Amide derivatives as gk activators

FIELD: chemistry.

SUBSTANCE: object of present invention is the following compounds: thiazol-2-ylamide 2-(3,4-dichlorophenoxy) hexanoic acid, 2-(4-fluorophenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-K-pyridin-2-ylhexaneamide, 2-(3,4-dichlorophenoxy)-4-methyl-N,3-thiazol-2-ylpentaneamide, 2-(1,1'-biphenyl-4-yloxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-isopropylphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(3-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, and others, named in the formula of invention. Present invention also relates to a pharmaceutical composition, which contains the invented compound as an active ingredient and use of compounds in preparing a medicinal agent which increases activity of glucose. The invention also pertains to a compound of formula (I) where G is -C(O)-; L1 is a direct bond, A is >N-, X is a direct bond, R1 is cyclohexyl, R3 is cyclohexyl, substituted with R34, R4 is hydrogen; R5 is thiazol-5-yl, substituted with R48.

EFFECT: obtaining compounds which can be used for preparing a medicinal agent which can be used for treating diseases caused by glucokinase deficiency, for preparing a medicinal agent for treating diseases where increased activity of glucokinase is favourable.

6 cl, 143 ex

 

The technical field to which the invention relates

This invention relates to compounds that are activators of glucokinase (GK) and which can be used for management, treatment, control or adjunctive treatment of diseases, where increasing glucokinase activity is beneficial.

Prior art

Diabetes is characterized by impaired glucose metabolism, manifested inter alia in the form of increased level of blood glucose in patients with diabetes. Underlying disease defects led to the division of diabetes into two major groups: type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), which occurs when patients in the pancreas no β-cells producing insulin, and type 2 diabetes or non-insulin dependent diabetes mellitus (NIDDM), which occurs in patients with impaired function of β-cells along with the spectrum of other defects.

Patients with type 1 diabetes currently treated with insulin, while the main part of the patients with type 2 diabetes treated with either sulfonylurea derivatives that stimulate the function of β-cells, or agents that enhance the tissue sensitivity of the patients towards insulin, or insulin. Among the agents used to increase the sensitivity of tissues to insulin typical example is Metformin.

Although derivatives, sulfonylureas are widely used for the treatment of NIDDM, this treatment is in most cases unsatisfactory: the large number of patients with NIDDM derivatives, sulfonylureas normalize the blood sugar level is not enough and patients, therefore, are at high risk of developing complications of diabetes. Also many patients gradually decreased ability to respond to treatment with sulfonylurea derivatives, and therefore, they are gradually forced to move on treatment with insulin. This transition of patients from oral hypoglycemic agents for treatment of insulin is usually attributed to depletion of β-cells in patients with NIDDM.

In normal subjects and in patients with diabetes, the liver produces glucose to avoid hypoglycemia. This glucose production is the result of either the release of glucose from stored glycogen, or the result of gluconeogenesis, which is an intracellular glucose synthesis de novo. When type 2 diabetes, however, the regulation of glucose output from the liver is poorly controlled and increases and can double after an overnight fast. Moreover, in these patients there is a high correlation between increased levels of glucose in plasma glucose and the rate of production of glucose by the liver. Kindred the production of glucose by the liver will be increased in diabetes type 1 if the disease is poorly controlled with insulin treatment.

Because the existing forms of diabetes does not lead to satisfactory control of blood glucose and, therefore, are unsatisfactory, there is a high need for new therapeutic approaches.

Atherosclerosis, a disease of the arteries as it is the leading cause of death in the United States and Western Europe. The sequence of development of pathology, leading to atherosclerosis and occlusal disease of the heart, is well known. The earliest stage in this sequence is the formation of "fatty streaks" in the carotid, coronary and cerebral arteries and in the aorta. These injuries are yellow in color due to the presence of fat, found primarily in the smooth muscle cells and macrophages lining layer of arteries and aorta. Further postulated that a large part of the cholesterol found in fatty streaks, in turn, stimulates the development of fibrous plaques, which consist of accumulated smooth muscle cells of the intima-loaded lipid and surrounded by extracellular lipids, collagen, elastin and proteoglycans. Cells with the matrix form of the fibrous capsule that covers the deeper sediments cell residues and more extracellular lipid is. Lipid is initially free and esterified cholesterol. The fibrous plaque is formed slowly and probably eventually becomes calcified and necrotic, leading to "complicated damage", which is the cause of occlusion of arteries and predisposition to parietal thrombosis and spasm of the arterial muscles, which is characterized by severe atherosclerosis.

Epidemiological data reliably indicate that hyperlipidemia is a primary risk factor for cardiovascular disease (CVD), leading to atherosclerosis. In recent years, leading specialists of medicine has resumed efforts to reduce the level of cholesterol in the plasma and on the reduction of cholesterol low-density lipoprotein in particular as a significant stage in the prevention of CVD. The upper limits of "normal" now, as you know, are significantly lower than expected so far. The result is that a large part of the population of Western countries, as it now appears, are at particularly high risk. Independent risk factors include intolerance to glucose, left ventricular hypertrophy, hypertension, and male gender. Cardiovascular disease is especially prevalent in patients with diabetes, at least partially, due to the creatures who for many independent risk factors in this group. Successful treatment of hyperlipidemia population and in patients with diabetes, in particular, is, therefore, exceptional medical importance.

Hypertension (or high blood pressure) is a condition that occurs in humans as a secondary symptom in relation to various other disorders, such as renal artery stenosis, pheochromocytoma, or endocrine disorders. However, hypertension is detected also in many patients, in which the agent or the breach, which the reason is unknown. Despite the fact that such "essential" hypertension is often associated with such disorders as obesity, diabetes, and hypertriglyceridemia, the relationship between these disorders is not clear. In addition, many patients have symptoms of high blood pressure occur in the absence of any other signs of disease or impairment.

It is known that hypertension can directly lead to heart failure, renal failure and shock (hemorrhage of the brain). These conditions can cause sudden death of the patient. Hypertension may also contribute to the development of atherosclerosis and coronary insufficiency. These conditions gradually weaken the patient and can lead to delayed death.

The true cause of essential hypertension is unknown, although suppose h is on a number of factors contributing to the occurrence of the disease. Among these factors, you can indicate stress, uncontrolled emotions, unregulated secretion of hormones (renin-angiotensin-aldosterone system), excessive salt and water due to kidney failure, thickening and hypertrophy of blood vessels, leading to narrowing of blood vessels, and genetic factors.

Produced the treatment of essential hypertension, bearing in mind the above factors. It was created and released on the market a wide range of beta-blockers, vasoconstrictors, angiotensin-converting enzyme inhibitors, and the like, as antihypertensive agents. It has been proven beneficial effect of these compounds in their application for the treatment of hypertension to prevent sudden death, such as in the result of heart failure, renal failure and hemorrhage of the brain. However, there remains the problem of the development of atherosclerosis or heart disease due to hypertension over a long period of time. This implies that although high blood pressure is reduced, the underlying essential hypertension the cause is not affected by this treatment.

Hypertension was associated with increased insulin levels in the blood, a condition known as hyperinsulinemia. Insulin, a peptide hormone, the primary action of which is to stimulate the utilization of GL the goats, protein synthesis and the formation and storage of neutral lipids, acts among other things as the growth of blood vessels and the amplifier delay of sodium in the kidneys. Data of the last functions can be performed without affecting glucose levels and are known causes of hypertension. The growth of peripheral vessels, for example, can cause narrowing of peripheral capillaries, and sodium retention increases blood volume. Thus, reducing the level of insulin in hyperinsulinemic patients can prevent abnormal growth of blood vessels and sodium retention in the kidneys caused by high insulin levels, and thereby alleviate hypertension.

Cardiac hypertrophy is a major risk factor for sudden death, myocardial infarction, congestive heart failure. These changes in the heart due, at least partially increased susceptibility to myocardial injury after ischemia and reperfusion, which may occur in outpatients and in-patients in the perioperative period. There is also an unmet medical need in preventing or minimizing adverse perioperative myocardial outcomes, particularly perioperative myocardial infarction. As nesanica and cardiac surgery are associated with things the public risk of myocardial infarction or death. Approximately 7 million patients undergoing neserdechno surgery, are considered at risk cases of perioperative death and severe heart complications in some groups of up to 20-25%. In addition, out of 400000 patients undergoing surgical annually coronary artery bypass surgery, perioperative myocardial infarction is determined to be 5%, and death in 1-2%. In this area at the present time there is no drug therapy that reduces damage to the heart tissue in perioperative myocardial ischemia or increases the resistance of the heart to episodes of ischemia. It can be expected that such therapy should preserve life and reduce hospitalizations, and improve quality of life and reduce the overall cost of maintaining the health of patients with high risk of disease.

Another area of the present invention is obesity or regulation of appetite.

Obesity is a well-known risk factor for many common diseases, such as atherosclerosis, hypertension and diabetes. The prevalence of obesity and also these diseases are increasing throughout the industrialized world. There are currently no reliable and acceptable pharmacological treatment for effective weight loss, in addition to training, diet and restrictions Pete the deposits. However, due to the indirect but important effect of obesity as a risk factor for mortality and overall disease it is important to find a method of treatment of obesity and/or the regulation of appetite.

The term obesity refers to an excess of adipose tissue. In this context, obesity is most convenient to consider it as any degree of redundancy in fat, which serves as a risk factor for health. The section between normal individuals and individuals with obesity may be approximate, but the risk factor in relation to health created by obesity, is probably continuous with the increase of obesity. The Framingham study showed that 20% excess relative to the desired weight clearly creates a risk to health (Mann GV N. Engl. J. Med291,226 (1974)). In the United States conciliation Commission on obesity national Institute of health agreed that a 20% increase in the relative weight or body mass index (BMI = body weight in kilograms divided by the square of height in meters) above 85% in young adults poses a risk to health. When applying this criterion from 20 to 30 percent of adult men and 30 to 40 percent of adult women in the United States are obese. (NIH, Ann Intern Med103,147 (1985)).

Even moderate obesity increases the risk of premature mortality is, diabetes, hypertension, atherosclerosis, gallstone disease and some types of cancer. In the industrial Western world, the prevalence of obesity has increased dramatically over the last few decades. Because of the high prevalence of obesity and its health consequences, prevention and treatment would be a high priority for public health.

When energy intake exceeds expenditure, the excess calories are stored in fat tissue, and if the net balance is maintained, obesity, i.e. there are two component mass balance and deviation from the norm with any party (or consumption expenditure) can lead to obesity.

The regulation of eating behavior are poorly understood. To some extent, the appetite is controlled by discrete areas of the hypothalamus: center meal in ventrolateral nucleus of the hypothalamus (VLH) and the center of saturation in ventromedial hypothalamus (VMH). The cortex receives positive signals from the center of the meal, which stimulates food intake and satiety modulates this process, sending inhibiting impulses in the center of the meal. Several regulatory processes can influence the data hypothalamic centers. The center of saturation can be activated by increasing glucose and/or insulin in the plasma, which accompanies the meal. The Indus is caravanne food distension of the stomach is another possible inhibiting factor. In addition, hypothalamic centers sensitive to catecholamines, and beta-adrenergic stimulation inhibits feeding behavior. Finally, the cerebral cortex controls feeding behavior, and impulses from the center of the meal in the cerebral cortex represents one of the signals. Consumption of food is also influenced by psychological, social and genetic factors.

Currently, there are many ways the induction of initial weight loss. Unfortunately, the initial weight loss is not optimal therapeutic purposes. On the contrary, the problem is that most obese patients eventually regain the weight. Effective means of establishing and/or maintaining weight loss is a major problem in the treatment of obesity today.

Glucokinase (GK) plays an important role in the homeostasis of blood glucose. GK catalyzes the phosphorylation of glucose, which is the rate-limiting reaction of glycolysis in hepatocytes and pancreatic β-cells. In the liver GK determines the speed and the seizure of glucose and glycogen synthesis, and believe that it is also essential for the regulation of various sensitive to glucose genes (Girard, J. et al., Annu Rev Nutr17, 325-352 (1997)). In β-cells of GK determines glucose utilization and thus necessary for stimulated glucose insulin secretion. GK t is the train is expressed in a population of neurons in the hypothalamus, where she could participate in feeding behavior, and in the intestine, where it could contribute to the secretion of anterointernal.

GK has two main distinguishing features: her expression, which is limited to tissues that require sensitivity to glucose (mainly liver and pancreatic β-cells), and S0,5for glucose, which is much higher (8-12 mm)than the other members of the family hexokinase. Due to the kinetic characteristics of change of the glucose level in the serum are also accompanied by changes in glucose metabolism in the liver, which in turn regulates the balance between glucose output from the liver and glucose consumption.

Thus, activators of glucokinase and can be used for the treatment of diseases, where increasing glucokinase is favorable. Thus, a need exists for agents that activate glucokinase and increase the enzymatic activity of glucokinase. Such agents would be useful for the treatment of diabetes type I and diabetes type II.

Patents WO 00/58293, WO 01/44216, WO/0183465, WO/0183478, WO/0185706 and WO 01/85707 owned by Hoffman-La Roche, disclose compounds as glucokinase activators for the treatment of type 2 diabetes.

Summary of the invention

In this invention proposed amide is proizvodnye, which are activators of glucokinase. Compounds of the present invention can be used as activators of glucokinase and thus can be used for management, treatment, control, and adjunctive treatment of diseases, where increasing glucokinase activity is beneficial. Such diseases include diabetes type I and diabetes type II. In the present invention proposed the following compounds, pharmaceutical compositions comprising the compounds, their use for increasing the activity of glucokinase, their application to obtain drugs for the treatment of specified diseases and conditions and the use of the compounds or pharmaceutical preparations of the present invention for treatment of the above diseases and conditions, as well as methods of treatment for these diseases and conditions, and these methods include introduction to the subject in need, an effective amount of compound according to the present invention.

In the present invention the application of the compounds according to the present invention for increasing the activity of glucokinase.

In the present invention the application of the compounds according to the present invention or pharmaceutical compositions according to the present invention for the treatment of hyperglycemia.

Currently the m invention proposed the use of compounds according to the present invention for obtaining medications for the treatment of hyperglycemia.

In the present invention the application of the compounds according to the present invention or pharmaceutical compositions according to the present invention for the treatment of IGT.

In the present invention the application of the compounds according to the present invention for obtaining medications for the treatment of IGT.

In the present invention the application of the compounds according to the present invention or pharmaceutical compositions according to the present invention for the treatment of syndrome X.

In the present invention the application of the compounds according to the present invention for obtaining medications for the treatment of syndrome X.

In the present invention the application of the compounds according to the present invention or pharmaceutical compositions according to the present invention for the treatment of type 2 diabetes.

In the present invention the application of the compounds according to the present invention for obtaining medications for the treatment of type 2 diabetes.

In the present invention the application of the compounds according to the present invention or pharmaceutical compositions according to the present invention for the treatment of type 1 diabetes.

In the present invention the application of the compounds according to the present invention for obtaining medications for the treatment of diabetes is type 1.

In the present invention the application of the compounds according to the present invention or pharmaceutical compositions according to the present invention for the treatment of dyslipidemia or hyperlipidemia.

In the present invention the application of the compounds according to the present invention for obtaining medications for the treatment of dyslipidemia or hyperlipidemia.

In the present invention the application of the compounds according to the present invention or pharmaceutical compositions according to the present invention for the treatment of hypertension.

In the present invention the application of the compounds according to the present invention for obtaining medications for the treatment of hypertension.

In the present invention the application of the compounds according to the present invention or pharmaceutical compositions according to the present invention is to reduce food intake.

In the present invention the application of the compounds according to the present invention for obtaining drugs that reduce food intake.

In the present invention the application of the compounds according to the present invention or pharmaceutical compositions according to the present invention for the regulation of appetite.

In the present invention the application of the compounds according to the SNO present invention to obtain drugs for the regulation of appetite.

In the present invention the application of the compounds according to the present invention or pharmaceutical compositions according to the present invention for the treatment or prevention of obesity.

In the present invention the application of the compounds according to the present invention for obtaining medications for treatment or prevention of obesity.

In the present invention the application of the compounds according to the present invention or pharmaceutical compositions according to the present invention for the regulation of feeding behavior.

In the present invention the application of the compounds according to the present invention for obtaining medications for the regulation of feeding behavior.

In the present invention the application of the compounds according to the present invention or pharmaceutical compositions according to the present invention to increase the secretion of anterointernal. In one implementation of the specified anterointernal is GLP-1.

In the present invention the application of the compounds according to the present invention for obtaining medicines to increase the secretion of anterointernal. In one implementation of the specified anterointernal is GLP-1.

In one implementation of the application according to the present invention, as described above, relates to the tunes, which includes treatment of additional anti-diabetic agent such as additional antidiabetic agent selected from insulin or insulin analogue, sulfonylureas, biguanides, meglitinide, sensitizer to insulin, thiazolidinediones of insulin sensitizer, an inhibitor of α-glucosidase, glycogen phosphorylase inhibitor and an agent acting on the ATP-dependent potassium channel in pancreatic β-cells.

In one implementation of the application according to the present invention, as described above, the regime, which includes the additional treatment antihyperlipidemic agent such as additional antihyperlipidemic agent selected from cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol and dextrothyroxine.

In one implementation of the application according to the present invention, as described above, the regime, which includes the additional treatment agent against obesity.

In one implementation of the application according to the present invention, as described above, the regime, which includes treatment of additional antihypertensive agent.

Other implementation aspects are defined in the attached claims.

Definitions

In here the structural formulae in the course of the present description, the following terms have the specified meanings:

Used herein, the term “optionally substituted” means that the group is either not substituted or substituted by one or more specified substituents. When this group substituted by more than one Deputy, the Deputy may be the same or different.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine or iodine.

The term “perhalogenated” denotes trifluoromethyl, trichloromethyl, tribromoethyl or triacetyl.

The use of consoles this structure: Cx-y-alkyl, Cx-yalkenyl, Cx-y-quinil, Cx-y-cycloalkyl or Cx-y-cycloalkyl-Cx-yalkenyl denote the radical designated type, containing from x to y carbon atoms.

Used herein, the term “alkyl”, alone or in combination, refers to a linear or branched chain saturated monovalent hydrocarbon radical containing from one to ten carbon atoms, for example C1-8-alkyl. Typical C1-8-alkyl groups include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylpentyl, neopentyl, n-pentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1,2,2-trimethylpropyl and the like. Used herein, the term “C1-8-alkyl” also who engages secondary C 3-8-alkyl and tertiary C4-8-alkyl.

Used herein, the term “alkylene”, separately or in combination, refers to a linear or branched chain saturated devalentino hydrocarbon radical containing from one to ten carbon atoms, for example C1-8-alkylene. Used here, examples of “alkylene” include, but are not limited to, methylene, ethylene and the like.

Used herein, the term “alkenyl”, separately or in combination, refers to a linear or branched chain monovalent hydrocarbon radical containing from two to ten carbon atoms and at least one carbon-carbon double bond, such as C2-8alkenyl. Typical C2-8-alkeline groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, Isopropenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl and the like.

Used herein, the term “albaniles”, separately or in combination, refers to a linear or branched chain devalentino hydrocarbon radical containing from two to ten carbon atoms and at least one carbon-carbon double bond, such as C(2-8)-albaniles. Typical C(2-8)and canrenone groups include, but not limited to, ethen-1,2-diyl, propene-1,3-diyl, methylene-1,1-diyl and the like.

Used herein, the term “quinil”, separately or in combination, refers to linear or branched hydrocarbon group containing from 2 to the specified number of carbon atoms and at least one triple carbon-carbon bond, such as C2-8-quinil. Typical C2-8-alkyline groups include, but are not limited to, ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 5-hexenyl, 2,4-hexadienyl and the like.

Used herein, the term “akinyan”, separately or in combination, refers to a linear or branched chain devalentino hydrocarbon radical containing from two to ten carbon atoms and at least one carbon-carbon triple bond, such as C2-8-akinyan. Typical C2-8-alkenylamine groups include, but are not limited to, Atin-1,2-diyl, propyne-1,3-diyl and the like.

Used herein, the term “cycloalkyl”, separately or in combination, refers to non-aromatic carbocyclic monovalent hydrocarbon radical containing from three to twelve carbon atoms and, optionally, one or more degrees of unsaturation, naprimer 3-8-cycloalkyl. Such a ring may be optionally condensed with one or more benzene rings or one or more other(s) cycloalkenyl(s) ring(s). Typical C3-8-cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

Used herein, the term “cycloalkyl”, separately or in combination, refers to non-aromatic carbocyclic devalentino hydrocarbon radical containing from three to twelve carbon atoms and optionally containing one or more degrees of unsaturation, for example, C3-8-cycloalkyl. Such a ring may be optionally condensed with one or more benzene rings or one or more other(s) cycloalkenyl(s) ring(s). Typical C3-8-cycloalkene groups include, but are not limited to, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl, cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl or cyclooctyl-1,5-diyl and the like.

Used herein, the term “heterocyclic” or the term “heterocyclyl”, separately or in combination, refers to a heterocyclic ring of from three to twelve members, containing one or more degrees is not what sidenote, containing one or more heteroatomic substituents selected from S, SO, SO2, O, or N, for example C3-8-heterocyclyl. Such a ring may be optionally condensed with one or more other(s) “heterocyclic(mi)” ring(s) or cycloalkyl(s) ring(s). Typical C3-8-heterocyclyl groups include, but are not limited to, tetrahydrofuran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, piperazine and the like.

Used herein, the term “heterocyclyl”, separately or in combination, refers to deradicalise heterocyclic ring of from three to twelve members optionally containing one or more degrees of unsaturation containing one or more heteroatoms selected from S, SO, SO2, O, or N. Such a ring may be optionally condensed with one or more benzene rings or one or more other “heterocyclic” rings or cycloalkyl rings. Examples of “getireceklerine” include, but are not limited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, Piran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl, piperazine-1,4-diyl and the like.

Used herein, the term “alkoxy”, alone or in combination is AI, refers to the monovalent radical RaO-, where Rarepresents an alkyl, as defined above, for example, C(1-8)-alkyl, giving C(1-8)-alkoxy. Typical C(1-8)-alkoxygroup include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentox, isopentane, hexose, isohexane and the like.

Used herein, the term “alkylthio”, separately or in combination, refers to a linear or branched monovalent to radical, including alkyl group, as described above, linked through divalently the sulfur atom having its free valence bond from the sulfur atom, for example, C1-8-alkylthio. Typical C1-8-ancilliary include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio and the like.

Used herein, the term “alkoxycarbonyl” refers to the monovalent radical RaOC(O)-, where Rarepresents an alkyl, as described above, for example, C1-8-alkoxycarbonyl. Typical C1-8-alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, second-butoxycarbonyl, tert-butoxycarbonyl, 3-methylbutanoyl, n-hexoxyethanol and the like.

IP is olshey herein, the term “carbarnoyl” refers to the NH 2C(O)-.

Used herein, the term “aryl” refers to carbocyclic aromatic cyclic radical with, for example, from 6 to 8 atoms as members or radical in the aromatic ring system containing, for example, from 12 to 18 atoms as members. Aryl is also intended to include the partially hydrogenated derivatives of carbocyclic systems.

Used herein, the term “heteroaryl”, alone or in combination, refers to an aromatic cyclic radical containing, for example, from 5 to 7 atoms as members, or to the radical in the aromatic ring system containing, for example, from 7 to 18 atoms as members and containing one or more heteroatoms selected from the heteroatoms nitrogen, oxygen or sulfur, where N-oxides and monoxide sulfur and sulfur dioxides are permissible substitutions heteroatoms; such as, for example, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolin, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, chinoline, ethenolysis, benzofuranyl, benzothiophene, indolyl and indazoles and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of heterocyclic systems listed below.

Examples of the aryl" and "heteroaryl" include, but not limited to, phenyl, biphenyl, inden, fluoren, naphthyl

(1-naphthyl, 2-naphthyl)anthracene (1-anthracene, 2-anthracene,

3-anthracene), thiophene (2-thienyl, 3-thienyl), furyl (2-furyl,

3-furyl), indolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, hinzelin, fluorenyl, xantener, isoindolyl, benzhydryl, acridines, thiazolyl, pyrrolyl

(1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyrazolyl (1-pyrazolyl,

3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl), imidazolyl

(1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazole-1-yl, 1,2,3-triazole-4-yl

1,2,3-triazole-5-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (isooctane-3-yl, isooctane-4-yl, isooctane-5-yl), isothiazole (isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl) thiazolyl

(2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl

(2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), chinolin (2-chinolin, 3-chinolin, 4-chinolin, 5-chinolin, 6-chinolin, 7-chinolin, 8-chinolin), ethanolic (1-ethanolic, 3-ethanolic, 4-ethanolic, 5-ethanolic, 6-ethanolic, 7-ethanolic,

8-ethanolic), benzo[b]furanyl (2 - benzo[b]furanyl,

3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl,

6-benzo[b]furanyl, 7-is Enzo[b]furanyl),

2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl),

3-(2,3-dihydro-benzo[b]furanyl),

4-(2,3-dihydro-benzo[b]furanyl),

5-(2,3-dihydro-benzo[b]furanyl),

6-(2,3-dihydro-benzo[b]furanyl),

7-(2,3-dihydro-benzo[b]furanyl)),

benzo[b]thiophenyl, (benzo[b]thiophene-2-yl, benzo[b]thiophene-3-yl, benzo[b]thiophene-4-yl, benzo[b]thiophene-5-yl, benzo[b]thiophene-6-yl, benzo[b]thiophene-7-yl), 2,3-dihydro-benzo[b]thiophenyl, (2,3-dihydro-benzo[b]thiophene-2-yl, 2,3-dihydro-benzo[b]thiophene-3-yl,

2,3-dihydro-benzo[b]thiophene-4-yl, 2,3-dihydro-benzo[b]thiophene-5-yl, 2,3-dihydro-benzo[b]thiophene-6-yl, 2,3-dihydro-benzo[b]thiophene-7-yl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl,

5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazoles,

3-indazole, 4-indazole, 5-indazole, 6-indazole,

7-indazole), benzimidazolyl (1-benzimidazolyl,

2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl,

6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (2-benzoxazolyl, 3-benzoxazolyl,

4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl,

7-benzoxazolyl), benzothiazolyl (2-benzothiazolyl,

4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl,

7 - benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl,

3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepin

(5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepin-2-yl,

5H-dibenz[b,f]azepin-3-yl, 5H-dibenz[b,f]azepin-4-yl,

5H-diben is[b,f]azepin-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine, 10,11-dihydro-5H-dibenz[b,f]azepin-1-yl 10,11-dihydro-5H-dibenz[b,f]azepin-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepin-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepin-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepin-5-yl), benzo[1,3]dioxol

(2-benzo[1,3]dioxol, 4-benzo[1,3]dioxol, 5-benzo[1,3]dioxol, 6-benzo[1,3]dioxol, 7-benzo[1,3]dioxol), and tetrazolyl

(5-tetrazolyl, N-tetrazolyl).

The present invention relates also to a partially or fully saturated analogues of cyclic systems listed above.

Used herein, the term “condensed arylheteroacetic” refers to an aryl group fused with heterocyclyl group, both of which have two common atoms and where the aryl group represents a site of substitution. Used here, examples of the “condensed allheterocou” include 4-(2,3-benzo-dioxin), 3,4-methylenedioxy-1-phenyl and the like.

Used herein, the term “condensed heterocyclisation” refers to heterocyclyl group condensed with an aryl group, both of which have two common atom, and where heterocyclyl group represents a site of substitution. Used here, examples of the “condensed heterocyclisation” include 2-(1,3-benzodioxol) and the like.

Used herein, the term “condensed heteroalicyclic” refers to heteroaryl group, condensed with heterocyclyl group, both of which have two common atom, and where the heteroaryl group represents a site of substitution. Used here, examples of the “condensed heteroalicyclic include 1,2,3,4-tetrahydro-beta-carbolin and the like.

Used herein, the term “condensed heterocyclisation” refers to heterocyclyl group fused with a heteroaryl group, both of which have two common atom, and where heterocyclyl group represents a site of substitution. Used here, examples of the “condensed geterotsiklicheskikh” include 2-[1,3]-dioxolo[4,5-c]pyridine and the like.

Used herein, the term “condensed aristically” refers to an aryl group fused with cycloalkyl group, both of which have two common atoms and where the aryl group represents a site of substitution. Used here, examples of the “condensed killglance” include 5-indolyl, 6-(1,2,3,4-tetrahydronaphthyl) and the like.

Used herein, the term “condensed cycloalkenyl” refers to cycloalkyl group condensed with an aryl group, both of which have two common atom, and where cycloalkyl group represents a site of substitution. Used here, examples of “condenser the bath cycloalkenyl include 1 indanyl, 2 indanyl, 1-(1,2,3,4-tetrahydronaphthyl) and the like.

Used herein, the term “condensed heteroalicyclic” refers to a heteroaryl group fused with cycloalkyl group, both of which have two common atom, and where the heteroaryl group represents a site of substitution. Used here, examples of the “condensed heteroalicyclic” include 5-Aza-6-indanyl and the like.

Used herein, the term “condensed cycloalkylcarbonyl” refers to cycloalkyl group fused with a heteroaryl group, both of which have two common atom, and where cycloalkyl group represents a site of substitution. Used here, examples of the “condensed cycloalkylcarbonyl” include 5-Aza-1-indanyl and the like.

Used herein, the term “Allen”, separately or in combination, refers to carbocyclic aromatic cyclic diradical or aromatic cyclic system of diradicals. Examples of arylene” include, but are not limited to, benzene-1,4-diyl, naphthalene-1,8-diyl and the like.

Used herein, the term “heteroaryl”, separately or in combination, refers to a five - to seven-membered aromatic cyclic diradical or aromatic cyclic system of diradical containing one renesola heteroatoms, selected from the heteroatoms nitrogen, oxygen or sulfur, where N-oxides and monoxide sulphur and sulphur dioxides are permitted by the substitution of heteroatoms. Used here, examples of heteroaryl are furan-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazol-2,5-diyl, 1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl, 1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl, pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl and the like.

Used herein, the term “alkylsulfanyl” refers to the group RaS-, where Rarepresents an alkyl as described above.

Used herein, the term “alkylsulfanyl” refers to the group RaS(O)-, where Rarepresents an alkyl as described above.

Used herein, the term “alkylsulfonyl” refers to the group RaSO2-where Rarepresents an alkyl as described above.

Used herein, the term “acyl” refers to the group RaC(O)-, where Rarepresents alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl or heterocyclyl, as described above.

Used herein, the term “aroyl” refers to the group RaC(O)-, where Rarepresents aryl as described above.

Used herein, the term “heteroaryl” refers to the group RaC(O)-, where Rais heteroaryl, as described above.

Used herein, the term which is acyloxy” refers to the group R aC(O)O-, Rarepresents alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl or heterocyclyl, as described above.

Used herein, the term “urologic” refers to the group RaC(O)O-, Rarepresents aryl as described above.

Used herein, the term “heteroaromatic” refers to the group RaC(O)O-, Rais heteroaryl, as described above.

When the terms "alkyl" and "aryl" or any root appear in the name of a substituent (for example, allakariallak), they should be interpreted as including those limitations given above for "alkyl" and "aryl".

Used herein, the term “oxo” shall apply to the Deputy =O.

Used herein, the term “mercapto” shall refer to the Vice-SH.

Used herein, the term “carboxy” shall refer to the Vice-COOH.

Used herein, the term “cyano” shall refer to the Vice-CN.

Used herein, the term “aminosulfonyl” shall apply to the Deputy SO2NH2.

Used herein, the term “sulfanyl” shall apply to the Deputy-S-.

Used herein, the term “sulfenyl” shall apply to the Deputy-S(O)-.

Used herein, the term “sulfonyl” shall apply to the Deputy-S(O)2-.

Used here Ter is in “direct link”, which is part of the structurally modified this connection, refers to the direct connection of alternate adjacent (previous or subsequent) to the modified unit is defined as "direct connection".

Used herein, the term “lower” refers to a group having one to six carbons, and this can be shown in the form of Cx-6. The lower alkyl can thus be shown as C1-6-alkyl, while the lowest alkylen can be shown as C2-6-alkylen.

Radical, such as Cx-y-cycloalkyl-Ca-balkenyl must indicate that the attachment point of a radical is partially radicals mentioned last.

Used herein, the term “optional” means that the described(s) subsequent event(I) may or may not occur, and includes both the event(I)that(s) is(Yat), and events that do not occur.

Used herein, the term “substituted” refers to substitution specified by the Deputy or deputies, and resolved multiple degrees of substitution, unless otherwise specified.

Used herein, the terms "contain" or "containing" may refer to the combined substitutions at any position of the above alkyl, alkenyl, alkynylaryl or cycloalkenyl the substituents which together with one or more of any of O, S, SO, SO2, N, or N-alkyl, including, for example, -CH2-O-CH2-, -CH2-SO2-CH2-, -CH2-NH-CH3and so on.

Certain of the above terms can occur in structural formulas more than once and if such occurrence each term shall be defined independently of the others.

Used herein, the term “MES” is a complex of different stoichiometry formed by the dissolved substance (in this invention the compound of formula (I), (II) or (III)) and a solvent. Such solvents for the purposes of the present invention may not affect the biological activity of the solute. Solvents can be, as an example, water, ethanol or acetic acid.

Used herein, the term “biogerontology ester” is an ester drug substance (in this invention, compounds of formula (I), (II) or (III)), which either a) does not affect the biological activity of a generic substance, but adds that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is easily transformed in vivo by the subject in the biologically active principle. The advantage is, for example, that biogerontology ester when oral intake is absorbed by the intestine and converted into (I) in the plasma. In the art there are many such examples, and they include, as an example, esters of lower Akilov (for example, C1-C4), esters of lower aryloxyalkyl, esters of lower alkoxyalkanols, esters of alkoxysilane, esters of alkalinisation and esters of Kalinov.

Used herein, the term “biogerontology amide” is an amide of medicinal substance (in this invention compounds of General formula (I), (II) or (III)), which either a) does not interfere with the biological activity of the parent substance but adds that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject in the biologically active principle. The advantage is, for example, that biogerontology amide when administered orally is absorbed by the intestine and converted into (I) in the plasma. In the art there are many such examples, and they include, as an example, amides of lower Akilov, amides of α-amino acids, amides of alkoxyaryl and amides of alkylaminocarbonyl.

Used herein, the term “prodrug” includes biohydrology amides and biogerontology esters and also encompasses a) compounds in which b is hidrogliserima functional group such prodrugs are included in the compound of formula (I): for example, the lactam formed by a carboxyl group in R2and Amin in R4and b) compounds which may be oxidized or restored biologically at a given functional group with obtaining medicinal substances of the formula (I). Examples of such functional groups include, but are not limited to, 1,4-dihydropyridines, N-alkylsulphonyl-1,4-dihydropyridines, 1,4-cyclohexadiene, tert-butyl and the like.

The term “pharmacologically effective amount” shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, animal or human that is expected by the researcher or doctor. This number can be therapeutically effective amount. The term “therapeutically effective amount” shall mean that amount of drug or pharmaceutical agent that will elicit the expected therapeutic response of an animal or human.

Used herein, the term "treatment" or "cure" means the treatment and recovery of a patient to combat disease, disorder or condition. The term is intended to include the full spectrum of treatment for this disorder from which the patient suffers, such as delay the development of diseases, disorders or conditions that facilitate or weakening sent the MOU diseases and complications and/or recovery or elimination of diseases, disorders or conditions. The patient being treated, preferably is a mammal, in particular humans.

Detailed description of the invention

In one implementation of the present invention is proposed carboxamide or sulfonamidnuyu activator of glucokinase, having a heteroatom in the alpha, beta or gamma position relative to the carboxamide or sulfonamida respectively.

In one implementation of the present invention proposed compounds of General formula (I)

where

G represents-S(O)2- or-C(O)-;

A represents >N, and

X represents a direct bond, -O-, -S-, -S(O)-, -S(O)2- or-N(R6)-, where

R6represents hydrogen or alkyl which may be optionally substituted by one or more substituents R16, R17and R18and

L1represents -(CH2)n-C(R9)(R10)m-Y-, or a direct link, where

n is an integer from 1 to 6,

R9and R10independently from each other selected from alkyl or cycloalkyl, optionally substituted by one or more substituents R19, R20and R21; or aryl, optionally substituted by one or more substituents R 40, R41, R42and R43,

m is an integer from 0 to 1, and

Y represents a direct bond, -O-, or-N(R7)-, where

R7represents hydrogen or alkyl which may be optionally substituted by one or more substituents R22, R23and R24;

or

X represents alkylene, which may be optionally substituted by one or more substituents R25, R26and R27or a direct link, and

L1represents-O - or-N(R8)-, where

R8represents hydrogen or alkyl which may be optionally substituted by one or more substituents R28, R29and R30;

or

A represents >C(R2)-, where R2represents hydrogen or alkyl, optionally substituted by one or more substituents R31, R32and R33and

X represents-O-, -S-, -S(O)-, -S(O)2- or-N(R6)-, where

R2specified above, and

L1represents -(CH2)n-Y-, or a direct link, where

n is an integer from 1 to 6, and

Y represents a direct bond, O, or-N(R7)-, where

R7specified above;

or

X represents alkylene, which may be optionally substituted by one or more substituents R25, R26R 27or a direct link, and

L1represents-O - or-N(R8)-, where

R8specified above;

R1and R3independently from each other selected from alkyl, alkenyl, quinil, cycloalkyl and heterocyclyl, optionally substituted by one or more substituents R34, R35and R36; or aryl, heteroaryl, condensed heterocyclisation, condensed heteroalicyclic, condensed geterotsiklicheskikh, condensed killglance, condensed cycloalkenyl, condensed heteroalicyclic and condensed cycloalkylcarbonyl, optionally substituted by one or more substituents R44, R45, R46and R47;

or

R1and R3taken together with the atoms to which they are attached, may form cycloalkyl or heterocyclyl ring, optionally substituted by one or more substituents R34, R35and R36and optionally condensed with a heteroaryl or aryl ring, optionally substituted by one or more substituents R44, R45, R46and R47;

or where A represents >C(R2)-, then

R1and R2taken together with the atoms to which they are attached, may form cyclea kilroe or heterocyclyl ring, optionally substituted by one or more substituents R34, R35and R36and optionally condensed with a heteroaryl or aryl ring, optionally substituted by one or more substituents R44, R45, R46and R47;

or

R2and R3taken together with the atoms to which they are attached, may form cycloalkyl or heterocyclyl ring, optionally substituted by one or more substituents R34, R35and R37and optionally condensed with a heteroaryl or aryl ring, optionally substituted by one or more substituents R44, R45, R46and R47;

R4represents hydrogen or alkyl, optionally substituted by one or more substituents R37, R38and R39; and

R5represents aryl or heteroaryl, optionally substituted by one or more substituents R48, R49, R50and R51;

where

R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34,

R35, R36, R37, R38and R39independently from each other selected from the

-CHF2, -CF3, -OF 3, -OCHF2, -OCH2CF3, -OCF2CHF2, -S(O)2CF3,

-SCF3, -OR52-NR52R53, -SR52, -NR52S(O)2R53, -S(O)2NR52R53,

-S(O)NR52R53, -S(O)R52, -S(O)2R52, -C(O)NR52R53, -OC(O)NR52R53,

-NR52C(O)R53, -CH2C(O)NR52R53, -OCH2C(O)NR52R53, -CH2OR52, -CH2NR52R53, -OC(O)R52, -C(O)R52and-C(O)OR52; C2-6-alkenyl and C2-6-quinil, which may be optionally substituted by one or more substituents selected from-CN, -CF3, -OCF3, -OR52, -NR52R53and C1-6-alkyl, C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkoxy, C3-8-cycloalkane, C3-8-cycloalkyl-C1-6-alkylthio, C3-8-cycloalkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-quinil, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-quinil, heterocyclyl-Cl-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-quinil, aryl, aryloxy, aryloxyalkyl, Arola, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, the Rila-C 2-6-alkenyl, aryl-C2-6-quinil, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl and heteroaryl-C2-6-quinil, which aryl and heteroaryl part is optionally can be substituted by one or more substituents selected from halogen, -C(O)OR52, -CN, -CF3, -OCF3, -NO2, -OR52, -NR52R53and C1-6-alkyl;

R40, R41, R42, R43, R44, R45, R46and R47independently from each other, selected from halogen, -CN, -CH2CN, -CHF2, -CF3, -OCF3, -OCHF2,

-OCH2CF3, -OCF2CHF2, -S(O)2CF3, -SCF3, -NO2, -OR52, -NR52R53, -SR52,

-NR52S(O)2R53, -S(O)2NR52R53, -S(O)NR52R53, -S(O)R52, -S(O)2R52,

-C(O)NR52R53, -OC(O)NR52R53, -NR52C(O)R53, -CH2C(O)NR52R53,

-OCH2C(O)NR52R53, -CH2OR52, -CH2NR52R53, -OC(O)R52, -C(O)R52and

-C(O)OR52;

C1-6-alkyl, C2-6-alkenyl and C2-6-quinil, which may not necessarily be substituted by one or more substituents selected from-CN, -CF3, -OCF3, -OR52, -NR52R53and C1-6-alkyl;

C3-8-cycloalkyl, C4-8 -cycloalkenyl, heterocyclyl,

C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkoxy,

C3-8-cycloalkane, C3-8-cycloalkyl-C1-6-alkylthio,

C3-8-cycloalkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-quinil, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-quinil, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-quinil, aryl, aryloxy, aryloxyalkyl, Arola, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-quinil, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl and heteroaryl-C2-6-quinil, of which the aryl and heteroaryl optionally can be substituted by one or more substituents selected from halogen, -C(O)OR52, -CN, -CF3, -OCF3, -NO2, -OR52, -NR52R53and C1-6-alkyl;

and

two of R40, R41, R42and R43or two of R44, R45, R46and R47on adjacent carbon atoms can be independently taken together with the formation of-O-CH2-O-, where

R52and R53independently of one another represent hydrogen, C1-6-alkyl, aryl-C1-6-alkyl or the reel;

or

R52and R53when they are attached to the same nitrogen atom, together with the indicated nitrogen atom may form a 3-8-membered heterocyclic ring, optionally containing one or two additional heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds; and

R48, R49, R50and R51independently from each other selected from the

halogen, perfluoroalkyl, cyano, alkyl-Z-, aryl-Z-,

aryl-alkylene-Z-, N(R63)(R64)-Z-; and R65-W-alkylene-Z-; where

Z and W are independently from each other selected from a direct link, alkylene, -O-, -N(R66)-, -S-, -SO2-, -C(O)N(R66)-, -N(R66)C(O) -, - N(R66)C(O)N(R67)-, -N(R66)SO2-, -SO2N(R66)-, -C(O)C-, -OC(O)- and-N(R66)SO2N(R67)-; where

R66and R67independently from each other represent hydrogen or alkyl;

R63, R64and R65selected from the group consisting of hydrogen, aryl, alkyl and arylalkyl-; or

R63and R64can be taken together to form a ring having the formula -(CH2)j-E-(CH2)k-linked to the nitrogen atom is attached to R63and R64where

j is an integer from 1 to 4;

k is an integer from 1 to 4; and

E represents a direct the script, -CH2-, -O-, -S-, -S(O2)-, -C(O)-, -C(O)N(H)-, -NHC(O)-, -NHC(O)N(H)-, -NHSO2-, -SO2NH-, -C(O)O-, -OC(O)-, -NHSO2NH-,

where

R68and R69selected from the group consisting of hydrogen, aryl, alkyl and arylalkyl-;

or their pharmaceutically acceptable salt, MES or prodrug.

In one implementation of the present invention proposed compounds of General formula (II)

where

G represents-S(O)2- or-C(O)-;

R2represents hydrogen or alkyl which may be optionally substituted by one or more substituents R31, R32and R33;

X represents-O-, -S-, -S(O)-, -S(O)2- or-N(R6)-, where

R6specified above;

L1represents -(CH2)n-Y-, or a direct link, where

n is an integer from 1 to 6,

Y represents a direct bond, O or-N(R7)-, where

R7specified above;

R1and R3independently from each other selected from alkyl, alkenyl, quinil, cycloalkyl and heterocyclyl, optionally substituted by one or more substituents R34, R35and R36; or aryl, heteroaryl, condensed heterocyclisation, condensed heteroalicyclic, condensed geterotsiklicheskikh, condensers the frame of killglance, condensed cycloalkenyl, condensed heteroalicyclic and condensed cycloalkylcarbonyl, optionally substituted by one or more substituents R44, R45, R46and R47;

or

R1and R2can be taken together with the atoms to which they are attached, with the formation of cycloalkenes or heterocyclyl ring, optionally substituted by one or more substituents R34, R35and R36and optionally condensed with a heteroaryl or aryl ring, optionally substituted by one or more substituents R44, R45, R46and R47;

R4specified above; and

R5specified above;

where R31, R32, R33, R34, R35, R36, R44, R45, R46and R47above,

or their pharmaceutically acceptable salt, MES or prodrug.

In one implementation of the present invention proposed compounds of General formula (II)

where

G represents-S(O)2- or-C(O)-, and

X represents-O-, -S-, -S(O)-, -S(O)2- or-N(R6)-, where

R6specified above, and

L1represents -(CH2)n-Y-, or a direct link, where

n is an integer from 1 to 6, and

Y represents CR is needful communication, O or-N(R7)-, where

R7specified above;

or

X represents alkylene, which may be optionally substituted by one or more substituents R25, R26and R27or a direct link, and

L1represents-O - or-N(R8)-, where

R8specified above;

R1selected from alkyl, alkenyl, quinil, cycloalkyl and heterocyclyl, optionally substituted by one or more substituents R34, R35and R36; or aryl, heteroaryl, condensed heterocyclisation, condensed heteroalicyclic, condensed geterotsiklicheskikh, condensed killglance, condensed cycloalkenyl, condensed heteroalicyclic and condensed cycloalkylcarbonyl, optionally substituted by one or more substituents R44, R45, R46and R47;

or

R2and R3together with the atoms to which they are attached, form cycloalkyl or heterocyclyl ring, optionally substituted by one or more substituents R34, R35and R36and optionally condensed with a heteroaryl or aryl ring, optionally substituted by one or more substituents R44, R45, R46and R47;

R4the uke is an above; and

R5specified above;

where R25, R26, R27, R34, R35, R36, R44, R45, R46and R47specified above;

or their pharmaceutically acceptable salt, MES or prodrug.

In one implementation of the present invention proposed compounds of General formula (II)

where

G represents-S(O)2- or-C(O)-;

R2represents hydrogen or alkyl, which optionally can be substituted by one or more substituents R31, R32and R33;

X represents alkylene, which may be optionally substituted by one or more substituents R25, R26and R27or a direct link;

L1represents-O - or-N(R8)-, where R8specified above;

R1and R3independently from each other selected from alkyl, alkenyl, quinil, cycloalkyl and heterocyclyl, optionally substituted by one or more substituents R34, R35and R36; or aryl, heteroaryl, condensed heterocyclisation, condensed heteroalicyclic, condensed geterotsiklicheskikh, condensed killglance, condensed cycloalkenyl, condensed heteroalicyclic and condensed cycloalkyl is roarie, optionally substituted by one or more substituents R44, R45, R46and R47;

or

R1and R2may together with the atoms to which they are attached, form cycloalkyl or heterocyclyl ring, optionally substituted by one or more substituents R34, R35and R36and optionally condensed with a heteroaryl or aryl ring, optionally substituted by one or more substituents R44, R45, R46and R47;

or

R2and R3may together with the atoms to which they are attached, form cycloalkyl or heterocyclyl ring, optionally substituted by one or more substituents R34, R35and R36and optionally condensed with a heteroaryl or aryl ring, optionally substituted by one or more substituents R44, R45, R46and R47;

R4specified above; and

R5specified above;

where R25, R26, R27, R31, R32, R33, R34, R35, R36, R44, R45, R46and R47specified above;

or their pharmaceutically acceptable salt, MES or prodrug.

In one implementation of the present invention proposed compounds of General formula (III)

where

G represents-S(O)2- or-C(O)-; and

X represents a direct bond, -O-, -S-, -S(O)-, -S(O)2- or-N(R6)-, where

R6specified above, and

L1represents -(CH2)n-C(R9)(R10)m-Y-, or a direct link, where

n is an integer from 1 to 6,

R9and R10specified above;

m is an integer from 0 to 1, and

Y represents a direct bond, -O-, or-N(R7)-, where

R7specified above;

or

X represents alkylene, which may be optionally substituted by one or more substituents R25, R26and R27or a direct link, and

L1represents-O - or-N(R8)-; where

R8specified above;

R1and R3independently from each other selected from alkyl, alkenyl, quinil, cycloalkyl and heterocyclyl, optionally substituted by one or more substituents R34, R35and R36or aryl, heteroaryl, condensed heterocyclisation, condensed heteroalicyclic, condensed geterotsiklicheskikh, condensed killglance, condensed cycloalkenyl, condensed heteroalicyclic and condensed cycloalkylcarbonyl, optionally substituted by one or more substituents R44 , R45, R46and R47;

or

R1and R3may together with the atoms to which they are attached, form cycloalkyl or heterocyclyl ring, optionally substituted by one or more substituents R34, R35and R36and optionally condensed with a heteroaryl or aryl ring, optionally substituted by one or more substituents R44, R45, R46and R47;

R4specified above; and

R5specified above;

where R25, R26, R27, R34, R35, R36, R44, R45, R46and R47specified above;

or their pharmaceutically acceptable salt, MES or prodrug.

Additional implementation data realizations clear from the accompanying claims.

The present invention also proposed a connection according to the present invention for use as a medicine.

In one implementation of the present invention proposed a connection according to the present invention for the treatment of hyperglycemia.

In one implementation of the present invention proposed a connection according to the present invention for the treatment of IGT.

In one implementation of the present invention proposed a connection according to the present invention for the treatment of syndrome X.

In one is the implementation of the present invention proposed a connection according to the present invention for the treatment of type 2 diabetes.

In one implementation of the present invention proposed a connection according to the present invention for the treatment of type 1 diabetes.

In one implementation of the present invention proposed a connection according to the present invention for the treatment of dyslipidemia or hyperlipidemia.

In one implementation of the present invention proposed a connection according to the present invention for the treatment of hypertension.

In one implementation of the present invention proposed a connection according to the present invention for the treatment or prevention of obesity.

In one implementation of the present invention proposed a connection according to the present invention is to reduce food intake.

In one implementation of the present invention proposed a connection according to the present invention for the regulation of appetite.

In one implementation of the present invention proposed a connection according to the present invention for the regulation of feeding behavior.

In one implementation of the present invention proposed a connection according to the present invention for increasing the secretion of anterointernal. In an additional implementation of the specified centeronscreen is a GLP-1.

The present invention also proposed a pharmaceutical composition comprising as an asset of the second ingredient, at least one compound according to the present invention together with one or more pharmaceutically acceptable carriers or excipients in a unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compounds according to the present invention.

In one implementation of the pharmaceutical composition according to the present invention includes additional anti-diabetic agent.

In one implementation of this additional antidiabetic agent is an insulin or insulin analogue.

In one implementation of this additional anti-diabetic agent is a sulfonylurea.

In one implementation of this additional anti-diabetic agent is biguanid.

In one implementation of this additional anti-diabetic agent is meglitinide.

In one implementation of this additional anti-diabetic agent is a photosensitizer to insulin.

In one implementation of this additional anti-diabetic agent is thiazolidindiones sensitizer to insulin.

In the bottom the implementation of specified additional anti-diabetic agent is an inhibitor of α-glucosidase.

In one implementation of this additional anti-diabetic agent is an inhibitor of glycogen phosphorylase.

In one implementation of this additional anti-diabetic agent is an agent acting on the ATP-dependent potassium channel of the pancreatic β-cells.

In one implementation of the pharmaceutical composition according to the present invention includes additional antihyperlipidemic agent.

In one implementation of this additional antihyperlipidemic agent is a cholestyramine.

In one implementation of this additional antihyperlipidemic agent is a colestipol.

In one implementation of this additional antihyperlipidemic agent is a clofibrate.

In one implementation of this additional antihyperlipidemic agent is gemfibrozil.

In one implementation of this additional antihyperlipidemic agent is a lovastatin.

In one implementation of this additional antihyperlipidemic agent represents pravastatin.

In one implementation of this additional antihyperlipidemic agent represents simvastatin.

In one implementation, the specified stage is nitely antihyperlipidemic agent is probucol.

In one implementation of this additional antihyperlipidemic agent is dextrothyroxine.

In the scope of the present invention includes the individual enantiomers of the compounds represented by formula (I)above, as well as any wholly or partially racemic mixtures. The present invention also covers the individual enantiomers of the compounds represented by formula (I)above, in the form of mixtures of their diastereoisomers in which one or more stereocentres inverted.

Compounds of the present invention are activators of glucokinase and, as such, can be used to activate glucokinase.

Accordingly, in the present invention, a method of activating glucokinase in a patient in need thereof, the method comprises the introduction to the needy in the subject compounds of the present invention, preferably the compounds of formula (I), (II) or (III), preferably a pharmacologically effective amount, more preferably in a therapeutically effective amount. In the present invention proposed a method of reducing the level of glucose in a patient in need thereof, the method comprises the introduction to the needy in the subject compounds of the present invention, preferably the compounds of formula (I), (II) or (III),preferably a pharmacologically effective amount, more preferably in a therapeutically effective amount. In the present invention a method of prevention and/or treatment of diseases in humans associated with glucokinase deficiency, a patient in need thereof, the method comprises the introduction to the needy in the human therapeutically effective amounts of compounds of the present invention, preferably the compounds of formula (I), (II) or (III). Used here, the phrase "requiring the subject" includes subjects related to mammals, preferably people who either suffer from one or more of the above diseases or pathological conditions, or are at risk for such. Accordingly, in the context of the method of therapy of the present invention the method also includes a method of prophylaxis of a subject is a mammal, either before diagnosis such(fir) disease(s) or pathological(these) condition(s). Other implementation of such methods will be apparent from the subsequent description.

Compounds according to the present invention can be used to treat disorders, diseases and conditions where the activation of glucokinase is favorable.

Accordingly, the compounds of the present invention can be used to treat hyperslices and, IGT (abnormal glucose tolerance, syndrome of resistance to insulin, syndrome X, type 1 diabetes, type 2 diabetes, dyslipidemia, dyslipoproteinemia (disturbed level of lipoproteins in the blood), including diabetic dyslipidemia, hyperlipidemia, hyperlipoproteinemias (excess of lipoproteins in the blood), including type I and II-a (hypercholesterolemia), II-b, III, IV (hypertriglyceridemia) and V (hypertriglyceridemia), hyperlipoproteinemias and obesity. Moreover, they can be suitable for the treatment of albuminuria, cardiovascular diseases such as cardiac hypertrophy, hypertension and arteriosclerosis, including atherosclerosis, disorders of the gastrointestinal tract; acute pancreatitis; and for the regulation of appetite or violations of consumption.

In one implementation of the method according to the present invention an effective amount of a compound according to the present invention is in the range from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg and especially preferred from about 0.5 mg to about 500 mg per day.

In one implementation of the method according to the present invention the method is used by the scheme, which includes treatment of additional anti-diabetic agent such as additional anti-diabetic agent selected from the of Sulina or insulin analogue, sulfonylureas, biguanides, meglitinide, sensitizer to insulin, thiazolidinediones sensitizer to insulin, an inhibitor of α-glucosidase, glycogen phosphorylase inhibitor and an agent acting on the ATP-dependent potassium channel of the pancreatic β-cells.

In one implementation of the method according to the present invention the method is used by the scheme, which includes the additional treatment antihyperlipidemic agent such as additional antihyperlipidemic agent selected from cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol and dextrothyroxine.

In one implementation of the method according to the present invention the method is used by the scheme, which includes the additional treatment agent against obesity.

In one implementation of the method according to the present invention the method is used by the scheme, which includes treatment of additional antihypertensive agent.

Accordingly, in an additional aspect, the invention relates to a compound according to the present invention for use as a medicine.

The invention also relates to pharmaceutical compositions comprising as active ingredient at least one compound of the present invention together with one or several and pharmaceutically acceptable carriers or excipients.

The pharmaceutical composition is preferably in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compounds of the present invention, such as compound of formula (I), (II) or (III).

In one implementation of the present invention compounds of the present invention is used for getting medicines for the treatment of hyperglycemia. Used herein, the term hyperglycemia is used, as is usual in the art, with reference, for example, on the report of the expert Committee on the diagnosis and classification of diabetes mellitus, published in Diabetes Care 20,1183-1197, (1997), but usually it is used to refer to the increased level of plasma glucose greater than approximately 110 mg/DL. Compounds of the present invention is effective in lowering blood glucose levels both fasting and after a meal.

In one implementation of the present invention compounds of the present invention is used to obtain a pharmaceutical composition for the treatment of IGT.

In one implementation of the present invention compounds of the present invention is used to obtain a pharmaceutical composition for the treatment of syndrome X

In one implementation of the present invention compounds of the present invention is used to obtain a pharmaceutical composition for the treatment of type 2 diabetes. Such treatment includes, for example, treatment with the aim pause the progression from IGT to type 2 diabetes, as well as to pause the progression of type 2 diabetes from not requiring insulin to require insulin injections.

In one implementation of the present invention compounds of the present invention is used to obtain a pharmaceutical composition for the treatment of type 1 diabetes. Such treatment is usually accompanied by insulin.

In one implementation of the present invention compounds of the present invention is used to obtain a pharmaceutical composition for the treatment of dyslipidemia and hyperlipidemia.

In one implementation of the present invention compounds of the present invention is used to obtain a pharmaceutical composition for the treatment of obesity.

In another aspect of the present invention the treatment of the patient by the compounds of the present invention is combined with diet and/or exercise.

In the present invention the methods of activation of glucokinase in a mammal, the methods include the introduction to the needy in the activation of glucokinase to the mammal a therapeutically ODA is divided by the number of compounds of the present invention, such as a compound of formula (I), (II) or (III)above, in the form of his uniform or polymorphic crystalline form or forms, an amorphous form, a single enantiomer, a racemic mixture, a single stereoisomer, mixture of stereoisomers, a single diastereoisomer, a mixture of diastereoisomers, MES, pharmaceutically acceptable salt, MES, prodrugs, bioerosive ether or bioerosive amide.

In the present invention, a method of activating glucokinase including the stage of introduction of the needy in the mammal a pharmacologically effective amount of the compounds of the present invention. The invention additionally proposed pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compounds of the present invention, sufficient for activation of glucokinase. The number that activates glucokinase can be an amount that reduces or inhibits the activity of PTP-basics of the subject.

The present invention additionally proposed pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compounds of the present invention sufficient to treat diabetes type I.

The present invention also offers the wife of the pharmaceutical composition, including pharmaceutically acceptable carrier and a pharmacologically effective amount of the compounds of the present invention sufficient to treat type II diabetes.

Compounds of the present invention can be introduced to any mammal in need of activating glucokinase. Such mammals may include, for example, horses, cows, sheep, pigs, mice, dogs, cats, primates, such as chimpanzees, gorillas, rhesus monkeys, and most preferably human.

In an additional aspect of the present invention compounds of the present invention is administered in combination with one or more additional active substances in any suitable ratios. Such additional active agents can be selected from antidiabetic agents, antihyperlipidemic agents, agents against obesity, antihypertensive agents and agents for the treatment of complications resulting from or associated with diabetes.

Suitable antidiabetic agents include insulin derivatives, GLP-1 (like peptide-1), such as disclosed in the patent WO 98/08871 (Novo Nordisk A/S), which is incorporated herein by reference, as well as orally active hypoglycemic agents.

Suitable orally active hypoglycemic agents preferably include imidazoline pressed into the nye sulfonylureas, biguanides, meglitinide, oxadiazolidine preparations, thiazolidinediones, insulin sensitizers, inhibitors of α-glucosidase, agents acting on the ATP-dependent potassium channel of the pancreatic β-cells, for example agents that open potassium channels, such as disclosed in patents WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S), which is incorporated herein by reference, agents, opening potassium channels, such as ornithin, blocker of potassium channels, such as nateglinide or BTS-67582, glucagon antagonists, such as disclosed in patents WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals,Inc.), all of which are incorporated herein by reference, agonists of GLP-1, such as disclosed in the patent WO 00/42026 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which is incorporated herein by reference, inhibitors of DPP-IV (dipeptidylpeptidase-IV)inhibitors of PTP-basics (protein-tyrosinosis), inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, modulators of the seizure of glucose, inhibitors of GSK-3 (kinase-3 glikogensintetazy), compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents, compounds lowering food intake, PPAR agonists (receptor activator of peroxisome proliferation) and RXR (retinoid X receptor), such as ALRT-268, LG-1268 or LG-1069.

In one implementation of this is subramania compounds of the present invention is administered in combination with insulin or insulin analogs.

In one implementation of the present invention compounds of the present invention is administered in combination with sulfonylurea derivatives, such as tolbutamide, chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride, glicazide or gliburid.

In one implementation of the present invention compounds of the present invention is administered in combination with biguanides, such as Metformin.

In one implementation of the present invention compounds of the present invention is administered in combination with meglitinides, such as Repaglinide or sinapinic/nateglinide.

In one implementation of the present invention compounds of the present invention is administered in combination with thiazolidinediones the sensitizer to insulin, such as troglitazone, ciglitazone, pioglitazone, rosiglitazone, eaglecasino, darglitazone, englitazone, CS-011/CI-1037 or T 174 or the compounds disclosed in the patents WO 97/41097 (DRF-2344), WO 97/41119, WO97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which is incorporated herein by reference.

In one implementation of the present invention compounds of the present invention is administered in combination with a sensitizer to insulin, such as GI 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in the patents WO 99/19313 (NN622/DRF-2725), WO 00/50414, WO 00/63191, WO 00/6192, WO 00/63193 (Dr. Reddy's Research Foundation) and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO 00/63189 (Novo Nordisk A/S), which is incorporated herein by reference.

In one implementation of the present invention compounds of the present invention is administered in combination with inhibitors of α-glucosidase, such as voglibose, emiglitate, miglitol or acarbose.

In one implementation of the present invention compounds of the present invention is administered in combination with a glycogen phosphorylase inhibitor, for example the compounds disclosed in the patent WO 97/09040 (Novo Nordisk A/S).

In one implementation of the present invention compounds of the present invention is administered in combination with an agent acting on the ATP-dependent potassium channel of the pancreatic β-cells, for example, tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or Repaglinide.

In one implementation of the present invention compounds of the present invention is administered in combination with nateglinide.

In one implementation of the present invention compounds of the present invention is administered in combination with an antihyperlipidemic agent or antilipidemic agent, such as cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol and dextrothyroxine.

In another aspect of this image is the shadow of compounds of the present invention is administered in combination with more than one of the aforementioned compounds, for example, in combination with Metformin and sulfonylurea derivatives such as gliburid; with derivatives of sulfonylurea and acarbose; nateglinide and Metformin; acarbose and Metformin; with derivatives of sulfonylurea, Metformin and troglitazone; with insulin and derivatives of sulfonylurea; insulin and Metformin; insulin, Metformin and sulfonylurea derivatives; with insulin and troglitazone; insulin and lovastatin, and the like.

Moreover, the compounds according to the present invention can be introduced in combination with one or more agents, anti-obesity or agents that regulate appetite.

Such agents can be selected from the group consisting of agonists CART (transcript regulated by cocaine and amphetamine), antagonists of NPY (neuropeptide Y), MC3 agonist (melanocortin 3), MC4 agonists (melanocortin 4), antagonists of orexin, agonists of TNF (tumor necrosis factor)agonists, CRF (corticotropin releasing factor)antagonists of CRF BP (binding protein of the corticotropin-releasing factor)agonists of urocortin, β3-adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH agonists (melanocytestimulating hormone), antagonists of MCH (melanocarcinoma hormone)agonists, CCK (cholecystokinin), inhibitors of serotonin reuptake (luoxetine, seroxat or citalopram), reuptake inhibitors of serotonin and norepinephrine agonists 5HT (serotonin)agonists of bombezin, antagonists Galanina, growth hormone, growth factors such as prolactin or placental lactogenic, compounds that cause the release of growth hormone, TRH agonists (tireotropin-releasing hormone), modulators of the UCP 2 or 3 (decoupling protein 2 or 3), leptin agonists, DA agonists (dopamine) (bromocriptine, dobracina), inhibitors of lipase/amylase, modulators of PPAR, RXR modulators, TRβ agonist, adrenergic agents, Central nervous system stimulant, inhibitors AGRP (protein related gene agouti), antagonists of H3 histamine receptors, such as disclosed in patents WO 00/42023, WO 00/63208 and WO 00/64884, which is incorporated herein by reference, basis 4, agonists of GLP-1 and derived neurotrophic factor cilia. Additional agents against obesity are bupropion (an antidepressant), topiramate (anticonvulsant), ecopipam (antagonist of D1/D5 dopamine receptors) and naltrexone (an opioid antagonist).

In one implementation of the present invention, the agent against obesity is a leptin.

In one implementation of the present invention, the agent against obesity is a serotonin and inhibitor reuptake of norepinephrine, such as sibutramine.

In one implementation, the attachment of the present invention, the agent against obesity is a lipase inhibitor, for example orlistat.

In one implementation of the present invention, the agent against obesity is an adrenergic agent that stimulates the Central nervous system, such as dexamfetamine, amphetamine, phentermine, mazindol, phendimetrazine, diethylpropion, fenfluramine or dexfenfluramin.

Moreover, the compounds of the present invention can be introduced in combination with one or more antihypertensive agents. Examples of antihypertensive agents are β-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE inhibitors (angiotensin-converting enzyme), such as benazepril, captopril, enalapril, fosinopril, lisinopril, inapril and ramipril, calcium channel blockers, such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and α-blockers such as doxazosin, urapidil, prazosin and terazosin. Additional reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

It should be clear that any suitable combination of the compounds according to the present invention with diet and/or exercise one or more of the above compounds and, optionally, with one or more other active substances considered as included in the scope of the present invention.

The pharmacist is ical composition

Compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers or excipients in the form of single or multiple doses. The pharmaceutical compositions according to the present invention can be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional methods, such as those disclosed in Remington: The Science and Practice of Pharmacy, 19thEdition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

The pharmaceutical compositions may be specially prepared for administration by any suitable route, such as oral, rectal, nasal, pulmonary, local (including hominids and sublingual), transdermal, vnutristennaya, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, and the oral route is preferred. Note that the preferred path must depend on the condition and age of the exposed treatment of the subject, the nature of the condition being treated, and the selected active ingredient.

Pharmaceutical compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, mouth is key, pills, pills, pellets, powders and granules. When it is appropriate, you can get them with coatings such as enteric coatings, or they can be designed to provide controlled release of the active ingredient, such as a permanent or prolonged release, in accordance with methods well known in the art.

Liquid dosage forms for oral administration include solutions, emulsions, aqueous or oily suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous suitable for injection solutions, dispersions, suspensions or emulsions, and sterile powders for a suitable sterile injection solutions or dispersions prior to use. Have in mind also the compositions of the injectable depot, because they are included in the scope of the present invention.

Other suitable forms of introduction include suppositories, sprays, ointments, creams, gels, aspirates, skin patches, implants, etc.

The usual oral dose is in the range from about 0.001 to about 100 mg/kg of body weight per day, preferably from about 0.01 to about 50 mg/kg of body weight per day and more preferably from about 0.05 to the roughly 10 mg/kg of body weight per day, enter in one or more doses, such as from 1 to 3 doses. The exact dose depends on the frequency and route of administration, sex, age, weight and General condition of the subject treated of the subject, the nature and severity of the subject to treatment condition and subject to any treatment of comorbidities and other factors evident to experts in the field of technology.

The compositions can be appropriately presented in unit dosage form using methods known to experts in this field of technology. Conventional unit dosage form for oral administration one or more times per day, such as from 1 to 3 times a day, can contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferably from about 0.5 to about 200 mg

For parenteral routes such as intravenous, vnutriobolochechnoe, intramuscular and similar introduction, the usual dose is of the order of approximately half of the dose used for oral administration.

The compounds of this invention are typically used in free form or in the form of its pharmaceutically acceptable salts. Examples are additive salt of the acid and compounds containing the group of free base and additive salt bases and compounds containing g is the SCP of the free acid. The term “pharmaceutically acceptable salts” refers to non-toxic salts of the compounds of this invention are usually obtained by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. When the compound of the present invention, such as compound of formula (I), (II) or (III)contains a free base such salts get in the usual way, by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable acid. When the compound of the present invention, such as compound of formula (I), (II) or (III)contains a free acid, a salt such get in the usual way, by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable base. Physiologically acceptable salts of the compounds with a hydroxyl group include the anion of the compounds in combination with a suitable cation such as sodium ion or ammonium. Other salts which are not pharmaceutically acceptable may be used to produce compounds of the present invention, and they form an additional aspect of the present invention.

For parenteral administration can be used solutions of the new compounds is of the formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil. Such aqueous solutions, if necessary, must be properly buffered, aqueous diluent doing is isotonic with sufficient amount of salt or glucose. Aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous or intraperitoneal administration. Used sterile water environment can be easily obtained using standard methods known to experts in this field of technology.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, white clay, sucrose, cyclodextrin, talc, gelatin, agar, pectin, gum, magnesium stearate, stearic acid and the lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, amines, fatty acids, polyoxyethylene and water. Similarly, the carrier or diluent may include any known in the art are continuously released substance, such as glycerylmonostearate or glycerylmonostearate, alone or in mixture with wax. The pharmaceutical compositions formed by the combination of the new compounds of the present invention and pharmaceutically acceptable carriers, then it is easy to introduce in many dosage forms suitable for the disclosed routes of administration. Drugs can be duly proposed as a standard dosage forms using methods known in the field of pharmacy.

The preparations according to the present invention suitable for oral administration may be proposed in the form of discrete units such as capsules or tablets, each contains a predetermined amount of the active ingredient and may include a suitable filler. Moreover, suitable for oral administration, the preparations can be in the form of powder or granules, a solution or suspension in aqueous or non-aqueous liquid or liquid emulsion of oil in water or water in oil.

Compositions intended for oral use can be obtained according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavors, colorants and preservatives, to provide pharmaceutically elegant and pleasant drugs. Tablets may contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients which are suitable for the production of tablets. These fillers can be, for example, inert diluents, such as carbonate feces is tion, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating or spray agents, for example corn starch or alginic acid; binding agents, for example starch, gelatin or gum; and wetting agents such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or they can be coated using known methods to delay disintegration and absorption in the gastrointestinal tract with thereby providing a continuous action over a longer period of time. For example, can be applied to the retaining substance, such as glycerylmonostearate or glycerylmonostearate. You can also cover the methods described in U.S. patents Nos. 4356108; 4166452 and 4265874 included here as a reference, with the formation of an osmotic therapeutic tablets for controlled release.

Preparations for oral administration may be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions can soda in order to reap the active compounds in a mixture with fillers, suitable for aqueous suspensions. Such fillers are suspendresume agents, such as carboxymethylcellulose sodium, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone resin tragakant and Arabian gum; dispersing or moisturizing agents may be natural fosfatados, such as lectin, or condensation products of accelerated with fatty acids, such as polyoxyethylenesorbitan, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecanol-toxicitya, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as monooleate of polyoxyethylenesorbitan, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides hexitol, for example monooleate of polyethylenimine. Aqueous suspensions may also contain one or more dyes, one or more flavoring agents and one or more sweeteners, such as sucrose or saccharin.

Oil suspensions can be obtained by suspendirovanie active ingredient in a vegetable oil such as peanut oil, sesame oil or cottonseed oil, or in mineral oil such as liquid paraffin. Oil the e suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. To provide amenities to oral medication can be added sweeteners, such as those mentioned above, and flavoring agents. Song data can be conserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for receiving the aqueous slurry by adding water, to give the active compound in a mixture with dispersing or wetting agent, suspenders agent and one or more preservatives. Suitable dispersing or moisturizing agents and suspendresume agents shown above. Can also be additional fillers, such as sweeteners, flavorings and colorings.

The pharmaceutical compositions of the present invention may also be in the form of emulsions of oil in water. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be natural resins, such as the Arabian gum or resin tragakant, natural phosphatides, for example soy bean, lecithin, and esters or partial esters, leading start from fatty acids and anhydrides hexitol, such as orbitonasal, and products condenses and these partial esters with ethylene oxide, for example polyoxyethylenesorbitan. The emulsion may also contain sweeteners and flavorings.

Syrups and elixirs may be formulated with sweeteners, such as glycerin, propylene glycol, sorbitol or sucrose. Such compositions may also contain softening agent, a preservative and flavoring and coloring. The pharmaceutical compositions can be in the form of sterile suitable for injection, aqueous or oil suspensions. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspendida agents described above. Sterile suitable for injection drug may also be suitable for sterile injectable solution or suspension in a nontoxic acceptable for parenteral use diluent or solvent, for example in the form of a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used, you can specify the water, ringer's solution and isotonic solution of sodium chloride. In addition, as a solvent or suspendida environment convenient to use sterile non-volatile oil. This can be used any soft non-volatile oil with synthetic mono - or diglycerides. In addition, when receiving suitable for injection compositions are PR is the application of fatty acids, such as oleic acid.

The composition can also be in the form of suppositories for rectal administration of the compounds of the present invention. Song data can be obtained by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature but liquid at rectal temperature and therefore, should melt in the rectum to release the drug. Such substances include, for example, cocoa butter and polyethylene glycols.

For local use provided creams, ointments, jellies, solutions, suspensions, etc. containing compounds of the present invention. For this application the compositions for local application must include compositions for rinsing the mouth and gargling.

Compounds of the present invention can also be administered in the form of liposomal delivery systems, such as small single-layer vesicles, large single-layer and multi-layered vesicles vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

In addition, some of the compounds of the present invention may form a solvate with water or common organic solvents. Such a solvate is also covered by the scope of the present invention.

Thus, in the following implementation of the proposed f is rmaceuticals composition, containing the compound of the present invention or its pharmaceutically acceptable salt, MES or prodrug, and one or more pharmaceutically acceptable carriers, excipients or diluents.

If for oral administration use solid media, the preparation can be tableted, placed in a hard gelatin capsule in powder form or granular or it can be in the form of tablets or pads. The amount of solid carrier may vary, but generally should be from about 25 mg to about 1, If used carrier liquid, the drug may be in the form of a syrup, emulsion, soft gelatin capsule or sterile suitable for the injection of fluids, such as aqueous or non-aqueous liquid suspension or solution.

A typical tablet which can be obtained by conventional tabletting methods may include:

Basis:
Active connection (in the form
free compound or its salts)
5.0 mg
Lactosan Ph. Eur.and 67.8 mg
Pulp of microcrystal. (Avicel)of 31.4 mg
Amberlite® IRP88*1.0 mg
Magnesium stearate Ph. Eur.Dost. Qty
Floor
The hypromelloseApprox. 9 mg
Mywacett 9-40 T**Approx. 0.9 mg
* Polacrilin potassium NF, baking powder tablets, Rohm and Haas.
** The acylated monoglyceride used as plasticizer for film coating.

If desired, the pharmaceutical composition of the present invention may include a connection according to the present invention in combination with an additional active substances, such as described above.

In the present invention is also a method of synthesis of compounds useful as intermediates in obtaining the compounds of formula (I) along with methods of making compounds of formula (I). Connections can be easily obtained in accordance with the following schemes of reactions (in which all variables are defined above unless specifically) using readily available starting materials, reagents and conventional% the dur synthesis. In these reactions is also possible to use variants which are in themselves well-known specialists in the field of technology, but who are not mentioned in detail.

Reduction

In the schemes and in the examples the following abbreviations are used:

d= days
g= grams
hour= hours
Hz= Hz
kDa= kilodaltons
l= litres
M= mol
mbar= millibar
mg= milligrams
min= minutes
ml= ml
mm= millimoles
mmol= mmol
mol= moles
N.= normal
ppm= millionth share
psi= pounds per square inch
APCI= atmospheric pressure chemical ionization
ESI= electrospray ionization
in/at= intravenous
M/z= the ratio of mass-to-charge
so pl.= melting point
MS= mass spectrometry
NMR= spectroscopy nuclear magnetic resonance
p/o= oral
Rf= relative mobility in TLC
br rate.= room temperature
n/a= subcutaneous
TLC= thin-layer chromatography
tr= retention time
BOP= (1 benzothiazolinone)Tris(dimethylamino)phosphonium hexaflurophosphate
DHM= dichloromethane
DIEA= diisopropylethylamine
DMF= N,N-dimethylformamide
DMPU= 1,3-dimethylpropyleneurea
DMSO= sulfoxide
EDC= 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
A simple ether= diethyl ether
EtOAc= acetate
HMPA= triamide hexamethylphosphoric acid
HOBt= 1-hydroxybenzotriazole
'lah= alumoweld lithium
LDA= diisopropylamide lithium
MeOH= methanol
NMM= N-methylmorpholine, 4-methylmorpholin
TEA= triethylamine
TFU= triperoxonane acid
THF= tetrahydrofuran
THP= tetrahydropyranyl
TTF= fluoro-N,N,N'-tetramethylguanidine hexaphosphate

Schema reactions

If it is not stated specifically, the variables in the diagrams are given for the formula (I).

Scheme 1 describes the formation of compounds of formula (I).

Scheme 1

L6represents -(CH2)n-C(R9)(R10)m-, where n, m, R9and R10are defined by the formula (I).

Sulphonylchloride (3) can be treated with the amine (4) in the presence of a tertiary amine base such as TEA, obtaining (5)where G represents S(O)2. R59may be R4or R59may be communication with a polymer base, such as a Wang resin. The processing of such polymeric bases (5) TFU in a suitable solvent, such as dichloromethane, the AET (I), where R4represents H. (1) can be treated with the amine (4) getting (5) and then (I) in a similar way. Acid (2) can be activated by the processing of a carbodiimide reagent such as EDC, or binding agent, such as TFFH, in a solvent such as DHL or DMF, in the presence of (4) to obtain (5). (5) can be converted in a similar way in (I). Carbonylchloride (6) can be obtained by treatment of (4) with a reagent such as phosgene, diphosgene or triphosgene, in a solvent such as DHM, in the presence of a tertiary amine base such as TEA. Processing (8) of the compound (6) in the presence of a tertiary amine base such as TEA, gives (5) and so (I). Chlorosulfonated (7) can be obtained by treating (4) sulfurylchloride in the presence of a tertiary amine base such as TEA or DIEA. (7) can be processed (8) in a suitable solvent, such as DHM, in the presence of a tertiary amine base such as TEA or DIEA obtaining (5) and in a manner similar to the previous to obtaining (I).

Figure 2 describes how to obtain the compounds of formula (2).

Scheme 2

Ether (9), where PG2represents carboxyamide group, can be treated with N-bromosuccinimide in the presence of benzoyl peroxide to obtain (10)where R60is a bromide. Usually this procedure is repectfully, when R1represents aryl or heteroaryl. (10)where R60is a bromide, can be treated with the reagent R3-SH, R3-N(R8H or R3-OH and a base such as sodium hydride or tert-piperonyl potassium, obtaining (11)where X represents S, N(R6or O, respectively. (11) may be subjected to removal of protection, for example, with aqueous bases, where PG2represents methyl or ethyl, obtaining (2). When L1represents a direct bond, processing (9) base, such as LDA and an oxidizing agent, such as sulfonyl-oxaziridine reagent, gives (10)where R60represents OH. Processing such reagent R3-LG1where LG1represents a nucleophilic group, such as Br, Cl, I or a sulfonate, and a base, such as DBU or sodium hydride, gives (11). Next, the processing of (12) with two equivalents of a strong base such as LDA, and the reagent R3-S-LG2where LG2represents arylsulfonate group or halogen, gives (2)where X represents S.

Figure 3 describes the alternative obtaining the compounds of formula (2).

Scheme 3

Amin (13) can be alkylated by alkylhalogenide R3-CH2-LG1where LG1represents a nucleophilic group, such to the to toilet, or bromide, or iodide, in the presence of a base such as potassium carbonate, in a solvent such as DMF, to obtain (14). Alternative (13) can be treated with an aldehyde R3-CHO in the presence of a reducing agent, such as Lamborgini sodium, obtaining (14). Amin (14) can be treated with the reagent LG1-L1-COO-PG2where LG1represents a nucleophilic group, such as tosylate, iodide or bromide, in the presence of an organic base, such as potassium carbonate, in a solvent such as DMF, to obtain (15). PG2represents a protective group of carboxyl, such as allyl or methyl, or benzyl, which can be removed by hydrolysis, for example, in an aqueous solution of a base to obtain (2). The hydroxyether (16) can be processed R3-LG1in the presence of a base, such as DBU, DIEA or sodium hydride, to obtain (18)where X represents O. Alternative (16) can be processed by methanesulfonamido, toluensulfonate or triftormetilfullerenov anhydride to obtain (17)where R61represents arylsulfonate or alkylsulfonate group. (17) can then be processed R3-XH, where X represents O, S or N-R6in the presence of a suitable base, such as TEA, DIEA NaH, DBU, tert-piperonyl potassium or the like, to receive the drug (18). (18) may be subjected to removal of protection, as described above, to obtain (2).

Scheme 4 describes the alternative obtaining compounds of formula (I).

Scheme 4

L6is a described for scheme 1.

Acid (2) can be processed by oxalylamino or thionyl chloride in a solvent such as DHM, and then sodium azide with getting acylating intermediate compounds. Alternative (2) can be processed by diphenylphosphorylacetate in the presence of a base, such as DIEA, obtaining acylating intermediate compounds. Anilazine intermediate compound is heated at a temperature of from 25 to 100°C To produce isocyanate (19), which can be treated with the amine (4) to obtain (20). Alternative (19) can be hydrolyzed in a weak aqueous acid or weak aqueous base to obtain amine (20). Amin (20) can be treated with an aldehyde or a ketone, comprising the group of R6in the presence of a reducing agent, such as triacetoxyborohydride sodium, obtaining (23). (23) can be treated with reagents (6) or (7) in a manner analogous to scheme 1, to obtain (24). Amin (20) can be treated with reagents (6) or (7) in a similar fashion to obtain (22). When R30represents a solid base, such as Wang resin, (22) and (24) can be about is by TFU, as in scheme 1, to obtain (I).

In the above schemes “PG1” represents aminosidine group. Used herein, the term “aminosidine group” refers to substituents of the amino group commonly used to block or protect the amino group in the interaction with other functional groups of the compounds. Examples of such aminosidine groups include the formyl group, trityloxy group, phthalimidopropyl, trichloroethylene group, chloroacetyl, bromoacetyl and joazeiro groups, blocking groups, urethane-type (used here as a “PG1such as benzyloxycarbonyl,

4-phenylbenzoxazole, 2-methylbenzyloxycarbonyl,

4-methoxybenzenesulfonyl, 4-forantimicrobial,

4-chlorobenzenesulfonyl, 3-chlorobenzenesulfonyl,

2-chlorobenzenesulfonyl, 2,4-dichlorobenzenesulfonyl,

4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,

4-nitrobenzenesulfonyl, 4-cyanobenzeneboronic,2-(4-xenil)isopropoxycarbonyl, 1,1-diffenret-1-jocstarbunny,

1,1-diphenylprop-1-jocstarbunny, 2-phenylprop-2-jocstarbunny, 2-(para-toluyl)prop-2-jocstarbunny, cyclopentanecarbonyl, 1-methylcyclopentadienyl, cyclohexyloxycarbonyl,

1-methylcyclohexanecarboxylic,

2-methylcyclohexanecarboxylic

2-(4-toluensulfonyl)etoxycarbonyl,

2-(methylsulphonyl)etoxycarbonyl,

2-(triphenylphosphino)etoxycarbonyl, 9-fluorenylmethoxycarbonyl (“FMOC”), tert-butoxycarbonyl (“BOC”),

2-(trimethylsilyl)etoxycarbonyl, allyloxycarbonyl,

1-(trimethylsilylmethyl)prop-1-relaxerror,

5-basiccollection, 4-acetoxybenzoic, 2,2,2-trichlorocyanuric, 2-ethinyl-2-propoxycarbonyl, cyclopropanecarbonyl, 4-(decyloxy)benzyloxycarbonyl, isobornylacitate, 1-piperidinylcarbonyl and the like, benzoylmethylecgonine group, 2-(nitro)phenylsulfinyl group, diphenylphosphinomethyl group and the like aminosidine group. View used aminosidine group is not decisive in the case, if a protected amino group is stable to the conditions subsequent(future) reaction(s) of other provisions of the compounds of formula (I) and can be removed at the desired time without destroying the rest of the molecule. Preferred aminosidine groups are allyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl and triticina group. Similar aminosidine group used in the field of technology of the cephalosporin, penicillin and peptide, are also covered by the above terms. Additional examples of groups that belong to specified Westermann, described J.W. Barton, “Protective Groups in Organic Chemistry”, J.G.W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 2, and T.W. Greene, “Protective Groups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1981, Chapter 7. Related to this, the term “protected amino” denotes an amino group, a substituted aminosidine group discussed above. In the above schemes “PG2” represents a protective group of carboxyl. Used herein, the term “protective group carboxyl” refers to substituents of the carboxylic group, usually used to block or protect the-OH group in the interaction with other functional groups of the compounds. Examples of such alcohol-protecting groups include the 2-tetrahydropyranyloxy group, 2-ethoxyethylene group, trityloxy group, methyl group, ethyl group, allyl group, trimethylsilylamodimethicone group, 2,2,2-trichlorethylene group, benzyl group and trialkylsilyl group, examples of which are trimethylsilyl, tert-butyldimethylsilyl, phenyldimethylsilane, triisopropylsilyl and existimatio. The selection of the used protective group carboxyl is not decisive in the case, if a protected alcohol group stable under the conditions subsequent(future) reaction(s) of other provisions of the compounds of formula and can be removed at the desired time without destroying the rest of the molecule. Additional examples of groups, which pertained to the above terms described J.W. Barton, “Protective Groups in Organic Chemistry”, J.G.W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, and T.W. Greene, “Protective Groups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1981. Related to this, the term “protected carboxyl” denotes a carboxyl group, substituted by a protective group carboxyl discussed above.

EXAMPLES

General method A. Synthesis of 2-aryloxyalkanoic acids

To a mixture of ethyl or methyl ester 2-hydroxyalkanoate acid (2.0 mmol), phenol (2.4 mmol) and triphenylphosphine (to 0.63 g, 2.4 mmol) in anhydrous THF (6 ml) was added dropwise diisopropylethylamine (of 0.47 ml, 2.4 mmol) under stirring at 0°C. the Mixture was stirred at 0°C for 1 hour and then at 25°C for 8 hours. The solvent is removed and the residue purified using flash chromatography [silica, a mixture of ethyl acetate-hexane (1:9)] to obtain ethyl or methyl ester 2-aryloxyalkanoic acid. The ester is dissolved in methanol (10 ml) and was added 1 M solution of lithium hydroxide (5 ml). The resulting mixture is stirred for 2 hours at 25°C. the Reaction mixture was concentrated in vacuo. The residue is acidified with diluted Hcl and extracted with ethyl acetate (2x10 ml). The organic layer is dried (Na2SO4) and concentrate to obtain the desired 2-aryloxyalkanoic acid.

General method b : Synthesis of 2-aryloxyalkanoic acids

To a mixture of phenol (2 mmol) and tert-BU the oxide of potassium (0,47 g, 4.2 mmol) in DMF (6 ml) is rapidly added a solution of 2-Bromhexine acid in DMF (2 ml) at 0°C. the Reaction mixture was stirred at 25°C for 15 hours. The resulting mixture was poured into cold 1 N. Hcl (10 ml) and extracted with ether (2x20 ml). The combined extracts washed with saturated salt solution, dried (Na2SO4) and concentrated in vacuo to obtain the desired acid with a yield of 70-80%. The crude acid is used as such in obtaining amides.

General method C. Synthesis of 2-alkyl - and 2-arylthioureas acids

A mixture of methyl ester akriluksusnoy acid (10 mmol), NBS (10.5 mmol) and benzoyl peroxide (0.2 mmol) in Cl4(50 ml) is refluxed for 5 hours. Fallen in sediment succinimide filtered and the filtrate concentrated in vacuo. The residue is dissolved in ethyl acetate (50 ml) and washed with water (I ml), Na2HCO3(G ml) and saturated salt solution (g ml) and dried (betwedn. Na2SO4). Concentration in vacuo gives the methyl ester of 2-bromo-2-akriluksusnoy acid with the release of 75-82%.

To a solution of methyl ester of 2-bromo-2-akriluksusnoy acid (2 mmol) in THF (8 ml) is added alkylthiol (2.4 mmol) and then Et3N (4.4 mmol). The mixture is stirred at 25°C for 2 hours. The reaction mixture was concentrated in vacuo and the residue purified using flash chromatography (silicon dioxide, a mixture of hexa is-acetic acid ethyl ester 1:9) to give the methyl ester of 2-alkylthio-2-akriluksusnoy acid. A similar procedure is applicable for the synthesis of methyl ester of 2-aaltio-2-akriluksusnoy acid.

General method D. Synthesis of 2-alkyl - and 2-arylthioureas acids

To a solution of methyl ester of 2-hydroxy-2-akriluksusnoy acid (2 mmol) in CH2Cl2(8 ml) was added MsCl (2.4 mmol) and Et3N (4.4 mmol) at 0°C and stirred for 1 hour. To this solution add alkylthiol (2.4 mmol) at 0°C and stirred for 2 hours. The mixture was concentrated in vacuo and the residue is dissolved in ethyl acetate (30 ml). The organic layer was washed with water (2x20 ml), saturated salt solution (2x20 ml) and dried (betwedn. Na2SO4). Concentration in vacuo gives an oil which is purified using flash chromatography (silica, hexane-ethyl acetate, 9:1) to give the methyl ester of 2-alkylthio-2-akriluksusnoy acid. A similar procedure was adapted for the synthesis of methyl ester of 2-aaltio-2-akriluksusnoy acid. Hydrolysis of this ester were carried out as described in procedure A.

General method E. the Synthesis of heteroaryl substituted amides alkanovykh acids

To a solution of 2-aryloxyalkanoic acid (0.25 mmol) in THF (3 ml) is added TFFH (80 mg, 0.3 mmol) and DIEA (0.1 ml). The mixture is stirred for 30 min and add amine (0.6 mmol). The contents stirred for 10 h is concentrated in vacuo. The residue is purified using flash chromatography [silica, a mixture of ethyl acetate-hexane, (3:7)] to give the desired amide.

General method F. the Synthesis of heteroaromatic amides aryl-N-cycloalkyl amino acids

N-Boc-relaminarization connect with the heteroaromatic amine, as described in procedure E. the Protected N-Boc amide of relaminarization (2 mmol) is treated with 4 N. HCl in dioxane (5 ml). The mixture is stirred at 25°C for 30 minutes the Solution was concentrated in vacuo and the residue is treated with TEA (5 mmol). The mixture is diluted with ethyl acetate (30 ml). The organic layer was washed with water (2x20 ml), saturated salt solution (2x20 ml) and dried (Na2SO4). Concentration in vacuo gives the corresponding Boc protected amine. The amine (1 mmol) is treated with cycloalkanones (1.1 mmol) in 1,2-dichloroethane. The mixture is stirred at 25°C for 30 minutes To this solution add triacetoxyborohydride sodium (1.1 mmol) and the mixture is stirred for 12 hours. The mixture was concentrated in vacuo and the residue is dissolved in ethyl acetate (30 ml). The solution was washed with water (2x20 ml) and saturated salt solution (2x20 ml) and dried (betwedn. Na2SO4). Concentration in vacuo and purification via flash chromatography (silica, hexane-ethyl acetate, 7:3) gives aryl-N-cycloalkenyl with access 52-63%.

General method G. the Synthesis of substituted alkanovykh acids/b>

To a solution of alanovoy acid (1.0 g, 5 mmol) in a mixture of anhydrous THF (10 ml) and HMPA (5 ml) added dropwise LDA (5 ml, 2 M in a mixture of heptane/THF/ethylbenzene) at -78°C. the Contents stirred for 1 hour at -78°C. and then at 25°C for 30 minutes, the Reaction mixture was again cooled to -78°C and added dropwise a solution of bromoalkane (5 mmol) in THF (5 ml). The cooling bath is removed and the contents stirred for 12 h at 25°C. the Contents of the vessel was poured into cold 1 N. HCl (30 ml) and extracted with ethyl acetate (3x50 ml). The combined extracts washed with saturated salt solution, dried (Na2SO4) and concentrate. The residue is purified using flash chromatography (silica, 1% methanol in chloroform) to give the corresponding acid.

General method H. Synthesis of ureas through acylated

To a solution of carboxylic acid (0.5 mmol) in anhydrous dichloromethane (2 ml) is added a drop of DMF and oxalicacid (88 μl, 1 mmol) in °C. the Contents stirred for 10 min at 0°C. and then at 25°C for 1 hour. Volatiles are removed in vacuo and the residue is dissolved in dichloroethane (4 ml). Add sodium azide (195 mg, 3 mmol)and the mixture is heated at 80°C for 3 hours. The resulting isocyanate solution is cooled and added the amine (1 mmol). The resulting mixture is heated at 80°C for 12 hours. The solvent is removed by rotary and is a soaring glider and the residue purified using flash chromatography [silica, a mixture of ethyl acetate-dichloromethane (1:4)] to obtain the corresponding urea.

General method I. Reductive amination

The amine was dissolved in anhydrous THF (0.1 to 1 M) in a round bottom vessel and then to the solution was added the aldehyde or ketone (1 EQ. or a slight excess) and stirred for several minutes at 25°C. Add triacetoxyborohydride sodium (2 EQ.) and the mixture is stirred at room temp. Then the reaction mixture is washed with saturated sodium bicarbonate (200 ml) and extracted with ethyl acetate. The organic extracts are combined, dried and concentrated in vacuo to obtain the product in the form of a secondary or tertiary amine.

A common way J. Getting ureas through carbamoylated

Secondary amine (1 EQ.) dissolve in DHM (0.1 to 1 M)and add triethylamine (1-3 EQ.). Then add triphosgene (1-3 EQ.) at -20°C. After a few hours at 25°C. to the reaction mixture, the primary or secondary amine (1 EQ.). After spending the educt mixture is subjected to water treatment. Concentration in vacuo gives the quality of the product urea.

General method K. amine Alkylation

The amine was dissolved in anhydrous DMF and to the solution add the carbonate of an alkali metal (1-5 EQ.). Add alkylhalides or alkylsulfonate (1-5 EQ.), and the resulting mixture is stirred for some of the hours at a temperature of from 0°C. to 100°C. The mixture is then subjected to water treatment. Drying and concentration give alkilirovanny Amin.

A common way L. Getting amine on the polymer-based

Primary or secondary amine (5 EQ.) dissolved in DCE (1-5 M), then to the solution was added functionalized 2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene on a solid base (1 EQ. based on the content of the aldehyde function) and stirred for 30 minutes To the mixture of acetic acid (0.5 EQ.), then add triacetoxyborohydride sodium (5 EQ.). The resin mixture is stirred at 25°C. for 4-48 hours, then washed with three successive cycles of DMF/methanol/DHM. After that, the resin is dried in vacuum to obtain a primary or secondary amine on the polymer basis.

A common way M. Obtaining carbamylcholine on polymer-based

Primary or secondary 4-aminomethyl-3-methoxyphenoxy)-1-iterpolation on a solid base (1 equiv.) treated with triphosgene (2 EQ.) in the presence of DHM (0.1 to 3 M) and diisopropylethylamine (3-10 equiv.). The product on a solid support is then washed with three cycles of DMF/methanol/DHM. After that, the resin is dried in vacuum to obtain the corresponding carbonylchloride.

General method N. Getting ureas based on polymers of carbamoylated

Carbamoylated on the polymeric base (1.0 g, of 1.46 mmol, 1 EQ.) obrabatyvaimym or secondary amine (3-10 equiv.) in the presence of DCE (0,02-3 M) and diisopropylethylamine (3-20 EQ.). Through 1-10 hours the resin was washed with three cycles of DMF/methanol/DHM and dried in vacuum to obtain urea.

General method A. Alkylation of urea, carbamate or amide nitrogen in the polymer base

To the corresponding urea, carbamate or amide based on polymers containing the free NH group (1 EQ.) 0,117 g, 0.73 mmol), added tert-piperonyl potassium (3-10 equiv.). The mixture of resin is stirred for 1 hour at 25°C and then add 3-10 EQ. alkylhalogenide or alkylsulfonate. After 16 hours, the polymer was washed with three cycles of DMF/methanol/DHM and dried in vacuum to obtain alkylated product.

General method P. Cleavage from solid basics

The polymer is treated with a solution TFU (5-50%.about. in DHM, excess) at 25°C for removal of product from the polymer base. Filtration and concentration in vacuum to give the product.

A common way Q. Obtain N,O-dimethyl-N-hydroxycarboxylic

Carboxylic acid (1 EQ.) in DHM (0,02-2 M) is treated with N,O-dimethylhydroxylamine-hydrochloride (1 EQ.) and triethylamine (1 EQ.). Add DCC, EDC or other carbodiimide reagent (1 EQ.). After 1-24 h, the solution was concentrated in vacuo and the residue is removed by filtration. Alternatively, the mixture can be subjected to water treatment. The filtrate was concentrated in vacuo. The product is used directly or cleansing the Ute chromatography on silica gel.

A common way R. Obtaining ketones of N,O-dimethyl-N-hydroxycarboxylic

Organolithium or magnetogenesis reagent obtained in situ or commercially available, is treated in THF or ether (0,02-1 M) N,O-dimethyl-N-hydroxycarbamide (1 EQ.) at temperatures from -20°C to 25°C., After spending amide mixture is subjected to water treatment. Concentration in vacuo gives the ketone product.

General method S1. Obtaining secondary alcohol from a ketone

The ketone (1 EQ.) in ethanol or methanol (0,02-2 M) is treated with sodium borohydride (0.25 to 2 EQ.) at -0°C-25°C With subsequent aqueous processing of obtaining a secondary alcohol.

A common way S2. Obtaining secondary alcohol from a ketone

Ketone 1 EQ. in THF or ether (0,02-2 M) process alumohydrides reagent, such as LiAlH4(0.25 to 2 equiv.) at -78°C-25°C, followed by quenching and filtration, which gives a secondary alcohol.

A common way S3. The tertiary alcohol from a ketone

The ketone (1 EQ.) in THF or ether (0,02-2 M) is treated with organolithium or magnetogenesis reagent at a temperature of from -78°C to 25°C. Water treatment gives a tertiary alcohol.

A common way T. Getting chloroformiate

A solution of the alcohol (1 EQ. (0,259 g, 1.0 mmol) in DHM (0.02-2 M) 10 ml) is treated with triethylamine (excess)) and phosgene (1.5 EQ., solution in toluene) at -20°C and displacement is more within 1-5 hours. The excess triethylamine and phosgene is removed in vacuum. Chloroformiate the product is used immediately.

A common way u Getting carbamates

The solution chloroformate (1 EQ.) in DHM (0,02-2 M) is treated with tertiary amine (2-5 EQ.)mmol) and primary or secondary amine (1 EQ.). After spending the educt mixture is subjected to water treatment. Concentration in vacuo gives a urethane product.

A common way X. Obtaining urea through carbonyldiimidazole:

Secondary amine (1 EQ.) dissolved in DCE (0.1 to 1 M) and to the solution was added a catalytic amount of DMAP (5 mg). After that add carbonyldiimidazole (1-1 .5 EQ.) and the reaction mixture is heated at 80°C for 1 hour. After tracking precipitation to the reaction mixture, the primary or secondary amine (1 EQ.). After spending the educt mixture is subjected to chromatography on silica gel using mixtures of ethyl acetate and hexane (3:7) to give the desired urea.

Example 1

The thiazole-2-alamid 2-(3,4-dichlorophenoxy)hexanoic acid

2-(3,4-Dichlorophenoxy)hexanoic acid (0.3 g, 55%) was obtained from ethyl 2-hydroxyhexanoate (0.32 g, 2.0 mmol) and 3,4-dichlorophenol (0.39 g, 2.4 mmol) according to General method A. a Solution of this acid (69 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-amine is thiazole (60 mg, 0.6 mmol) according to General method E to obtain thiazol-2-ylamide 2-(3,4-dichlorophenoxy)hexanoic acid (64 mg, 72%).

LC-MS (m/z): 360 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.89 (t, 3H), 1.30 and is 1.51 (m, 4H), 2,02 (m, 2H), 4,73 (t, 1H), 6,76 (DD, 1H), 7,03 (DD, 2H), 7,33 (d, 1H), 7,49 (d, 1H), 9,98 (user., 1H).

Example 2

2-(4-Pertenece)-N-1,3-thiazol-2-rexanne

2-(4-Pertenece)hexanoic acid (0,23 g, 52%) was obtained from ethyl 2-hydroxyhexanoate (0.32 g, 2.0 mmol) and 4-terfenol (0.27 g, 2.4 mmol) according to General method A. a Solution of this acid (56 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(4-pertenece)-N-1,3-thiazol-2-rexanne (58 mg, 76%).

LC-MS (m/z): 309 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.89 (t, 3H), 1.32 to 1,50 (m, 4H), of 1.99 (m, 2H), 4,69 (t, 1H), for 6.81-6,84 (m, 2H), 6,94-7,02 (m, 3H), 7,50 (d, 1H), 10,24 (user., 1H).

Example 3

2-(4-Methoxyphenoxy)-N-1,3-thiazol-2-rexanne

2-(4-Methoxyphenoxy)hexanoic acid (0,23 g, 48%) was obtained from ethyl 2-hydroxyhexanoate (0.32 g, 2.0 mmol) and 4-methoxyphenol (0.3 g, 2.4 mmol) according to General method A. a Solution of this acid (60 mg, 0.25 in) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(4-methoxyphenol the si)-N-1,3-thiazol-2-recanalize (130 mg, 82%).

LC-MS (m/z): 321 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.89 (t, 3H), 1,31-of 1.52 (m, 4H), to 1.98 (m, 2H), 3,74 (s, 3H), of 4.67 (t, 1H), PC 6.82 (m, 4H), 7,01 (d, 1H), 7,52 (d, 1H), 10,33 (user., 1H).

Example 4

2-(4-Methoxyphenoxy)-N-pyridin-2-rexanne

A solution of 2-(4-methoxyphenoxy)hexanoic acid (60 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminopyridine (56 mg, 0.6 mmol) according to General method E to obtain 2-(4-methoxyphenoxy)-N-pyridin-2-recanalize (58 mg, 75%).

LC-MS (m/z): 315 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.89 (t, 3H), 1.32 to of 1.52 (m, 4H), to 1.98 (m, 2H), 3,74 (s, 3H), 4,55 (t, 1H), PC 6.82 (DD, 2H), 6.90 to (DD, 2H), 7,03 (m, 2H), of 7.70 (t, 1H), compared to 8.26 (m, 1H), 8,83 (user., 1H).

Example 5

2-(3,4-Dichlorophenoxy)-4-methyl-N-1,3-thiazol-2-ilistened

2-(3,4-Dichlorophenoxy)-4-methylpentanol acid (0.26 g, 46%) was obtained from methyl 2-hydroxy-4-methylpentanoate (0.32 g, 2.0 mmol) and 3,4-dichlorophenol (0.39 g, 2.4 mmol) according to General method A. a Solution of this acid (69 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(3,4-dichlorophenoxy)-4-methyl-N-1,3-thiazol-2-ilistened (74 mg, 82%).

LC-MS (m/z): 359 (M + H)+

1H NMR (400 MHz, CDCl3): δ 0,99 (m, 4H), of 1.80 (m, 1H), 1.93 and (m, 2H), 4,74 (m, 1H), of 6.71 (m, 1H), of 6.96 (m, 1H), 7,05 (d, 1H), 7,30 (DD, 1H), 7,54 (s, 1H), 10,50 (user., 1H.

Example 6

2-(1,1'-Biphenyl-4-yloxy)-N-1,3-thiazol-2-rexanne

2-(3,4-Phenyleneoxy)hexanoic acid (0.15 g, 26%) was obtained from ethyl 2-hydroxyhexanoate (0.32 g, 2.0 mmol) and 4-hydroxybiphenyl (0.39 g, 2.4 mmol) according to General method A. a Solution of this acid (71 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(1,1'-biphenyl-4-yloxy)-N-1,3-the thiazole-2-recanalize (60 mg, 66%).

LC-MS (m/z): 367 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.90 (t, 3H), 1,34-and 1.54 (m, 4H), 2,04 (m, 2H), 4,82 (t, 1H), 6,95 (DD, 2H), 7,02 (d, 1H), 7,31-7,53 (m, 8H), 10,45 (user., 1H).

Example 7

2-(4-Isopropylphenoxy)-N-1,3-thiazol-2-rexanne

2-(4-Isopropylphenoxy)hexanoic acid (0,23 g, 46%) was obtained from ethyl 2-hydroxyhexanoate (0.32 g, 2.0 mmol) and 4-isopropylphenol (0.33 g, 2.4 mmol) according to General method A. a Solution of this acid (63 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(4-isopropylphenoxy)-N-1,3-thiazol-2-rexanne (68 mg, 82%).

LC-MS (m/z): 333 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.89 (t, 3H), 1,21 (DD, 6H), 1.32 to 1,50 (m, 4H), 2,00 (m, 2H), 2,84 (m, 1H), 4,74 (m, 1H), 6,84 (DD, 2H), 7,00 (d, 1H), 7,14 (DD, 2H), 7,47 (d, 1H), 9,95 (user., 1H).

Example 8

2-(3-Meth is xopenex)-N-1,3-thiazol-2-rexanne

2-(3-Methoxyphenoxy)hexanoic acid (0,37 g, 82%) was obtained from 2-Bromhexine acid (0.39 g, 2.0 mmol) and 3-methoxyphenol (0.25 g, 2.0 mmol) according to General method B. a Solution of this crude acid (60 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(3-methoxyphenoxy)-N-1,3-thiazol-2-recanalize (61 mg, 75%).

LC-MS (m/z): 321 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.89 (t, 3H), 1.30 and is 1.51 (m, 4H), of 1.99 (m, 2H), 3,76 (s, 3H), of 4.77 (t, 1H), 6,47-6,59 (m, 3H), of 7.00 (d, 1H), 7,17 (m, 2H), 7,50 (d, 1H), of 10.05 (user., 1H).

Example 9

2-(2,3-Dimethoxyphenoxy)-N-1,3-thiazol-2-rexanne

2-(2,3-Dimethoxyphenoxy)hexanoic acid (0.34 g, 64%) was obtained from 2-Bromhexine acid (0.39 g, 2.0 mmol) and 2,3-dimethoxyphenol (0.31 g, 2.0 mmol) according to General method B. a Solution of this crude acid (67 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(2,3-dimethoxyphenoxy)-N-1,3-thiazol-2-recanalize (64 mg, 73%).

LC-MS (m/z): 351 (M + H)+

1H NMR (400 MHz, CDCl3): δ to 0.92 (t, 3H), of 1.40 (m, 2H), 1.57 in (m, 2H), 1,98-2,12 (m, 2H), of 3.84 (s, 3H), of 3.97 (s, 3H), 4,71 (t, 1H), 6,60 of 6.66 (m, 2H), 6,95-6,98 (m, 2H), 7,49 (d, 1H), 10,80 (user., 1H).

Example 10

2-(3,4-Dimethoxyphenoxy)-N-1,3-thiazol-2-rexanne/u>

2-(3,4-Dimethoxyphenoxy)hexanoic acid (0.34 g, 63%) was obtained from 2-Bromhexine acid (0.39 g, 2.0 mmol) and 3,4-dimethoxyphenol (0.31 g, 2.0 mmol) according to General method B. a Solution of this crude acid (67 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(3,4-dimethoxyphenoxy)-N-1,3-thiazol-2-recanalize (61 mg, 69%).

LC-MS (m/z): 351 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.90 (t, 3H), 1.32 to a rate of 1.51 (m, 4H), 1,98-2,02 (m, 2H), 3,81 (s, 3H), 3,85 (s, 3H), 4,71 (t, 1H), 6,37 (m, 1H), 6,53 (m, 1H), of 6.71 (DD, 1H), 7,00 (d, 1H), of 7.48 (s, 1H), 10,00 (user., 1H).

Example 11

2-(3,5-Dimethoxyphenoxy)-N-1,3-thiazol-2-rexanne

2-(3,5-Dimethoxyphenoxy)hexanoic acid (0,43 g, 81%) was obtained from 2-Bromhexine acid (0.39 g, 2.0 mmol) and 3,5-dimethoxyphenol (0.31 g, 2.0 mmol) according to General method B. a Solution of this crude acid (67 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(3,5-dimethoxyphenoxy)-N-1,3-thiazol-2-recanalize (77 mg, 89%).

LC-MS (m/z): 351 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.89 (t, 3H), 1,31-1,49 (m, 4H), 1,98-2,02 (m, 2H, in), 3.75 (s, 6H), was 4.76 (t, 1H), 6,09 (d, 2H), 6,12 (d, 1H), 7,01 (d, 1H), 7,47 (d, 1H), 9,75 (user., 1H).

Example 12

2-(2-Naphthyloxy)-N-1,3-thiazol-2-ILEC unamed

2-(2-Naphthoxy)hexanoic acid (0.39 g, 75%) was obtained from 2-Bromhexine acid (0.39 g, 2.0 mmol) and 2-naphthol (0,29 g, 2.0 mmol) according to General method B. a Solution of this crude acid (65 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(2-naphthyloxy)-N-1,3-thiazol-2-recanalize (62 mg, 73%).

LC-MS (m/z): 341 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.90 (t, 3H), 1.32 to and 1.56 (m, 4H), 2,03-2,11 (m, 2H), 4.95 points (t, 1H),? 7.04 baby mortality (m, 1H), 7,15-7,51 (m, 5H), of 7.70 (d, 1H), 7,80 (m, 2H), 9,77 (user., 1H).

Example 13

2-(2,4-Divergence)-N-1,3-thiazol-2-rexanne

2-(4,4-Divergence)hexanoic acid (0.34 g, 71%) was obtained from 2-Bromhexine acid (0.39 g, 2.0 mmol) and 2,4-differenoe (0.26 g, 2.0 mmol) according to General method B. a Solution of this crude acid (61 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(2,4-divergence)-N-1,3-thiazol-2-recanalize (61 mg, 74%).

LC-MS (m/z): 327 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1.25 and of 1.54 (m, 7H), 1,98-2,05 (m, 2H), 4,69 (t, 1H), 6,76 (m, 1H), 6,86-7,01 (m, 3H), 7,58 (m, 1H), 10,9 (user., 1H).

Example 14

2-(3,4-Divergence)-N-1,3-thiazol-2-rexanne

2-(3,4-Divergence)hexanoic acid is the (0.4 g, 82%) is obtained from 2-Bromhexine acid (0.39 g, 2.0 mmol) and 3,4-differenoe (0.26 g, 2.0 mmol) according to General method B. a Solution of this crude acid (61 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(3,4-divergence)-N-1,3-thiazol-2-recanalize (71 mg, 88%).

LC-MS (m/z): 327 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.89 (t, 3H), 1.32 to 1,50 (m, 4H), 1,97-2,03 (m, 2H), 4,69 (t, 1H), 6,59 (m, 1H),6.73 x(m, 1H), 7.03 is-7,11 (m, 2H), 7,50 (m, 1H), 10,1 (user., 1H).

Example 15

2-(1,3-Benzodioxol-5-yloxy)-N-1,3-thiazol-2-rexanne

2-(3,4-Methylenedioxyphenoxy)hexanoic acid (0,42 g, 83%) was obtained from 2-Bromhexine acid (0.39 g, 2.0 mmol) and 3,4-methylenedioxyphenol (0.28 g, 2.0 mmol) according to General method B. a Solution of this crude acid (63 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(1,3-benzodioxol-5-yloxy)-N-1,3-the thiazole-2-recanalize (75 mg, 91%).

LC-MS (m/z): 335 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.89 (t, 3H), 1,31-1,49 (m, 4H), of 1.95 (m, 2H)and 4.65 (t, 1H), to 5.93 (m, 2H), 6,33 (DD, 1H), 6,51 (d, 1H), of 6.68 (d, 1H), 7,00 (d, 1H), 7,47 (m, 1H), 9,89 (user., 1H).

Example 16

2-(4-Methylsulfinylphenyl)-N-1,3-thiazol-2-rexanne

2-(4-Methylsulfinylphenyl)-hexane is a new acid (0,37 g, 66%) was obtained from 2-Bromhexine acid (0.39 g, 2.0 mmol) and 4-methylsulfonylbenzoyl (0.35 g, 2.0 mmol) according to General method B. a Solution of this crude acid (70 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(4-methylsulfinylphenyl)-N-1,3-thiazol-2-recanalize (80 mg, 88%).

LC-MS (m/z): 369 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.90 (t, 3H), 1,35-of 1.52 (m, 4H), 2,07 (m, 2H), to 3.02 (s, 3H), to 4.87 (t, 1H), 7,02 (DD, 2H), 7,05 (d, 1H), 7,52 (d, 1H), 7,86 (m, 1H), 10,45 (user., 1H).

Example 17

2-(2,4,6-Trichlorophenoxy)-N-1,3-thiazol-2-rexanne

2-(2,4,6-Trichlorophenoxy)hexanoic acid (0,48 g, 76%) was obtained from 2-Bromhexine acid (0.39 g, 2.0 mmol) and 2,4,6-trichlorophenol (0.4 g, 2.0 mmol) according to General method B. a Solution of this crude acid (80 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(2,4,6-trichlorophenoxy)-N-1,3-thiazol-2-recanalize (77 mg, 79%).

LC-MS (m/z): 393 (M + H)+

1H NMR (400 MHz, CDCl3): δ 6 of 0.87 (t, 3H), 1,31 (m, 2H), 1,62 (m, 2H), 1.85 to of 2.09 (m, 2H), 4.92 in (t, 1H), 7,02 (DD, 1H), 7,26 (DD, 1H), 7,35 (d, 1H), 7,49 (d, 1H), 10,24 (user., 1H).

Example 18

2-(2,4-Dichlorophenoxy)-N-1,3-thiazol-2-rexanne

2-(2,4-Dichlorphenoxy)hexanoic acid (0.4 g, 72%) is to obtain 2-Bromhexine acid (0.39 g, 2.0 mmol) and 2,4-dichlorphenol (0.33 g, 2.0 mmol) according to General method B. a Solution of this crude acid (69 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(2,4-dichlorophenoxy)-N-1,3-thiazol-2-recanalize (81 mg, 91%).

LC-MS (m/z): 359 (M + H)+

1H NMR (400 MHz, CDCl3): δ 6 of 0.90 (t, 3H), 1.32 to 1,50 (m, 4H), 2,04-of 2.08 (m, 2H), 4,80 (t, 1H), at 6.84 (d, 1H), 7,01 (DD, 1H), 7,18 (m, 1H), 7,42 (DD, 1H), of 7.48 (DD, 1H), 9,98 (user., 1H).

Example 19

2-(4-Phenoxyphenoxy)-N-1,3-thiazol-2-rexanne

2-(4-Phenoxyphenoxy)hexanoic acid (0.52 g, 87%) was obtained from 2-Bromhexine acid (0.39 g, 2.0 mmol) and 4-phenoxyphenol (0,37 g, 2.0 mmol) according to General method B. a Solution of this crude acid (75 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(4-phenoxyphenoxy)-N-1,3-thiazol-2-recanalize (87 mg, 92%).

LC-MS (m/z): 383 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.90 (t, 3H), 1,33-and 1.54 (m, 4H), for 2.01 (m, 2H), 4.72 in (t, 1H), 6.87 in-was 7.08 (m, 8H), 7,30 (m, 2H), 7,50 (d, 1H), 10,07 (user., 1H).

Example 20

2-(4-Cianfrocca)-N-1,3-thiazol-2-rexanne

2-(4-Cianfrocca)hexanoic acid (0.35 g, 75%) was obtained from 2-Bromhexine acid (0.39 g, 2.0 mmol) and 4-cyanophora (0.24 g, 2.0 mmol) in soo is according to the General method B. The solution of this crude acid (58 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(4-cianfrocca)-N-1,3-thiazol-2-recanalize (67 mg, 86%).

LC-MS (m/z): 316 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.91 (t, 3H), 1.32 to-1,49 (m, 4H), 2,02-to 2.06 (m, 2H), around 4.85 (t, 1H), 7,00 (DD, 1H),? 7.04 baby mortality (d, 2H), 7,47 (d, 1H), to 7.61 (DD, 1H), 9,65 (user., 1H).

Example 21

2-(4-Chloro-3-triptoreline)-N-1,3-thiazol-2-rexanne

2-(4-Chloro-3-triptoreline)hexanoic acid (0.50 g, 82%) was obtained from 2-Bromhexine acid (0.39 g, 2.0 mmol) and 2-chloro-5-hydroxybenzonitrile (0.39 g, 2.0 mmol) according to General method B. a Solution of this crude acid (77 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(4-chloro-3-triptoreline)-N-1,3-thiazol-2-recanalize (80 mg, 82%).

LC-MS (m/z): 393 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.91 (t, 3H), 1,35-1,49 (m, 4H), 2.00 in 2,04 (m, 2H), 4,79 (t, 1H), 6,99 (DD, 1H),? 7.04 baby mortality (d, 1H), 7,25-7,49 (m, 3H), 9,90 (user., 1H).

Example 22

2-(4-Methoxyphenoxy)-N-1,3-thiazol-2-elephantid

To a mixture of 4-methoxyphenol (0.25 g, 2.0 mmol) and tert-butoxide potassium (235 mg, 2.1 mmol) in DMF (4 ml) is rapidly added a solution of ethyl 2-bromoheptanoate (of 0.47 g, 2.0 mmol) in DMF (2 ml) is ri 0°C. The reaction mixture was stirred at 25°C for 15 hours. The content was poured into water (20 ml) and extracted with ether (2x20 ml). The combined extracts are concentrated and the residue is dissolved in THF (5 ml). To a solution of THF was added 1 n lithium hydroxide (10 ml) and the contents stirred for 2 hours. The resulting mixture was poured into cold 1 N. HCl (10 ml) and extracted with ether (2x20 ml). The combined extracts washed with saturated salt solution, dried (Na2SO4) and concentrated in vacuo to obtain the desired acid (0,43 g, 83%).

The solution of this crude acid (63 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(4-methoxyphenoxy)-N-1,3-thiazol-2-reptantia (65 mg, 78%).

LC-MS (m/z): 335 (M + H)+

1H NMR (400 MHz, CDCl3): δ 0,86 (t, 3H), 1,27-of 1.30 (m, 2H), 1,46-is 1.51 (m, 2H), 1,94 of 1.99 (m, 2H, in), 3.75 (s, 3H), of 4.67 (t, 1H), 6,77-6,87 (m, 4H), 7,00 (DD, 1H), 7,49 (d, 1H), 10,15 (user., 1H).

Example 23

2-(4-Pertenece)-N-1,3-thiazol-2-elephantid

To a mixture of 4-terfenol (0,22 g, 2.0 mmol) and tert-butoxide potassium (235 mg, 2.1 mmol) in DMF (4 ml) is rapidly added a solution of ethyl 2-bromoheptanoate (of 0.47 g, 2.0 mmol) in DMF (2 ml) at 0°C. the Reaction mixture was stirred at 25°C for 15 hours. The content was poured into water (20 ml) and extracted with ether (2x20 ml). The combined extracts the end of tryout and the residue is dissolved in THF (5 ml). To a solution of THF was added 1 n lithium hydroxide (10 ml)and the contents stirred for 2 hours. The resulting mixture was poured into cold 1 N. HCl (10 ml) and extracted with ether (2x20 ml). The combined extracts washed with saturated salt solution, dried (anhydrous Na2SO4) and concentrated in vacuo to obtain the desired acid (0.35 g, 74%).

The solution of this crude acid (60 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(4-pertenece)-N-1,3-thiazol-2-reptantia (65 mg, 78%).

LC-MS (m/z): 323 (M + H)+

1H NMR (400 MHz, CDCl3): δ 0,86 (t, 3H), of 1.29 (m, 4H), to 1.48 (m, 2H), 1,98 is 2.01 (m, 2H), 4,70 (m, 1H), 6,84-7,00 (2 m, 4H), 7,01 (d, 1H), of 7.48 (d, 1H), 10,00 (user., 1H).

Example 24

2-(3,4-Dichlorophenoxy)-3-cyclopentyl-N-1,3-thiazol-2-ylpropionic

2-(3,4-Dichlorophenoxy)-3-cyclopentylpropionic acid (0,43 g, 72%) was obtained from 2-bromo-3-cyclopentylpropionic acid (0,44 g, 2.0 mmol) and 3,4-dichlorophenol (0.33 g, 2.0 mmol) according to General method B. a Solution of this crude acid (75 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(3,4-divergence)-N-1,3-thiazol-2-recanalize (75 mg, 78%).

LC-MS (m/z): 385 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 1.16 (m, 2H), 1,50-2,08 (some is that m, 9H), to 4.73 (m, 1H), of 6.71 (m, 1H), of 6.96 (m, 1H), 7,05 (d, 1H), 7,33 (d, 1H), of 7.48 (d, 1H), 10,50 (user., 1H).

Example 25

2-(4-Methoxyphenoxy)-3-cyclopentyl-N-1,3-thiazol-2-ylpropionic

2-(4-Methoxyphenoxy)-3-cyclopentylpropionic acid (0.36 g, 68%) was obtained from 2-bromo-3-cyclopentylpropionic acid (0,44 g, 2.0 mmol) and 4-methoxyphenol (0.25 g, 2.0 mmol) according to General method B. a Solution of this crude acid (65 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(4-methoxyphenoxy)-3-cyclopentyl-N-1,3-thiazol-2-ylpropionic (73 mg, 85%).

LC-MS (m/z): 347 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 1.16 (m, 2H), 1,50-2,08 (some m, 9H), of 3.75 (s, 3H), of 4.67 (m, 1H), for 6.81 (m, 4H), of 7.00 (d, 1H), 7,54 (d, 1H), 10,59 (user., 1H).

Example 26

The thiazole-2-alamid 2-(4-chlorophenylsulfonyl)hexanoic acid

To a mixture of ethyl 2-hydroxyhexanoate (0.32 g, 2.0 mmol), 4-chlorbenzoyl (0.35 g, 2.4 mmol) and triphenylphosphine (to 0.63 g, 2.4 mmol) in anhydrous THF (6 ml) was added dropwise diisopropylethylamine (of 0.47 ml, 2.4 mmol) under stirring at 0°C. the Mixture was stirred at 0°C for 1 hour and then at 25°C for 8 hours. The solvent is removed and the residue purified using flash chromatography [silica, a mixture of ethyl acetate-hexane (1:20)] to obtain the Teal, 2-(4-chlorophenylthio)hexanoate (0,22 g, 35%). This was dissolved in THF (4 ml) and was added 1 M solution of lithium hydroxide (10 ml) and the resulting mixture is stirred for 2 hours at 25°C. Acidification with dilute HCl followed by extraction with ether (2x20 ml) gave 2-(4-chlorophenylthio)hexanoic acid (183 mg, 91%).

The solution of this acid (64 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain thiazol-2-ylamide 2-(4-chlorophenylsulfonyl)hexanoic acid (74 mg, 82%).

LC-MS (m/z): 341 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.89 (t, 3H), 1,33-of 1.56 (m, 4H), equal to 1.82 (m, 1H), 2,02 (m, 1H), 3,74 (t, 1H), 7,02 (d, 1H), 7,19 (d, 2H), 7,28 (d, 2H), 7,42 (d, 1H), to 11.52 (user., 1H).

Example 27

Pyridine-2-alamid 2-(4-chlorophenylsulfonyl)hexanoic acid

A solution of 2-(4-chlorophenylthio)hexanoic acid (64 mg, 0.25 mmol) in THF (3 ml) is subjected to interaction with 2-aminopyridine (56 mg, 0.6 mmol) according to General method E to obtain pyridine-2-ylamide 2-(4-chlorophenylsulfonyl)hexanoic acid (70 mg, 85%).

LC-MS (m/z): 335 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.91 (t, 3H), 1,35-of 1.56 (m, 4H), 1,82-to 1.87 (m, 1H), 1,96-2,02 (m, 1H), of 3.73 (t, 1H), 7.03 is-7,06 (m, 1H), 7,22-7,25 (m, 2H), 7,30-7,33 (m, 2H), to 7.67-7,71 (m, 1H), 8,14 (d, 1H), compared to 8.26-of 8.28 (m, 1H), 8,80 (user., 1H).

Example 28

2-(Indolin-1-yl)-N-(1,3-thiazol-2-yl)hexanamide

2-Bromo-N-1,3-thiazol-2-yl is atanamir was obtained from 2-Bromhexine acid (0,19 g, 1 mmol) and 2-aminothiazole (0.1 g, 1 mmol)as described in procedure e To the reaction mixture were added jodoin (0.3 g, 2.5 mmol) and heated at 80°C for 12 hours. The reaction mixture was concentrated and was purified column chromatography (silica, 10-20% ethyl acetate in hexano) to obtain 2-(indolin-1-yl)-N-(1,3-thiazol-2-yl)hexanamide (120 mg, 38%).

LC-MS (m/z): 316 (M + H)+

Example 29

3-(4-Chlorophenyl)-N-pyridin-2-yl-3-(tetrahydro-2H-thiopyran-4-ylamino)propanamide

3-(4-Chlorophenyl)-N-pyridin-2-yl-3-(tetrahydro-2H-thiopyran-4-ylamino)propanamide (206 mg, 55%) was obtained from 3-N-Boc-3-(4-chlorophenyl)propionic acid (300 mg, 1 mmol), 2-aminopyridine (225 mg, 2.4 mmol) and 4-tetrahydrothiopyrano (127 mg, 1.1 mmol) according to General method F.

LC-MS (m/z): 377 (M + 2H)+

Example 30

3-(4-Chlorophenyl)-3-(tetrahydro-2H-thiopyran-4-ylamino)-N-1,3-thiazol-2-ylpropionic

3-(4-Chlorophenyl)-3-(tetrahydro-2H-thiopyran-4-ylamino)-N-1,3-thiazol-2-ylpropionic (198 mg, 52%) was obtained from 3-N-Boc-3-(4-chlorophenyl)propionic acid (300 mg, 1 mmol), 2-aminothiazole (240 mg, 2.4) and 4-tetrahydrothiopyrano (127 mg, 1.1 mmol) according to General method F.

LC-MS (m/z): 383 (M + 2H)+

Example 31

2-(3,4-Dichloraniline)-2-(4-chlorophenyl)-N-pyridin-2-ylacetamide

Dissolve the methyl ester 4-harmondale acid (402 mg, 2 mmol) and 3,4-dichlorobenzamide (0,48 mg, 2 mmol) in anhydrous ether (10 ml) are added to a suspension of silver oxide (1 g) in ether (10 ml) and stirred for 2 days. All solids filtered off and the filtrate is concentrated and purified column chromatography (silica, 10% ethyl acetate in hexano) to obtain the corresponding ester. Hydrolysis of this ester were carried out as described in procedure A, to obtain 2-(3,4-dichloraniline)-2-(4-chlorophenyl)acetic acid (358 mg, 52%). The solution of this acid (86 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-(3,4-dichloraniline)-2-(4-chlorophenyl)-N-pyridin-2-ylacetamide (72 mg, 68%).

LC-MS (m/z): 421 (M + H)+

1H NMR (400 MHz, CDCl3): δ to 4.52 (DD, 2H), 4,90 (s, 1H), 7,06 (m, 1H), 7,19 (DD, 1H), 7,37-7,44 (m, 6H), to 7.68 (m, 1H), 8,15 (DD, 1H), 8,29 (m, 1H), 9,06 (user., 1H).

Example 32

2-(3,4-Dichloraniline)-2-(4-chlorophenyl)-N-1,3-thiazol-2-ylacetamide

2-(3,4-Dichloraniline)-2-(4-chlorophenyl)acetic acid (86 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(3,4-dichloraniline)-2-(4-chlorophenyl)-N-1,3-thiazol-2-ylacetamide (68 mg, 65%).

LC-MS (m/z): 427 (M + H)+

Example 33

2-(4-Chlorophenyl)-2-(4-methylphenoxy)-N-pyridin-2-ilocate the ID

2-(4-methylphenoxy)2-(4-chlorophenyl)acetic acid (276 mg, 50%) is obtained from the methyl ester of 4-harmondale acid (402 mg, 2 mmol), 4-METHYLPHENOL (260 mg, 2.4 mmol) according to General method A. a Solution of this acid (70 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (60 mg, 0.6 mmol) according to General method E to obtain 2-(4-chlorophenyl)-2-(4-methylphenoxy)-N-pyridin-2-ylacetamide (63 mg, 72%).

LC-MS (m/z): 354 (M + H)+

Example 34

2-(4-Chlorophenyl)-2-(4-methylphenoxy)-N-1,3-thiazol-2 - ylacetamide

A solution of 2-(4-methylphenoxy)-2-(4-chlorophenyl)acetic acid (70 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(4-chlorophenyl)-2-(4-methylphenoxy)-N-1,3-thiazol-2-ylacetamide (66 mg, 74%).

LC-MS (m/z): 359 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 2.26 (s, 3H), 5,70 (s, 1H), for 6.81 (d, 2H), 7,01 (d, 1H), 7,05-was 7.08 (DD, 2H), 7,34 and 7.36 (DD, 2H), 7,47-to 7.50 (m, 3 H), 10,06 (user., 1H).

Example 35

2-(4-Bromophenoxy)-2-(4-chlorophenyl)-N-pyridin-2-ylacetamide

2-(4-Bromophenoxy)-2-(4-chlorophenyl)acetic acid (450 mg, 54%) was obtained from methyl ester 4-harmondale acid (402 mg, 2 mmol), 4-bromophenol (415 mg, 2.4 mmol) according to General method A. a Solution of this acid (104 mg, 0.25 mmol) in the THF is subjected to interaction with 2-aminopyridine (56 mg, 0.6 mmol) according to General method E to obtain 2-(4-bromophenoxy)-2-(4-chlorophenyl)-N-pyridin-2-ylacetamide (75 mg, 72%).

LC-MS (m/z): 418 (M + H)+

1H NMR (400 MHz, CDCl3): δ 5,59 (s, 1H), 6,84 (DD, 2H), 7,05-to 7.09 (DD, 1H), 7,31-7,38 (DD, 4H), of 7.48-to 7.50 (DD, 2H), to 7.67-7,72 (m, 1H), 8,17 (d, 1H), 8,29-8,30 (DD, 1H), 9,04 (user., 1H).

Example 36

2-(4-Bromophenoxy)-2-(4-chlorophenyl)-N-1,3-thiazol-2-ylacetamide

A solution of 2-(4-bromophenoxy)-2-(4-chlorophenyl)acetic acid (104 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, of 0.60 mmol) according to General method E to obtain 2-(4-bromophenoxy)-2-(4-chlorophenyl)-N-1,3-thiazol-2-ylacetamide (78 mg, 74%).

LC-MS (m/z): 424 (M + H)+

1H NMR (400 MHz, CDCl3): δ 5,70 (s, 1H), for 6.81 (d, 1H), 7,02-7,03 (d, 1H), 7,35-7,40 (m, 4H), 7,45-of 7.48 (m, 3H), 10,13 (user., 1H).

Example 37

2-(4-Chlorophenyl)-2-(4-pertenece)-N-1,3-thiazol-2-ylacetamide

2-(4-Pertenece)-2-(4-chlorophenyl)acetic acid (296 mg, 53%) was obtained from methyl ester 4-harmondale acid (402 mg, 2 mmol), 4-terfenol (269 mg, 2.4 mmol) according to General method A. a Solution of this acid (70 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, of 0.60 mmol) according to General method E to obtain 2-(4-chlorophenyl)-2-(4-pertenece)-N-1,3-thiazol-2-ylacetamide (71 mg, 78%).

LC-MS (m/z): 363 (M + H)+

2-(4-Chlorophenyl)-2-(3,4-dichlorophenoxy)-N-pyridin-2-ylacetamide

2-(3,4-Dichlorophenoxy)-2-(4-chlorophenyl)acetic acid (363 mg, 55%) was obtained from methyl ester 4-harmondale acid (402 mg, 2 mmol), 3,4-dichlorophenol (390 mg, 2.4 mmol) according to General method A. a Solution of this acid (83 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (56 mg, of 0.60 mmol) according to General method E to obtain 2-(4-chlorophenyl)-2-(3,4-dichlorophenoxy)-N-pyridin-2-ylacetamide (82 mg, 80%).

LC-MS (m/z): 408 (M + H)+

1H NMR (400 MHz, CDCl3): δ 4.92 in (s, 1H), 7,05-to 7.09 (m, 1H), 7,05 (d, 1H), 7,05-was 7.08 (DD, 2H), 7,7,34 and 7.36 (DD, 2H), 7,7,47 is 7.50 (m, 2H), 10,06 (user., 1H).

Example 39

2-(4-Bromophenoxy)-2-(4-bromophenyl)-N-pyridin-2-ylacetamide

2-(4-Bromophenoxy)-2-(4-bromophenyl)acetic acid (461 mg, 60%) was obtained from methyl ester 4-bromoindole acid (490 mg, 2 mmol) and 4-bromophenol (415 mg, 2.4 mmol) according to General method A. a Solution of this acid (96 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (56 mg, of 0.60 mmol) according to General method E to obtain 2-(4-bromophenoxy)-2-(4-bromophenyl)-N-pyridin-2-ylacetamide (104 mg, 90%).

LC-MS (m/z): 463 (M + H)+

1H NMR (400 MHz, CDCl3): δ to 5.57 (s, 1H), at 6.84 (d, 2H), 7,06-to 7.09 (t, 1H), 7,37 (d, 2H), 7,43 (d, 2H), 7,51 (d, 2H), 7,78-7,72 (t, 1H), 8,18 (d, 1H), 8,29 (d, 1H), 9,03 (1H).

Example 40

2-(4-Bromophenoxy)-2-(4-bromophenyl)-N-1,3-thiazol-2-ylacetamide

A solution of 2-(4-bromophenoxy)-2-(4-bromophenyl)acetic acid (96 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, of 0.60 mmol) according to General method E to obtain 2-(4-bromophenoxy)-2-(4-bromophenyl)-N-1,3-thiazol-2-ylacetamide (103 mg, 88%).

LC-MS (m/z): 469 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 5.68 (s, 1H), 6,76-of 6.78 (DD, 2H), 7,02 (d, 1H), 7,35 (d, 2H), 7,37 (d, 2H), 7,42 (d, 1H), 7,52 (d, 2H), 10,36 (user., 1H).

Example 41

2-(4-Bromophenyl)-2-(4-methylphenoxy)-N-pyridin-2-ylacetamide

2-(4-Methylphenoxy)-2-(4-bromophenyl)acetic acid (372 mg, 58%) was obtained from methyl ester 4-bromoindole acid (490 mg, 2 mmol), 4-METHYLPHENOL (260 mg, 2.4 mmol) according to General method A. a Solution of this acid (80 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (56 mg, 0.6 mmol) according to General method E to obtain 2-(4-bromophenyl)-2-(4-methylphenoxy)-N-pyridin-2-ylacetamide (89 mg, 90%).

LC-MS (m/z): 398 (M + H)+

1H NMR (400 MHz, CDCl3): δ, and 2.27 (s, 3H), to 5.58 (s, 1H), 6,85 (d, 2H), 7,07 (d, 3H), 7,45-7,52 (m, 4H), of 7.69 (t, 1H), 8,19 (d, 1H), 8,29 (d, 1H), 9,11 (s, 1H).

Example 42

2-(4-Bromophenyl)-2-(4-pertenece)-N-1,3-thiazol-2-ylacetamide

2-(4-Pertenece)-2-(4-bromophenyl)acetic Ki the lot (472 mg, 58%) is obtained from the methyl ester of 4-bromoindole acid (490 mg, 2 mmol) and 4-terfenol (268 mg, 2.4 mmol) according to General method A. a Solution of this acid (81 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 6.0 mmol) according to General method E to obtain 2-(4-bromophenyl)-2-(4-pertenece)-N-1,3-thiazol-2-ylacetamide (73 mg, 72%).

LC-MS (m/z): 408 (M + H)+

Example 43

2-(4-Bromophenyl)-2-phenoxy-N-1,3-thiazol-2-ylacetamide

2 Phenoxy-2-(4-bromophenyl)acetic acid (319 mg, 52%) was obtained from methyl ester 4-bromoindole acid (490 mg, 2 mmol), phenol (226 mg, 2.4 mmol) according to General method A. a Solution of this acid (76,78 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(4-bromophenyl)-2-phenoxy-N-1,3-thiazol-2-ylacetamide (82 mg, 85%).

LC-MS (m/z): 390 (M + H)+

1H NMR (400 MHz, CDCl3): δ 5,73 (s, 1H), 6,88-of 6.90 (DD, 2H), 7,01? 7.04 baby mortality (m, 2H), 7.24 to 7,28 (m, 2H), 7,43 (d, 2H), of 7.48-7,49 (DD, 1H), 7,50 (d, 2H), 10,50 (user., 1H).

Example 44

2-(4-Pertenece)-2-(4-forfinal)-N-pyridin-2-ylacetamide

2-(4-Pertenece)-2-(4-forfinal)acetic acid (317 mg, 60%) was obtained from methyl ester 4-farmindale acid (368 mg, 2 mmol) and 4-terfenol (268 mg, 2.4 mmol) according to General method A. Astor this acid (66 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (5 mg, 0.6 mmol) according to General method E to obtain 2-(4-pertenece)-2-(4-forfinal)-N-pyridin-2-ylacetamide (73 mg, 76%).

LC-MS (m/z): 341 (M + H)+

Example 45

2-(4-Pertenece)-2-(4-forfinal)-N-1,3-thiazol-2-ylacetamide

A solution of 2-(4-pertenece)-2-(4-forfinal)acetic acid (66 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(4-pertenece)-2-(4-forfinal)-N-1,3-thiazol-2-ylacetamide (73 mg, 84%).

LC-MS (m/z): 347 (M + H)+

1H NMR (400 MHz, CDCl3): δ 5,72 (d, 1H), 6,85 (m, 2H), 6,95 (m, 2H), 7,02 (m, 1H), was 7.08 (m, 2H), 7,50 (m, 2H), to 7.67 (m, 1H), 10,42 (user., 1H).

Example 46

2-(4-Forfinal)-2-(4-methoxyphenoxy)-N-1,3-thiazol-2-ylacetamide

2-(4-Methylphenoxy)-2-(4-forfinal)acetic acid (264 mg, 50%) is obtained from the methyl ester of 4-farmindale acid (368 mg, 2 mmol) and 4-METHYLPHENOL (259 mg, 2.4 mmol) according to General method A. a Solution of this acid (66 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(4-forfinal)-2-(4-methylphenoxy)-N-1,3-thiazol-2-ylacetamide (69 mg, 80%).

LC-MS (m/z): 347 (M + H)+

Example 47

2-(4-Forfinal)-2-phenoxy-N-1,3-thiazol-2-acetamide

A solution of 2-phenoxy-2-(4-forfinal)acetic acid (62 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(4-forfinal)-2-phenoxy-N-1,3-thiazol-2-ylacetamide (62 mg, 75%).

LC-MS (m/z): 329 (M + H)+

Example 48

2-(4-Bromophenoxy)-2-(4-forfinal)-N-pyridin-2-ylacetamide

2-(4-Bromophenoxy)-2-(4-forfinal)acetic acid (338 mg, 52%) was obtained from methyl ester 4-farmindale acid (368 mg, 2 mmol) and 4-bromophenol (415 mg, 2.4 mmol) according to General method A. a Solution of this acid (81 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (56 mg, 0.6 mmol) according to General method E to obtain 2-(4-bromophenoxy)-2-(4-forfinal)-N-pyridin-2-ylacetamide (86 mg, 86%).

LC-MS (m/z): 402 (M + H)+

Example 49

2-(4-Pertenece)-N-1,3-thiazol-2-yl-2-[4-(trifluoromethyl)phenyl]ndimethylacetamide

2-(4-Pertenece)-2-(4-triptoreline)acetic acid (390 mg, 62%) was obtained from methyl ester 4-cryptomaterial acid (468 mg, 2 mmol) and 4-terfenol (269 mg, 2.4 mmol) according to General method A. a Solution of this acid (79 mg, 0.5 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain the 2-(4-pertenece)-N-1,3-thiazol-2-yl-2-[4-(trifluoromethyl)phenyl]- ndimethylacetamide (87 mg, 88%).

LC-MS (m/z): 397 (M + H)+

1H NMR (400 MHz, CDCl3): δ 5,67 (s, 1H), 6,83 (m, 2H), 6,93 (m, 2H), 7,01 (m, 1H), 7,07 (m, 2H), 7,49 (m, 3H), or 10.60 (user., 1H).

Example 50

2-(4-Bromophenoxy)-N-pyridin-2-yl-2-[4-(trifluoromethyl)phenyl]ndimethylacetamide

2-(4-Bromophenoxy)-2-(4-triptoreline)acetic acid (405 mg, 54%) was obtained from methyl ester 4-cryptomaterial acid (468 mg, 2 mmol) and 4-bromophenol (415 mg, 2.4 mmol) according to General method A. a Solution of this acid (94 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (56 mg, 0.6 mmol) according to General method E to obtain 2-(4-bromophenoxy)-N-pyridin-2-yl-2-[4-(trifluoromethyl)phenyl]- ndimethylacetamide (102 mg, 90%).

LC-MS (m/z): 452 (M + H)+

Example 51

2-(3,4-Dichlorophenoxy)-2-(3,4-(dichlorophenyl)-N-1,3-thiazol-2-ylacetamide

2-(3,4-Dichlorophenoxy)-2-(3,4-dichlorophenyl)acetic acid (400 mg, 55%) is obtained from the methyl ester of 3,4-dichloraniline acid (468 mg, 2 mmol) and 3,4-dichlorophenol (389 mg, 2.4 mmol) according to General method A. a Solution of this acid (91 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(3,4-dichlorophenoxy)-2-(3,4-dichlorophenyl)-N-1,3-thiazol-2-ylacetamide (72 mg, 65%).

LC-MS (m/z): 447 (M + H)+

1H NMR (400 MHz, CDCl3: δ 4,94 (s, 1H), 7,07 (d, 1H), 7,14-7,16 (DD, 1H), 7.23 percent (d, 1H), 7,25 (d, 1H), 7,32 (d, 1H), 7,41 (d, 1H), 7,44 was 7.45 (DD, 1H), 7,53 (d, 1H), 11,04 (user., 1H).

Example 52

2-Cyclopentylmethyl-2-phenyl-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-phenylacetic acid (330 mg, 70%) was obtained from methyl ester 2-bromoferrocene acid (458 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method C. a Solution of this acid (59 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-phenyl-N-1,3-thiazol-2-ylacetamide (63 mg, 79%).

LC-MS (m/z): 319 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,48-of 1.55 (m, 4H), 1,72 (m, 2H), up to 1.98 (m, 2H), 3,11 (m, 1H), 4,80 (s, 1H), 7,00 (d, 1H), 7,26 and 7.36 (m, 5H), scored 8.38 (DD, 1H) and 10.9 (user., 1H).

Example 53

2-Cyclopentylmethyl-2-phenyl-N-pyridin-2-ylacetamide

A solution of 2-cyclopentyl-2-phenylacetic acid (59 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-phenyl-N-pyridin-2-ylacetamide (59 mg, 75%).

LC-MS (m/z): 313 (M + H)+

LC-MS (m/z): 314 (M + 2H)+

1H NMR (400 MHz, CDCl3): δ 1.56 to to 1.60 (m, 4H), to 1.76 (m, 2H), 2,03 (m, 2H), 3.15 in (m, 1H), 4,71 (s, 1H), 7,06 (DD, 1H), 7,26 and 7.36 (m, 5H), of 7.70 (t, 1H), 8,21 (d, 1H), 8,29 (DD, 1H), 9,26 (user., 1H).

p> Example 54

2-Cyclopentylmethyl-2-(4-forfinal)-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-(4-forfinal)acetic acid (345 mg, 68%) is obtained from the methyl ester of 2-bromo-2-(4-forfinal)acetic acid (494 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method C. a Solution of this acid (64 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-forfinal)-N-1,3-thiazol-2-ylacetamide (59 mg, 70%).

LC-MS (m/z: 337 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,48-of 1.62 (m, 4H), 1,68-of 1.78 (m, 2H), 1,94-2,04 (m, 2H), 3,06 is 3.15 (m, 1H), 4,79 (d, 1H), 7,01-7,05 (m, 2H), 7,37-7,41 (m, 1H), of 7.48-7,51 (m, 1H), 7,54 (d, 1H), to 7.59 (d,1H), 10,79 (user., 1H).

Example 55

2-Cyclopentylmethyl-2-(4-forfinal)-N-pyridin-2-ylacetamide

A solution of 2-cyclopentyl-2-(4-forfinal)acetic acid (64 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-forfinal)-N-pyridin-2-ylacetamide (60 mg, 72%).

LC-MS (m/z): 331 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,50-of 1.62 (m, 4H), was 1.69 and 1.80 (m, 2H), 1,87-of 2.08 (m, 2H), 3,09-and 3.16 (m, 1H), 4,69 (s, 1H), 7,01-7,07 (m, 3H), 7,40-the 7.43 (m, 2H), 7,70-7,72 (m, 1H), 8,19 (d, 1H), 8,29-8,31 (m, 1H), 9,26 (user., 1H).

Example 56

2-Cyclopent sulfanyl-2-(3-chlorophenyl)-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-(3-chlorophenyl)acetic acid (351 mg, 65%) is obtained from the methyl ester of 2-bromo-2-(3-chlorophenyl)acetic acid (527 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method C. a Solution of this acid (68 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(3-chlorophenyl)-N-1,3-thiazol-2-ylacetamide (63 mg, 72%).

LC-MS (m/z): 353 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,48 is 1.60 (m, 4H), by 1.68 to 1.76 (m, 2H), 1,94-2,04 (m, 2H), 3,06-3,14 (m, 1H), 4,74 (s, 1H),? 7.04 baby mortality-7,05 (d, 1H), 7,27-7,29 (m, 3H), 7,42 (s, 1H), 7,49-7,50 (d, 1H), 10,88 (user., 1H).

Example 57

2-Cyclopentylmethyl-2-(3-chlorophenyl)-N-pyridin-2-ylacetamide

A solution of 2-cyclopentyl-2-(3-chlorophenyl)acetic acid (68 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(3-chlorophenyl)-N-pyridin-2-ylacetamide (59 mg, 68%).

LC-MS (m/z): 347 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,52-of 1.64 (m, 4H), 1.70 to of 1.84 (m, 2H), 1,89-of 2.08 (m, 2H), 3,09 is 3.15 (m, 1H), 4,74 (s, 1H), 7,02-7,10 (m, 3H), 7,40-7,42 (m, 2H), 7,70-7,72 (m, 1H), 8,19 (d, 1H), 8,32-of 8.33 (m, 1H), 9,34 (user., 1H).

Example 58

2-Cyclopentylmethyl-2-(4-chloro)phenyl-N-pyridin-2-ylacetamide

2-C is Capetillo-2-(4-chlorophenyl)acetic acid (390 mg, 72%) is obtained from the methyl ester of 2-bromo-2-(4-chlorophenyl)acetic acid (528 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method C. a Solution of this acid (68 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-chlorophenyl)-N-pyridin-2-ylacetamide (62 mg, 72%).

LC-MS (m/z): 347 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,52-to 1.63 (m, 4H), 1,72-of 1.85 (m, 2H), 1,89 is 2.10 (m, 2H), 3,09-and 3.16 (m, 1H), 4.72 in (s, 1H), 7,02-to 7.09 (m, 3H), 7,42-7,44 (m, 2H), 7,71-7,73 (m, 1H), 8,19 (d, 1H), 8,31-8,32 (m, 1H), 9,25 (user., 1H).

Example 59

2-Cyclopentylmethyl-2-(4-bromophenyl)-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-(4-bromophenyl)acetic acid (441 mg, 70%) is obtained from the methyl ester of 2-bromo-2-(4-bromophenyl)acetic acid (616 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method C. a Solution of this acid (79 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-bromophenyl)-N-1,3-thiazol-2-ylacetamide (71 mg, 72%).

LC-MS (m/z): 398 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,48-to 1.61 (m, 4H), by 1.68 to 1.76 (m, 2H), 1,96-2,02 (m, 2H), 3,07-of 3.12 (m, 1H), 4,74 (s, 1H), 7,02 (d, 1H), 7,28-7,30 (DD, 1H), 7,37-7,44 (m, 1H), 7,49-7,52 (m, 1H), 7,52 (d, 1H), to 7.59 (d, 1H), 10,65 (user., 1H).

Example 60

2-kilometerscalgary-2-(4-bromophenyl)-N-pyridin-2-ylacetamide

A solution of 2-cyclopentyl-2-(4-bromophenyl)acetic acid (79 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-bromophenyl)-N-pyridin-2-ylacetamide (72 mg, 75%).

LC-MS (m/z): 392 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,50-of 1.64 (m, 4H), 1,69 of-1.83 (m, 2H), 1,87 is 2.10 (m, 2H), 3,09-3,17 (p, 1H)and 4.65 (s, 1H), 7,05-was 7.08 (DD, 1H), 7,31 and 7.36 (DD, 2H), 7,45-of 7.48 (m, 2H), 7.68 per-7,72 (m, 1H), 8,18 (d, 1H), 8,29-8,30 (m, 1H), 9,23 (user., 1H).

Example 61

2-Cyclopentylmethyl-2-(4-methoxyphenyl)-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-(4-methoxyphenyl)acetic acid (319 mg, 60%) was obtained from methyl ester 4-methoxymandelic acid (392 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method D. the Solution of this acid (67 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-methoxyphenyl)-N-1,3-thiazol-2-ylacetamide (65 mg, 75%).

LC-MS (m/z): 349 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,46-to 1.63 (m, 4H), 1,68-of 1.78 (m, 2H), 1.93 and e 2.06 (m, 2H), 3,06-3,13 (m, 1H), of 3.78 (s, 3H), and 4.75 (s, 1H), 6,84-to 6.88 (m, 2H), 7,00-7,02 (DD, 1H), 7,31-7,34 (m, 2H), 7,46-of 7.48 (DD, 1H), 10,41 (user., 1H).

Example 62

2-Cyclopentylmethyl-2-(4-methoxyphenyl)-N-pyridin-2-ylacetamide

A solution of 2-cyclopentyl-2-(4-methoxyphenyl)acetic acid (67 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-methoxyphenyl)-N-pyridin-2-ylacetamide (60 mg, 70%).

LC-MS (m/z): 343 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,50-of 1.66 (m, 4H), 1,69-of 1.81 (m, 2H), 1,86-2,07 (m, 2H), 3,09-and 3.16 (m, 1H), of 3.77 (s, 3H), of 4.67 (s, 1H), 6,85-6,87 (m, 2H), 7.03 is? 7.04 baby mortality (m, 1H), 7,25-7,38 (m, 2H), 7,66-7,71 (m, 1H), to 8.20 (d, 1H), 8,28-8,30 (m, 1H), 9,14 (user., 1H).

Example 63

2-Cyclopentylmethyl-2-(3-cyanophenyl)-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-(3-cyanophenyl)acetic acid (323 mg, 62%) was obtained from methyl ester 3-cyanoindole acid (382 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method D. the Solution of this acid (65 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(3-cyanophenyl)-N-1,3-thiazol-2-ylacetamide (64 mg, 74%).

LC-MS (m/z): 344 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,48-to 1.61 (m, 4H), 1,68-of 1.78 (m, 2H), 1,91-of 2.20 (m, 2H), 3,05-of 3.12 (m, 1H), 4,81 (s, 1H), 7,07-was 7.08 (d, 1H), 7,45-7,47 (t, 1H), 7,50-7,51 (d, 1H), 7,58-of 7.60 (d, 1H), 7.68 per-of 7.70 (d, 1H), 7,76 (s, 1H), 11,28 (user., 1H).

Example 64

2-Cyclopentylmethyl-2-(3-cyanophenyl)-N-pyridin-2-ylacetamide

A solution of 2-cyclopentyl-2-(3-cyanophenyl)acetic acid (65 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(3-cyanophenyl)-N-pyridin-2-ylacetamide (61 mg, 72%).

LC-MS (m/z): 338 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,51-of 1.62 (m, 4H), 1,73 and 1.80 (m, 2H), 1,92-of 2.08 (m, 2H), 3,09-3,17 (m, 1H), 4,71 (s, 1H), 7,08-7,11 (m, 2H), 7,43-7,47 (m, 1H), EUR 7.57-of 7.60 (m, 1H), 7.68 per to 7.75 (m, 3H), 8,19 (d, 1H), 8.30 to-8,32 (m, 1H), 9,44 (user., 1H).

Example 65

2-Cyclopentylmethyl-2-(4-cyanophenyl)-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-(4-cyanophenyl)acetic acid (313 mg, 60%) was obtained from methyl ester 4-cyanoindole acid (382 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method D. the Solution of this acid (65 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-cyanophenyl)-N-1,3-thiazol-2-ylacetamide (58 mg, 68%).

LC-MS (m/z): 344 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,46-of 1.57 (m, 4H), 1,72-of 1.78 (m, 2H), 1,94-2,04 (m, 2H), 3.04 from-of 3.12 (m, 1H), 4,82 (s, 1H), 7,02? 7.04 baby mortality (m, 2H), 7,42-7,44 (m, 1H), EUR 7.57 (d, 1H), 7,63-7,66 (DD, 1H), 7,80-to 7.84 (m, 1H), 8,21 is 8.22 (m, 1H), 10,41 (user., 1H).

Example 66

2-Cyclopentylmethyl-2-(4-cyanophenyl)-N-pyridin-2-ylacetamide

RAS is a thief 2-(cyclopentyl)-2-(4-cyanophenyl)acetic acid (65 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-cyanophenyl)-N-pyridin-2-ylacetamide (67 mg, 80%).

LC-MS (m/z): 338 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,54-to 1.61 (m, 4H), of 1.70 to 1.76 (m, 2H), 1,88-to 2.06 (m, 2H), 3,09-and 3.16 (m, 1H), 4.72 in (s, 1H), 7,07-7,10 (m, 2H), 7,55-EUR 7.57 (m, 2H), 7,62-to 7.64 (m, 1H), 7,69-7,74 (m, 1H), 8,16 (d, 1H), 8,29-8,31 (m, 1H), to 9.32 (user., 1H).

Example 67

2-Cyclopentylmethyl-2-(4-nitrophenyl)-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-(4-nitrophenyl)acetic acid (270 mg, 48%) obtained from the methyl ester of 2-bromo-2-(4-nitrophenyl)acetic acid (548 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method C. a Solution of this acid (70 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-nitrophenyl)-N-1,3-thiazol-2-ylacetamide (67 mg, 74%).

LC-MS (m/z): 364 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1.26 in (m, 4H), of 1.40 (m, 2H), of 1.66 (m, 2H), 3,44 (m, 1H), 4,87 (s, 1H), 7,03 (d, 1H), 7,42 (m, 2H), to 7.64 (d, 1H), 8,18 (m, 2H), and 11.2 (user., 1H).

Example 68

2-Cyclopentylmethyl-2-(4-nitrophenyl)-N-pyridin-2-ylacetamide

A solution of 2-cyclopentyl-2-(4-nitrophenyl)acetic acid (70 mg, 0.25 mmol) in THF subjected collaboration is July with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-nitrophenyl)-N-pyridin-2-ylacetamide (63 mg, 70%).

LC-MS (m/z): 358 (M + H)+

Example 69

2-Cyclopentylmethyl-2-(4-methylsulphonyl)phenyl-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-(4-methylsulfinylphenyl)acetic acid (471 mg, 75%) is obtained from the methyl ester of 2-bromo-2-(4-methylsulfinylphenyl)acetic acid (614 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method C. a Solution of this acid (79 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-methylsulfinylphenyl)-N-1,3-thiazol-2-ylacetamide (84 mg, 85%).

LC-MS (m/z): 397 (M + H)+

1H NMR (400 MHz, CDCl3): δ equal to 1.59 (m, 4H), of 1.75 (m, 2H), 2,04 (m, 2H), 3.04 from (s, 3H), of 3.13 (m, 1H), a 4.83 (s, 1H),? 7.04 baby mortality (d, 1H), 7,49 (d, 1H), 7.62mm (m, 2H), to 7.93 (m, 2H), 10,31 (user., 1H).

Example 70

2-Cyclopentylmethyl-2-(4-methylsulfinylphenyl)-N-pyridin-2-ylacetamide

A solution of 2-cyclopentyl-2-(4-methylsulfinylphenyl)acetic acid (79 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-methylsulfinylphenyl)-N-pyridin-2-ylacetamide (80 mg, 82%).

LC-MS (m/z): 391 (M + H)+

1H NMR (400 MHz, CDCl3): δ was 1.58 (m, 4H), of 1.75 (m, 2H), 2,03 (m, 2H), 3,03 (s, 3H), 3,14 (m, 1H), amounts to 4.76 (s, 1H), was 7.08 (m, 1H), 7,66 (m, 2H), of 7.70 (m, 1H), to $ 7.91 (m, 2H), 8,17 (d, 1H), 8,32 (m, 1H), to 9.32 (user., 1H).

Example 71

2-Cyclopentylmethyl-2-(4-trifluoromethyl)phenyl-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-(4-triptoreline)acetic acid (413 mg, 68%) is obtained from the methyl ester of 2-bromo-2-(4-triptoreline)acetic acid (594 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method C. a Solution of this acid (76 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-triptoreline)-N-1,3-thiazol-2-ylacetamide (82 mg, 85%).

LC-MS (m/z): 387 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,50-of 1.62 (m, 4H), 1,71 and 1.80 (m, 2H), 1,96-of 2.08 (m, 2H), 3,06-and 3.16 (m, 1H), 4,82 (s, 1H), 7.03 is-7,048 (d, 1H), of 7.48-7,49 (d, 1H), 7,53-of 7.55 (d, 2H), 7,6 to 7.62 (d, 2H), 10,51 (user., 1H).

Example 72

2-Cyclopentylmethyl-2-(4-trifluoromethyl)phenyl-N-pyridin-2-ylacetamide

A solution of 2-cyclopentyl-2-(4-triptoreline)acetic acid (76 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-triptoreline)-N-pyridin-2-ilace the amide (76 mg, 80%).

LC-MS (m/z): 381 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,57-of 1.65 (m, 4H), 1.70 to is 1.81 (m, 2H), 1.93 and-2,05 (m, 2H), 3,11-3,17 (m, 1H), 4.75 in (s, 1H), 7,06-7,10 (m, 1H), 7.24 to 7,25 (m, 1H), 7,56-to 7.61 (m, 3H), 7,69-7,74 (m, 1H), 8,19 (d, 1H), 8,29-8,31 (m, 1H), 9,34 (user., 1H).

Example 73

2-Cyclopentylmethyl-2-(3-trifloromethyl)-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-(3-trifloromethyl)acetic acid (416 mg, 65%) is obtained from the methyl ester of 2-bromo-2-(3-trifloromethyl)acetic acid (626 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method C. a Solution of this acid (80 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(3-trifloromethyl)-N-1,3-thiazol-2-ylacetamide (78 mg, 78%).

LC-MS (m/z): 403 (M + H)+

1H NMR (400 MHz, CDCl3): δ to 1.61 (m, 4H), of 1.75 (m, 2H), 2,02 (m, 2H), 3,13 (m, 1H), 4,77 (s, 1H), 7,03 (d, 1H), 7,18 (m, 1H), 7,27 (d, 1H), 7,33-7,40 (m, 2H), 7,47 (d, 1H), of 10.25 (user., 1H).

Example 74

2-Cyclopentylmethyl-2-(3-trifloromethyl)-N-pyridin-2-ylacetamide

A solution of 2-cyclopentyl-2-(3-trifloromethyl)acetic acid (80 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(3-triptime is oxyphenyl)-N-pyridin-2-ylacetamide (TTP-001176052)(71 mg, 72%).

LC-MS (m/z): 397 (M + H)+

1H NMR (400 MHz, CDCl3): δ was 1.58 (m, 4H), at 1.73 (m, 2H), 2,03 (m, 2H), 3,14 (m, 1H), 4,70 (s, 1H), 7,05-7,10 (m, 1H), 7,15 (m, 1H), 7,31 (d, 1H), was 7.36 (m, 2H), 7,71 (m, 1H), 8,19 (d, 1H), 8,31 (m, 1H) and a 9.25 (user., 1H).

Example 75

2-Cyclopentylmethyl-2-(4-trifloromethyl)-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-(4-trifloromethyl)acetic acid (448 mg, 70%) is obtained from the methyl ester of 2-bromo-2-(4-trifloromethyl)acetic acid (626 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method C. a Solution of this acid (80 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-trifloromethyl)-N-1,3-thiazol-2-ylacetamide (85 mg, 85%).

LC-MS (m/z): 403 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 1.55 (m, 4H), of 1.74 (m, 2H), 2,01 (m, 2H), 3,11 (m, 1H), 4,79 (s, 1H), 7,03 (d, 1H), 7,26 (m, 2H), 7,47 (m, 3H), 10,87 (user., 1H).

Example 76

2-Cyclopentylmethyl-2-(4-trifloromethyl)-N-pyridin-2-ylacetamide

A solution of 2-Cyclopentyl-2-(4-trifloromethyl)acetic acid (80 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-trifloromethyl)-N-pyridin-2-racetam is Yes (79 mg, 80%).

LC-MS (m/z): 397 (M + H)+

1H NMR (400 MHz, CDCl3): δ was 1.58 (m, 4H), of 1.74 (m, 2H), 2,04 (m, 2H), 3.15 in (m, 1H), 4,70 (s, 1H), was 7.08 (m, 1H), 7,18 (DD, 2H), 7,47 (DD, 2H), 7,71 (m, 1H), 8,19 (d, 1H), 8,31 (m, 1H), 9,25 (user., 1H).

Example 77

2-Cyclopentylmethyl-2-(4-phenyl)phenyl-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-(4-phenyl)phenylacetic acid (406 mg, 65%) was obtained from methyl ester 2-bromoferrocene acid (610 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method C. a Solution of this acid (78 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-phenyl)phenyl-N-1,3-thiazole-2-ylacetamide (69 mg, 70%).

LC-MS (m/z): 395 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,47-of 1.66 (m, 4H), 1,72-of 1.81 (m, 2H), 1,99-of 2.21 (m, 2H), 3,10-3,22 (p, 1H), a 4.83 (s, 1H), 6,99-7,01(m, 1H), 7,41-7,58 (m, 6H), 7,63-the 7.65 (m, 1H), to 7.67-to 7.77 (m, 1H), 8,03 (d, 1H), 8,56 (d, 1H), 10,42 (user., 1H).

Example 78

2-Cyclopentylmethyl-2-(4-phenyl)phenyl-N-pyridin-2-ylacetamide

A solution of 2-cyclopentyl-2-(4-phenyl)phenylacetic acid (78 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-phenyl)phenyl-N-pyridin-2-ylacetamide (76 mg, 78%).

LC-MS (m/z): 389 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,53-of 1.62 (m, 4H), 1,71-of 1.78 (m, 2H), 2,01-2,12 (m, 2H), is 3.08-3,20 (p, 1H), 4.92 in (s, 1H), 7,13-7,17 (m, 1H), 7,25-7,58 (m, 6H), to 7.61-to 7.67 (m, 1H), 7,71 to 7.75 (m, 1H), 7,82-7,86 (m, 1H), 8,29-8,31 (m, 1H), 8,33-at 8.36 (m, 1H), 8,46-8,48 (d, 1H), accounted for 10.39 (user., 1H).

Example 79

2-Cyclopentylmethyl-2-(4-phenoxyphenyl)-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-(4-phenoxyphenyl)acetic acid (459 mg, 70%) is obtained from the methyl ester of 2-bromo-(4-phenoxyphenyl)acetic acid (642 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method C. a Solution of this acid (82 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-phenoxyphenyl)-N-1,3-thiazol-2-ylacetamide (81 mg, 79%).

LC-MS (m/z): 411 (M + H)+

1H NMR (400 MHz, CDCl3): δ to 1.60 (m, 4H), of 1.75 (m, 2H), 2.05 is (m, 2H), 3.15 in (m, 1H), 4.72 in (s, 1H), 6,95 for 7.12 (m, 5H), 7,34 (t, 1H), 7,41 (d, 2H), 7,73 (t, 1H), 8,24 (d, 1H), 8.30 to (DD, 1H) and 9,39 (user.,1H).

Example 80

2-Cyclopentylmethyl-2-(4-phenoxyphenyl)-N-pyridin-2-ylacetamide

A solution of 2-cyclopentyl-2-(4-phenoxyphenyl)acetic acid (82 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(4-phenoxyphenyl)-N-pyridin-2-ylacetamide (79 mg, 78%).

LC-MS (/z): 405 (M + H) +

1H NMR (400 MHz, CDCl3): δ 1,53-of 1.56 (m, 4H), 1,72 (m, 2H), up to 1.98 (m, 2H), and 3.16 (m, 1H), 4,81 (s, 1H), 6,99 (m, 4H), 7,14 (m, 2H), 7,29-7,44 (m, 4H), 7,49 (t, 1H), 7,56 (d, 1H), 8,00 (DD, 1H) and 10.93 (user., 1H).

Example 81

2-Cyclopentylmethyl-2-(3,4-differenl)-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-(3,4-differenl)acetic acid (316 mg, 58%) is obtained from the methyl ester of 2-bromo-2-(3,4-differenl)acetic acid (530 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method C. a Solution of this acid (68 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(3,4-differenl)-N-1,3-thiazol-2-ylacetamide (66 mg, 75%).

LC-MS (m/z): 355 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,50-1,55 (m, 4H), 1.70 to around 1.74 (m, 2H), 1,87-2,02 (m, 2H), 3,03-to 3.09 (m, 1H), 4,74 (d, 1H), 7,06-to 7.18 (m, 1H), 7,28-7,34 (m, 1H), 7,70-7,74 (m, 1H), 8,19 (d, 1H), 8,29-8,31 (m, 1H), 9.28 are (user., 1H).

Example 82

2-Cyclopentylmethyl-2-(3,4-differenl)-N-pyridin-2-ylacetamide

A solution of 2-cyclopentyl-2-(3,4-differenl)acetic acid (68 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(3,4-differenl)-N-pyridin-2-ylacetamide (61 mg, 70%).

LC-MS (m/z): 349 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,50-of 1.62 (m, 4H), was 1.69 and 1.80 (m, 2H), 1,87-of 2.08 (m, 2H), 3,09-and 3.16 (m, 1H), 4,69 (s, 1H), 7,01-was 7.08 (m, 3H), 7,42-7,44 (m, 1H), 7,72-7,74 (m, 1H), 8,19 (d, 1H), 8.30 to-8,32 (m, 1H), 9,88 (user., 1H).

Example 83

2-Cyclopentylmethyl-2-(3,5-differenl)-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-(3,5-differenl)acetic acid (326 mg, 60%) is obtained from the methyl ester of 2-bromo-2-(3,5-differenl)acetic acid (530 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method C. a Solution of this acid (68 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(3,5-differenl)-N-1,3-thiazol-2-ylacetamide (62 mg, 70%).

LC-MS (m/z): 355 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,48-of 1.55 (m, 4H), 1,71 is 1.75 (m, 2H), 1,87-2,05 (m, 2H), 3.04 from-to 3.09 (m, 1H), 4.75 in (d, 1H), 7,08-7,16 (m, 1H), 7,26-7,32 (m, 1H), 7,71-7,74 (m, 1H), 8,19 (d, 1H), 8,29-8,32 (m, 1H), 9,66 (user., 1H).

Example 84

2-Cyclopentylmethyl-2-(3,5-differenl)-N-pyridin-2-ylacetamide

A solution of 2-cyclopentyl-2-(3,5-differenl)acetic acid (68 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(3,5-differenl)-N-pyridin-2-ylacetamide (66 mg, 76%).

LC-MS (m/z): 349 (M + H)+

Primer

2-Cyclopentylmethyl-2-{3,4-(methylenedioxy)phenyl}-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-{3,4-(methylenedioxy)phenyl}acetic acid (336 mg, 60%) is obtained from the methyl ester of 3,4-(methylendioxy)almond acid (420 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method D. the Solution of this acid (70 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-{3,4-(methylendioxy)phenyl}-N-1,3-thiazol-2-ylacetamide (59 mg, 65%).

LC-MS (m/z): 363 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,46-to 1.61 (m, 4H), 1,68-to 1.79 (m, 2H), 1,92-of 2.34 (m, 2H), 3,05-of 3.12 (m, 1H), 4,71 (s, 3H), 5,94-5,95 (m, 2H), 6,74 (d, 1H), at 6.84 (d, 1H), 6,94 (s, 1H), 7,02 (d, 1H), 7,49 (d, 1H), 10,61 (user., 1H).

Example 86

2-Cyclopentylmethyl-2-{3,4-(methylenedioxy)phenyl}-N-pyridin-2-ylacetamide

A solution of 2-cyclopentyl-2-{3,4-(methylenedioxy)phenyl}acetic acid (70 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-{3,4-(methylenedioxy)phenyl}-N-pyridin-2-ylacetamide (53 mg, 60%).

LC-MS (m/z): 357 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,48-of 1.62 (m, 4H), 1,67-of 1.78 (m, 2H), 1,92-of 2.08 (m, 2H), 3,06-3,14 (m, 1H), 4,62 (s, 3H), to 5.93 (d, 2H), 6,74 (d, 1H), 6.87 in (d, 1H), 6,95 (s, 1H), 7,02 and 7.6 (m, 1H), to 7.67-7,71 (t, 1H), 8,19 (d, 1H), 8,28 (d, 1H), 9,17 (s, 1H).

Example 87

2-Cyclopentylmethyl-2-[3,5-bis(trifluoromethyl)phenyl]-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-[3,5-bis(trifluoromethyl)phenyl]acetic acid (521 mg, 70%) is obtained from the methyl ester of 2-bromo-2-[3,5-bis(trifluoromethyl)phenyl]acetic acid (730 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method C. a Solution of this acid (93 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E from obtaining 2-cyclopentylmethyl-2-[3,5-bis(trifluoromethyl)phenyl]-N-1,3-thiazol-2-ylacetamide (93 mg, 82%).

LC-MS (m/z): 455 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,51-of 1.64 (m, 4H), 1,69-of 1.78 (m, 2H), 1,92 is 2.00 (m, 2H), 3,14-3,22 (p, 1H), 4,91 (s, 1H), of 7.48 (t, 1H), to 7.61 (t, 1H), 7,72 (d, 1H), 7,80 (user., 1H), 8,8,10 (s, 1H), 11,12 (user., 1H).

Example 88

2-Cyclopentylmethyl-2-[3,5-bis(trifluoromethyl)phenyl]-N-pyridin-2-ylacetamide

A solution of 2-cyclopentyl-2-[3,5-bis(trifluoromethyl)phenyl]acetic acid (93 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-[3,5-bis(trifluoromethyl)phenyl]-N-pyridin-2-ylacetamide (90 mg, 80%).

LC-MS (m/z): 449 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,52 is 1.60 (m, 4H), 1,4-of 1.78 (m, 2H), 1,92 of 1.99 (m, 2H), 3,26-of 3.32 (m, 1H), 4.92 in (s, 1H), of 7.48 (t, 1H), to 7.61 (t, 1H), 7,69 (s, 1H), of 7.75 (d, 1H), 8,10 (s, 1H), 8,12 (d, 1H), 8,21-of 8.33 (DD, 1H), 11,12 (user., 1H).

Example 89

2-Cyclopentylmethyl-2-(3-chloro-4-methoxy)phenyl-N-1,3-thiazol-2-ylacetamide

2 Cyclopentyl-2-(3-chloro-4-methoxyphenyl)acetic acid (421 mg, 70%) is obtained from the methyl ester of 2-bromo-2-(3-chloro-4-methoxyphenyl)acetic acid (588 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method C. a Solution of this acid (75 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(3-chloro-4-methoxyphenyl)-N-1,3-thiazol-2-ylacetamide (77 mg, 80%).

LC-MS (m/z): 383 (M + H)+

1H NMR (400 MHz, CDCl3): δ to 1.60 (m, 4H), of 1.75 (m, 2H), 2,03 (m, 2H), 3,12 (m, 1H), 3,90 (s, 3H), 4,70 (s, 1H), 6.89 in (m, 1H), 7,00 (DD, 1H), 7,29 (m, 1H), 7,31 (DD, 1H), 7,45 (DD, 1H), 9,96 (user., 1H).

Example 90

2-Cyclopentylmethyl-2-(3,4-dichlorophenyl)-N-thiazol-2-ylacetamide

2-(Cyclopentyl)-2-(3,4-dichlorophenyl)acetic acid (458 mg, 75%) is obtained from the methyl ester of 2-bromo-2-(3,4-dichlorophenyl)acetic acid (594 mg, 2 mmol) and Cyclopentanol (245 mg, 2.4 mmol) according to General method C. a Solution of this acid (76 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) in matched with the accordance with the General method E to obtain 2-cyclopentylmethyl-2-(3,4-dichlorophenyl)-N-thiazol-2-ylacetamide (87 mg, 90%).

LC-MS (m/z): 387 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,48-of 1.62 (m, 4H), 1,71 and 1.80 (m, 2H), 1,96-2,05 (m, 2H), is 3.08-3.15 in (m, 1H), 4,71 (s, 1H), 7.03 is? 7.04 baby mortality (DD, 1H), 7.24 to 7,26 (m, 1H), 7,41 (d, 1H), 7,47 (d, 1H), 7,51 (d, 1H) of 10.25 (user.,1H).

Example 91

N-(5-Bromo-1,3-thiazol-2-yl)-2-(cyclopentyl)-2-(3,4-dichlorophenyl)ndimethylacetamide

A solution of 2-(cyclopentyl)-2-(3,4-dichlorophenyl)acetic acid (76 mg, 0.25 mmol) in THF subjected to interaction with 2-amino-5-bromothiazole (107 mg, 0.6 mmol) according to General method E to obtain N-(5-bromo-1,3-thiazol-2-yl)-2-(cyclopentyl)-2-(3,4-dichlorophenyl)ndimethylacetamide (93 mg, 80%).

LC-MS (m/z): 467 (M + 2H)+

Example 92

2-Cyclopentylmethyl-2-(3,4-dichlorophenyl)-N-[(4-methoxycarbonylmethyl)-1,3-thiazol-2-yl]ndimethylacetamide

A solution of 2-cyclopentyl-2-(3,4-dichlorophenyl)acetic acid (76 mg, 0.25 mmol) in THF subjected to interaction with methyl-2-amino-4-thiazoleacetate (103 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(3,4-dichlorophenyl)-N-[(4-methoxycarbonylmethyl)-1,3-thiazol-2-yl]ndimethylacetamide (86 mg, 75%).

LC-MS (m/z): 459 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 1.56 (m, 4H), of 1.75 (m, 2H), 2,03 (m, 2H), 3,11 (m, 1H), and 3.72 (d, 5H), 4,70 (s, 1H), 6,84 (s, 1H), 7,24 (DD, 1H), 7,42 (d, 1H), 7,51 (d, 1H), 10,16 (user., 1H).

Example 93

2-Cyclopentylmethyl-2-(3,4-dichlorophenyl)-N-[(4-methylaminomethyl)-1,-thiazol-2-yl]ndimethylacetamide

2-Cyclopentylmethyl-2-(3,4-dichlorophenyl)-N-[(4-methoxycarbonylmethyl)-1,3-thiazol-2-yl]ndimethylacetamide (114 mg, 0.25 mmol) is heated for 2 H. a solution of methylamine in THF (5 ml) for 6 hours. This mixture is concentrated and the residue purified column chromatography (hexane-ethyl acetate, 1:1) to obtain 2-cyclopentylmethyl-2-(3,4-dichlorophenyl)-N-[(4-methylaminomethyl)-1,3-thiazol-2-yl]ndimethylacetamide (108, 95%).

LC-MS (m/z): 459 (M + H)+

1H NMR (400 MHz, CDCl3): δ was 1.58 (m, 4H), to 1.76 (m, 2H), 2,03 (m, 2H), 2,81 (d, 3H), of 3.12 (m, 1H), 3,63 (s, 2H), 4,74 (s, 1H), 6,79 (s, 1H), 7,27 (DD, 1H), 7,43 (d, 1H), 7,53 (d, 1H), 10,10 (user., 1H).

Example 94

2-(Cyclopentyl)-2-(3,4-dichlorophenyl)-N-1,3,4-thiadiazole-2-ylacetamide

A solution of 2-(cyclopentyl)-2-(3,4-dichlorophenyl)acetic acid (76 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiadiazole (120 mg, 1.2 mmol) according to General method E to obtain 2-(cyclopentyl)-2-(3,4-dichlorophenyl)-N-1,3,4-thiadiazole-2-ylacetamide (79 mg, 82%).

LC-MS (m/z): 389 (M + 2H)+

Example 95

2-Cyclopentylmethyl-2-(3,4-dichlorophenyl)-N-pyridin-2-ylacetamide

A solution of 2-(cyclopentyl)-2-(3,4-dichlorophenyl)acetic acid (76 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (56 mg, 0.6 mmol) according to General method E recip is of 2-cyclopentylmethyl-2-(3,4-dichlorophenyl)-N-pyridin-2-ylacetamide (84 mg, 88%).

LC-MS (m/z): 381 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,52-to 1.61 (m, 4H), 1,67-of 1.81 (m, 2H), 1,89 is 2.10 (m, 2H), is 3.08-3,17 (m, 1H), 4.72 in (s, 1H), 7.03 is-was 7.08 (m, 3H), 7,41-7,42 (m, 1H), 7,73 to 7.75 (m, 1H), 8,19 (d, 1H), 8,31-8,32 (m, 1H), 9,66 (user., 1H).

Example 96

2-Cyclopentylmethyl-2-(3,4-dichlorophenyl)-N-pyrimidine-2-ylacetamide

A solution of 2-(cyclopentyl)-2-(3,4-dichlorophenyl)acetic acid (76 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyrimidine (57 mg, 0.6 mmol) according to General method E to obtain 2-cyclopentylmethyl-2-(3,4-dichlorophenyl)-N-pyrimidine-2-ylacetamide (81 mg, 85%).

LC-MS (m/z): 382 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,53-of 1.57 (m, 4 H), 1.70 to about 1.75 (m, 2H), 1,99-2,04 (m, 2 H), 3,11-3,18 (m, 1H), 4.72 in (s, 1H), 7,07-to 7.09 (t, 1H), 7,39, (s, 1H), of 7.48 (t, 1H), to 7.64 (s, 1H), 8,11-8,13 (DD, 1H), 8,65 (d, 1H), 9,82 (user., 1H).

Example 97

2-Cyclohexylcarbonyl-2-(3,4-dichlorophenyl)-N-1,3-thiazol-2-ylacetamide

2 Cyclohexylthio-2-(3,4-dichlorophenyl)acetic acid (458 mg, 75%) is obtained from the methyl ester of 2-bromo-2-(3,4-dichlorophenyl)acetic acid (594 mg, 2 mmol) and cyclohexanol (278 mg, 2.4 mmol) according to General method C. a Solution of this acid (76 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-cyclohexylcarbonyl-2-(3,4-dichlorophenyl)-N-1,3-thiazol-2-ilaclama is a (72 mg, 72%).

LC-MS (m/z): 401 (M + H)+

1H NMR (400 MHz, CDCl3): δ 0,84-0.87 (m, 1H), 1,09-of 1.41 (m, 4H), 1,48-2,02 (m, 4H), 2,65-2,78 (m, 1H), 4,87 (s, 1H), 6,98? 7.04 baby mortality (DD, 1H), 7,33-to 7.35 (DD, 1H), 7,41-of 7.48 (m, 2H), 7,62-to 7.67(DD,1H), 11,64 (user.,1H).

Example 98

2-Cyclohexylcarbonyl-2-(3,4-dichlorophenyl)-N-pyridin-2-ylacetamide

A solution of 2-cyclohexylthio-2-(3,4-dichlorophenyl)acetic acid (76 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-cyclohexylcarbonyl-2-(3,4-dichlorophenyl)-N-pyridin-2-ylacetamide (TTP-00176116) (69 mg, 70%).

LC-MS (m/z): 395 (M + H)+

1H NMR (400 MHz, CDCl3): δ 0,81-0,89 (m, 1H), 1,24 to 1.47 (m, 4H), 1.60-to 2,11 (m, 4H), 2,74-of 2.81 (m, 1H), 4,66 (s, 1H), 7,06-7,10 (m, 1H), 7,26-7,33 (m, 1H), 7,37-7,41 (DD, 2H), 7,53 (d, 1H), 7,69-7,74 (m, 1H), 8,17 (d, 1H), 8,31-8,32 (DD, 1H), 9,34 (user., 1H).

Example 99

2-Isopropylphenyl-2-(3,4-dichlorophenyl)-N-1,3-thiazol-2-ylacetamide

2 Isopropylthio-2-(3,4-dichlorophenyl)acetic acid (458 mg, 75%) is obtained from the methyl ester of 2-bromo-2-(3,4-dichlorophenyl)acetic acid (594 mg, 2 mmol) and isopropanol (183 mg, 2.4 mmol) according to General method C. a Solution of this acid (76 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-isopropylphenyl-2-(3,4-dichlorophenyl)-N-1,3-thiazol-2-racetam is Yes (TTP-00176084) (67 mg, 74%).

LC-MS (m/z): 361 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,24-of 1.27 (DD, 6H), 2.91 in-3,10 (m, 1H), 4,77 (s, 1H), 7,01-7,03 (m, 1H), 7,25-7,29 (m, 1H), 7,37-7,41 (m, 1H), 7,51-of 7.55 (m, 1H), 7,97-to 7.99 (DD, 1H), 11,24 (user.,1H).

Example 100

2-Isopropylphenyl-2-(3,4-dichlorophenyl)-N-pyridin-2-ylacetamide

A solution of 2-isopropylthio-2-(3,4-dichlorophenyl)acetic acid (76 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-isopropylphenyl-2-(3,4-dichlorophenyl)-N-pyridin-2-ylacetamide (64 mg, 72%).

LC-MS (m/z): 355 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 1.30 and 1.33 (DD, 6H), 2,97 was 3.05 (m, 1H), 4,66 (s, 1H), 7,06-to 7.09 (m, 1H), 7,26-7,29 (m, 1H), 7,40 (d, 1H), 7,53 (d, 1H), 7.68 per-7,73 (m, 1H), 8,17 (d, 1H), 8,29-8,31 (m, 1H), 9,31 (user., 1H).

Example 101

2-Arylsulfonyl-2-(3,4-dichlorophenyl)-N-1,3-thiazol-2-ylacetamide

2 Allylthio-2-(3,4-dichlorophenyl)acetic acid (458 mg, 75%) is obtained from the methyl ester of 2-bromo-2-(3,4-dichlorophenyl)acetic acid (594 mg, 2 mmol) and arylthiol (178 mg, 2.4 mmol) according to General method C. a Solution of this acid (76 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-arylsulfonyl-2-(3,4-dichlorophenyl)-N-1,3-thiazol-2-ylacetamide (72 mg, 80%).

LC-MS (m/z): 359 (M + H)+

1H NMR (400 MHz, CDCl 3): δ 3,09 is 3.25 (m, 2H), 2.91 in-3,10 (m, 1H), 4,66 (s, 1H), of 5.05-5,16 (m, 2H), 5,73-of 5.82 (m, 1H), 7,05-7,07 (m, 1H), 7.24 to 7,27 (DD, 1H), 7,38-7,44 (DD, 1H), 7,52 (d, 1H), 7,94-of 7.97 (DD, 1H), 11,78 (user., 1H).

Example 102

2-(3,4-Dichlorophenyl)-2-(isobutyric)-N-pyridin-2-ylacetamide

2-(2-Methylpropane)-2-(3,4-dichlorophenyl)acetic acid (457 mg, 78%) is obtained from the methyl ester of 2-bromo-2-(3,4-dichlorophenyl)acetic acid (594 mg, 2 mmol) and 2-methylpropanol (216 mg, 2.4 mmol) according to General method C. a Solution of this acid (73 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (56 mg, 0.6 mmol) according to General method E to obtain 2-(3,4-dichlorophenyl)-2-(isobutyric)-N-pyridin-2-ylacetamide (69 mg, 88%).

LC-MS (m/z): 369 (M + H)+

1H NMR (400 MHz, CDCl3): δ 0,96-1,01 (DD, 7H), 1,82-1,89 (m, 1H), 2.49 USD is 2.51 (m, 2H), 5,3 (s, 1H), 7,08-to 7.09 (m, 1H), 7,26-7,29 (m, 1H), 7,41 (d, 1H), 7,54 (d, 1H), 7,69-7,73 (m, 1H), 8,17 (d, 1H), 8.30 to-8,32 (m,1H) 9,19 (user., 1H).

Example 103

2-(3,4-Dichlorophenyl)-2-(isobutyric)-N-1,3-thiazol-2-ylacetamide

A solution of 2-(2-methylpropane)-2-(3,4-dichlorophenyl)acetic acid (73 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(3,4-dichlorophenyl)-2-(isobutyric)-N-1,3-thiazol-2-ylacetamide (72 mg, 90%).

LC-MS (m/z): 375 (M + H)+

1H NMR (400 MHz, CDCl3): δ were 0.94 (d, 6H), to 1.76 (m, 1H), 2,4 (m, 2H), 4,67 (s, 1H), 7,06 (d, 1H), 7,30 (d, 1H), 7,41 (d, 1H), of 7.48 (d, 1H), 7,55 (s, 1H), 11,54 (user., 1H).

Example 104

2-(3,4-Dichlorophenyl)-2-[(2-furylmethyl)thio]-N-pyridin-2-ylacetamide

2-(2-Furylmethyl)-2-(3,4-dichlorophenyl)acetic acid (482 mg, 76%) obtained from the methyl ester of 2-bromo-2-(3,4-dichlorophenyl)acetic acid (594 mg, 2 mmol) and 2-furylmethyl (274 mg, 2.4 mmol) according to General method C. a Solution of this acid (79 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (56 mg, 0.6 mmol) according to General method E to obtain 2-(3,4-dichlorophenyl)-2-[(2-furylmethyl)thio]-N-pyridin-2-ylacetamide (80 mg, 82%).

LC-MS (m/z): 393 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 3.78 (DD, 2H), 4,56 (s, 1H), 6,24 (DD, 2H), 7,07 (t, 1H), 7,24 (d, 1H), 7,30 (d, 1H), 7,39 (d, 1H), 7,49 (s, 1H), of 7.70 (DD, 1H), 8,15 (d, 1H), compared to 8.26 (DD, 1H), 9,14 (user., 1H).

Example 105

2-(3,4-Dichlorophenyl)-2-[(2-furylmethyl)thio]-N-1,3-thiazol-2-ylacetamide

A solution of 2-(2-furylmethyl)-2-(3,4-dichlorophenyl)acetic acid (79 mg, 0.25 mmol) in THF subjected to interaction with 2-aminothiazole (60 mg, 0.6 mmol) according to General method E to obtain 2-(3,4-dichlorophenyl)-2-[(2-furylmethyl)thio]-N-1,3-thiazol-2-ylacetamide (85 mg, 85%).

LC-MS (m/z): 399 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 3.78 (DD, 2H), 4,67 (s, 1H), 6,14 (s, 1H), 6,23 (s, 1H), 7,02 (d, 1H), 7,24 (m, 2H), 7,37 (m, 2H), 7,49 (s, 1H), 11,41 (ears is., 1H).

Example 106

2-(4-Methylphenylthio)-2-phenyl)-N-pyridin-2-ylacetamide

2-(4-Methylphenylthio)-2-phenylacetic acid (310 mg, 60%) is obtained from the methyl ester of α-bromoferrocene acid (458 mg, 2 mmol) and 4-methylthiophenol (298 mg, 2.4 mmol) according to General method C. a Solution of this acid (65 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (57 mg, 0.6 mmol) according to General method E to obtain 2-(4-methylphenylthio)-2-phenyl-N-pyridin-2-ylacetamide (61 mg, 72%).

LC-MS (m/z): 335 (M + H)+

Example 107

2-(3,4-Dichlorophenyl)-2-[(2-furylmethyl)thio]-N-pyridin-2-ylacetamide

2-(4-Chlorophenylthio)-2-(3,4-dichlorophenyl)acetic acid (542 mg, 78%) is obtained from the methyl ester of 2-bromo-2-(3,4-dichlorophenyl)acetic acid (594 mg, 2 mmol), 4-chlorbenzoyl (347 mg, 2.4 mmol) according to General method C. a Solution of this acid (87 g, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (56 mg, 0.6 mmol) according to General method E to obtain 2-(3,4-dichlorophenyl)-2-[(2-furylmethyl)thio]-N-pyridin-2-ylacetamide (85 mg, 80%).

LC-MS (m/z): 423 (M + H)+

1H NMR (400 MHz, CDCl3): δ 4,88 (s, 1H), 7,06-7,10 (m, 1H), 7.24 to 7,27 (m, 3H), 7,31-7,34 (m, 2H), 7,42 (d, 1H), 7,51 (d, 1H), 7,69-7,73 (m, 1H), 8,13 (d, 1H), 8,27-8,29 (DD, 1H), 8,98 (user., 1H).

Example 108

2-[(4-Forfinal)thio]-N-pyridin-2-yl-2-4-(trifluoromethyl)phenyl]ndimethylacetamide

2-(4-Forfinally)-2-(4-triptoreline)acetic acid (760 mg, 92%) is obtained from the methyl ester of 2-hydroxy-2-(4-triptoreline)acetic acid (860 mg, 2.5 mmol) and 4-fermentative (308 mg, 2.4 mmol) according to General method D. the Solution of this acid (165 mg, 0.50 mmol) in THF subjected to interaction with 2-aminopyridine (56 mg, 0.6 mmol) according to General method E to obtain 2-[(4-Forfinal)thio]-N-pyridin-2-yl-2-[4-(trifluoromethyl)phenyl]ndimethylacetamide (0.12 g, 59%) as a solid.

LC-MS (m/z): 408 (M + 2H)+

Example 109

2-[(4-Forfinal)thio]-N-1,3-thiazol-2-yl-2-[4-(trifluoromethyl)phenyl]ndimethylacetamide

A solution of 2-(4-forfinally)-2-(4-triptoreline)acetic acid (165 mg, 0.50 mmol) in THF subjected to interaction with 2-aminothiazole (500 mg, 0.5 mmol) according to General method E to obtain 2-[(4-forfinal)thio]-N-1,3-thiazol-2-yl-2-[4-(trifluoromethyl)phenyl]ndimethylacetamide (93 mg, 45%) as a solid.

LC-MS (m/z): 414 (M + 2H)+

Example 110

2-[(4-Were)thio]-N-1,3-thiazol-2-yl-2-[4-(trifluoromethyl)phenyl]ndimethylacetamide

A solution of 2-(4-methylphenylthio)-2-(4-triptoreline)acetic acid (160 mg, 0.50 mmol) in THF subjected to interaction with 2-aminothiazole (0.50 g, 0.50 mmol) according to General method E to obtain the 2-[(4-were)thio]-N-1,3-thiazol-2-yl-2-[4-(trifluoromethyl)phenyl]ndimethylacetamide (94 mg, 45%).

LC-MS (m/z): 410 (M + 2H)+

Example 111

2-(4-Forfinal)-2-[(4-forfinal)thio]-N-pyridin-2-ylacetamide

2-(4-Forfinally)-2-(4-forfinal)acetic acid (400 mg, 75%) is obtained from the methyl ester of 2-hydroxy-2-(4-forfinal)acetic acid (368 mg, 2 mmol) and 4-fermentative (307 mg, 2.4 mmol) according to General method D. the Solution of this acid (66 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (56 mg, 0.6 mmol) according to General method E to obtain 2-(4-forfinal)-2-[(4-forfinal)thio]-N-pyridin-2-ylacetamide (73 mg, 82%).

LC-MS (m/z): 357 (M + H)+

1H NMR (400 MHz, CDCl3): δ 4,91 (s, 1H), 6,95-was 7.08 (m, 5H), 7,37-7,42 (m, 4H), of 7.70 (m, 1H), 8,15 (d, 1H), 8,27 (d, 1H), 8,94 (user., 1H).

Example 112

2-(4-Bromophenyl)-2-[(4-forfinal)thio]-N-pyridin-2-ylacetamide

2-(4-Forfinally)-2-(4-bromophenyl)acetic acid (593 mg, 87%) obtained from the methyl ester of 2-hydroxy-2-(4-bromophenyl)acetic acid (490 mg, 2 mmol) and 4-fermentative (307 mg, 2.4 mmol) according to General method D. the Solution of this acid (85 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (56 mg, 0.6 mmol) according to General method E to obtain 2-(4-bromophenyl)-2-[(4-forfinal)thio]-N-pyridin-2-ylacetamide (88 mg, 85%).

LC-MS (m/z): 419 (M + 2H)+

Example 113

2-(4-Bromophenyl)-2-[(4-IU is ylphenyl)thio]-N-pyridin-2-ylacetamide

2-(4-Methylphenylthio)-2-(4-bromophenyl)acetic acid (559 mg, 83%) is obtained from the methyl ester of 2-hydroxy-2-(4-bromophenyl)acetic acid (490 mg, 2 mmol) and 4-methylbenzamide (298 mg, 2.4 mmol) according to General method D. the Solution of this acid (84 mg, 0.25 mmol) in THF subjected to interaction with 2-aminopyridine (56 mg, 0.6 mmol) according to General method E to obtain 2-(4-bromophenyl)-2-[(4-were)thio]-N-pyridin-2-ylacetamide (85 mg, 82%).

LC-MS (m/z): 414 (M + H)+

1H NMR (400 MHz, CDCl3): δ to 2.29 (s, 3H), of 4.90 (s, 1H), 7,05 (DD, 1H), was 7.08 (d, 2H), 7,31 (m, 4H), 7,46 (d, 2H), 7,68 (t, 1H), 8,14 (d, 1H), 8,28 (d, 1H), 9,11 (user., 1H).

Example 114

N-[1-(4-Chlorophenyl)cyclopentyl]-N'-1,3-thiazol-2-rocephine

In accordance with the General method H 1-(4-chlorophenyl)-1-cyclopentanecarbonyl acid (112 mg, 0.5 mmol) is transformed into the corresponding acid chloride, which in turn gives 1-(4-chlorophenyl)-1-cyclopentadiene. This isocyanate is subjected to interaction with 2-aminothiazole (100 mg, 1.0 mmol) to give N-[1-(4-chlorophenyl)cyclopentyl]-N'-1,3-thiazol-2-rocephine (115 mg, 72%).

LC-MS (m/z): 322 (M + H)+

1H NMR (400 MHz, CDCl3): δ to 1.83 (m, 4H), 2,04 (m, 2H), 2,30 (m, 2H), 6,78 (d, 1H), 7,25 was 7.36 (m, 5H), 10,00 (user., 2H).

Example 115

N-[1-(4-Chlorophenyl)cyclopentyl]-N'-pyridine-2-rocephine

In accordance with the General method H 1-(4-chlorophenyl)-1-cyclopentanecarbonyl acid (112 mg, 0.5 mmol) is transformed into the corresponding acid chloride, which in turn gives 1-(4-chlorophenyl)-1-cyclopentadiene. This isocyanate is subjected to interaction with 2-aminopyridine (94 mg, 1.0 mmol) to give N-[1-(4-chlorophenyl)cyclopentyl]-N'-pyridine-2-rocephine (108 mg, 68%).

LC-MS (m/z): 316 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,80-of 1.92 (m, 4H), 2,02-of 2.09 (m, 2H), a 2.36-2.40 a (m, 2H), 6,32 (d, 1H), 6,83 (DD, 1H), 7,25 (m, 2H), 7,41 (m, 2H), 7,49 (m, 1H), 8,12 (d, 1H), 8,87 (user., 1H), 9,94 (user., 1H).

Example 116

N-[1-(4-Chlorophenyl)cyclohexyl]-N'-1,3-thiazol-2-rocephine

In accordance with the General method H 1-(4-chlorophenyl)-1-cyclohexanecarbonyl acid (119 mg, 0.5 mmol) is transformed into the corresponding acid chloride, which in turn gives 1-(4-chlorophenyl)-1-cyclohexylethane. This isocyanate is subjected to interaction with 2-aminothiazole (100 mg, 1.0 mmol) to give N-[1-(4-chlorophenyl)cyclohexyl]-N'-1,3-thiazol-2-rocephine (104 mg, 62%).

LC-MS (m/z): 336 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1.28 (in m, 1H), of 1.57 to 1.76 (m, 7H), and 2.26 (d, 2H), 6,80 (d, 1H), 7.24 to 7,34 (m, 5H), 10,00 (user., 2H).

Example 117

N-[1-(4-Chlorophenyl)cyclohexyl]-N'-pyridine-2-rocephine

In accordance with the General method H 1-(4-chlorophenyl)-1-cyclohexanecarbonyl the new acid (119 mg, 0.5 mmol) is transformed into the corresponding acid chloride, which in turn gives 1-(4-chlorophenyl)-1-cyclohexylethane. This isocyanate is subjected to interaction with 2-aminopyridine (94 mg, 1.0 mmol) to give N-[1-(4-chlorophenyl)cyclohexyl]-N'-pyridine-2-rocephine (106 mg, 65%).

LC-MS (m/z): 330 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 1.27 (m, 1H), 1,67 and 1.80 (m, 7H), of 2.38 (m, 2H), 6.30-in (user., 1H), 6.87 in (m, 1H), 7,25-7,41 (m, 4H), 7,51 (d, 1H), 8,17 (s, 1H), 8,40 (user., 1H), to 10.09 (user., 1H).

Example 118

1-(3-Benzyloxyphenyl)-1-isobutyl-3-(thiazol-2-yl)urea

1-(3-Benzyloxyphenyl)-1-isobutyl-3-(thiazol-2-yl)urea (27 mg, 70.9 per cent) is obtained from (3-benzyloxyphenyl)-1-isobutylamine (25 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 382 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1.00 m (d, 6H), of 2.21 (d, 2H), 2,36 (s, 2H), to 3.02 (m, 1H), at 6.84 (d, 1H), to 7.09 (m, 2H), 7,16 (t, 1H), 7,24 (s, 1H), 7,25 (m, 4H), EUR 7.57 (d, 1H), of 7.96 (d, 1H), 8,23 (user., 1H).

Example 119

1-(3,4-Dichlorophenyl)-1-isobutyl-3-(thiazol-2-yl)urea

1-(3,4-Dichlorophenyl)-1-isobutyl-3-(thiazol-2-yl)urea (24 mg, 70%) is obtained from (3,4-dichlorophenyl)-isobutylamine (20 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 344 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.97 (d, 6H), of 1.85 (m, 1H), 3,59 (d, 2H), 7,16 (s, 1H), 7,28 (d, 2H), 7,42 (DD, 1H), 7,56 (d, 1H), 8,80 (user., 1H).

Example 120

1-(4-Forfinal)-1-n-pentyl-3-(thiazol-2-yl)urea

1-(4-Forfinal)-1-n-pentyl-3-(thiazol-2-yl)urea (24 mg, 74,9%) is obtained from (4-forfinal)-n-pentylamine (18 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 308 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 0.87 (t, 3H), of 1.30 (m, 4H), 1,58 (m, 2H), 3,71 (t, 2H), 6.87 in (d, 1H), 7,24 (m, 4H), 7,29 (d, 1H), 7,60 (user., 1H).

Example 121

1-(3,4-Methylenedioxybenzyl)-1-(3,4-dichlorobenzyl)-3-(thiazol-2-yl)urea

1-(3,4-Methylenedioxybenzyl)-1-(3,4-dichlorobenzyl)-3-(thiazol-2-yl)urea (29 mg, 66.5 per cent) is obtained from N-(3,4-methylenedioxybenzyl)-N-(3,4-dichlorobenzyl)amine (30 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 436 (M + H)+

1H NMR (400 MHz, CDCl3): δ 4,43 (s, 2H), 4.53-in (s, 2H), 5,96 (s, 2H), 6,76 (d, 1H), 6,84 (s, 1H), 7,19 (s, 1H), 7,31 (d, 2H), 7,40 (d, 2H), scored 8.38 (d, 1H), 9,73 (user., 1H).

Example 122

1-(4-Forfinal)-1-cyclopentyl-3-(thiazol-2-yl)urea

1-(4-Forfinal)-1-cyclopentyl-3-(thiazol-2-yl)urea (19 mg, 62.2 per cent) derived from 4-forpricecontrol (18 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 306 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,25 (m, 4H), of 1.55 (m, 2H), 1,96 (m, 2H), 4,85 (p, 1H), 6,85 (d, 1H), 7,19 (m, 2H), 7,25 (m, 2H), to 7.67 (user., 1H), 8,18 (d, 1H).

Example 123

1-(3,4-Dichlorobenzyl)-1-[ethyl-(2-thiophene)]-3-(thiazol-2-yl)urea

1-(3,4-Dichlorobenzyl)-1-[2-(2-thienyl)ethyl]-3-(thiazol-2-yl)urea (33 mg, 80.3 per cent) is obtained from 3,4-dichlorobenzyl-[2-(2-thienyl)ethyl]amine (28 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 412 (M + H)+

1H NMR (400 MHz, CDCl3): δ 3,10 (t, 2H), 3,62 (t, 2H), of 4.45 (s, 2H), 6,84 (DD, 2H), 6,94 (m, 1H), 7,15 (t, 1H), 7,29 (d, 1H), 7,38 (s, 1H), 7,40 (m, 1H), 8,02 (d, 1H), 9,74 (user., 1H).

Example 124

1-(3,4-Dichlorobenzyl)-1-isobutyl-3-(thiazol-2-yl)urea

1-(3,4-Dichlorobenzyl)-1-isobutyl-3-(thiazol-2-yl)urea (26 mg, 72.2 per cent) is obtained from 3,4-dichlorobenzonitrile (23 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 358 (M + H)+

1H NMR (400 MHz, CDCl3): δ to 0.92 (d, 6H), 2,03 (m, 1H), 3,11 (d, 2H), 4,59 (s, 2H), to 6.88 (d, 1H), was 7.08 (DD, 1H), 7,32 (m, 2H), 7,41 (d, 1H), 8,66 (user., 1H).

Example 125

1-(4-Forfinal)-1-cyclohexylmethyl-3-(thiazol-2-yl)urea

1-(4-Forfinal)-1-cyclohexylmethyl-3-(thiazol-2-yl)urea (20 mg, 60%) is obtained from cyclohexylmethyl-4-ftoheia the ina (21 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 334 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1.06 a (m, 2H), 1,17 (m, 4H), of 1.52 (m, 1H), 1,71 (m, 4H)and 3.59 (d, 2H), 6,86 (d, 1H), 7,18 (d, 1H), 7.24 to 7,31 (m, 4H), to 7.64 (user., 1H).

Example 126

1-(3-Chlorophenacyl)-1-isobutyl-3-(thiazol-2-yl)urea

1-(3-Chlorophenacyl)-1-isobutyl-3-(thiazol-2-yl)urea (22 mg, 65,3%) is obtained from (3-chlorophenolate)isobutylamine (20 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 338 (M + H)+

1H NMR (400 MHz, CDCl3): δ to 0.92 (d, 6H), 1,99 (m, 1H), 2,90 (t, 2H), to 3.02 (d, 2H), of 3.56 (t, 2H), 6.87 in (d, 1H), 7,11 (s, 1H), 7,21 (d, 2H), 7.23 percent (s, 1H), 7,34 (d, 1H), 8,31 (user., 1H).

Example 127

1-(2-Ethoxybenzyl)-1-isobutyl-3-(thiazol-2-yl)urea

1-(2-Ethoxybenzyl)-1-isobutyl-3-(thiazol-2-yl)urea (23 mg, 69%) is obtained from (2-ethoxyphenyl)isobutylamine (20 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 320 (M + H)+

1H NMR (400 MHz, CDCl3): δ were 0.94 (d, 6H), to 1.48 (t, 3H), 2,11 (m, 1H), 3,28 (d, 2H), 4,17 (square, 2H), 4.53-in (s, 2H), 6,83 (d, 1H), 6,92 (DD, 1H), 7,20 (m, 1H), 7.23 percent (s, 1H), 7,31 (m, 2H), 8,76 (user., 1H).

Example 128

1-(4-Forfinal)-1-(4-tetrahydropyranyl)-3-(thiazol-2-yl)urea

1-(4-shall terphenyl)-1-(4-tetrahydropyranyl)-3-(thiazol-2-yl)urea (25 mg, 73,7%) is obtained from 4-forfinal-4-tetrahydrofurfurylamine (21 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 338 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,49 (m, 2H), 2,20 (d, 2H), 2,65 (d, 2H), 2,84 (2H), 4,51 (m, 1H), 6,86 (d, 1H), 7,19 (d, 2H), 7,21 (d, 1H), 7,25 (d, 2H), 7,46 (user., 1H).

Example 129

1-(3,4-Dichlorobenzyl)-1-cyclohexylmethyl-3-(thiazol-2-yl)urea

1-(3,4-Dichlorobenzyl)-1-cyclohexylmethyl-3-(thiazol-2-yl)urea (30 mg, 75,6%) is obtained from N-(3,4-dichlorobenzyl)-N-(cyclohexylmethyl)amine (26 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 398 (M + H)+

1H NMR (400 MHz, CDCl3): δ 0,92 (m, 2H), 1,16-of 1.23 (m, 3H), 1,69-of 1.74 (m, 6H), 3,11 (d, 2H), 4,58 (s, 2H), to 6.88 (d, 1H), 7,10 (d, 1H), 7,30 (m, 2H), 7,32 (s, 1H), 8,58 (user., 1H).

Example 130

1-(3-Methylpyridin)-1-(cyclohexylmethyl)-3-(thiazol-2-yl)urea

1-(3-Pyridinylmethyl)-1-cyclohexylmethyl-3-(thiazol-2-yl)urea (26 mg, 78,8%) is obtained from N-(3-pyridinylmethyl)-N-(cyclohexylmethyl)amine (20 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 331 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,25 (m, 4H), and 1.56 (m, 6H), of 1.74 (m, 1H), 2,17 (d, 2H), 4,63 (s, 2H), to 6.88 (d, 1H), 6,93 (d, 1H), 7,29 (s, 1H), 7,34 (d, 1H), 7,66 (d, 1H), 8,54 (d, 1H), 9,45 (user., H).

Example 131

1-(2-Ethoxybenzyl)-1-cyclohexylmethyl-3-(thiazol-2-yl)urea

1-(2-Ethoxybenzyl)-1-cyclohexylmethyl-3-(thiazol-2-yl)urea (29 mg, 77,7%) is obtained from N-(2-ethoxybenzyl)-N-(cyclohexylmethyl)amine (24 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 374 (M + H)+

1H NMR (400 MHz, CDCl3): δ 0,98 (m, 2H), 1,16-of 1.26 (m, 2H), 1,49 (t, 3H), of 1.64 (m, 1H), 1,68-of 1.84 (m, 6H), of 3.28 (d, 2H), 4,14 (square, 2H), 4.53-in (s, 2H), at 6.84 (d, 1H), 6,94 (DD, 1H), 7,21 (d, 1H), 7,24 (s, 1H), 7,29 (d, 2H), 8,82 (user., 1H).

Example 132

1-(3,4-Dichlorobenzyl)-1-cyclopentyl-3-(thiazol-2-yl)urea

1-(3,4-Dichlorobenzyl)-1-cyclopentyl-3-(thiazol-2-yl)urea (25 mg, 67,8%) is obtained from N-(3,4-dichlorobenzyl)-N-cyclopentylamine (24 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 370 (M + H)+

1H NMR (400 MHz, CDCl3): δ of 1.29 (m, 2H), 1,48-166 (m, 4H), of 1.92 (m, 2H), 3,12 (m, 1H), 4,48 (s, 2H), 6.87 in (d, 1H), 7,01 (DD, 1H), 7,31 (d, 1H), 7,38 (d, 1H), 7,42 (s, 1H), 8,76 (user., 1H).

Example 133

1-(2-Ethoxybenzyl)-1-cyclopentyl-3-(thiazol-2-yl)urea

1-(2-Ethoxybenzyl)-1-cyclopentyl-3-(thiazol-2-yl)urea (26 mg, 75,3%) is obtained from N-(2-ethoxybenzyl)-N-cyclopentylamine (21 mg, 0.1 mmol) according to General method X with obtaining the decree is spent in the connection header.

LC-MS (m/z): 346 (M + H)+

Example 134

1-(3,4-Dichlorobenzyl)-1-(4-tetrahydropyranyl)-3-(thiazol-2-yl)urea

1-(3,4-Dichlorobenzyl)-1-(4-tetrahydropyranyl)-3-(thiazol-2-yl)urea (31 mg, 80.5 per cent) is obtained from N-(3,4-dichlorobenzyl)-N-(4-tetrahydropyranyl)amine (25 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 386 (M + H)+

Example 135

1-(3,4-Dichlorobenzyl)-1-(4-tetrahydropyranyl)-3-(thiazol-2-yl)urea

1-(3,4-Dichlorobenzyl)-1-(4-tetrahydropyranyl)-3-(thiazol-2-yl)urea (33 mg, 82.3 per cent) is obtained from N-(3,4-dichlorobenzyl)-N-(4-tetrahydropyranyl)amine (28 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 402 (M + H)+

1H NMR (400 MHz, CDCl3): δ 1,25 (m, 2H), 1,74 (m, 4H), 2,04 (m, 2H), 4,25 (m, 1H), 4,51 (s, 2H), 6,85 (d, 1H), 7,07 (DD, 1H), 7,24 (s, 1H), 7,34 (d, 1H), 7,42 (d, 1H), 8,45 (user., 1H).

Example 136

1-(3-Chlorophenacyl)-1-(4-tetrahydropyranyl)-3-(thiazol-2-yl)urea

1-(3-Chlorophenacyl)-1-(4-tetrahydropyranyl)-3-(thiazol-2-yl)urea (25 mg, 65,3%) is obtained from N-(3-chlorophenacyl)-N-(4-tetrahydropyranyl)amine (26 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 382 (M + 1)+

1H NMR (400 MHz, CDCl3): δ 1,24 (m, 2H), 1,87 (t, 2H), 2,63 is 2.75 (m, 4H), 2,89 (t, 2H), 3,47 (t, 2H), 4,08 (m, 1H), 6.87 in (d, 1H), was 7.08 (DD, 1H), 7,18 (s, 1H), 7,20-of 7.23 (m, 2H), 7,30 (d, 1H), 9,14 (user., 1H).

Example 137

1-(4-Forfinal)-1-isobutyl-3-(thiazol-2-yl)urea

1-(4-Forfinal)-1-(isobutyl)-3-(thiazol-2-yl)urea (19 mg, 64.8 per cent) is obtained from N-(4-forfinal)-N-isobutylamine (16 mg, 0.1 mmol) according to General method X with obtaining specified in the connection header.

LC-MS (m/z): 294 (M + 1)+

1H NMR (400 MHz, CDCl3): δ of 0.96 (d, 6H), 2,82 (m, 1H), 4,13 (d, 2H), 6,83 (d, 1H), 6.89 in (DD, 1H), 7,17 (d, 1H), 7,22 (d, 1H), 7,24 (d, 1H), 7,29 (d, 1H), 8,28 (user., 1H).

Example 138

2-Cyclopentyl-1-(3,4-dichlorophenyl)ethylpyridine-2-ylcarbamate

To a solution of cyclopentyloxy acid (0.64 g, 5.00 mmol) in DHM (50 ml) is added N,O-dimethylhydroxylamine hydrochloride (0,80 g, 5.00 mmol) and triethylamine (0,696 mg, 5.00 mmol). The mixture is stirred at room temp. within 5 minutes To the solution was added DCC (of 1.03 g, 5.00 mmol). After 3 hours the solution was concentrated in vacuo, the residue suspended in a minimal amount of acetone and the insoluble white solid removed by filtration. The filtrate is evaporated to dryness. Chromatography on silica gel using a mixture of hexane-ethyl acetate (95:5 to 70:30) as eluent gave N,O-dimethylcyclopentene (0,72 g, 84,2%) as white is on solid.

LC-MS (m/z): 172 (M + 1)+

Magnesium metal (0,073 g, 3.00 mmol) in THF (25 ml) is treated with 1-bromo-3,4-dichlorobenzene (of 0.565 mg of 2.50 mmol). Add a catalytic amount of iodine (0.005 g) and the solution stirred at room temp. until the disappearance of the orange color. To the reaction mixture is added N,O-dimethylcyclopentene (0,43 g of 2.50 mmol). After 4 hours the mixture is subjected to water treatment. Concentration in vacuo gave 1-(3,4-dichlorophenyl)-2-cyclopentylphenol (0,613 g, 94.5%of the) in the form of oil.

1-(3,4-Dichlorophenyl)-2-cyclopentylphenol (0,259 g, 1.0 mmol) in DHM (10 ml) is treated with TEA (0.2 ml, 1.50 mmol) and phosgene (0.75 ml, 1.50 mmol in 20% toluene) at -20°C. After 3 h, the excess phosgene and triethylamine removed in vacuum to give the desired product 1-(3,4-dichlorophenyl)-2-cyclopentylpropionate (0.25 g, 77.6 per cent) in the form of oil.

To a solution of 1-(3,4-dichlorophenyl)-2-cyclopentylpropionate (0.16 g, 0.50 mmol) in DHM (5 ml) is added DIEA (0.17 ml, 1.0 mmol) and 2-aminopyridine (0,047 g, 0.5 mmol). The mixture is subjected to water treatment. Concentration in vacuo gives 2-cyclopentyl-1-(3,4-dichlorophenyl)ethylpyridine-2-ylcarbamate (0,153 g, 80.9 per cent) in the form of oil.

LC-MS (m/z): 379 (M + 1)+

1H NMR (400 MHz, CDCl3): δ 1,12-1,24 (m, 2H), 1,50-and 1.54 (m, 4H), 1,58 (m, 2H), 1,76 of-1.83 (m, 2H), by 2.55 (m, 1H), 5,62 (t, 1H), 6,95 (d, 1H), 7,20 (m, 1H), 7,38 (s, 1H), 7,41 (m, 2H), 7,45 (d, 1H), 8,00 (d, 1H), 9,46 (user., 1H).

Example 139

2-Cyclopentyl-1-(3,4-dichlorophenyl)the Teal-1,3-thiazol-2-ylcarbamate

1-(3,4-Dichlorophenyl)-2-cyclopentylacetic (0.16 g, 0.50 mmol) synthesized from 1-(3,4-dichlorophenyl)-2-cyclopentylamine in accordance with the General method T. Chloroformiate processed according to the General method U using 2-aminothiazole obtaining 2-cyclopentyl-1-(3,4-dichlorophenyl)ethyl-1,3-thiazol-2-ylcarbamate (0,175 g, 90,9%) as oil.

LC-MS (m/z): 385 (M + 1)+

1H NMR (400 MHz, CDCl3): δ 0,94-1,12 (m, 2H), 1,46 is 1.60 (m, 6H), 1.70 to to 1.82 (m, 2H), of 2.51 (m, 1H), with 4.64 (t, 1H), 7,12 (d, 1H), 7,42 (d, 1H), 7,94 (d, 1H), 8.30 to (d, 1H), 8,54 (DD, 1H), 9,62 (user., 1H).

Example 140

(2-[3-Cyclohexyl-2-(4-methoxyphenoxy)propionamido]- thiazol-4-yl)acetic acid

Stage A:

Obtain 2-bromo-3-cyclohexylpropionate

3-Chlorhexidine acid (14.9 g, or 95.7 mmol) was dissolved in CCl4(15 ml)was added SOCl2(27,6 ml, 382,9 mmol) and the reaction mixture was heated at 65°C for 30 minutes the Reaction mixture was cooled and successively added finely powdered N-bromosuccinimide (20.4 g, 114,8 mmol), then CCl2(75 ml) and, finally, 15 drops of 48% HBR. The reaction mixture was heated at 70°C for 10 min and then at 85°C until staining reaction mixture in a light yellow color (about 2 hours).

The reaction mixture was cooled to room temp. and RA is the solvent and excess thionyl chloride was removed under reduced pressure. The residue was filtered with suction and the solid was washed CCl4(Chml). The solvent was removed and the residue person to distil using speakers are small in size with obtaining oil.

1H-NMR (DMSO-d6): δ 4,43 (t, 1H); of 1.85 (m, 2H); of 1.65 (m, 5H); of 1.36 (m, 1H); to 1.14 (m, 3H); to 0.92 (m, 2H).

Stage B:

Obtaining the ethyl ester of [2-(2-bromo-3-cyclohexylpropionate)thiazol-4-yl]acetic acid

The above 2-bromo-3-cyclohexylpropionate (1.0 g, of 3.94 mmol) was dissolved in THF (15 ml), was added ethyl 2-amino-4-thiazoleacetate (1.5 g, 7.9 mmol) and left overnight. Was added THF (20 ml) and the reaction mixture was filtered. The filtrate was evaporated in vacuum to obtain yellow coloured oil.

1H-NMR (DMSO-d6): Selected data δ 12,59 (s, 1H); 7,07 (s, 1H); 4,71 (t, 3H); 4.09 to (t, 2H); 3,70 (s, 2H); of 1.18 (t, 3H).

HPLC-MS (method B): m/z = 405 (M+1); Rt= br4.61 minutes

Stage C:

Obtaining the ethyl ester of [2-(3-cyclohexyl-2-(4-methoxyphenoxy)propionamido)thiazol-4-yl]acetic acid

The above ethyl ester [2-(2-bromo-3-cyclohexylpropionate)thiazol-4-yl]acetic acid (0.3 g, of 0.74 mmol) was dissolved in DMF (10 ml), was added potassium carbonate (0.51 g, 3.72 mmol) and 4-methoxyphenol (0.28 g, of 2.23 mmol), left for about 15 min at 50°C, after which the reaction see what camping was left overnight at 75°C. The reaction mixture was poured into water (30 ml) and was extracted with EtOAc (50 ml), which in turn was washed with water (3x15 ml).

The solvent was removed in vacuum to obtain a brown oil, which was purified on Waters Deltprep 4000 (20→90% CH3CN 40 min, 20 ml/min, Rt=35 min Solvent A = water, solvent B = CH3CN, solvent C = mixture of 0.5% TFU/water).

HPLC-MS (method B): m/z = 447 (M+1); Rt= 4,92 minutes

Stage D:

The above ethyl ester [2-(3-cyclohexyl-2-(4-methoxyphenoxy)propionamido)thiazol-4-yl]acetic acid (0.05 g, 0.11 mmol) was dissolved in EtOH (5 ml), was added NaOH (1 ad, 1 ml) and the reaction mixture was left for 2 hours. The solvent is evaporated in vacuo, added water (5 ml) and the pH was brought to 1 N. HCl until acidic. The precipitate was filtered, washed with water and dried in a vacuum oven to obtain specified in the connection header.

1H-NMR (DMSO-d6): Selected data 12,51 (s, 1H); 12,41(s, 1H); 6,98 (s, 1H); at 6.84 (s, 4H); is 4.85 (m, 1H); to 3.67 (s, 3H); of 3.60 (s, 2H);

HPLC-MS (method B): m/z = 419 (M+1); Rt= 4,74 minutes

Example 141

1-Cyclopentylmethyl-1-(3,4-dichlorophenyl)-3-thiazol-2-rocephine

3,4-Dichloraniline (16,1 g, 100 mmol) dissolved in anhydrous THF (200 ml) in a round bottom vessel and then to the solution add cyclopentanecarboxaldehyde (9.81 g, 100 mmol) and stirred for 10 min at room temp. To the PE klonoa mixture of molecular sieve (4 g, 4 Å), and then add triacetoxyborohydride sodium (21.1 g, 200 mmol) and the mixture was stirred at 25°C for 12 hours. The reaction mixture was then filtered through silica gel, washed with saturated sodium bicarbonate (200 ml) and extracted with ethyl acetate (3x200 ml). The organic extracts are combined, dried (sodium sulfate), filtered and concentrated in vacuo to obtain N-cyclopentylmethyl-3,4-dichloraniline (23,8 g, 98.7 per cent) in the form of oil (LC-MS: m/z = 245 (M+1), Rt= 2,92 min).

N-Cyclopentylmethyl-3,4-dichloraniline (1,21 g, 5.00 mmol) dissolved in anhydrous DHM (25 ml) and to the solution is added triethylamine (1.4 ml, 10.0 mmol). Then at -20°C add triphosgene (2,97 g, 10.0 mmol) and the resulting mixture is stirred and allow it to warm to 25°C for 3 hours. To the reaction mixture warmed to room temp. 2-aminothiazol (0.50 g, 5.0 mmol) and stirred for 12 hours. After spending the initial substances that are monitored with TLC and LC-MS, the mixture washed with water (50 ml) and extracted with ethyl acetate (3x50 ml). The organic extracts are combined, dried (sodium sulfate), filtered and concentrated in vacuo to obtain 1-cyclopentylmethyl-1-(3,4-dichlorophenyl)-3-thiazol-2-rocephine (1.42 g, 76,5 %) as a pale yellow solid.

LC-MS: m/z = 371 (M+1)+

Example 142

1-Cyclopentyl-1-(3,4-dichlorophenyl)-3-thiazol-2-rocephine

To a stirred solution of 3,4-dichloraniline (of 1.62 g, 10 mmol), Cyclopentanone (1.80 ml, 20.0 mmol) and acetic acid (3.4 ml, 60,0 mmol) in 75 ml of 1,2-dichloroethane are added dropwise triacetoxyborohydride sodium (5.3g, 25,0 mmol). The resulting suspension is stirred for 48 hours at 25°C. the Reaction mixture is subjected to water treatment aqueous sodium bicarbonate and ethyl acetate. The combined organic extracts dried and concentrated in vacuo to obtain N-cyclopentyl-3,4-dichloraniline, which is used without further purification.

To a solution of N-cyclopentyl-3,4-dichloraniline (230 mg, 1.0 mmol) in THF add carbonyldiimidazole (178 mg, 1.1 mmol). The mixture is stirred for 1 hour at 25°C., then add 2-aminothiazole (100 mg, 1.0 mmol). The reaction mixture is then stirred for 16 h at 25°C. the Reaction mixture was concentrated and the residue purified by chromatography on silica gel to obtain 1-cyclopentyl-1-(3,4-dichlorophenyl)-3-thiazol-2-rocephine in the form of a solid (30 mg, yield 10%).

LC-MS: m/z = 379 (M+1)+

Example 143

1-(3,4-dichlorophenyl)-1-propyl-3-thiazol-2-rocephine

2-Aminothiazol (5.0 g, 50.0 mmol) was dissolved in DCE (20 ml), and then to the solution was added 2-(4-formyl-3-methoxyphenoxy)iterpolation on a solid basis (6,9 g, 10.0 mmol, loading: of 1.46 mmol/g) and stirred in t is within 30 minutes To the mixture of acetic acid (2.1 ml, 5.0 mmol), and then add triacetoxyborohydride sodium (10,56 g, 50.0 mmol). The mixture of resin is stirred at room temp. for 16 hours, then washed with three changes of DMF/methanol/DHM. Then the resin is dried in vacuum to obtain 2-aminothiazole on a solid basis.

Corresponding to the above starting material on the solid basis of 2-amino-thiazol-N-2-(3-methoxybenzyloxy)iterpolation (5.0 g, 7,3 mmol) is treated with triphosgene (5.30 g, 17.8 mmol) in the presence of DHM (25 ml) and diisopropylethylamine (7,63 ml that 43.8 mmol). After this product on a solid support is washed DHM. Then the resin is dried in vacuum to obtain the corresponding carbonylchloride N[2-(3-methoxybenzyloxy)iterpolation-2-aminothiazoline.

Appropriate carbonylchloride resin (1.0 g, of 1.46 mmol) is treated with 3,4-dichloroaniline (1,17 g, 7,30 mmol) in the presence of DCE (25 ml) and diisopropylethylamine (2,24 ml, 14.6 mmol). The product on a solid support is then washed with three changes of DMF/methanol/DHM, dried in vacuum, obtaining the appropriate urea N - [2-(3-methoxybenzyloxy)iterpolation-2-aminothiazol-N'-3,4-dichlorophenylphosphine.

To the corresponding urea (N[2-(3-methoxybenzyloxy)iterpolation-2-aminothiazol-3,4-dichlorophenylamino) (0,117 g, 0.73 mmol)is added tert-piperonyl potassium (3,65 ml, 3.65 mmol, 1 M solution in THF). With the ect resin is stirred for 1 hour at room temp., then to the mixture of resin was added 1-bromopropane (of 0.332 ml, 3.65 mmol) and stirred for 16 hours. The product on a solid support is then washed with three changes of DMF/methanol/DHM, dried in vacuum, obtaining the appropriate profilirovannoj urea N - [2-(3-methoxybenzyloxy)iterpolation-2-aminothiazol, -N'-(3,4-dichlorophenyl), N'-propylacetic.

Corresponding to the above urea is then treated TFU (5 ml, 5% solution in DHM) for removal of solid fundamentals with obtaining specified in the title compound 1-(3,4-dichlorophenyl)-1-propyl-3-thiazol-2-rocephine (0,163 g, 67,9%) as a pale yellow solid.

LC-MS: m/z = 331 (M+1)+

BIOLOGICAL TESTING

Analysis of glucokinase (I)

The activity of glucokinase test spectrometrically in combination with glucose-6-phosphatedehydrogenase to determine the activation of glucokinase connection. The ultimate environment for test contains 50 mm Hepes, pH of 7.1, 50 mm KCl, 5 mm MgCl2, 2 mm dithiothreitol, 0.6 mm NADP, 1 mm ATP, of € 0.195 μm G-6-P dehydrogenase (Sigma), 15 nm recombinant human glucokinase. Glucokinase is glucokinase human liver, shortened from the N-end N-terminal His-tag(His)8-VEQILA......Q466) and expressed in E. coli as a soluble protein with enzymatic activity comparable with that extracted from the liver GK. This Glu is Okidata is a minor splicing variant of human liver (Proc. Natl. Acad. Sci. U.S.A.88, 7294-7297 (1991). As indicated, the gene shortened from the N-Terminus and contains a His-tag ((His8)-VEQILA......Q466) in accordance with standard procedure. Shortened form represents options and liver, and pancreatic GK, amino acid sequence which is fully conservative after the first 15 N-terminal amino acids. Protein is expressed as a soluble protein inE. coliBL21 DE3 under control of the T7 promoter. The enzymatic activity of labeled His shortened from the N-Terminus of recombinant glucokinase comparable to that extracted from the liver GK. Purification of labeled His human glucokinase (hGK) is produced as follows: the precipitate of E.coli cells from 50 ml of culture resuspended in 5 ml buffer A for extraction (25 mm Hepes, pH 8.0, 1 mm MgCl2, 150 mm NaCl, 2 mm mercaptoethanol) with the addition of 0.25 mg/ml lysozyme and 50 μg/ml of sodium azide. After 5 minutes at room temperature, add 5 ml of buffer for extraction of B (1.5 M NaCl, 100 mm CaCl2, 100 mm MgCl2, 0.02 mg/ml Gnkazy 1 tablet of protease inhibitor: 1 tablet per 20 ml buffer). The extract is then centrifuged at 15000g for 30 minutes. The resulting supernatant is applied on a 1 ml column of chelating metal affinity chromatography

(MCAC), equilibrated Ni2+. The column was washed with 2 volumes of buffer A containing 20 mm imidazole and the bound labeled his hGK then elute with OSU 20-minute gradient of imidazole from 20 to 500 mm in buffer A. Fractions analyzed by electrophoresis in a gel with DDS-Na and combine the fractions containing hGK (mm: 52 kDa). Finally, for the final cleaning and replacement of the buffer used stage of gel filtration. Containing hGK fraction applied to a column for gel filtration Superdex 75 (16/60) and elute with buffer B (25 mm Hepes, pH 8.0, 1 mm MgCl2, 150 mm NaCl, 1 mm dithiothreitol). Purified hGK analyzed by electrophoresis in a gel with DDS-Na and mass spectrometry, MALDI, and, finally, before freezing add 20% glycerol. The output from a 50 ml culture of E. coli is typically approximately 2-3 mg hGK with a purity of >90%.

Test the connection, type in the hole in DMSO at a final concentration

2.5% in a quantity sufficient to obtain the desired concentration of the compound, for example 50 μm. The reaction is initiated by addition of glucose at a final concentration of 2 mm. For analysis using 96-well UV flatbed and used the finite size of the test is 200 µl/well. Tablet incubated at 25°C for 5 min and the kinetics measured at 340 nm in a SpectraMax every 30 seconds for 5 minutes. The results for each compound is expressed as the ratio of the activation of glucokinase in relation to activation glucokinase enzyme in the test without a connection after subtraction of Blanca", measured in the absence of the enzyme glucokinase and connections. Connection kadogos examples show an activating effect on glucokinase in this test. The connection that at concentrations equal to or below 30 microns, provides the activity of glucokinase 1.3 times higher compared to the result of analysis in the absence of the connection is an activator of glucokinase.

Although the invention has been described and illustrated with reference to certain preferred embodiment, specialists in the art should understand that it can be made various changes, modifications and substitutions without going beyond the spirit and scope of the present invention. For example, due to variations in the sensitivity of the exposed treatment of diseases(diseases) of a mammal, as defined by glucokinase deficiency may be applicable effective dose other than the preferred doses installed here above. Similarly, the observed specific pharmacological responses may vary depending on the specific active compounds or whether pharmaceutical carriers, as well as the type of drug used and the method of administration, and such expected variations or differences in the results are discussed in accordance with the objectives and the practical application of the present invention.

1. The connection, which is a
the thiazole-2-alamid 2-(3,4-dichlorophenoxy)hexanoic acid,
2-(4-perfe is hydroxy)-N-1,3-thiazol-2-rexanne,
2-(4-methoxyphenoxy)-N-1,3-thiazol-2-rexanne,
2-(4-methoxyphenoxy)-N-pyridin-2-rexanne,
2-(3,4-dichlorophenoxy)-4-methyl-N-1,3-thiazol-2-ilistened,
2-(1,1'-biphenyl-4-yloxy)-N-1,3-thiazol-2-rexanne,
2-(4-isopropylphenoxy)-N-1,3-thiazol-2-rexanne,
2-(3-methoxyphenoxy)-N-1,3-thiazol-2-rexanne,
2-(2,3-dimethoxyphenoxy)-N-1,3-thiazol-2-rexanne,
2-(3,4-dimethoxyphenoxy)-N-1,3-thiazol-2-rexanne,
2-(3,5-dimethoxyphenoxy)-N-1,3-thiazol-2-rexanne,
2-(2-naphthyloxy)-N-1,3-thiazol-2-rexanne,
2-(2,4-divergence)-N-1,3-thiazol-2-rexanne,
2-(3,4-divergence)-N-1,3-thiazol-2-rexanne,
2-(1,3-benzodioxol-5-yloxy)-N-1,3-thiazol-2-rexanne,
2-(4-methylsulfinylphenyl)-N-1,3-thiazol-2-rexanne,
2-(2,4,6-trichlorophenoxy)-N-1,3-thiazol-2-rexanne,
2-(2,4-dichlorophenoxy)-N-1,3-thiazol-2-rexanne,
2-(4-phenoxyphenoxy)-N-1,3-thiazol-2-rexanne,
2-(4-cianfrocca)-N-1,3-thiazol-2-rexanne,
2-(4-chloro-3-triptoreline)-N-1,3-thiazol-2-rexanne,
2-(4-methoxyphenoxy)-N-1,3-thiazol-2-elephantid,
2-(4-pertenece)-N-1,3-thiazol-2-elephantid,
2-(3,4-dichlorophenoxy)-3-cyclopentyl-N-1,3-thiazol-2-ylpropionic,
2-(4-methoxyphenoxy)-3-cyclopentyl-N-1,3-thiazol-2-ylpropionic,
the thiazole-2-alamid 2-(4-chlorophenylsulfonyl)hexanoic acid,
pyridine-2-alamid 2-(4-chloro-phenylsulfanyl)hexanoic acid,
2-(indol-1-yl)-N-(1,3-thiazol-yl)hexanamide,
3-(4-chlorophenyl)-N-pyridin-2-yl-3-(tetrahydro-2H-thiopyran-4-ylamino)propanamide,
3-(4-chlorophenyl)-3-(tetrahydro-2H-thiopyran-4-ylamino)-N-1,3-thiazol-2-ylpropionic,
2-(3,4-dichloraniline)-2-(4-chlorophenyl)-N-pyridin-2-ylacetamide,
2-(3,4-dichloraniline)-2-(4-chlorophenyl)-N-1,3-thiazol-2-ylacetamide,
2-(4-chlorophenyl)-2-(4-methylphenoxy)-N-pyridin-2-ylacetamide,
2-(4-chlorophenyl)-2-(4-methylphenoxy)-N-1,3-thiazol-2-ylacetamide,
2-(4-bromophenoxy)-2-(4-chlorophenyl)-N-pyridin-2-ylacetamide,
2-(4-bromophenoxy)-2-(4-chlorophenyl)-N-1,3-thiazol-2-ylacetamide,
2-(4-chlorophenyl)-2-(4-pertenece)-N-1,3-thiazol-2-ylacetamide,
2-(4-chlorophenyl)-2-(3,4-dichlorophenoxy)-N-pyridin-2-ylacetamide,
2-(4-bromophenoxy)-2-(4-bromophenyl)-N-pyridin-2-ylacetamide,
2-(4-bromophenoxy)-2-(4-bromophenyl)-N-1,3-thiazol-2-ylacetamide,
2-(4-bromophenyl)-2-(4-methylphenoxy)-N-pyridin-2-ylacetamide,
2-(4-bromophenyl)-2-(4-pertenece)-N-1,3-thiazol-2-ylacetamide,
2-(4-bromophenyl)-2-phenoxy-N-1,3-thiazol-2-ylacetamide,
2-(4-pertenece)-2-(4-forfinal)-N-pyridin-2-ylacetamide,
2-(4-pertenece)-2-(4-forfinal)-N-1,3-thiazol-2-ylacetamide,
2-(4-forfinal)-2-(4-methylphenoxy)-N-1,3-thiazol-2-ylacetamide,
2-(4-forfinal)-2-phenoxy-N-1,3-thiazol-2-ylacetamide,
2-(4-bromophenoxy)-2-(4-forfinal)-N-pyridin-2-ylacetamide,
2-(4-pertenece)-N-1,3-thiazol-2-yl-2-[4-(trifluoromethyl)phenyl]acetamide", she
2-(4-bromophenoxy)-N-pyridin-2-yl-2-[4-(trifluoromethyl)phenyl]acetamide", she
2-(3,4-dichlorophenoxy)-2-(3,4-DIH arvanil)-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-phenyl-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-phenyl-N-pyridin-2-ylacetamide,
2-cyclopentylmethyl-2-(4-forfinal)-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-(4-forfinal)-N-pyridin-2-ylacetamide,
2-cyclopentylmethyl-2-(3-chlorophenyl)-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-(3-chlorophenyl)-N-pyridin-2-ylacetamide,
2-cyclopentylmethyl-2-(4-chlorophenyl-N-pyridine-2-ylacetamide,
2-cyclopentylmethyl-2-(4-bromophenyl)-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-(4-bromophenyl)-N-pyridin-2-ylacetamide,
2-cyclopentylmethyl-2-(4-methoxyphenyl)-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-(4-methoxyphenyl)-N-pyridin-2-ylacetamide,
2-cyclopentylmethyl-2-(3-cyanophenyl)-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-(3-cyanophenyl)-N-pyridin-2-ylacetamide,
2-cyclopentylmethyl-2-(4-cyanophenyl)-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-(4-cyanophenyl)-N-pyridin-2-ylacetamide,
2-cyclopentylmethyl-2-(4-nitrophenyl)-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-(4-nitrophenyl)-N-pyridin-2-ylacetamide,
2-cyclopentylmethyl-2-(4-methylsulphonyl)phenyl-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-(4-methylsulphonyl)phenyl-N-pyridin-2-ylacetamide,
2-cyclopentylmethyl-2-(4-trifluoromethyl)phenyl-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2(4-trifluoromethyl)phenyl-N-pyridin-2-ylacetamide,
2-cyclopentylmethyl-2-(3-trifloromethyl)-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-(3-trifloromethyl)-N-pyridin-2-ylacetamide,
2-cyclopentylmethyl-2-(4-trifloromethyl)-N-13-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-(4-trifloromethyl)-N-pyridin-2-ylacetamide,
2-cyclopentylmethyl-2-(4-phenyl)phenyl-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-(4-phenyl)phenyl-N-pyridin-2-ylacetamide,
2-cyclopentylmethyl-2-(4-phenoxyphenyl)-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-(4-phenoxyphenyl)-N-pyridin-2-ylacetamide,
2-cyclopentylmethyl-2-(3,4-differenl)-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-(3,4-differenl)-N-pyridin-2-ylacetamide,
2-cyclopentylmethyl-2-(3,5-differenl)-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-(3,5-differenl)-N-pyridin-2-ylacetamide,
2-cyclopentylmethyl-2-{3,4-(methylenedioxy)phenyl}-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-{3,4-(methylenedioxy)phenyl}-N-pyridin-2-ylacetamide,
2-cyclopentylmethyl-2-[3,5-bis(trifluoromethyl)phenyl]-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-[3,5-bis(trifluoromethyl)phenyl]-N-pyridin-2-ylacetamide,
2-cyclopentylmethyl-2-(3-chloro-4-methoxy)phenyl-N-1,3-thiazol-2-ylacetamide,
2-cyclopentylmethyl-2-(3,4-dichlorophenyl)-N-thiazol-2-ylacetamide,
N-(5-bromo-1,3-thiazol-2-yl)-2-(cyclopentyl)-2-(3,4-dichlor the Nile)ndimethylacetamide,
2-cyclopentylmethyl-2-(3,4-dichlorophenyl)-N-[(4-methoxycarbonylmethyl)-1,3-thiazol-2-yl]acetamide", she
2-cyclopentylmethyl-2-(3,4-dichlorophenyl)-N-[(4-methylaminomethyl)-1,3-thiazol-2-yl]acetamide", she
2-(cyclopentyl)-2-(3,4-dichlorophenyl)-N-1,3,4-thiadiazole-2-ylacetamide,
2-cyclopentylmethyl-2-(3,4-dichlorophenyl)-N-pyridinyl-2-ylacetamide,
2-cyclopentylmethyl-2-(3,4-dichlorophenyl)-N-pyrimidine-2-ylacetamide,
2-cyclohexylcarbonyl-2-(3,4-dichlorophenyl)-N-1,3-thiazol-2-ylacetamide,
2-cyclohexylcarbonyl-2-(3,4-dichlorophenyl)-N-pyridin-2-ylacetamide,
2-isopropylphenyl-2-(3,4-dichlorophenyl)-N-1,3-thiazol-2-ylacetamide,
2-isopropylphenyl-2-(3,4-dichlorophenyl)-N-pyridin-2-ylacetamide,
2-arylsulfonyl-2-(3,4-dichlorophenyl)-N-1,3-thiazol-2-ylacetamide,
2-(3,4-dichlorophenyl)-2-(isobutyric)-N-pyridin-2-ylacetamide,
2-(3,4-dichlorophenyl)-2-(isobutyric)-N-1,3-thiazol-2-ylacetamide,
2-(3,4-dichlorophenyl)-2-[(2-furylmethyl)thio]-N-pyridin-2-ylacetamide,
2-(3,4-dichlorophenyl)-2-[(2-furylmethyl)thio]-N-1,3-thiazol-2-ylacetamide,
2-(4-methylthio)-2-phenyl-N-pyridin-2-ylacetamide,
2-(3,4-dichlorophenyl)-2-[(2-furylmethyl)thio]-N-pyridin-2-ylacetamide,
2-[(4-forfinal)thio]-N-pyridin-2-yl-2-[4-(trifluoromethyl)phenyl]acetamide", she
2-[(4-forfinal)thio]-N-1,3-thiazol-2-yl-2-[4-(trifluoromethyl)phenyl]acetamide", she
2-[(4-were)thio]-N-1,3-thiazol-2-yl-2-[4-(trifluoromethyl)phenyl]acetamide", she
2-(4-forfinal)-2-[(4-forfinal)thio]-N-pyridin-2-ylacetamide, 2-(4-bromophenyl)-2-[(4-forfinal)thio]-N-pyridin-2-ylacetamide,
2-(4-bromophenyl)-2-[(4-were)thio]-N-pyridin-2-ylacetamide,
N-[1-(4-chlorophenyl)cyclopentyl]-N'-1,3-thiazol-2-rocephine,
N-[1-(4-chlorophenyl)cyclopentyl]-N'-pyridine-2-rocephine,
N-[1-(4-chlorophenyl)cyclohexyl]-N'-1,3-thiazol-2-rocephine,
N-[1-(4-chlorophenyl)cyclohexyl]-N-pyridin-2-rocephine,
1-(3-benzyloxyphenyl)-1-isobutyl-3-(thiazol-2-yl)urea,
1-(3,4-dichlorophenyl)-1-isobutyl-3-(thiazol-2-yl)urea,
1-(4-forfinal)-1-n-pentyl-3-(thiazol-2-yl)urea,
1-(3,4-methylenedioxybenzyl)-1-(3,4-dichlorobenzyl)-3-(thiazol-2-yl)urea,
1-(4-forfinal)-1-cyclopentyl-3-(thiazol-2-yl)urea,
1-(3,4-dichlorobenzyl)-1-[ethyl-(2-thiophene)]-3-(thiazol-2-yl)urea,
1-(3,4-dichlorobenzyl)-1-isobutyl-3-(thiazol-2-yl)urea,
1-(4-forfinal)-1-cyclohexylmethyl-3-(thiazol-2-yl)urea,
1-(3-chlorophenacyl)-1-isobutyl-3-(thiazol-2-yl)urea,
1-(2-ethoxybenzyl)-1-isobutyl-3-(thiazol-2-yl)urea,
1-(4-forfinal)-1-(4-tetrahydropyranyl)-3-(thiazol-2-yl)urea,
1-(3,4-dichlorobenzyl)-1-cyclohexylmethyl-3-(thiazol-2-yl)urea,
1-(3-methylpyridin)-1-(cyclohexylmethyl)-3-(thiazol-2-yl)urea,
1-(2-ethoxybenzyl)-1-cyclohexylmethyl-3-(thiazol-2-yl)urea,
1-(3,4-dichlorobenzyl)-1-cyclopentyl-3-(thiazol-2-yl)urea,
1-(2-ethoxybenzyl)-1-cyclopentyl-3-(thiazol-2-yl)urea,
1-(3,4-dichlorobenzyl)-1-(4-tetrahydropyranyl)-3-(thiazol-2-yl)urea,
1-(3,4-dichlorobenzyl)-1-(4-tetrahydropyranyl)-3-(thiazol-2-yl)urea,
1-(3-chlorophenacyl)-1-(4-tetrahydropyranyl)-3-(thiazol-2-yl)urea,
1-(4-forfinal)-1-isobutyl-3-(thiazol-2-yl)urea,
2-cyclopentyl-1-(3,4-dichlorophenyl)ethylpyridine-2-ylcarbamate,
2-cyclopentyl-1-(3,4-dichlorophenyl)ethyl 1,3-thiazol-2-ylcarbamate,
(2-[3-cyclohexyl-2-(4-methoxyphenoxy)propionamido]thiazol-4-yl) acetic acid,
1-cyclopentylmethyl-1-(3,4-dichlorophenyl)-3-thiazol-2-yl-urea,
1-cyclopentyl-1-(3,4-dichlorophenyl)-3-thiazol-2-yl-urea, or
1-(3,4-dichlorophenyl)-1-propyl-3-thiazol-2-yl-urea.

2. The compound according to claim 1, for obtaining a medicinal product for the treatment of diseases defined by glucokinase deficiency.

3. The compound according to claim 1, for obtaining a medicinal product for the treatment of diseases, for which the increase in glucokinase is successful.

4. Pharmaceutical composition having the properties of a glucokinase activator comprising as an active ingredient, the compound according to claim 1 together with one or more pharmaceutically acceptable carriers or excipients.

5. The use of compounds according to claim 1, for preparing a medicinal product, increasing the activity of glucokinase.

6. The compound of General formula (I)

where G represents-C(O)-;
L1represents a direct bond,
And represents >N, and
X p is ecstasy a direct link,
R1represents cyclohexyl,
R3represents cyclohexyl, substituted R34,
R34represents-OR52,
R52represents propyl,
R4represents hydrogen;
R5represents thiazol-5-yl, substituted R48,
R48is an R65-W-methylene-Z-,
R65represents hydrogen,
W represents-OC(O)- and
Z represents-S-.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

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: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention can be used for treating or preventing diseases and conditions, mediated by peroxisome proliferator activated gamma receptor (PPARγ). In formula (I) W represents a COOH group or -COOC-C1-C4alkyl; Y represents NH; Z represents S or O; X represents O; R1-R6 each independently represents a hydrogen atom or substitute, chosen from a group consisting of: C1-C4-alkyl, thienyl or phenyl, where phenyl is optionally substituted with one or more substitutes, independently chosen from a group consisting of C1-C4-alkyl, C1-C4-alkoxy, a halogen atom; -NO2 and -CN; A represents C1-C4-alkyl, -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, aryl, chosen from a group consisting of phenyl, naphthyl, or heteroaryl, chosen from a group consisting of oxazolyl, isoxazolyl, thienyl, pyridyl, thiazolyl, thiadiazolyl, benzo[b]thienyl, imidazolyl, indolyl and carbazolyl, where aryl and heteroaryl are substituted or not substituted with one or more substitutes, independently chosen from a group consisting of C1-C4-alkyl, C1-C4-alkoxy, phenyl and a halogen atom; and n is an integer from 0 to 4. The invention also relates to a pharmaceutical composition, containing the invented compound as an active component, use of the compounds to make a medicinal agent, and method of treatment.

EFFECT: obtaining new biologically active compounds.

22 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invented compounds have inhibitory activity towards protein kinase. In formula 1a m lies between 0 and 1, R1 is chosen from a group which includes hydrogen, methyl, isopropyl, imidazolylpropyl, piperazinylpropyl, pyridinyl, diethylaminopropyl, hydroxyethyl, pyrimidinyl, morpholinopropyl, phenyl, cyclopropyl, morpholinoethyl, benzyl and morpholino, where any of pyridinyl, imidazolyl, piperazinyl or pyrimidinyl in R1 are optionally substituted with 1-3 radicals, independently chosen from a group, which includes methyl, methylamine, dimethylaminomethyl, cycloproylamine, hydroxyethylamine, diethylaminopropylamine, pyrrolydinylmethyl, morpholino, morpholinomethyl, piperazinylmethyl and piperazinyl, where any of morpholino and piperazinyl in R1 are optionally further substituted with a radical, chosen from a group which includes methyl, hydroxyethyl and ethyl, R2, R3 and R5 each represents hydrogen, R4 represents methyl, L is chosen from a group which includes -NR5C(O)- and -C(O)NR5-, R10 represents trifluoromethyl, and R11 is chosen from a group which includes halogen, morpholinomethyl, piperazinyl, optionally substituted with a methyl, ethyl or hydroxyethyl group; piperazinylmethyl, optionally substituted with a methyl or ethyl group, imidazolyl, optionally substituted with methyl, pyrrolidinylmethoxy and piperidinyl, optionally substituted with a hydroxy group.

EFFECT: more effective treatment.

4 cl, 1 tbl, 3 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

FIELD: chemistry.

SUBSTANCE: described are derivatives of 1,3,4-oxadiazol-2-on of formula (I) , where ARYL represents phenyl; Z represents -O(CH2)n- and n represents independent integer number from 1 to 5; X represents S; R1 represents C1-6alkyl; R2 represents phenyl, substituted with C1-6perfluoralkyl; or its pharmaceutically acceptable salt; based on it pharmaceutical composition; and method of disease treatment, where disease can be modulated by activity of PPAR-delta binding.

EFFECT: obtaining compounds which possess agonistic or antagonistic activity.

7 cl, 5 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invented compounds have antagonist properties towards CB1 receptors. In formula (I) , R1 is a lower alkoxy, (lower alkyl amino)-(lower alkoxy) or -N(Ra)Rb; Ra is hydrogen, lower alkyl, carbamoyl-(lower alkyl), hydroxy-(lower alkyl), dihydroxy-(lower alkyl), lower alkynyl, lower alkoxy, (lower alkoxy)-(lower alkyl), di-(lower alkylamino)-(lower alkyl), C3-6cycloalkyl; or Ra is a phenyl-(lower alkyl) group, where the phenyl fragment can be optionally mono-substituted, independently, by lower alkyl, lower alkoxy or halogen; or Ra is a 5- or 6-member heteroaromatic ring system, containing one or two nitrogen atoms in the ring, where the said heteroaromatic ring system is bonded to the remaining part of the molecule by lower alkylene; or Ra is a 5-, 6- or 7-member saturated heterocyclic ring system, containing one nitrogen heteroatom, where the said heterocyclic ring system is optionally mono-substituted by lower alkyl; Rb is hydrogen, lower alkyl or (lower alkoxy)-(lower alkyl); or Ra and Rb together with a nitrogen atom to which they are bonded, for a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring system, optionally containing an extra heteroatom, which is chosen from nitrogen, oxygen or sulphur, where the said heterocyclic ring system is optionally mono- or disubstituted, independently, by lower alkyl, hydroxy group, hydroxy-(lower alkyl), lower alkoxy, (lower alkoxy)-(lower alkyl) group, cyano group, halogen, phenyl and/or benzyl; R2 is hydrogen or lower alkyl; R3 is phenyl, mono- or disubstituted, independently, by lower alkoxy, halogen, or perfluoro-(low alkoxy) group; and R4 is phenyl, which is mono- or disubstituted with a halogen.

EFFECT: new compounds have useful biological properties.

18 cl, 195 ex

FIELD: chemistry, medicine.

SUBSTANCE: in the general formula (I): X is oxygen atom; R1 is C1-10-alkyl , substituted if necessary by phenyl or thienyl group; or R1 is C3-7-cycloalkyl, thienyl, pyridinyl; the thienyl groups can be substituted if necessary by 1-2 C1-3-alkyl groups; phenyl can be substituted if necessary by 1-2 halogen atoms; R2 is C1-6-alkyl; or R2 is C3-7-cycloalkyl, phenyl or pyridinyl; phenyl if necessary can be substituted by one or more halogen atoms or by the CN, C1-3-alkyl, C1-3-alkoxyl, C1-3-fluoroalkyl groups; R3 is C1-6-alkyl; R4 is hydrogen atom or C1-6-alkyl; R5 and R5' are independently of each other the hydrogen atom, hydroxyl; or R5 and R5' form together the oxo-group; n is integer value in the range from 0 to 3; R6 is independently of each other hydrogen atom, halogen atom, C1-3-alkyl, C1-3-alkoxyl.

EFFECT: compounds of present invention can find application as pharmaceutical for pathology treatment where the inhibitor of β-amiloyd peptide β-A4 is useful.

8 cl, 1 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new benzimidazole derivatives with general formula (I), where A represents -CH2-, -C(O), -C(O)-C(Ra)(Rb)-, X represents a -CH- radical; Ra and Rb independently represent a hydrogen atom or (C1-C6)alkyl radical; R1 represents a hydrogen atom or (C1-C8)alkyl radical; R2 represents a (C1-C8)alkyl radical; R3 represents -(CH2)P-Z3, -C(O)-Z'3 or -C(O)-NH-Z"3; Z3 represents (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl-N(RN)carbonyl, (C3-C7)cycloalkyl, aryl, arylthio or heteroaryl radical, Z3 is bonded to the -(CH2)P- through a carbon atom, heteroaryl radical, which is a 5-10- member heteroaryl, which contains 1-2 identical or different heteroatoms, chosen from sulphur, nitrogen or oxygen, and optionally substituted with one or more identical or different substitutes, chosen from halogen, nitro group or -(CH2)P'-V30-Y3; aryl radical, chosen from phenyl or naphthyl, optionally substituted with one or more identical or different substitutes, chosen from halogen, nitro group, cyano group, (C2-C6)alkenyl, pyrrolidinyl, phenyl, phenyloxy, phenylalkyloxy, 5-7- member heteroaryl, containing 1-3 nitrogen atoms and -(CH2)p'-V31-Y3; V30 represents -O-, -C(O)-, -C(O)-O- or a covalent bond; V31 represents -O-, -S-, -SO2-, -C(O)-, -C(O)-O-, -N(RN)-, -NH-C(O)- or a covalent bond; Y3 represents a hydrogen atom or (C1-C6)alkyl radical, optionally substituted with one or more identical or different halogen radicals; RN represents a hydrogen atom or (C1-C6)alkyl radical; Z3 represents a radical with a given formula (see below); Z'3 represents a phenyl radical, optionally substituted with one ore more identical or different substitutes, chosen from -(CH2)P"-V'3-Y'3; V'3 represents -O-; Y'3 represents a hydrogen atom or (C1-C6)alkyl radical; Z"3 represents a hydrogen atom or -(CH2)q-A"3 radical; A"3 represents (C1-C6)alkyl, phenyl or thienyl radical; alkyl or phenyl radical can be optionally substituted with one or more identical or different substitutes, chosen from halogen and -V"3-Y"3; V"3 represents -O-, -C(O)-, -C(O)-O- or a covalent bond; Y"3 represents a hydrogen atom or (C1-C6)alkyl radical; p is an integer from 0 to 6; p' and p" independently represent an integer from 0 to 1; q is an integer from 0 to 2; R4 represents a radical with formula -(CH2)S-R'4; R'4 represents a 5-7- member heterocycloalkyl, containing at least one nitrogen atom and optionally substituted with (C1-C6)alkyl; or a radical with formula -NW4W'4; W4 represents a hydrogen atom; W'4 represents a hydrogen atom; s is an integer from 0 to 6; in racemic or enantiomeric form or any combination of the said forms, or its pharmaceutically acceptable salt. The invention also relates to a method of obtaining a compound in paragraph 1, a pharmaceutical composition based on the said compound and its use in making a medicinal agent.

EFFECT: new benzimidazole derivatives have good affinity to certain subtypes of melanocortin receptors.

26 cl, 8 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: present invention refers to compounds of general formula (I) in the state of base salt or acid-addition salt, to method of their preparation and to the pharmaceutical composition thereof In the said formula R1 is (C1-C6)alkyl; (C3-C7)cycloalkyl unsubstituted or substituted once or more than once; (C3-C7)cycloalkylmethyl unsubstituted or substituted once or more than once; phenyl unsubstituted or substituted ; benzyl unsubstituted or substituted once or twice ; thienyl unsubstituted or substituted ; R2 is atom hydrogen or (C1-C3)alkyl; R3 is (C1-C5)alkyl; R4, R5, R6, R7, each R8 and R9 independently represents the atom of hydrogen, atom of halogen, (C1-C7)alkyl, (C1-C5)alkoxy or trifluoromethyl radical; n is 0, 1 or 2; Alk is (C1-C4)alkyl.

EFFECT: new compounds possess useful biological activity.

5 cl, 5 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of formula (I): and to its salts with acid, where: R1 and R2 represent hydrogen; Q represents (CH2)m-X-(CH2)n-A; A represents direct bond, O, SO2, NR5; X represents direct bond, O, SO2, C(O) or NR5; Z represents group selected from : m and n represent, each independently, 0, 1, 2, 3 or 4; p represents 1, 2, 3 or 4; q represents 0, 1 or 2; dotted line means that R8 and/or R9 can be situated in any position of benzothiophene ring; R3 and R8 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11 or NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10; when Q-Z represents n 0, 1 or 2 and p represents 1, one of R3 and R8 represents hydroxy, nitro, NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CONR10R11, and the other represents hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11 OSO2NR10R11, NR12SO2NR10R11, CO2R10; R4 and R9 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CHO; when p represents 2, 3 or 4, R9 can be similar or different; R6 and R7 represent hydrogen; each R5, R10, R11 and R12 represents hydrogen; when Z represents and p represents 1, then R8 and R9 can also together with phenyl ring form benzoxathiazine dioxide. Invention also relates to pharmaceutical composition and to application of derivatives by any of ii.1-25.

EFFECT: obtaining novel biologically active compounds which possess inhibiting activity with respect to aromatase and/or steroid-sulfatase and/or carboanhydrase.

36 cl, 67 ex, 5 tbl

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: invention refers to Sertaconasole mononitrate process by reaction of 1-(2,4-dichlorphenyl)-2-(1H-imidazole-1-yl)ethanol and 3-bromomethyl-7-chlorbenzo[b]thiophene with tetrabutylammonium hydrosulphate and sodium hydroxide in toluene at 30-45°C. Produced free base of Sertaconasole is transferred into Sertaconasole mononitrate monohydrate with the latter being transferred into Sertaconasole mononitrate. There is disclosed and characterised intermediate Sertaconasole mononitrate monohydrate.

EFFECT: method allows simplifying process technology considerably.

6 cl, 5 dwg, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) where R1 stands for hydrogen or linear, branched, saturated or unsaturated hydrocarbon radical; D stands for nitrogen atom or C-R2; E stands for nitrogen atom or C-R3; F stands for nitrogen atom or C-R4; G stands for nitrogen atom or C-R5; R2, R3, R4 and R5 are identical or different and individually represent hydrogen, halogen, alkoxy, linear or branched, saturated or unsaturated hydrocarbon radical; W stands for oxygen atom; X stands for radical of formula radical -(CH2)k-C(O)-(CH2)m-, -(CH2)n- or -(CH2)r-O-(CH2)s-, where k, m, r and s are equal to integers 0 to 6, and n is equal to an integer 1 to 6. Said radicals are optionally substituted with one or more substitutes independently chosen from the group consisting of R7; Y stands for radical of formula radical -(CH2)i-NH-C(O)-(CH2)j-, -(CH2)n-, -(CH2)r-O-(CH2)s-, -(CH2)t-NH-(CH2)u-, where i, j, n, r, s, t and u are equal to integers 0 to 6. Said radicals are optionally substituted C1-3alkyl, or C1-3alkyl-C1-3alkylsulphonylamino; radicals R7, B, R8, A, R9 are as it is presented in the patent claim. The invention also describes the pharmaceutical composition possessing inhibitory activity of receptor tyrosine kinase to KDR receptor including described compounds.

EFFECT: compounds possess inhibitory activity of receptor tyrosine kinase to KDR receptor and can be effective in therapy of the diseases associated uncontrolled angiogenesis.

29 cl, 746 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with general formula I, where R1 represents -(CHR')q-aryl or -(CHR')q-thiophen, which are unsubstituted or mono-, di- or tri-substituted with (inferior)alkyl, (inferior)alkoxy, CF3 or haloid, or represents (inferior)alkyl, (inferior)alkenyl, -(CH2)n-Si(CH3)3, -(CH2)n-O-(inferior)alkyl, -(CH2)n-S- (inferior)alkyl, -(CH2)q-cycloalkyl, -(CH2)n-[CH(OH)]m-(CF2)p-CHqF(3-q), or represents -(CH2)n-CR2-CF3, where two radicals R together with a carbon atom form a cycloalkyl ring; R' represents hydrogen or (inferior)alkyl; n is 1, 2 or 3; m is 0 or 1; p is 0, 1,2, 3, 4, 5 or 6; q is 0, 1, 2 or 3; R2 represents hydrogen or (inferior)alkyl; R3 represents hydrogen, (inferior)alkyl, CH2F, aryl, optionally mono-, di- or tri-substituted with a haloid, or represents -(CH2)nNR5R6, where R5 and R6 independently represent hydrogen or (inferior)alkyl; R4 represents one of the following groups a) or b), where R7 represents inferior)alkyl or -(CH2)ncycloalkyl; R8 and R9 independently represent hydrogen, (inferior)alkyl, -(CH2)n-cycloalkyl or -C(O)-phenyl. The invention also relates to pharmaceutically used acid addition salts of these compounds, optically pure enantiomers, racemates or diastereomeric mixtures, as well as compounds with general formula I-1, and medicinal agent.

EFFECT: obtaining new biologically active compounds, designed for inhibiting γ-secretase.

16 cl, 83 ex

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

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