benzamide

Specified in the title compound (113 mg) was obtained from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (300 mg) andN-(CIS-4-aminocyclohexane)-3-chloro-4-fermentated obtained in stage A of example 31 (582 mg), using the technique of stage C of example 168.

1H NMR (300 MHz, DMSO-d6, δ): 1,61-of 2.09 (m, 8H), 3,91-4,17 (m, 2H), 7,01 for 7.12 (m, 1H), 7,35-7,47 (m, 1H), 7,49-to 7.59 (m, 1H), 7,88-7,98 (m, 1H), 8,11-8,18 (m, 1H), 8,25-to 8.41 (m, 2H), 9,10 was 9.33 (m, 1H), 12,58-12,78 (m, 1H); ESI MS m/z 388 [M (free)++1, 100%].

Example 187

The hydrochloride of 3-chloro-4-fluoro-N-{CIS-4-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]cyclohexyl}benzamide

Stage A: Synthesis of 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine.

To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1,00 g) in DMF (10 ml) in an atmosphere of N2was added 60% NaH in oil (287 mg) and the mixture was stirred at ambient temperature for 10 minutes To the mixture was added logmean (0.45 ml) and the mixture was stirred at ambient temperature for 3 hours. The reaction extinguished saturated aqueous NH4Cl and the aqueous layer was extracted with EtOAc (three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (silica gel, 50% EtOAc in hexane) to obtain specified in the connection header (999 mg).

1H NMR (300 MHz, CDCl3, δ): 3,90 (s, 3H), of 6.61 (d, J=3.6 Hz, 1H), 7,22 (d, J=3.6 Hz, 1H), 8,65 (s, 1H); ESI MS m/z 168 [M (free)++1, 100%].

Stage B: Synthesis of hydrochloride of 3-chloro-4-fluoro-N-{CIS-4-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]cyclohexyl}benzamide.

Specified in the title compound (765 mg) was obtained from 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (400 mg) andN-(CIS-4-aminocyclohexane)-3-chloro-4-fermentated obtained in stage A of example 31 (711 mg), using the technique of stage C of example 168.

1H NMR (300 MHz, DMSO-d6, δ): 1,64-2,11 (m, 8H), 3,81 (s, 3H), 3,91-to 4.23 (m, 2H), 7,00-7,17 (m, 1H), 7,40-to 7.59 (m, 2H), 7,87-7,98 (m, 1H), 8,14 (DD, J=7,1, 2.2 Hz, 1H), 8,29-to 8.41 (m, 2H), 9,17-9,37 (m, 1H); ESI MS m/z 402 [M (free)++1, 100%].

Example 188

Hydrochloride 3,4,5-Cryptor-N-{CIS-4-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]cyclohexyl}benzamide

Specified in the title compound (168 mg) was obtained fromN-(CIS-4-aminocyclohexane)-3,4,5-triterpenoid obtained in stage A of example 168 (487 mg), and 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (250 mg) using the technique of stage C of example 168.

1H NMR (300 MHz, DMSO-d6, δ): 1,60-of 2.15 (m, 8H), 3,81 (s, 3H), 3,90-4.26 deaths (m, 2H), 6,94-7,17 (m, 1H), 7,35-7,53 (m, 1H), 7,73-7,98 (m, 2H), by 8.22-of 8.47 (m, 2H), 9,14-9,42 (m, 1H); ESI MS m/z 404 [M (free)++1, 100%].

Example 189

The hydrochloride of 3-chloro-N-{CIS-4-[(7-ethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]cyclohexyl}-4-fermentated

Stage A: With ntes 4-chloro-7-ethyl-7H-pyrrolo[2,3-d]pyrimidine.

Specified in the title compound (577 mg) was obtained from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg) and iodoethane (0,31 ml) using the technique of stage A of example 187.

1H NMR (300 MHz, CDCl3, δ): 1.50 in (t, J=7,3 Hz, 3H), 4,34 (sq, J=7,3 Hz, 2H), is 6.61 (d, J=3.6 Hz, 1H), 7,27 (d, J=3.6 Hz, 1H), 8,64 (s, 1H); ESI MS m/z 182 (M++1, 100%).

Stage B: Synthesis of hydrochloride of 3-chloro-N-{CIS-4-[(7-ethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]cyclohexyl}-4-fermentated.

Specified in the title compound (299 mg) was obtained from 4-chloro-7-ethyl-7H-pyrrolo[2,3-d]pyrimidine (250 mg) andN-(CIS-4-aminocyclohexane)-3-chloro-4-fermentated obtained in stage A of example 31 (410 mg), using the technique of stage C of example 168.

1H NMR (300 MHz, DMSO-d6, δ): to 1.37 (t, J=7.2 Hz, 3H), 1,63-of 2.08 (m, 8H), 3,92-4,20 (m, 2H), 4.26 deaths (sq, J=7,3 Hz, 2H), 7.03 is-7,13 (m, 1H), 7,47-to 7.59 (m, 2H), 7,88-of 7.97 (m, 1H), 8,14 (DD, J=7,2, 2.1 Hz, 1H), 8,27-8,39 (m, 2H), 9,18-9,35 (m, 1H); ESI MS m/z 416 [M (free)++1, 100%].

Example 190

The hydrochloride of 3-chloro-4-fluoro-N-{CIS-4-[(9-methyl-9H-purine-6-yl)amino]cyclohexyl}benzamide

Stage A: Synthesis of 6-chloro-9-methyl-9H-purine.

Specified in the title compound (1.08 g) was obtained from 6-chloro-9H-purine (2.00 g) and iodomethane (0,96 ml) using the technique of stage A of example 187.

1H NMR (300 MHz, CDCl3, δ): 3,95 (s, 3H), 8,12 (s, 1H), 8,78 (s, 1H); ESI MS m/z 182 (M++1, 100%).

Stage B: Synthesis of hydrochloride of 3-the ers-4-fluoro- N-{CIS-4-[(9-methyl-9H-purine-6-yl)amino]cyclohexyl}benzamide.

Specified in the title compound (170 mg) was obtained from 6-chloro-9-methyl-9H-purine (250 mg) andN-(CIS-4-aminocyclohexane)-3-chloro-4-fermentated obtained in stage A of example 31 (410 mg), using the technique of stage C of example 168.

1H NMR (300 MHz, DMSO-d6, δ): 1,61-to 2.06 (m, 8H), 3,83 (s, 3H), 3,86-or 4.31 (m, 2H), 4,72-to 4.98 (m, 1H), of 7.48-to 7.59 (m, 1H), 7,86-to 7.95 (m, 1H), 8,11 (DD, J=7,3, 2.2 Hz, 1H), 8,20-8,61 (m, 3H); ESI MS m/z 403 [M (free)++1, 90%], 425 [M (free)++23, 100%].

Example 191

HydrochlorideCIS-N-(3-chloro-4-forfinal)-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexanecarboxylic

Stage A: Synthesis ofCIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexanecarboxylic acid.

To a suspension of (6-chloro-2-methylpyrimidin-4-yl)amine, obtained in stage B of example 5 (20,0 g)in toluene (300 ml) in an atmosphere of N2addedCIS-4-aminocyclohexanecarboxylic acid (16.7 g), biphenyl-2-yl(di-tert-butyl)phosphine (346 mg), palladium (II) acetate (260 mg) andtert-piperonyl sodium (21,6 g). The mixture is stirred at the boiling point under reflux for 6 hours and cooled to ambient temperature. To the mixture was added 1M aqueous NaOH (300 ml) and the two layers were separated. The aqueous layer was washed with EtOAc. The aqueous layer was cooled in an ice bath and add the Lyali concentrated HCl (15 ml) (pH 6). The precipitate was collected by filtration, washed with H2O and EtOAc and dried at 80°C under reduced pressure to obtain specified in the title compound (22.1 g).

1H NMR (300 MHz, CDCl3, δ): 1,64-of 2.16 (m, 8H), 2,35-2,48 (m, 4H), 3,10 (s, 6H), 3.46 in-3,59 (m, 1H), 5,11 (s, 1H), total of 8.74-8,84 (m, 1H); ESI MS m/z 279 (M++1, 100%).

Stage B: Synthesis of hydrochlorideCIS-N-(3-chloro-4-forfinal)-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexanecarboxylic.

To a suspension ofCIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexanecarboxylic acid (180 mg) and 3-chloro-4-foronline (114 mg) in DMF (2 ml) was added Et3N (0,22 ml), HOBt-H2O (150 mg) and EDC-HCl (150 mg). The mixture was stirred at ambient temperature for 14 hours. To the mixture was added water (20 ml) and the aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, 20% to 50% EtOAc in hexane) to give colorless oil. To the solution obtained above oil in EtOAc (10 ml) was added 4M hydrogen chloride in EtOAc (0.5 ml). The mixture was stirred at ambient temperature for 1 hour and concentrated. The residue is suspended in Et2O (10 ml) and the suspension was stirred at ambient temperature for 4 hours. Sludge is gathered and filtering washed Et2O and dried at 80°C under reduced pressure to obtain specified in the title compound (27 mg).

1H NMR (300 MHz, CDCl3, δ): 1,53-of 1.73 (m, 2H), 1,81-2,02 (m, 4H), 2,13-of 2.34 (m, 2H), 2,37-of 2.58 (m, 4H), 3,03-to 3.36 (m, 6H), 3,76-to 3.89 (m, 1H), 5,17 (s, 1H), of 6.96 for 7.12 (m, 1H), of 7.64-to 7.77 (m, 1H), 8,02 is 8.22 (m, 1H), 8,80-8,93 (m, 1H), of 9.30-9,46 (m, 1H); ESI MS m/z 406 [M (free)++1, 100%].

Example 192

HydrochlorideCIS-N-(3,4-differenl)-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexanecarboxylic

To a suspension ofCIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexanecarboxylic acid obtained in stage A of example 191 (2.1 g)in CHCl3(21 ml) was added thionyl chloride (1,21 ml) and DMF (6 mg). The mixture is stirred at the boiling point under reflux for 1.5 hours, concentrated under reduced pressure and the residue was dissolved in CHCl3(4,9 ml). To a solution of 3,4-diferencia (223 mg) in CHCl3(3 ml) was added Et3N (0,42 ml) and the acid chloride obtained above in CHCl3(1 ml). The mixture was stirred at ambient temperature for 14 hours and was added to saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3(three times). The combined organic layer was dried over MgSO4was filtered , concentrated under reduced pressure and was purified liquid medium pressure chromatography (NH-silica gel, from 11% to 50% EtOAc-hexane) to give a colorless oil. To the solution obtained above oil in EtOAc (10 ml) was added 4M hydrogen chloride in EtOAc (0.5 ml). The mixture was stirred at ambient temperature for 1 hour and concentrated under reduced pressure. A suspension of the residue in Et2O (10 ml) was stirred at ambient temperature for 4 hours. The precipitate was collected by filtration, washed with Et2O and dried at 80°C under reduced pressure to obtain specified in the title compound (102 mg).

1H NMR (300 MHz, CDCl3, δ): 1,51-is 2.37 (m, 8H), 2.40 a is 2.55 (s, 4H), 3,07 (users, 3H), 3,31 (users, 3H), of 3.77-3,91 (m, 1H), 5,18 (s, 1H), 6,98 for 7.12 (m, 1H), 7,56-7,66 (m, 1H), of 7.96-8,07 (m, 1H), 8,82 (d, J=9.8 Hz, 1H), of 9.21-9.28 are (m, 1H), 13,10-13,26 (m, 1H); ESI MS m/z 390 [M (free)++1, 100%].

Example 193

HydrochlorideCIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}-N-(3,4,5-tryptophanyl)cyclohexanecarboxylic

Specified in the title compound (173 mg) was obtained from 3,4,5-triptorelin (254 mg) using the method of example 192.

1H NMR (300 MHz, CDCl3, δ): 1,54-1,72 (m, 2H), 1,81 is 2.01 (m, 4H), 2,15-of 2.36 (m, 2H), 2.40 a is 2.55 (m, 4H), 3,07 (users, 3H), 3,31 (users, 3H), 3,80-3,90 (m, 1H), 5,18 (s, 1H), 7,69-7,81 (m, 2H), 8,79 (d, J=9.6 Hz, 1H), 9,37 (users, 1H), of 13.05 (users, 1H); ESI MS m/z 408 [M (free)++1, 100%].

Example 194

The hydrochloride of 3-chloro-4-forfinal-CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}of cyclohexanecarboxylate

Specified in the header link is (4 mg) was obtained from 3-chloro-4-terfenol (254 mg) using the method of example 192.

1H NMR (300 MHz, CDCl3, δ): 1,61 is 2.33 (m, 8H), 2,38-of 2.56 (m, 3H), 2,60-2,77 (m, 1H), 2.91 in-3,44 (m, 6H), 3,48-3,71 (m, 1H), 5,10 (s, 1H), 6,91-7,34 (m, 3H), scored 8.38-8,55 (m, 1H); ESI MS m/z 407 [M (free)++1, 100%].

Example 195

HydrochlorideCIS-N-(3,5-dichlorophenyl)-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexanecarboxylic

Specified in the title compound (35 mg) was obtained from 3,5-dichlorphenol (282 mg) using the method of example 192.

1H NMR (300 MHz, CDCl3, δ): 1,72-2,31 (m, 8H), 2.49 USD (s, 3H), 2,60-by 2.73 (m, 1H), 2,97-to 3.41 (m, 6H), 3,52-3,68 (m, 1H), 5,11 (s, 1H), was 7.08 (d, J=1.9 Hz, 2H), 7,21-7,24 (m, 1H), 8,49 (d, J=7,1 Hz, 1H); ESI MS m/z 423 [M (free)++1, 100%].

Example 196

Hydrochloride 3,4-differenl-CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}of cyclohexanecarboxylate

Specified in the title compound (3 mg) was obtained from 3,4-differenoe (225 mg) using the method of example 192.

1H NMR (300 MHz, CDCl3, δ): 1,69 of-2.32 (m, 8H), 2.49 USD (s, 3H), 2,58-2,77 (m, 1H), 2,93-to 3.41 (m, 6H), 3,51-to 3.67 (m, 1H), 5,11 (s, 1H), 6,82-7,24 (m, 3H), 8,32-8,58 (m, 1H); ESI MS m/z 391 [M (free)++1, 100%].

Example 197-274

To a suspension of poly(4-vinylpyridine) - derivatives) (150 ml) in CHCl3(200 ml) was addedN-(CIS-4-aminocyclohexane)-2,N',N'-trimethylpyridine-4,6-diamine obtained in stage C of example 6 (60 mmol)in CHCl3(200 ml) and the acid chloride (120 mmol) in CHCl3(200 ml) at ambient temperature. After AC is shivani at the same temperature for 14 hours the mixture was filtered and concentrated under reduced pressure. To the residue was added CHCl3(685 ml) and PSA (300 ml). After stirring at ambient temperature for 14 hours, the mixture was purified by chromatography on silica gel (NH-silica gel, 50%→100% EtOAc in hexane and silica gel, CHCl3→6% 2M NH3/MeOH in CHCl3) to give the desired product. The product was identified by ESI-MS or APCI-MS.

Example 275-352

To a suspension of 1-cyclohexyl-3-methylolacrylamide (150 ml) in CHCl3(400 ml) was addedN-(CIS-4-aminocyclohexane)-2,N',N'-trimethylpyridine-4,6-diamine obtained in stage C of example 6 (30 mmol)in CHCl3(200 ml) and carboxylic acid (60 mmol) in CHCl3(200 ml) at ambient temperature. After stirring at the same temperature for 13 hours, the mixture was filtered through NH-silica gel. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (silica gel, CHCl3→6% 2M NH3/MeOH in CHCl3) to give the desired product. The product was identified by ESI-MS or APCI-MS.

Example 353-410

To a solution of half the mass of the amide product obtained in examples 197-274 in THF (200 ml) was added 1M complex borohydride-THF in THF (300 ml). The mixture was stirred at 80°C for 1 hour and concentrated under reduced pressure. To the residue was added 1M aqueous HCl (300 ml) and THF (200 ml). The mixture was stirred is at 80°C for 1 hour and concentrated under reduced pressure. The residue was distributed between CHCl3and 2M aqueous sodium hydroxide. The aqueous layer was extracted with CHCl3(300 ml, twice) and EtOAc (300 ml). The combined organic layers were dried over MgSO4concentrated under reduced pressure and was purified by chromatography on silica gel (silica gel, 33% EtOAc in hexane→6% 2M

NH3/MeOH in CHCl3) to give the desired product. The product was identified by ESI-MS or APCI-MS.

Example 411-451

To a solution ofN-(CIS-4-aminocyclohexane)-2,N',N'-trimethylpyridine-4,6-diamine obtained in stage C of example 6 (30 mmol)in DMSO (300 ml) was added isocyanate or isothiocyanate (60 mmol) in DMSO (200 ml) at ambient temperature. The mixture was stirred at the same temperature for 12 hours and filtered through SCX. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (silica gel, 50% EtOAc in hexane→6% 2M NH3/MeOH in CHCl3) to give the desired product. The product was identified by ESI-MS or APCI-MS.

Example 452-522

To a suspension of poly(4-vinylpyridine) - derivatives) (75 ml) in CHCl3(200 ml) was addedN-(CIS-4-aminocyclohexane)-2,N',N'-trimethylpyridine-4,6-diamine obtained in stage C of example 6 (30 mmol)in CHCl3(200 ml) and chloroformic or sulphonylchloride (60 mmol) in CHCl3(200 ml) at ambient temperature is Reda. After stirring at the same temperature for 14 hours the mixture was filtered and concentrated under reduced pressure. To the residue was added CHCl3(685 ml) and PSA (300 ml). After stirring at ambient temperature for 14 hours, the mixture was purified by chromatography on silica gel (NH-silica gel, 50%→100% EtOAc in hexane and silica gel, 33% EtOAc in hexane→6% 2M NH3/MeOH in CHCl3) to give the desired product. The product was identified by ESI-MS or APCI-MS.

td align="center"> 394
(M+H) 261td align="left"> N'-(CIS-4-{[(3,4-differenl)methyl]amino}cyclohexyl)-N,N,2-trimethylpyridine-4,6-diamine 370
(M+H)
no otherConnection nameMSclass
1972-[(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)amino]-2-oxo-1-fenilatilamin426
(M+H)
3
198N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide484
(M+H)
3
199N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)ndimethylacetamide292
(M+H)
3
200N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide354
(M+H)
2
201N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl) - biphenyl-4-carboxamid430
(M+H)
3
2024-tert-butyl-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide410
(M+H)
3
203N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-1-benzothiophen-2-carboxamide409(M)3
204N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-{4-[(phenylmethyl)oxy]phenyl}ndimethylacetamide474
(M+H)
3
2054-bromo-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide432
(M+H)
3
206 N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-[(phenylmethyl)oxy]ndimethylacetamide398
(M+H)
3
207N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2,1,3-benzoxadiazole-5-carboxamide396
(M+H)
3
2084-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide388
(M+H)
2
2092-[(4-chlorophenyl)oxy]-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)ndimethylacetamide418
(M+H)
3
210(2E)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-phenylprop-2-ename380
(M+H)
3
211N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)cyclopropanecarboxamide318
(M+H)
3
212 N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)cyclohexanecarboxylic360
(M+H)
3
2132-(4-chlorophenyl)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)ndimethylacetamide402
(M+H)
3
2141-(4-chlorophenyl)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)cyclopentanecarboxylic456
(M+H)
1
2153-(2-chloro-6-forfinal)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-5-methylisoxazol-4-carboxamide487
(M+H)
1
2164-[(4-chlorophenyl)sulfonyl]-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-methylthiophene-2-carboxamide548
(M+H)
3
2174-(dimethylamino)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide397
(M+H)
3
218N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4-diflorasone390
(M+H)
1
219N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4-bis(metiloksi)benzamid414
(M+H)
3
220N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-(ethyloxy)benzamide398
(M+H)
3
221N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-perbenzoic372
(M+H)
3
222N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)furan-2-carboxamide344
(M+H)
3
223N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)isoxazol-5-carboxamid345
(M+H)
3
224N-(CIS-4-{[6-(is metilamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-itbased 480
(M+H)
3
225N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)morpholine-4-carboxamide363
(M+H)
3
226N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-(methylthio)pyridine-3-carboxamide401
(M+H)
3
227Methyl-4-{[(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)amino]carbonyl}benzoate412
(M+H)
3
228N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-5-methyl-2-phenyl-2H-1,2,3-triazole-4-carboxamide435
(M+H)
3
229N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide376
(M+H)
3
230N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-(4-IU is okefenoke)-5-nitrobenzamide 521
(M+H)
2
231N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)naphthalen-2-carboxamide404
(M+H)
3
232N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-nitrobenzamide399
(M+H)
3
233N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-1-(4-nitrophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide533
(M+H)
3
234N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-(phenyloxy)ndimethylacetamide384
(M+H)
3
235N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-phenylacetamide368
(M+H)
3
236(2R)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-phenylcyclopropanecarboxylic3
237N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-1,3-benzodioxol-5-carboxamid398
(M+H)
3
238N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide488
(M+H)
3
239N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-[(2-nitrophenyl)oxy]ndimethylacetamide429
(M+H)
3
240N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)cinoxacin-2-carboxamide406
(M+H)
3
241N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-(trifluoromethyl)benzamid422
(M+H)
3
242N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-methylbenzamide 368
(M+H)
3
243N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiophene-2-carboxamide360
(M+H)
3
244N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-[(pentafluorophenyl)oxy]ndimethylacetamide474
(M+H)
3
2452-[3,4-bis(metiloksi)phenyl]-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)ndimethylacetamide428
(M+H)
3
246N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-(phenylthio)ndimethylacetamide400
(M+H)
3
247N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-9-oxo-9H-fluoren-4-carboxamid456
(M+H)
3
248N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-[(trifluoromethyl)oxy]benzamide3
249N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-fluoro-2-(trifluoromethyl)benzamid440
(M+H)
3
250N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-(4-forfinal)ndimethylacetamide386
(M+H)
3
251N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-(heptyloxy)benzamid468
(M+H)
3
252N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-pentylbenzene424
(M+H)
3
253N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)cyclopentanecarboxylic346
(M+H)
3
254N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-nonylbenzene480
(M+H)
3
255N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-{[4-(1,1-dimethylethyl)phenyl]oxy}ndimethylacetamide440
(M+H)
3
2563-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-perbenzoic406
(M+H)
1
2572-cyclopentyl-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)ndimethylacetamide360
(M+H)
3
258N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-phenylpropanamide382
(M+H)
3
2594-cyano-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide379
(M+H)
3
260N-[4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-2-(naphthalen-1 sulfonylamino)-3-phenylpropionamide587
(M+H)
3
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-[(trifluoromethyl)thio]benzamide454
(M+H)
3
262(2E)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-[3-(trifluoromethyl)phenyl]prop-2-ename448
(M+H)
3
263(2E)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-(4-nitrophenyl)prop-2-ename425
(M+H)
3
2642-(2-bromophenyl)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)ndimethylacetamide446
(M+H)
3
265(2E)-3-(2-chlorophenyl)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)prop-2-ename414
(M+H)
3
266N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-(phenylthio)pyridine-3-carboxamide463
(M+H)
3
267N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-(1,1-dimethylethyl)-1-(phenylmethyl)-1H-pyrazole-5-carboxamide490
(M+H)
3
2682-[(4-chlorophenyl)oxy]-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-methylpropanamide446
(M+H)
3
269(2E)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-{4-[(trifluoromethyl)oxy]phenyl}prop-2-ename464
(M+H)
3
2701-[(2,4-dichlorophenyl)methyl]-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-(1,1-dimethylethyl)-1H-pyrazole-5-carboxamide558
(M+H)
3
2716-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2H-chromen-3-carboxamide442
(M+H)
3
2725-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-1-methyl-1H-pyrazole-4-carbox the amide 392
(M+H)
3
273N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-[(4-methyl-2-oxo-2H-chromen-8-yl)oxy]ndimethylacetamide466
(M+H)
3
274N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)ndimethylacetamide437
(M+H)
3
2752-[(4-acetylphenyl)oxy]-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)ndimethylacetamide426
(M+H)
3
276N-((1S)-2-{[(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)amino]carbonyl}cyclohexyl)benzamide479
(M+H)
3
277N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-1-{[4-(1,1-dimethylethyl)phenyl]sulfonyl}prolinamide543
(M+H)
3
2782-cyclohex-1-EN-1-yl-N-(CIS- 372
(M+H)
3
2792-cyclohexyl-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)ndimethylacetamide374
(M+H)
3
280N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-[(4-methylpyrimidin-2-yl)thio]ndimethylacetamide416
(M+H)
3
2813-[(4-chlorophenyl)sulfonyl]-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)butanamide494
(M+H)
3
282N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-5-oxo-1-(2-thienylmethyl)pyrrolidin-3-carboxamide457
(M+H)
3
283N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2,5-dimethyl-1-(2-thienylmethyl)-1H-pyrrol-3-carboxamide467
(M+H)
3
284N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-the l]amino}cyclohexyl)-2-(2-forbiden-4-yl)propanamide 476
(M+H)
3
285N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-5-iodine-2-furamide470
(M+H)
3
286N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-[4-(1-oxo-1,3-dihydro-2H-isoindole-2-yl)phenyl]propanamide513
(M+H)
3
287N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-(2-itfinal)ndimethylacetamide494
(M+H)
3
288N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-5-(4-were)thiophene-3-carboxamide450
(M+H)
3
289N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ndimethylacetamide465
(M+H)
3
290N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-[6-(IU is yloxy)-3-oxo-2,3-dihydro-1H-inden-1-yl]ndimethylacetamide 452
(M+H)
3
291N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-[7-(metiloksi)-2-oxo-2H-chromen-4-yl]ndimethylacetamide466
(M+H)
3
292N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-[4-(methylsulphonyl)phenyl]-4-oxobutanamide488
(M+H)
3
293N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-5-(metiloksi)-1H-indole-2-carboxamide423
(M+H)
3
294N-(2,4-differenl)-2-{2-[(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)amino]-2-oxoethyl}benzamide523
(M+H)
3
2952-(2-{[2,5-bis(metiloksi)phenyl]amino}-2-oxoethyl)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide547
(M+H)
3
2962-{2-[(CIS-4-{[6-(dim is thylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)amino]-2-oxoethyl}-N-[4-(1-methylethyl)phenyl]benzamide 529
(M+H)
3
2972-{2-[(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)amino]-2-oxoethyl}-N-{4-[(trifluoromethyl)oxy]phenyl}benzamide571
(M+H)
3
298N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-(4-nitrophenyl)butanamide441
(M+H)
3
299N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-oxo-2,3-dihydro-1H-inden-1-carboxamid408
(M+H)
3
300N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-[4-(phenyloxy)phenyl]ndimethylacetamide460
(M+H)
3
301N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-11-phenylendiamin494
(M+H)
3
302N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl is)-2-(pyridine-4-ylthio)ndimethylacetamide 401
(M+H)
3
303N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N2-phenylglycinate383
(M+H)
3
304N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-[(4-forfinal)carbonyl]benzamide476
(M+H)
3
305N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-(2-phenylethyl)benzamide458
(M+H)
3
306N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-(ethylthio)-2,2-diphenylacetamide504
(M+H)
1
307N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4'-(trifluoromethyl)biphenyl-2-carboxamide498
(M+H)
3
308N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-7-nitro-9H-fluoren-4-carboxamid 487
(M+H)
3
309(2S)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-[3-(phenylcarbamoyl)phenyl]propanamide486
(M+H)
3
3102-[(4-chlorophenyl)thio]-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-(4-were)-4-oxobutanamide566
(M+H)
3
311N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-(4-forfinal)-2-[(4-were)thio]-4-oxobutanamide550
(M+H)
3
312N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-[4-(2-thienylboronic)phenyl]propanamide492
(M+H)
3
313N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-{4-[(trifluoromethyl)oxy]phenyl}ndimethylacetamide452
(M+H)
3
314N-(CIS-4-{[6-(dimethyl is Ino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4,4,4-Cryptor-3-methylbutanoic 388
(M+H)
3
315N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-{4-[(trifluoromethyl)thio]phenyl}ndimethylacetamide468
(M+H)
3
316N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-5-(2-thienyl)pentanone416
(M+H)
3
317N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N2-[(4-were)sulfonyl]glycinamide461
(M+H)
3
318N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-{5-[(phenylmethyl)oxy]-1H-indol-3-yl}ndimethylacetamide513
(M+H)
3
319N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-(3-were)benzene-1,2-dicarboxamide487
(M+H)
3
320N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]am is but}cyclohexyl)-3-methyl-4-oxo-2-phenyl-4H-chromen-8-carboxamide 512
(M+H)
3
321phenylmethyl 3-[(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)amino]-3-oxo-2-phenylpropanoate502
(M+H)
3
3222-{[3,5-bis(trifluoromethyl)phenyl]carbonyl}-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide594
(M+H)
3
323N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-[(3-methyl-1-benzothieno-2-yl)carbonyl]benzamide528
(M+H)
3
324N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-9-oxo-9H-fluoren-2-carboxamide456
(M+H)
3
325N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl) - biphenyl-2-carboxamide430
(M+H)
3
326N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]AMI is about}cyclohexyl)-4-(phenyloxy)benzamid 446
(M+H)
3
327N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-9H-xanthene-9-carboxamide458
(M+H)
3
328N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-[(1S)-1-phenylethyl]benzene-1,2-dicarboxamide501
(M+H)
3
329N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-[(phenylmethyl)oxy]benzamide460
(M+H)
3
330N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-[(4-were)carbonyl]benzamide472
(M+H)
3
331N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-[(phenyloxy)methyl]benzamide460
(M+H)
3
332N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-naphthalen-1 and the benzene-1,2-dicarboxamide 523
(M+H)
3
333N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)anthracene-2-carboxamide454
(M+H)
3
334N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4'-heptylbiphenyl-4-carboxamid528
(M+H)
3
3352-[4-(4-chlorophenyl)-2-phenyl-1,3-thiazol-5-yl]-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)ndimethylacetamide561
(M+H)
3
336N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-[(phenylmethyl)thio]ndimethylacetamide414
(M+H)
3
337N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-phenylbutyramide396
(M+H)
3
3382-(1-benzothieno-3-yl)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl) - acetone is 424
(M+H)
3
3392-(2,3-dihydro-1H-inden-2-yl)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)ndimethylacetamide408
(M+H)
3
3404-[3,4-bis(metiloksi)phenyl]-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)butanamide456
(M+H)
3
3414-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)butanamide454
(M+H)
3
342N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-1-[(4-were)sulfonyl]-1H-pyrrol-3-carboxamide497
(M+H)
3
343N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-(methylsulphonyl)benzamid432
(M+H)
3
3445-acetyl-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrene the Jn-4-yl]amino}cyclohexyl)thiophene-2-carboxamide 402
(M+H)
3
3453-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-[(1-methylethyl)sulfonyl]-5-(methylthio)thiophene-2-carboxamide546
(M+H)
3
346N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-5-(methylsulphonyl)thiophene-2-carboxamide438
(M+H)
3
347N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-(1,3-oxazol-5-yl)benzamid421
(M+H)
3
348N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-1-(phenylsulfonyl)-1H-indol-3-carboxamide533
(M+H)
3
349N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-oxo-2-phenylacetamide382
(M+H)
3
350N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-and the]amino}cyclohexyl)-2-oxo-2-(2,4,6-trimetilfenil)ndimethylacetamide 424
(M+H)
3
351(2R,5S)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-5-phenyl-2-(phenylcarbamoyl)cyclohexanecarboxylic540
(M+H)
3
352N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-(9H-fluoren-9-ilidene)ndimethylacetamide454
(M+H)
3
3532-{[(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)amino]methyl}anthracene-9,10-dione470
(M+H)
3
354N,N,2-trimethyl-N'-{CIS-4-[(phenylmethyl)amino]cyclohexyl}pyrimidine-4,6-diamine340
(M+H)
3
355N'-{CIS-4-[(biphenyl-4-ylmethyl)amino]cyclohexyl}-N,N,2-trimethylpyridine-4,6-diamine416
(M+H)
3
356N'-[CIS-4-({[4-(1,1-dimethylethyl)phenyl]methyl}amino)cyclohexyl]-N,N,2-trimethylpyridine-4,6-diamine 396
(M+H)
3
357N'-{CIS-4-[(1-benzothieno-2-ylmethyl)amino]cyclohexyl}-N,N,2-trimethylpyridine-4,6-diamine396
(M+H)
3
358N'-(CIS-4-{[(4-bromophenyl)methyl]amino}cyclohexyl)-N,N,2-trimethylpyridine-4,6-diamine418
(M+H)
3
359N,N,2-trimethyl-N'-[CIS-4-({2-[(phenylmethyl)oxy]ethyl}amino)cyclohexyl]pyrimidine-4,6-diamine384
(M+H)
3
360N'-(CIS-4-{[(4-chlorophenyl)methyl]amino}cyclohexyl)-N,N,2-trimethylpyridine-4,6-diamine374
(M+H)
3
361N'-[CIS-4-({2-[(4-chlorophenyl)oxy]ethyl}amino)cyclohexyl]-N,N,2-trimethylpyridine-4,6-diamine404
(M+H)
3
362N'-{CIS-4-[(cyclopropylmethyl)amino]cyclohexyl}-N,N,2-trimethylpyridine-4,6-diamine304
(M+H)
3
63 N'-{CIS-4-[(cyclohexylmethyl)amino]cyclohexyl}-N,N,2-trimethylpyridine-4,6-diamine346
(M+H)
3
364N'-(CIS-4-{[2-(4-chlorophenyl)ethyl]amino}cyclohexyl)-N,N,2-trimethylpyridine-4,6-diamine388
(M+H)
3
365N'-[CIS-4-({[1-(4-chlorophenyl)cyclopentyl]methyl}amino)cyclohexyl]-N,N,2-trimethylpyridine-4,6-diamine442
(M+H)
3
366N'-[CIS-4-({[3-(2-chloro-6-forfinal)-5-methylisoxazol-4-yl]methyl}amino)cyclohexyl]-N,N,2-trimethylpyridine-4,6-diamine473
(M+H)
3
367N'-{CIS-4-[({4-[(4-chlorophenyl)sulfonyl]-3-methyl-2-thienyl}methyl)amino]cyclohexyl}-N,N,2-trimethylpyridine-4,6-diamine534
(M+H)
3
368N'-[CIS-4-({[4-(dimethylamino)phenyl]methyl}amino)cyclohexyl]-N,N,2-trimethylpyridine-4,6-diamine383
(M+H)
3
369376
(M+H)
3
370N'-[CIS-4-({[3,4-bis(metiloksi)phenyl]methyl}amino)cyclohexyl]-N,N,2-trimethylpyridine-4,6-diamine400
(M+H)
3
371N'-[CIS-4-({[4-(ethyloxy)phenyl]methyl}amino)cyclohexyl]-N,N,2-trimethylpyridine-4,6-diamine384
(M+H)
3
372N'-(CIS-4-{[(4-forfinal)methyl]amino}cyclohexyl)-N,N,2-trimethylpyridine-4,6-diamine358
(M+H)
3
373N'-{CIS-4-[(furan-2-ylmethyl)amino]cyclohexyl}-N,N,2-trimethylpyridine-4,6-diamine330
(M+H)
3
374N'-{CIS-4-[(isoxazol-5-ylmethyl)amino]cyclohexyl}-N,N,2-trimethylpyridine-4,6-diamine331
(M+H)
3
375N'-(CIS-4-{[(2-itfinal)methyl]amino}cyclohexyl)-N,N,2-timetype is kidin-4,6-diamine 466
(M+H)
3
376N,N,2-trimethyl-N'-(CIS-4-{[(5-methyl-2-phenyl-2H-1,2,3-triazole-4-yl)methyl]amino}cyclohexyl)pyrimidine-4,6-diamine421
(M+H)
3
377N,N,2-trimethyl-N'-(CIS-4-{[(2-{[4-(metiloksi)phenyl]oxy}-5-nitrophenyl)methyl]amino}cyclohexyl)pyrimidine-4,6-diamine507
(M+H)
3
378N,N,2-trimethyl-N'-{CIS-4-[(naphthalen-2-ylmethyl)amino]cyclohexyl}pyrimidine-4,6-diamine390
(M+H)
3
379N,N,2-trimethyl-N'-(CIS-4-{[(3-nitrophenyl)methyl]amino}cyclohexyl)pyrimidine-4,6-diamine385
(M+H)
3
380N,N,2-trimethyl-N'-[CIS-4-({[1-(4-nitrophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methyl}amino)cyclohexyl]pyrimidine-4,6-diamine519
(M+H)
3
381N,N,2-trimethyl-N'-(CIS-4-{[2-(phenyloxy)ethyl]amino}cyclohexyl)pyrimidine-4,6-diamine3
382N,N,2-trimethyl-N'-{CIS-4-[(2-phenylethyl)amino]cyclohexyl}pyrimidine-4,6-diamine354
(M+H)
3
383N,N,2-trimethyl-N'-[CIS-4-({[(2R)-2-vinylcyclopropyl]methyl}amino)cyclohexyl]pyrimidine-4,6-diamine380
(M+H)
3
384N,N,2-trimethyl-N'-[CIS-4-({[1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-yl]methyl}amino)cyclohexyl]pyrimidine-4,6-diamine474
(M+H)
3
385N,N,2-trimethyl-N'-[CIS-4-({2-[(2-nitrophenyl)oxy]ethyl}amino)cyclohexyl]pyrimidine-4,6-diamine415
(M+H)
3
386N,N,2-trimethyl-N'-[CIS-4-({[3-(trifluoromethyl)phenyl]methyl}amino)cyclohexyl]pyrimidine-4,6-diamine408
(M+H)
3
387N,N,2-trimethyl-N'-(CIS-4-{[(4-were)methyl]amino}cyclohexyl)pyrimidine-4,6-diamine354
(M+H)
388N,N,2-trimethyl-N'-{CIS-4-[(2-thienylmethyl)amino]cyclohexyl}pyrimidine-4,6-diamine346
(M+H)
3
389N,N,2-trimethyl-N'-[CIS-4-({2-[(pentafluorophenyl)oxy]ethyl}amino)cyclohexyl]pyrimidine-4,6-diamine460
(M+H)
3
390N'-[CIS-4-({2-[3,4-bis(metiloksi)phenyl]ethyl}amino)cyclohexyl]-N,N,2-trimethylpyridine-4,6-diamine414
(M+H)
3
391N,N,2-trimethyl-N'-(CIS-4-{[2-(phenylthio)ethyl]amino}cyclohexyl)pyrimidine-4,6-diamine386
(M+H)
3
3924-{[(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)amino]methyl}-9H-fluoren-9-he442
(M+H)
3
393N,N,2-trimethyl-N'-{CIS-4-[({4-[(trifluoromethyl)oxy]phenyl}methyl)amino]cyclohexyl}pyrimidine-4,6-diamine424
(M+H)
3
394 N'-[CIS-4-({[4-fluoro-2-(trifluoromethyl)phenyl]methyl}amino)cyclohexyl]-N,N,2-trimethylpyridine-4,6-diamine426
(M+H)
3
395N'-(CIS-4-{[2-(4-forfinal)ethyl]amino}cyclohexyl)-N,N,2-trimethylpyridine-4,6-diamine372
(M+H)
3
396N'-[CIS-4-({[4-(heptyloxy)phenyl]methyl}amino)cyclohexyl]-N,N,2-trimethylpyridine-4,6-diamine454
(M+H)
3
397N,N,2-trimethyl-N'-(CIS-4-{[(4-pentylphenol)methyl]amino}cyclohexyl)pyrimidine-4,6-diamine410
(M+H)
3
398N'-{CIS-4-[(cyclopentylmethyl)amino]cyclohexyl}-N,N,2-trimethylpyridine-4,6-diamine332
(M+H)
3
399N,N,2-trimethyl-N'-(CIS-4-{[(4-nonylphenyl)methyl]amino}cyclohexyl)pyrimidine-4,6-diamine466
(M+H)
3
400N'-{CIS-4-[(2-{[4-(1,1-dimethylethyl)phenyl]oxy}ethyl)amino]t is logaxis}-N,N,2-trimethylpyridine-4,6-diamine 426
(M+H)
3
401N'-(CIS-4-{[(3-chloro-4-forfinal)methyl]amino}cyclohexyl)-N,N,2-trimethylpyridine-4,6-diamine392
(M+H)
3
402N'-{CIS-4-[(2-cyclopentylacetyl)amino]cyclohexyl}-N,N,2-trimethylpyridine-4,6-diamine346
(M+H)
3
403N,N,2-trimethyl-N'-{CIS-4-[(3-phenylpropyl)amino]cyclohexyl}pyrimidine-4,6-diamine368
(M+H)
3
404N-[(1S)-2-[(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)amino]-1-(phenylmethyl)ethyl]naphthalen-1-sulfonamide573
(M+H)
3
405N,N,2-trimethyl-N'-{CIS-4-[({4-(trifluoromethyl)thio]phenyl}methyl)amino]cyclohexyl}pyrimidine-4,6-diamine440
(M+H)
3
406N'-(CIS-4-{[2-(2-bromophenyl)ethyl]amino}cyclohexyl)-N,N,2-trimethylpyridine-4,6-diamine432
3
407N'-[CIS-4-({[3-(1,1-dimethylethyl)-1-(phenylmethyl)-1H-pyrazole-5-yl]methyl}amino)cyclohexyl]-N,N,2-trimethylpyridine-4,6-diamine476
(M+H)
3
408N'-[CIS-4-({2-[(4-chlorophenyl)oxy]-2-methylpropyl}amino)cyclohexyl]-N,N,2-trimethylpyridine-4,6-diamine432
(M+H)
3
409N'-[CIS-4-({[1-[(2,4-dichlorophenyl)methyl]-3-(1,1-dimethylethyl)-1H-pyrazole-5-yl]methyl}amino)cyclohexyl]-N,N,2-trimethylpyridine-4,6-diamine544
(M+H)
3
410N'-(CIS-4-{[(5-chloro-1-methyl-1H-pyrazole-4-yl)methyl]amino}cyclohexyl)-N,N,2-trimethylpyridine-4,6-diamine378
(M+H)
3
411methyl-N-{[(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)amino]carbonyl}phenylalanine455
(M+H)
3
412N-[(2-chlorophenyl)methyl]-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]aminocyclohexane)urea 417
(M+H)
3
413N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-[(4-forfinal)methyl]urea401
(M+H)
3
414N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-(diphenylmethyl)urea459
(M+H)
3
415N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-[1-(1-naphthyl)ethyl]urea447
(M+H)
1
416N-(4-bromo-2,6-dimetilfenil)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)urea475
(M+H)
1
417N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-(2,4,6-trimetilfenil)urea411
(M+H)
3
418N-(4-chloro-2-were)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)m is Cavina 417
(M+H)
3
419N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-[2-ethyl-6-(1-methylethyl)phenyl]urea439
(M+H)
3
420N-(4-bromo-2-were)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)urea461
(M+H)
3
421N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-(2-ethyl-6-were)urea411
(M+H)
3
422N-(2-tert-butyl-6-were)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)urea439
(M+H)
2
423N-[2,6-dibromo-4-(1-methylethyl)phenyl]-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)urea567
(M+H)
3
424N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}C is clohessy)-N'-{2-[(trifluoromethyl)oxy]phenyl}urea 453
(M+H)
3
425N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-(3,4,5-trimethoxyphenyl)urea459
(M+H)
1
426N-(5-chloro-2,4-acid)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)urea463
(M+H)
2
427N-[3-(cyclopentyloxy)-4-(metiloksi)phenyl]-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)urea483
(M+H)
3
428N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-[2-(ethyloxy)phenyl]urea413
(M+H)
3
429N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-(2,4,6-tribromophenyl)urea603
(M+H)
1
430N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}Ziklag the KSIL)-N'-(2,4,6-trichlorophenyl)urea 471
(M+H)
3
431N-(2,4-dibromo-6-forfinal)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)urea543
(M+H)
3
432N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-naphthalen-1-rocephine419
(M+H)
3
433N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-(3-methyl-5-phenylisoxazol-4-yl)urea450
(M+H)
3
434N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-(2,2-diphenylether)thiourea489
(M+H)
3
435N-[4-bromo-2-(trifluoromethyl)phenyl]-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiourea532
(M+H)
3
436N-(4-bromo-2,6-dimetilfenil)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin is n-4-yl]amino}cyclohexyl)thiourea 492
(M+H)
2
437N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-musicindiaonline427
(M+H)
2
438N-(2,6-diethylphenyl)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiourea441
(M+H)
2
439N-(2,4-dichloro-6-were)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiourea468
(M+H)
2
440N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-[4-(dimethylamino)-1-naphthyl]thiourea478
(M+H)
3
441N-{4-bromo-2-[(trifluoromethyl)oxy]phenyl}-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiourea548
(M+H)
3
442N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cycle is hexyl)-N'-(3,4,5-trimethoxyphenyl)thiourea 475
(M+H)
1
443N-(5-chloro-2,4-acid)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiourea480
(M+H)
2
444N-[2,4-bis(metiloksi)phenyl]-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiourea445
(M+H)
3
445N-[3,4-bis(metiloksi)phenyl]-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiourea445
(M+H)
3
446N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-[2-(ethyloxy)phenyl]thiourea429
(M+H)
3
447N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-(2,4,6-tribromophenyl)thiourea621
(M+H)
1
448N-(2,4-dibromo-6-forfinal)-N'-(CIS-4-{[6-(dimethylamino)-2-mate the pyrimidine-4-yl]amino}cyclohexyl)thiourea 559
(M+H)
3
449N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-(4-itfinal)thiourea511
(M+H)
3
450N-(4-cyanophenyl)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiourea410
(M+H)
3
451Methyl-3-({[(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)amino]carbonothioyl}amino)-4-methylthiophene-2-carboxylate463
(M+H)
3
4522.2-dimethylpropyl(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate364
(M+H)
3
453[4,5-bis(metiloksi)-2-nitrophenyl]methyl (CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate489
(M+H)
3
4543-(trifluoromethyl)phenyl(CIS-4-{[6-(dimethylamino)-2-mate the pyrimidine-4-yl]amino}cyclohexyl)carbamate 438
(M+H)
3
4554-bromophenyl(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate448
(M+H)
3
4562-(metiloksi)phenyl(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate400
(M+H)
3
4572-(metiloksi)ethyl(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate352
(M+H)
3
458octyl(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate406
(M+H)
3
459ethyl(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate322
(M+H)
3
460(4-nitrophenyl)methyl(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate429
(M+H)
3
461naphthalen-2-yl(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate420
(M+H)
3
462prop-2-EN-1-yl(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate334
(M+H)
3
463phenylmethyl(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate384
(M+H)
3
464phenyl(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate370
(M+H)
3
465(2S,5R)-5-methyl-2-(1-methylethyl)cyclohexyl(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate432
(M+H)
3
4664-were(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate384
(M+H)
3
467methyl(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate308
(M+H)
3
468(2-chlorophenyl)methyl(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate418
(M+H)
3
4699H-fluoren-9-ylmethyl(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate472
(M+H)
3
4702,2,2-trichlorethyl(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)carbamate424
(M+H)
3
471(E)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-phenylacetophenone416
(M+H)
3
472N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-1-[3-(trifluoromethyl)phenyl]methanesulfonamide472
(M+H)
3
473 1-(3,4-dichlorophenyl)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)methanesulfonamide472
(M+H)
3
474N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-1-(4-forfinal)methanesulfonamide422
(M+H)
3
475N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-1-(2-nitrophenyl)methanesulfonamide449
(M+H)
3
476N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-1-phenylmethanesulfonyl404
(M+H)
3
477N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-naphthalen-1-retensioned468
(M+H)
3
478N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)methanesulfonamide328
(M+H)
3
479 N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)propane-2-sulfonamide356
(M+H)
3
480N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)octane-1-sulfonamide426
(M+H)
3
481Methyl-2-{[(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)amino]sulfonyl}benzoate448
(M+H)
3
482N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-etinilestradiol416
(M+H)
3
483N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-(trifluoromethyl)benzosulfimide458
(M+H)
3
4844-acetyl-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzosulfimide432
(M+H)
3
4853-N-( CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-methylbenzenesulfonamide438
(M+H)
3
486N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2,4,6-trimethylbenzenesulfonamide432
(M+H)
3
487N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-propylbenzenesulfonyl432
(M+H)
3
488N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-(1,1-dimethylpropyl)benzosulfimide460
(M+H)
3
489N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl) - biphenyl-4-sulfonamide466
(M+H)
3
4905-(dimethylamino)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)naphthalen-1-sulfonamide483
(M+H)
3
491 N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-[(trifluoromethyl)oxy]benzosulfimide474
(M+H)
3
492N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-[(trifluoromethyl)oxy]benzosulfimide474
(M+H)
3
493N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-(metiloksi)benzosulfimide420
(M+H)
3
4944-(bucalossi)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzosulfimide462
(M+H)
3
4953,5-dichloro-4-[(2-chloro-4-nitrophenyl)oxy]-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzosulfimide629
(M+H)
3
496N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-(phenyloxy)benzosulfimide482
(M+H)
3
4974-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]oxy}-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzosulfimide585
(M+H)
3
498N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-(methylsulphonyl)benzosulfimide468
(M+H)
3
4993-cyano-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzosulfimide415
(M+H)
3
5003-bromo-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzosulfimide468
(M+H)
3
5014-bromo-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-[(trifluoromethyl)oxy]benzosulfimide552
(M+H)
3
5023,4-dichloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzosulfimide 458
(M+H)
3
503N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-forbindelsesfaneblad408
(M+H)
3
504N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-nitrobenzenesulfonamide435
(M+H)
3
505N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)naphthalen-1-sulfonamide440
(M+H)
3
506ethyl-4-{[(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)amino]sulfonyl}-2-methyl-1,5-diphenyl-1H-pyrrole-3-carboxylate617
(M+H)
3
507methyl-5-{[(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)amino]sulfonyl}-1-methyl-1H-pyrrole-2-carboxylate451
(M+H)
3
508methyl-5-{[(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohex who yl)amino]sulfonyl}-2-methylfuran-3-carboxylate 452
(M+H)
3
509N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-(TRIFLUOROACETYL)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide541
(M+H)
3
5105-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiophene-2-sulfonamide589
(M+H)
3
5115-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-methyl-1-benzothiophen-2-sulfonamide494
(M+H)
3
512N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)for 3,5-dimethylisoxazol-4-sulfonamide409
(M+H)
3
513N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-1,3,5-trimethyl-1H-pyrazole-4-sulfonamide422
(M+H)
3
514etil-(4-chlorophenyl)-4-{[( CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)amino]sulfonyl}-2-methyl-1-phenyl-1H-pyrrole-3-carboxylate651
(M+H)
3
515N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-5-[1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl]thiophene-2-sulfonamide544
(M+H)
3
5161-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-1H-pyrrol-2-sulfonamide558
(M+H)
3
517N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-5-isoxazol-3-althofen-2-sulfonamide463
(M+H)
3
518methyl-5-{[(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)amino]sulfonyl}-4-(metiloksi)thiophene-3-carboxylate484
(M+H)
3
519N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-(phenylsulfonyl)thiophene-2-Sul is foamed 536
(M+H)
3
5205-bromo-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiophene-2-sulfonamide474
(M+H)
3
5217-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2,1,3-benzoxadiazole-4-sulfonamide466
(M+H)
3
522N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)quinoline-8-sulfonamide441
(M+H)
3

Methods of analysis

Analysis to determine the constitutive activity endogenic GPCR

Example 523

Analysis of the accumulation of intracellular IP3

On day 1 cells to migrate can be applied to 24-hole tablets, usually 1×105cells/well (although this number can be optimized). On day 2 cells can be transliterate through the initial mixing of 0.25 μg DNA (e.g., vector or pCMV vector pCMV containing polynucleotide encoding the receptor) in 50 μl of DMEM without serum/well and 2 μl of lipofectamine in 50 μl of DMEM without serum/lunch is. Solutions are gently mixed and incubated for 15-30 min at room temperature. Cells are washed with 0.5 ml PBS and mixed with 400 μl of medium without serum with the medium for transfection and added to the cells. The cells are then incubated for 3-4 hours at 37°C/5%CO2and then Wednesday for transfection removed and replaced with medium for normal growth of 1 ml/well. On day 3 cells mark3H-myoinositol. In brief, the medium is removed and cells are washed with 0.5 ml PBS. Then well add 0.5 ml of medium without Inositol/without serum (GIBCO BRL) with 0.25 µci3H-myoinositol/well and the cells incubated for 16-18 hours over night at 37°C/5%CO2. On day 4 the cells are washed with 0.5 ml PBS and added to 0.45 ml of medium for analysis containing medium without Inositol/without serum, 10 μm pargyline, 10 mm lithium chloride or 0.4 ml of medium for analysis and 50 µl of 10× metastation (ket) to a final concentration of 10 μm. The cells are then incubated for 30 min at 37°C. the cells are Then washed with 0.5 ml PBS and well add 200 ál of fresh/chilled ice stop solution (1M KOH; 18 mm Na borate; 3.8 mm EDTA). The solution is kept on ice for 5-10 min or until lysis of the cells and then neutralized with 200 μl of fresh/chilled ice neutralizing solution (7.5% of HCl). Then the lysate is transferred into 1.5 ml Eppendorf tubes in a test tube add 1 ml of a mixture of chloroform/methanol (1:2). The solution is treated at the center is efuge type "vortex" for 15 seconds, and the upper phase is applied on the anion-exchange resin Biorad AG1-X8™ (100-200 mesh). First, the resin is washed with water at 1:1.25 wt./about. and applied to the column, 0.9 ml of the upper phase. The column was washed with 10 ml of 5 mm myoinositol and 10 ml of a mixture of 5 mm borate Na/60 mm Na formate. Inittestcase elute in scintillation vials containing 10 ml scintillation cocktail with 2 ml of a mixture of 0.1 m formic acid/1 M ammonium formate. Column recovered by washing with 10 ml of a mixture of 0.1 m formic acid/3M ammonium formate and twice washed with H2O and stored at 4°C in the water.

Example 524

High-performance functional screening: FLIPR™

Next, to confirm the basic properties used the function-based analysis, denoted by FLIPR™ (fluorometrically tablet reader to visualize) and FDSS6000TM(functional system for screening drugs). In this analysis use endogeny, constantly active variant of the MCH receptor.

The FLIPR assays and FDSS is able to determine the intracellular concentration of Ca2+in cells that can be used to assess activation of the receptor and to determine whether the connection candidate, for example, antagonist, inverse agonist or agonist for the associated with Gq protein-coupled receptor. The concentration of free Ca2+in the cytosol of a cell is extremely low, whereas its concentration in the extracellular fluid and the endoplasmic reticu the mind (EPR) is very high. Thus, there is a high gradient in the direction of Ca2+in the cytosol across the plasma membrane or EPR. System FLIPR™ and FDSS6000™ (Molecular Devices Corporation, HAMAMATSU Photonics K.K.) is designed for functional cell-based assays, such as measurement of intracellular calcium concentration for high-throughput screening. Measurement of fluorescence associated with the calcium release upon activation associated with Gq protein-coupled receptors. Associated with Gi or Go receptors not so easy to control via FLIPR™ and FDSS6000™, as these G-proteins are not associated with calcium signaling.

System fluorometrically tablet readers to visualize used for fast kinetic measurements of intracellular fluorescence in a 96-well microplate (or 384-well microplate). By FLIPR™ or FDSS6000™ enable simultaneous measurement of fluorescence in all holes every second with high intensity and precision. These systems are ideal for measurements in cell-based functional assays, such as flow monitoring intracellular calcium that occurs within a few seconds after activation associated with Gq protein-coupled receptors.

In brief, cells were planted in 96 wells at 5.5×104cells/well the complete culture medium (modified Dulbecco Wednesday Needle with 10% fetal calf serum, 2 mm L-glutamine, 1 mm sodium pyruvate and 0.5 mg/ml G418, pH 7,4) for analysis the next day. On the day of analysis, the medium is removed and cells are incubated with 100 μl of buffer for download (4 μm Fluo4-AM in complete culture medium containing 2.5 mm probenicid, 0.5 mg/ml and 0.2% bovine serum albumin) in an incubator with 5% CO2at 37°C for 1 hour. The buffer load is removed and cells are washed with wash buffer (balanced salt Hanks solution containing 2.5 mm probenicid, 20 mm HEPES, 0.5 mg/ml and 0.2% bovine serum albumin, pH 7,4). To the cells, add 150 ál of wash buffer containing various concentrations of the test compound and the cells are incubated in an incubator with 5% CO2at 37°C for 30 minutes To each well add fifty ál of wash buffer containing different concentrations of MCH, and see caused by MCH transient changes in [Ca2+]iusing FLIPR or FDSS in 96-well tablets during exposure of 488 nm and emission 530 nm for 290 seconds. When testing the potency of the compound as an antagonist, using 50 nm MCH.

The use of FLIPR™ and FDSS6000™ can be performed by following the manufacturer's instructions (Molecular Device Corporation HAMAMATSU Photonics K.K.).

Specific examples are given below.

No. of connections IC50(nm)
Example 7101
Example 2426

The results are shown in the tables in the examples and the table below, in accordance with the following particular classification.

Class 1: the percentage of the control at 10-7M was less than 40%, or the value of the IC50was less than 50 nm.

Class 2: the percentage of the control at 10-7M was 40%-60%, or the value of the IC50ranged from 50 nm to 200 nm.

Class 3: the percentage of the control at 10-7M was more than 60%, or the value of the IC50was more than 200 nm.

No. AveclassNo. AveclassNo. AveclassNo. AveclassNo. Aveclass
13171332169 21853
2218134317011863
3319335317131872
4320336317231882
5121137317331893
61 22338317431903
7723239217531911
8124140117631922
9225241317711931
101262423178 31943
11127243217911953
12228344118031963
1322934521813
1413034631823
153 3124731833
16232116831843

Example 525

Analysis of the receptor binding

In addition to those described in this description of methods other assessment methods test compounds is to determine the affinity of binding to MCH receptor. This type of analysis usually requires a radioactively labeled ligand to the receptor, MCH. In the absence of known ligands for the receptor, MCH and radioactive labels the compounds of formula (I) can be marked with radioactive isotope and used in the analysis to assess the affinity of test compounds for MCH receptor.

Radioactively labeled compound of formula (I)that communicates with the MCH, can be used in the screening analysis to identify/evaluate compounds. In General terms, a newly synthesized or identified compound (e.g., test compound) which can be evaluated on its ability to reduce binding of the "radio-labeled compounds of formula (I)with the MCH receptor. Accordingly, the ability to compete with the "radio-labeled compound of formula (I)or radioactively labeled ligand for MCH binding to MCH receptor directly correlates with the binding affinity of the tested compounds with MCH receptor.

Protocol analysis to determine the binding of the receptor with MCH:

A. Receiving MCH receptor

The 293 cells (human kidney, ATCC), transtorno was transfusional 10 mg MCH receptor of human and 60 μl of lipofectamine (15 cm Cup), were grown in the Cup for 24 hours (75% of confluentus) with replacement of medium and removed with 10 ml/Cup buffer Hepes-EDTA (20 mm Hepes+10 mm EDTA, pH 7,4). The cells are then centrifuged in a centrifuge Beckman Coulter for 20 minutes, 17000 rpm (rotor JA-25.50). Next, the precipitate resuspended in 20 mm Hepes+1 mm EDTA, pH 7.4 and homogenized in 50 ml Dounce homogenizer homogenizer and centrifuged again. After removal of the supernatant, the sediment prior to use in the analysis of binding can be stored at -80°C. for use in the analysis of membrane thawed on ice for 20 minutes and then add 10 ml of incubation buffer (20 mm Hepes, 1 mm MgCl2, 100 mm NaCl, pH 7,4). Then the membranes are centrifuged in a centrifuge of the type "Vortex" to resuspendable coarse sediment membranes and homogenized in a Brinkmann homogenizer PT-3100 transmitter station homogenizer for 15 seconds at setting 6. The concentration membranes the protein determined using the analysis of proteins BRL Bradford protein assay.

B. analysis of the binding

For total binding, a total volume of 50 μl of appropriately diluted membranes (diluted in buffer for analysis containing 50 mm Tris HCl (pH of 7.4), 10 mm MgCl2and 1 mm EDTA; 5-50 μg protein) is added to 96-well polypropylene plates to micrometrology followed by addition of 100 μl of buffer for analysis, and 50 μl of radioactively labelled ligand MCH. For nonspecific binding instead of 100 μl of buffer for analysis were added to 50 µl and before adding 50 ál of radioactively labelled ligand MCH was added 50 μl of 10 μm cooled MCH. Then the plates were incubated at room temperature for 60-120 minutes. The binding reaction was stopped by filtration tablets for analysis through the filter tablet Devices Microplate GF/C Unifilter using 96-well tablet of harvestore Brandell, followed by washing with cold 50 mm Tris HCl, pH of 7.4, containing 0.9% NaCl. Then the bottom of the filtration tablet sealed to each well is added 50 μl of Optiphase Supermix, top tablets sealed and tablets counted in the scintillation counter MicroBeta Trilux. To study the competition connection instead of adding 100 μl of buffer for analysis to the appropriate wells add 100 ál of appropriately diluted test compound, followed by adding 50 μl of radioactively Machen is on MCH ligand.

C. Calculations

The test compounds were first evaluated at 1 and 0.1 mm, and then in the concentration range chosen so that the average dose caused approximately 50% inhibition of binding of radioactively labelled ligand MCH (i.e. the IC50). Specific binding in the absence of test compounds (BO) represents the difference between total binding (BT) and nonspecific binding (NSB) and similarly specific binding (in the presence of test compound) (B) represents the difference of the binding when replacing (BD) minus non-specific binding (NSB). IC50determined on the basis of the curve of inhibition of response, charts, logit-log% B/BOdepending on the concentration of the tested compounds.

Kicalculated by converting Cheng and Prustoff:

Ki=IC50/(1+[L]/KD)

where [L] is used in the analysis of the concentration of radioactively labeled ligand MCH and KDrepresents the dissociation constant of radioactively labeled ligand MCH determined independently under the same binding conditions.

It is assumed that each of the described or cited in this description of the patents, applications, publications and other published documents included in this description by reference in the whole Saint is her fullness.

Specialists in this field will be obvious that you can spend many changes and modifications of the preferred embodiments of the invention and that such changes and modifications can be performed without departing from the essence and scope of the invention. Thus, it is assumed that the appended claims cover all such equivalent variations as falling in the scope of the present invention.

1. The compound of formula (I)

where Q represents:
or
R1selected from the group consisting of:
(i) carbocyclic aryl, and
carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:
halogen,
cyano,
nitro,
C1-10of alkyl,
C1-10the alkyl substituted by substituent(s)independently selected from the group consisting of:
halogen,
C1-9alkoxy,
C1-9alkoxy substituted by substituent(s)independently selected from the group consisting of:
halogen,
mono-C1-5alkylamino, and
(ii) heterocyclyl and
heterocyclyl substituted by substituent(s)independently selected from the group consisting of:
halogen,
C1-5of alkyl;
R2represents a C1-5alkyl, C1-5alkyl substituted by halogen, C1-5al the sludge, substituted by a carbocyclic aryl, C1-5alkoxy, -N(R2a)(R2b); where R2aand R2beach independently represents hydrogen, C1-5alkyl or C1-5alkyl substituted by substituent(s)independently selected from the group consisting of:
hydroxy,
carbocyclic aryl;
L represents the formula (IIIa)
,
where R3and R4each represents hydrogen; A represents a single bond, and B represents a single bond or-CH2-;
Z1, Z3and Z4each independently represents hydrogen, halogen, C1-5alkyl, C1-5alkyl, substituted by a carbocyclic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carbocyclic aryl, heterocyclyl or substituted heterocyclyl;
Z2represents hydrogen, C1-5alkyl, C1-5alkyl, substituted by a carbocyclic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carbocyclic aryl, heterocyclyl or substituted heterocyclyl;
Y represents-C(O)NH-, -C(O)-, -C(S)NH-, -C(O)O - or-CH2-;
where carbocyclic aryl represents phenyl;
heterocyclyl represents 1H-indolyl, 9H-xantener, benzo[1,3]dioxole, furyl, imidazolyl, isoxazolyl, morpholinyl, piperazinil, piperine is, pyridyl, pyrrolidyl;
halogen represents fluorine, chlorine, bromine or iodine;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1,
where Q is formula (IIa); Z1represents hydrogen, halogen, C1-5alkyl or C1-5alkoxy, or its pharmaceutically acceptable salt.

3. The compound according to claim 2, where R1selected from the group consisting of:
(i) carbocyclic aryl, and
carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:
halogen,
cyano,
nitro,
C1-9the alkyl and
C1-9of alkyl, substituted with halogen,
C1-7alkoxy and
C1-7alkoxy substituted by halogen,
(ii) heterocyclyl and
heterocyclyl substituted by substituent(s)independently selected from the group consisting of:
halogen,
C1-5of alkyl;
where carbocyclic aryl represents phenyl;
heterocyclyl represents 1H-indolyl, 9H-xantener, benzo[1,3]dioxole, furyl, imidazolyl, isoxazolyl, morpholinyl, piperazin, pyridyl or pyrrolidyl;
halogen represents fluorine, chlorine, bromine or iodine;
or its pharmaceutically acceptable salt.

4. The compound according to claim 3,
where R2represents a C1-5alkyl, C1-5alkoxy, or-N(R2a)(R2b); where R2aand R2beach independently represents ogorodili C 1-5alkyl;
B represents a single bond or-CH2-;
Z1represents hydrogen, C1-5alkyl or C1-5alkoxy; Z2represents hydrogen or C1-5alkyl;
or its pharmaceutically acceptable salt.

5. The compound according to claim 4,
where R1selected from the group consisting of: (i) carbocyclic aryl, and
carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:
halogen,
cyano,
nitro,
C1-5of alkyl,
C1-5of alkyl, substituted with halogen,
C1-5alkoxy,
C1-5alkoxy substituted by halogen,
(ii) heterocyclyl and
heterocyclyl substituted by substituent(s)independently selected from the group consisting of:
halogen,
C1-5of alkyl;
R2represents-N(R2a)(R2b); where R2aand R2beach independently represents hydrogen or C1-5alkyl;
B represents a single bond or-CH2-;
Z1represents hydrogen or C1-5alkyl; Z2represents hydrogen
or C1-5alkyl;
where carbocyclic aryl represents phenyl;
heterocyclyl represents 1H-indolyl, 9H-xantener, furyl, morpholinyl, piperidyl, pyridyl or pyrrolidyl;
halogen represents fluorine, chlorine or bromine;
or the pharmacist who Cesky acceptable salt.

6. The compound according to claim 5,
where R1selected from the group consisting of: (i) carbocyclic aryl, and
carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:
halogen,
C1-5of alkyl,
C1-5of alkyl, substituted with halogen,
C1-5alkoxy and
C1-5alkoxy substituted by halogen,
(ii) heterocyclyl and
heterocyclyl, substituted with halogen;
where carbocyclic aryl represents phenyl;
heterocyclyl represents furyl, pyridyl or pyrrolidyl;
halogen represents fluorine, chlorine or bromine;
or its pharmaceutically acceptable salt.

7. A compound selected from the group consisting of:
N-(CIS-4-{[6-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-3,4-differentated;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-fermentated;
4-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-fermentated;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)for 3,5-differentated;
3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-(triptoreline)benzamide;
3-chloro-4-fluoro-N-(CIS-4-{[2-methyl-6-(methylamino)pyrimidine-4-yl]amino}cyclohexyl)benzamide;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-fermentated;
4-chloro-N-(CIS-4-{[6-(dimethylene is about)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-fluoro-5-(trifluoromethyl)benzamide;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)for 3,5-bis(trifluoromethyl)benzamide;
3-chloro-4-fluoro-N-{CIS-4-[(2-methyl-6-piperidine-1-Yeremey-4-yl)amino]cyclohexyl}benzamide;
3-chloro-4-fluoro-N-{CIS-4-[(2-methyl-6-morpholine-4-Yeremey-4-yl)amino]cyclohexyl}benzamide;
3-chloro-4-fluoro-N-{CIS-4-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]cyclohexyl}benzamide;
3,4,5-Cryptor-N-{CIS-4-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]cyclohexyl}benzamide;
3,4,5-Cryptor-N-(CIS-4-{[2-methyl-6-(methylamino)pyrimidine-4-yl]amino}cyclohexyl)benzamide;
CIS-N-(3,4-differenl)-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexanecarboxylate;
1-(4-chlorophenyl)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)cyclopentanecarboxylate;
3-(2-chloro-6-forfinal)-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-5-methylisoxazol-4-carboxamide;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-(4-methoxyphenoxy)-5-nitrobenzamide;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-5-iodine-2-furamide;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-2-(ethylthio)-2,2-diphenylacetamide;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-9H-xanthene-9-Carbo is samida;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-[1-(1-naphthyl)ethyl]urea;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-(3,4,5-trimethoxyphenyl)urea;
N-(5-chloro-2,4-acid)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)urea;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-(2,4,6-tribromophenyl)urea;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-musicindiaonline;
N-(2,6-diethylphenyl)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiourea;
N-(2,4-dichloro-6-were)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiourea;
N-(5-chloro-2,4-acid)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiourea;
N-[4-bromo-2-(trifluoromethyl)phenyl]-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiourea;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-nitrobenzamide;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-diethoxybenzene;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethoxybenzene;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-diethoxybenzene;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-isopropoxybenzoic the IDA;
3-bromo-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-fermentated;
4 deformedarse-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;
4-chloro-N-[CIS-4(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-methylbenzamide;
3 deformedarse-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;
3-chloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-methylbenzamide;
4-bromo-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-dimethoxybenzamide;
4-cyano-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-methoxybenzamide;
3-cyano-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-methoxybenzamide;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-fluoro-3-methylbenzamide;
4-bromo-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-methylbenzamide;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-fluoro-4-methylbenzamide;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethylbenzamide;
3-bromo-N-[CIS-4-(b-dimethylamine is-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-fluoro-4-cryptomelane;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-triphtalocyaninine;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-methylbenzamide;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-methylbenzamide;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-4-cryptomelane;
[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]amide 2,2-debtorrent[1,3]dioxol-5-carboxylic acid;
N-{CIS-4-[(1H-indol-2-ylmethyl)amino]cyclohexyl}-2,N',N'-trimethylpyridine-4,6-diamine;
2,N,N-trimethyl-N'-[CIS-4-(3-triphtalocyaninine)cyclohexyl]pyrimidine-4,6-diamine;
N-[CIS-4-(3,4-diferentiating)cyclohexyl]-2,N',N'-trimethylpyridine-4,6-diamine;
1-(3,4-acid)-3-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]urea;
1-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-(2-ethoxyphenyl)urea;
1-(4-benzyloxyphenyl)-3-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]urea;
3,5-dibromo-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;
3-bromo-4-chloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;
4-chloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohex the l]-3-cryptomelane;
2-(3,5-bistrifluormethylbenzene)-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-2-hydroxyacetamido;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-fluoro-4-cryptomelane;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-triphtalocyaninine;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-methoxybenzamide;
4-chloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]benzamide;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-cryptomelane;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-4-cryptomelane;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-methylbenzamide;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]for 3,5-differentated;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-ethylbenzamide;
[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]amide 2,2-debtorrent[1,3]dioxol-5-carboxylic acid;
N-[CIS-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3-fluoro-4-methylbenzamide;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-4-fermentated;
3,4-dichloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]ansamed;
4-bromo-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]benzamide;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-3,4-differentated;
3,5-dichloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]benzamide;
3-chloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-4-fermentated;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-4-fluoro-3-methylbenzamide and
3-chloro-N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]benzamide;
or its pharmaceutically acceptable salt.

8. A compound selected from the group consisting of:
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4-differentated;
N-(CIS-4-{[6-(dimethylamino)-2-ethylpyrimidine-4-yl]amino}cyclohexyl)-3,4-differentated;
3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-fermentated;
3,4-dichloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide;
3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-5-fermentated;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4,5-triterpenoid;
5-bromo-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)nicotinamide;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-4-ftor-(trifluoromethyl)benzamide;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-(trifluoromethyl)benzamide;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-3-(triptoreline)benzamide;
3,5-dichloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide;
3-chloro-N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)benzamide;
3-chloro-4-fluoro-N-{CIS-4-[(2-methyl-6-pyrrolidin-1-Yeremey-4-yl)amino]cyclohexyl}benzamide;
N-(CIS-4-{[6-(dimethylamino)-2-ethylpyrimidine-4-yl]amino}cyclohexyl)-3,4,5-triterpenoid;
CIS-N-(3-chloro-4-forfinal)-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexanecarboxylate;
N-(CIS-4-{[2-benzyl-6-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-3-chloro-4-fermentated;
CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}-N-(3,4,5-tryptophanyl)cyclohexanecarboxylate;
N-(4-bromo-2,6-dimetilfenil)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)urea;
N-(4-bromo-2,6-dimetilfenil)-N'-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)thiourea;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-(3,4,5-trimethoxyphenyl)thiourea;
N-(CIS-4-{[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}cyclohexyl)-N'-(2,4,6-tribromophenyl)thiourea;
[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]amide 5-bromofuran-2-carboxylic what Islami;
N-[CIS-(3,5-dimethoxyphenethylamine)cyclohexyl]-2,N',N'-trimethylpyridine-4,6-diamine;
N-[CIS-4-(3-bromobenzylamine)cyclohexyl]-2,N',N'-trimethylpyridine-4,6-diamine;
1-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]-3-(3-methoxyphenyl)urea;
1-(3,5-differenl)-3-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexyl]urea;
N-[CIS-4-(6-dimethylamino-2-methylsulfonylamino-4-ylamino)cyclohexyl]-3,4-differentated;
N-[CIS-4-(6-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-differentated;
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]for 3,5-bitreversed and
N-[CIS-4-(6-dimethylamino-2-methylpyrimidin-4-ylamino)cyclohexylmethyl]-4-triphtalocyaninine;
or its pharmaceutically acceptable salt.

9. The compound according to claim 1,
where Q is the formula (IIb); R2represents-N(R2a)(R2b); where R2aand R2beach independently represents hydrogen, C1-5alkyl or C1-5alkyl substituted by substituent(s)independently selected from the group consisting of:
hydroxy,
carbocyclic aryl;
or its pharmaceutically acceptable salt.

10. The connection according to claim 9 where R1selected from the group consisting of:
(i) carbocyclic aryl, and
carbocyclic aryl substituted by substituent(s)independently selected from the gr is PPI, consisting of:
halogen,
cyano,
nitro,
C1-9of alkyl,
C1-9of alkyl, substituted with halogen,
C1-7alkoxy and
C1-7alkoxy substituted by halogen,
(ii) heterocyclyl and
heterocyclyl substituted by substituent(s)independently selected from the group consisting of:
halogen and
C1-5of alkyl;
where carbocyclic aryl represents phenyl;
heterocyclyl represents 1H-indolyl, 9H-xantener, benzo[1,3]dioxole, furyl, isoxazolyl, morpholinyl, pyridyl or pyrrolidyl;
halogen represents fluorine, chlorine, bromine or iodine;
or its pharmaceutically acceptable salt.

11. The connection of claim 10,
where R2represents-N(R2a)(R2b); where R2aand R2beach independently represents hydrogen, C1-5alkyl or C1-5alkyl, substituted hydroxy;
B represents a single bond or-CH2-;
Z3and Z4each independently represents hydrogen, halogen, C1-5alkyl,
mono-C1-5alkylamino or di-C1-5alkylamino;
or its pharmaceutically acceptable salt.

12. Connection to item 11,
where R1selected from the group consisting of: (i) carbocyclic aryl, and
carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:
halogen,
cyano,
C1-5al the sludge,
C1-5of alkyl, substituted with halogen,
C1-5alkoxy and
C1-5alkoxy substituted by halogen,
(ii) heterocyclyl and
heterocyclyl, substituted with halogen;
R2represents-N(R2a)(R2b); where R2aand R2beach independently represents hydrogen or C1-5alkyl;
Z3and Z4each independently represents hydrogen, C1-5alkyl, mono-C1-5alkylamino or di-C1-5alkylamino; and
Y represents-C(O)-;
where carbocyclic aryl represents phenyl;
heterocyclyl represents a furyl or pyridyl;
halogen represents fluorine, chlorine or bromine;
or its pharmaceutically acceptable salt.

13. The connection indicated in paragraph 12
where R1selected from the group consisting of: carbocyclic aryl, and
carbocyclic aryl substituted by substituent(s)independently selected from the group consisting of:
halogen,
cyano and
C1-5alkoxy;
Z3represents hydrogen when Z4represents a C1-5alkyl; or Z3represents a C1-5alkyl, mono-C1-5alkylamino or di-C1-5alkylamino, when Z4represents hydrogen;
or its pharmaceutically acceptable salt.

14. A compound selected from the group consisting of:
3-chloro-N-(CIS-4-{[2-(dimethylamino)-6-methylpurine the Jn-4-yl]amino}cyclohexyl)-4-fermentated;
N-(CIS-4-{[2-(dimethylamino)-6-methylpyrimidin-4-yl]amino}cyclohexyl)-3,4-differentated;
N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3-methoxybenzamide;
N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3-cryptomelane;
N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-bitreversed;
[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]amide,2-debtorrent[1,3]dioxol-5-carboxylic acid;
4-cyano-N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;
4-chloro-N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;
N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethylbenzamide;
N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-differentated;
5-bromo-N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]nicotinamide;
[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]amide 5-bromofuran-2-carboxylic acid;
3,5-dibromo-N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;
N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethoxybenzene;
2-(3,5-bistrifluormethylbenzene)-N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-2-hydroxyacetamido;
2-(4-bromophenyl)-N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-the laminitis)cyclohexyl]-2-hydroxyacetamido;
N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-diethoxybenzene;
3-bromo-N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-4-fermentated;
N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethoxybenzene;
N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-3-cryptomelane;
N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-bitreversed;
[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]amide 2,2-debtorrent[1,3]dioxol-5-carboxylic acid;
4-chloro-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;
N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethylbenzamide;
[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-4-methylbenzamide;
5-bromo-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]nicotinamide;
[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]amide 5-bromofuran-2-carboxylic acid;
3,5-dibromo-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;
N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-3-ethoxybenzene;
2-(3,5-bistrifluormethylbenzene)-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-2-hydroxyacetamido;
2-(4-bromophenyl)-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-ylamino)cyclohexyl]-2-hydroxyacetamido;
N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-diethoxybenzene and
3-bromo-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-4-fermentated;
or its pharmaceutically acceptable salt.

15. A compound selected from the group consisting of:
3-chloro-N-(CIS-4-{[2-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-4-fermentated;
N-(CIS-4-{[2,6-bis(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-3,4-differentated;
N-(CIS-4-{[2-benzyl-6-(dimethylamino)pyrimidine-4-yl]amino}cyclohexyl)-3-chloro-4-fermentated;
3,4-dichloro-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;
4-cyano-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;
N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-diethoxybenzene;
3-chloro-N-[CIS-4-(2-dimethylamino-6-methylpyrimidin-4-ylamino)cyclohexyl]-5-fermentated;
N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl] - for 3,5-dimethoxybenzamide;
3,4-dichloro-N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]benzamide;
N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-3,4-diethoxybenzene and
3-chloro-N-[CIS-4-(2-dimethylamino-5-methylpyrimidin-4-ylamino)cyclohexyl]-5-fermentated;
or its pharmaceutically acceptable salt.

16. Pharmaceutical composition having activity is the ratio of the sit, containing a therapeutically effective amount of a compound according to any one of claims 1 to 15 in combination with a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to a tetrazole compound with general formula I , where X3 and X4 are independently N and C, where one of X3 and X4 is certainly C; P is phenyl; m equals 1 or 2, where if m equals 1, R1 is bonded to P through a carbon atom on ring P in the meta-position of ring P relative the point at which P is bonded to X3, and if m equals 2, R1 is bonded to P through a carbon atom on ring P in positions 2 and 5 of ring P; R1 is halogen, C1-6alkyl, OC1-6alkyl or cyano group; X1 is C2-3alkyl, C2-3alkenyl, NR3, O, S, CR3R4, SO, SO2; X2 is a bond, CR3R4, O, S, NR3, SO, SO2; R3 and R4 are independently chosen from a group which consists of hydrogen, hydroxy, C1-6alkyl; Q is triazolyl, piperazinyl, or triazole or imidazole ring, condensed with a 6- or 7-member heterocyclic ring with one or two N atoms as heteroatoms; R is C1-6alkyl, C3-6cycloalkyl, pyridinyl, which can be substituted with a nitro, cyano, halogen or OC1-4alkyl group; phenyl, which can be substituted with a halogen, C1-4alkyl, OC1-4alkyl group; (CO)OC1-4alkyl; pyrimidinyl, which can be substituted with a OC1-4alkyl group; p equals 0, 1 or 2, or pharmaceutically acceptable salt or hydrate thereof.

EFFECT: invention also relates to method of inhibiting activity of mGluR5 receptors.

11 cl, 44 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns novel compounds of formula (1a), formula (1b), formula (1c) and formula (1d), as well as pharmaceutical composition based on them and their application in medicine obtainment. R1-R4, G, W, X, X1, U, V, a, b are defined in the invention claim.

EFFECT: compound with antagonistic effect on vasopressin V1A receptor.

73 cl, 133 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns compounds of the formula and other compounds listed in cl. 1 of invention claim, and pharmaceutical composition based on them, as well as method of mGluR5 receptor activity inhibition involving claimed compounds.

EFFECT: application in treatment and prevention of diseases mediated by mGluR5 receptor activity.

4 cl, 18 dwg, 1009 ex

FIELD: medicine.

SUBSTANCE: according to the invention there is provided substituted indolequinoxalines of the formula (I), where R1 represents hydrogen or represents one or more similar or different substituent in positions from 7 to 10, selected of the group of halogen, low alkyl/alkoxy, hydroxy, triflouromethyl, trichloromethyl, triflouromethoxy, R2 represents similar or different C1-C4 alkyl substituents, X represents CO or CH2, Y represents OH, NH2, NH-(CH2)n-R3, where R3 represents low alkyl, OH, NH2, NHR4 or NR5R6, where R4, R5 and R6 represent low alkyl or cycloalkyl independently and n represents integer from 2 to 4 provided that X represents CH2, Y represents OH or NH-(CH2)n-OH and its pharmaceutically acceptable salt. There is also provided pharmaceutical composition, containing these compounds, methods of compound producing, formula (I).

EFFECT: compounds are applied as medicine for treatment and prevention of autoimmune diseases.

15 cl, 1 ex, 5 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to antagonists of serotonin 5-HT6 receptors - substituted 4-sulphonylpyrazoles and 3-sulphonyl-pyrazolo[1,5-a]pyrimidines of general formula 1 or general formula 1.2. These compounds can be used for treating and preventing development of different cognitive and neurodegenerative diseases of the central nervous system. In general formulae 1 and 1.2, 1 1.2 respectively, Ar is optionally substituted phenyl or optionally substituted 5-6-member heteroaryl, containing a nitrogen, oxygen or sulphur atom as a heteroatom; R1 is a hydrogen atom, optionally substituted C1-C5 alkyl, lower acyl or optionally substituted phenyl; R2 is an optionally substituted amino group or substituted hydroxy group or R1, together with the nitrogen atom to which it is bonded, and R2, together with the carbon atom to which it is bonded, form a substituted pyrimidine ring; R3 is a hydrogen atom, optionally substituted C1-C5alkyl, substituted hydroxyl group or substituted sulphanyl group, R5 is a hydrogen atom, optionally substituted C1-C5alkyl, substituted hydroxyl group or substituted sulphanyl group, R7 and R9 independently represent a hydrogen atom, C1-C3alkyl or phenyl, R8 is a hydrogen atom.

EFFECT: new compounds have useful biological properties.

13 cl, 2 dwg, 4 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: new derivative of diaminopyrroloquinazolines of formula (I) and their pharmaceutically acceptable salts possess properties of proteintyrosine posphatase PTP1 inhibitors which can be used for treating the diseases mediated by action of the latter, particularly for decreasing glucose content in blood. In formula (I) , A stands for 6-membered aromatic ring, or 5- or 6-membered aromatic ring which contains 1 or 2 heteroatoms chosen from S, N and O; R1 is specified from the group including the following radicals: C1-6alkyl, hydroxyC1-6alkyl, mono- or dihydroxy-substituted C1-6alkyl, phenyl-(C1-6alkyl), benzyloxyC1-6alkyl and phenyl-(C1-6alkoxy)C1-6alkyl; R2 is specified from the group including the following radicals: hydrogen, C1-6alkyl, hydroxyC1-6alkyl, mono- or dihydroxy-substituted C1-6alkyl, phenyl-(C1-6alkyl) and phenyl-(C1-6alkoxy)C1-6alkyl; R3 represents hydrogen or methyl; Ra is specified from the group including the following radicals: hydrogen, C1-6alkyl, C1-6alkoxy, hydroxyC1-6alkyl, mono- or dihydroxy-substituted C1-6alkyl, phenyl(C1-6alkyl), benzyloxyC1-6alkyl or ; R10 represents hydrogen or ; x and y separately stand for integers 0 to 4; Rb and Rc are separately specified from the group including the following radicals: hydrogen, C1-6alkyl, perfluorochemical C1-6alkyl, substituted C1-6alkyl, C1-6alkoxy, phenoxy, halogen, (unsubstituted C1-6alkyl)-(substituted phenyl)-(C1-6alkyl), phenyl-(C1-6alkoxy) or ; R11 represents hydrogen, phenyl or unsubstituted C1-6alkyl; p stands for integer 0 to 1; Rd represents hydrogen, substituted C1-6alkyl or perfluorochemical C1-6alkyl; Re represents hydrogen, halogen, substituted C1-6alkyl and perfluorochemical C1-6alkyl; Rf represents hydrogen or C1-6alkyl; the substitutes found in alkyl groups are independently specified from the following groups: hydroxy, C1-6alkoxy, C1-6alkanoyl; and the substitutes found in substituted phenyl as Rb and Rc, are independently specified from the following groups: C1-6alkyl, C1-6alkoxy, hydroxyC1-6alkyl, hydroxyl, hydroxylC1-6alkoxy, halogen, perfluorC1-6alkyl and C1-6alkanoyl.

EFFECT: improved properties of the derivatives.

29 cl, 2 dwg, 48 ex

FIELD: medicine.

SUBSTANCE: invention covers new pyrrolopyrimidine and pyrrolotriazine derivatives substituted with carbamoyl group of formula [I], characterised as a CRF (corticotrophin release factor) receptor antagonist. The compounds can be effective as a therapeutic or preventive agent for such diseases, as depression, anxiety, Alzheimer's disease, Parkinson's disease, etc. in formula [I]: E means N or CR10; R1 means -OR4, -S(O)1R4 or-NR4R5; R2 means hydrogen, C1-6alkyl; R3 means hydrogen; R4 and R5 are identical or different, and independently mean hydrogen, C1-9alkyl, di(C3-7cycloalkyl)-C1-6alkyl, C1-6alkoxy-C1-6alkyl, di(C1-6alkoxy)-C1-6alkyl, hydroxy-C1-6alkyl, cyano-C1-6alkyl, carbamoyl-C1-6alkyl or di(C1-6alkyl)amino-C2-6alkyl, or R4 and R5 together form (CH2)m-A-(CH2)n where A means CHR9; R9 means hydrogen, hydroxy-C1-6alkyl, or cyano-C1-6alkyl; R10 means hydrogen; I means an integer 0, 1 and 2; m means an integer 1, 2, 3 and 4; n means an integer 0, 1, 2 and 3; Ar means phenyl, and specified phenyl is substituted by one or more substitutes being identical or different, and chosen from the group consisting of halogen, C1-6alkyl, trifluoromethyl; their individual isomers or pharmaceutically acceptable salts.

EFFECT: extended application.

9 cl, 2 dwg, 2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I where R1 stands for phenyl; G stands for C1-C7-alkylene; Q stands for -NH-; and X stands for C1-C7- alkylene, or to its salts. In addition, the invention concerns a pharmaceutical composition, to application of compound of formula I as defined in claims 1-5 item, as well as the method for making the compound of formula I.

EFFECT: production of the new biologically active compounds inhibiting protein tyrosine kinase.

8 cl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to new pyridine derivatives or to their pharmaceutically acceptable salts of general formula 1: wherein R1, R2, R3, R4, R5, R6 and R7 are independently chosen from the group including hydrogen atom, halogen, amino, C1-C6lower alkyl, C2-C6lower alkenyl, C1-C6lower alkoxy, C1-C10alkylamino, C4-C9cycloalkylamino, C4-C9heterocycloalkylamino, C1-C10aralkylamino, arylamino, acylamino, saturated heterocyclyl, acyloxy, aryl, heteroaryl, C1-C10aralkyl, aryloxy; X represents oxygen or sulphur atom; Y represents oxygen atom or N-R8, wherein R8 is chosen from the group including hydrogen atom; aforesaid aryl group is chosen from phenyl, naphthyl and condensed phenyl group; aforesaid heteroaryl and saturated heterocyclic groups represent pentagonal or hexagonal heterocyclic ring containing 1 to 2 heteroatoms chosen from oxygen, nitrogen and sulphur atom; or condensed heterocyclic ring; and aforesaid aryl and heteroaryl groups are those that 1 to 4 assistants chosen from group including halogen, C1-C6lower alkyl, C1-C6lower alkoxy are substituted. And specified compounds or their pharmaceutically acceptable salt of formula 1 are not compounds as follows 6-methyl-3,4-dihydro-pyrano[3,4-c]pyridin-1-one, 5-vinyl-3,4-dihydro-pyrano[3,4-c]pyridin-1-one, 6-methyl-8-furan-2-yl-3,4- dihydropyrano[3,4-c]pyridin-1-one, 3-tert-butyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-8-one and dimethyl ether (3S)-6,8-dimethyl-1-oxo-1,2,3,4-tetrahydro-[2,7]naphthyridine-3,5-dicarboxylic acids.

EFFECT: compounds possess inhibitory action with respect to formation of cytokines involved in inflammatory reactions, can be used as a therapeutic agent for treatment of inflammatory diseases, immune diseases, chronic inflammations; it provides antiinflammatory and analgesic action.

21 cl, 7 tbl, 144 ex

FIELD: chemistry.

SUBSTANCE: described is novel application of 2-methylthio-5-methyl-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-on. Substance possesses anti-viral activity with respect to flue A (H5N1) virus, West Nile virus and other viral infections. Wide-spectrum anti-viral activity is discovered for the first time.

EFFECT: obtaining anti-viral substance with wide spectrum of action.

1 cl, 8 tbl, 4 ex

Comt inhibitors // 2354655

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of formula I where R1 stands for H, CN, halogen, -COR2, -S(O)xR2, C1-C12alkyl, C2-C12alkenyl, C3-C8dicloalkyl, aryl group, heteroaryl group standing for 5- or 6-merous aromatic mono- or bicyclic heterocyclic group with 1-2 heteroatoms, chosen of N or S, C3-C8cycloalkyl-(C1-C3)alkyl or group aril-(C1-C3)alkyl; alkyl, alkenyl, cycloalkyl, aryl and heteroaryl groups can be optionally substituted with halogen, C1-C6alkyl, group-COR2; R2 stands for -N(R3,R3'), C1-C6alkyl, C3-C8cycloalkyl, aryl, heteroaryl which stands for 5- or 6-merous aromatic mono- or bicyclic heterocyclic group with 1-2 heteroatoms chosen of N, C3-C8cycloalkyl-(C1-C3) alkyl or aril-(C1-C3)alkyl; C1-C6alkyl, C3-C8cycloalkyl, aryl, heteroaryl can be optionally substituted with halogen, C1-C6alkyl; R3 and R3' independently stands for hydrogen or (C1-C3)alkyl; x stands for 0, 1 or 2; and also to their esters, hydrolyzed in physiological environment, and to their pharmaceutically acceptable salts. The invention also concerns a medical product.

EFFECT: production of new biologically active compounds active as COMT inhibitor.

17 cl, 19 ex, 1 tbl

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention provides novel N6-substituted adenine-based heterocyclic compounds depicted by general formula I: , for which meanings of radicals are presented in description, and pharmaceutically acceptable salts thereof manifesting anticancer, mitotic, immunosuppressive, and antiaging activities for vegetable, animal, and human cells, and methods for preparation thereof. Included are also pharmaceutical compositions, cosmetic preparations, and growth regulators, which contain indicated derivatives as active components. Application of indicated derivatives for preparing therapeutical preparations, and cosmetic preparations are also described.

EFFECT: expanded synthetic possibilities in adenine series and increased choice of various biologically active agents.

10 cl, 10 dwg, 9 tbl, 14 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts wherein rings A and B represent optionally substituted benzene rings; R1 represents alkyl, hydroxyl, thiol, carbonyl, sulfinyl, unsubstituted or substituted sulfonyl group and others; R2 represents hydrogen atom, hydroxyl, amino-group, alkyl, unsubstituted or substituted carbonyl group or halogen atom; Z represents oxygen atom or group -N(R3)- wherein R3 and R4 represent hydrogen atom or alkyl group under condition that N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidineamine is excluded. Compounds of the formula (I) or their salts possess antagonistic activity with respect to tachykinin NK1-receptors and can be used in medicine in treatment and prophylaxis of inflammatory, allergic diseases, pain, migraine, diseases of central nervous system, digestive organs and others.

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

18 cl, 138 tbl, 527 ex

The invention relates to the derivatives of purine, which has antiviral activity against human cytomegalovirus and human immunodeficiency virus type 1, of General formula:

where n = 0 to 4; m = 0 to 3; R1= N, HE or NH2; R2= HE, NH2, acetylamino or benzoylamine; R3= H or lower alkyl (C1-C4; R4= H, lower alkyl (C1-C4or phenyl; X = CH2, O, S, NH or C(O)O; and Y = CH2, CH=CH, C(O), or ordinary communication; Ar = phenyl, pyridyl, naphthyl or substituted phenyl of the formula

where independently R5-R9= alkyl1-C8cycloalkyl C5-C6, 1-substituted, allyl, phenyl, benzyl, F, Cl, Br, J, trifluoromethyl, alkoxy, C1-C5phenoxy, benzyloxy, benzoyloxy, cyano, carboxy, acetyl, or nitro, antiviral effect of the most active compounds against human cytomegalovirus in vitro manifests itself in concentrations of 0.01-0,0005M and is characterized by selectivity 1-400 thousand

The invention relates to new compounds of General formulas I, II, III

< / BR>
or their pharmaceutically acceptable salts, in which the dotted lines indicate optional double bonds; A is-CR7or N; - - NR1R2, -CR1R2R11, -C(= CR2R12R1, -NHCHR1R2, -ОСHR1R2, -SCHR1R2, -CHR2OR12,

-CHR2SR12, -C(S)R2or-C(O)R2N-ethyl-2,2,2-triptorelin; G is oxygen, sulfur, NH, NH3hydrogen, methoxy, ethoxy, triptoreline, methyl, ethyl, dimethoxy, NH2, NHCH3N(CH3)2or trifluoromethyl; Y Is N; Z is NH, O, S, -N(C1-C2alkyl) or-C(R13R14), where R13and R14independently of one another represent hydrogen, trifluoromethyl or methyl, or one of the elements of R13and R14is cyano and the other is hydrogen or stands; R1- C1-C6alkyl which may be optionally substituted by one or two substituents R8independently from each other selected from the group comprising hydroxy, fluorine, chlorine, bromine, iodine, CF3C1-C4alkoxy, -O-CO-(C1-C4alkyl), where (C1-C2- C1-C12alkyl, aryl or -(C1-C4alkylene)aryl, where aryl is phenyl, naphthyl; R3is methyl, ethyl, fluorine, chlorine, bromine, iodine, cyano, methoxy, OCF3, methylthio, methylsulphonyl, CH2HE or CH2OCH3; R4is hydrogen, C1-C4alkyl, fluorine, chlorine, bromine, iodine, C1-C4alkoxy, triptoreline, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CF3, amino, nitro, -NH(C1-C4alkyl), -N(CH3)2, -NHCOCH3, -NHCONHCH3, hydroxy, -CO(C1-C4alkyl), -Cho, COOH, cyano, or-COO(C1-C4alkyl), where C1-C4the alkyl may be substituted by one Deputy chosen from the group comprising hydroxy, amino, -NHCOCH3, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, fluorine, chlorine, cyano, nitro; R5is phenyl, naphthyl, pyridyl, pyrimidyl, where each of the above groups R5substituted with one to three substituents that are independently from each other selected from fluorine, chlorine, C1-C6the alkyl or C1-C6alkoxyl, or one Deputy chosen from the group comprising hydroxy, iodine, bromine, formyl, cyano, nitro, trifluoromethyl, amino, -(C1-C6these groups of R5may be optionally substituted with one hydroxy-group; R6is hydrogen or C1-C6alkyl; R7is hydrogen, methyl; R11is hydrogen, hydroxy, fluorine or methoxy; R12is hydrogen or C1-C4alkyl, and R16and R17independently of one another represent hydrogen, hydroxy, methyl, ethyl, methoxy or ethoxy, except that both R16and R17cannot both be methoxy or ethoxy; or R16and R17together form oxo (=O) group; provided that if G is an atom of oxygen, sulfur, NH or NCH3he is joined by a double bond to a five-membered ring of the formula III, and further provided that R6is absent when the nitrogen atom to which it is linked, is attached by a double bond to an adjacent carbon atom in the ring

The invention relates to novel 2,6,9-triple-substituted purine derivative of General formula I, having the effect of selective inhibitors of kinases of the cell cycle, which can be used, for example, for the treatment of, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, diabetes type I, multiple sclerosis, and for the treatment of cancer, cardiovascular diseases such as restenosis, etc

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds with formula I: , in which: R1 is R6C(O)-, HC(O)-, R6SO2-, R6OC(O)-, (R6)2NC(O)-, R6-, (R6)2NC(O)C(O)-; R2 is a hydrogen atom, -CF3 or R8; R3 is a hydrogen atom or (C1-C4)aliphatic group-; R4 is -COOH; R5 is -CH2F or -CH2O-2,3,5,6- tetrafluorophenyl; R6 is (C1-C12)aliphatic or (C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-; and where R6 is substituted with up to 6 substitutes, independently chosen from R; R is a halogen atom, OR7 and -R7; R7 is (C1-C6)aliphatic group-, (C3-C10)cycloaliphatic group; R8 is (C1-C12)aliphatic- or (C3-C10)cycloaliphatic group; to a pharmaceutical composition with caspase-inhibiting activity, based on compound with formula I, to methods of treatment as well as to methods of inhibiting caspase-mediated functions and to a method of reducing production of IGIF or IFN-β. The invention also relates to a method of preserving cells, as well as to a method of producing compound with formula I.

EFFECT: new compounds are obtained and described, which can be used for treating diseases in the development of which caspase activity takes part.

34 cl, 4 tbl, 43 ex

FIELD: medicine.

SUBSTANCE: invention refers to salt N,2-dimetyl-6-[7-(2-morpholinoethoxy)chinoline-4-iloxy]benzofuran-3-carboxamide, particularly bismaleate N,2-dimetyl-6-[7-(2-morpholinoethoxy)chinoline-4-iloxy]benzofuran-3-carboxamide with antitumor activity.

EFFECT: cancer treatment availability.

11 cl, 35 dwg, 9 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new a compound of formula I or formula II, or to its pharmaceutically acceptable salts, I II, where X is S; R1 is H or C1-C6alkyl; R2 is NR5R6; R3 is aryl, substituted with a halogen; R4 is H; R5 is H; R6 is H; R7 is CH2NR8R9 where R8 is H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), heterocycle(C1-C6alkyl), heterocycle(C2-C6alkenyl), hydroxyl(C1-C6alkyl), hydroxyl(C2-C6alkyl), C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbamoyl(C1-C6alkyl); where the above mentioned aryl is an aromatic ring and is not substituted or substituted with one to three substituting groups, each of which, independently from the others, is chosen from: methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, trifluoromethyl, trifluoromethoxy, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl), dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, phenyl(C1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy), R9 is H, C1-C10alkyl, heterocycle(C1-C6alkyl) or heterocycle(C2-C6alkenyl); where the above mentioned heterocycle represents a 5-member saturated monocyclic ring system, consisting of carbon atoms, as well as heteroatoms, chosen from a group comprising N, O, and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes NO2, aryl(C1-C6alkyl), arylsulphonyl; or R8 and R9 together with nitrogen, to which they are bonded, form a heterocycle, which represents a 5 - 7-member saturated monocyclic ring system, consisting of carbon atoms, as well as one to three heteroatoms, chosen from a group comprising N, O and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes C1-C6alkoxy, hydroxy, C1-C6alkyl, C2-C6-alkenyl, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), aryl(C1-C6alkoxy) and pyrimidin-2-yl; and m equals 0. The invention also relates to a pharmaceutical composition, as well as to use of formula I or formula II compounds.

EFFECT: obtaining new biologically active compounds, with inhibitory properties towards casein kinase 1ε.

32 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to N-substituted aniline and diphenylamine analogues, chosen from 3,4-bisdifluoromethoxy-(3-carboxyphenyl)-N-(5-(2-chloropyridinylmethyl))-aniline, 3,4-bisdifluoromethoxy - N-(3-carboxyphenyl) - N-(3-(2-chloropyridylmethyl))-aniline, 3,4 - bisdifluoromethoxy - N-(3-carboxyphenyl) - N-(4-(3,5-dimethylisoxazolylmethyl)) aniline, 3 - cyclopentyloxy - 4-methoxy - N-(3-aminocarbonylphenyl) - N-(3-pyridylmethyl) aniline and other compounds given in paragraph 1 of the formula of invention and to their pharmaceutically acceptable salts as inhibitors of PDE4 enzyme.

EFFECT: compounds can be used for treating and preventing diseases caused by activity of the PDE4 enzyme.

15 cl, 8 dwg, 58 ex

FIELD: chemistry.

SUBSTANCE: in formula (1) compound, cysteinprotease is cathepsin K, cathepsin S, cathepsin L or cathepsin B. In formula (I) R is , AA1 is a bond, AA2 is a bond, R7 and R8 each independently represents hydrogen, C1-8 alkyl, CycA or C1-8 alkyl, substituted CycA, R9 is hydrogen, values of the rest of the radicals are given in the formula of invention. The invention also relates to a pharmaceutical composition, containing a formula (I) compound as an active ingredient, to a cysteinprotease inhibitor, method of inhibiting cysteinprotease, use of formula (I) compound in obtaining cysteinprotease inhibitor.

EFFECT: compound has inhibitory activity towards cysteinprotease.

10 cl, 16 tbl, 8 dwg, 224 ex

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